CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review)
α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms. The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs,...
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| Автори: | , , , , , , |
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| Мова: | Англійська |
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V.I.Vernadsky Institute of General and Inorganic Chemistry
2025
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Ukrainian Chemistry Journal| _version_ | 1871466182634110976 |
|---|---|
| author | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_facet | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Jianlin Han",
"institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:56Z |
| description | α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms. The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs, particularly hepatitis C virus (HCV) NS3/4A protease inhibitors. Indeed, ACC has been instrumental in the development of multiple generations of potent HCV treatments, with ongoing efforts focused on further improvements and refinements. The inherent steric constraints of these derivatives present a significant challenge for their synthesis, especially in enantiomerically pure form. This article provides a comprehensive overview of synthetic methodologies reported in the literature for the preparation of ACC and its derivatives. The synthetic strategies discussed herein are organized based on key transformations, including dialkylation of nucleophilic glycine equivalents, cyclopropanation of carbenoid glycine equivalents, and addition reactions to dehydroamino acids. Particular emphasis is placed on asymmetric approaches that enable the preparation of these tailor-made amino acids in enantiomerically pure form. Furthermore, aspects of Self-Disproportionation of Enantiomers (SDE) relevant to enantioselective catalysis are highlighted. By compiling these methodologies, we aim to provide a comprehensive resource and a source of inspiration for researchers in synthetic and medicinal chemistry, as well as drug discovery. |
| doi_str_mv | 10.33609/2708-129X.91.10.2025.27-71 |
| first_indexed | 2026-03-12T15:49:41Z |
| format | Article |
| fulltext |
27
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.10.2025.27-71
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS
OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.
Alicja Wzorek1, Jianlin Han2, Taizo Ono3, Karel D. Klika4,
Daniel Baecker5, Wei Zhang6, Vadim A. Soloshonok7*.
1 Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland;
2 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,
College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
3 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
4 Research & Development Center, Archer Daniels Midland,
1001 N Brush College Rd., Decatur, IL 62521, USA;
5 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy,
Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany;
6 Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;
7 IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain
e-mail: vadimsoloshonok@gmail.com
α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant
kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms.
The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs,
particularly hepatitis C virus (HCV) NS3/4A protease inhibitors. Indeed, ACC has been instrumental
in the development of multiple generations of potent HCV treatments, with ongoing efforts focused
on further improvements and refinements. The inherent steric constraints of these derivatives present
a significant challenge for their synthesis, especially in enantiomerically pure form. This article pro-
vides a comprehensive overview of synthetic methodologies reported in the literature for the prepa-
ration of ACC and its derivatives. The synthetic strategies discussed herein are organized based on
key transformations, including dialkylation of nucleophilic glycine equivalents, cyclopropanation of
carbenoid glycine equivalents, and addition reactions to dehydroamino acids. Particular emphasis
is placed on asymmetric approaches that enable the preparation of these tailor-made amino acids in
enantiomerically pure form. Furthermore, aspects of Self-Disproportionation of Enantiomers (SDE)
relevant to enantioselective catalysis are highlighted. By compiling these methodologies, we aim to
provide a comprehensive resource and a source of inspiration for researchers in synthetic and medi
cinal chemistry, as well as drug discovery.
Key words: Amino Acids, Pharmaceuticals, Cyclopropane, Chirality, Synthesis, Nucleophilic Gly-
cine Equivalents, Carbenoid Glycine Equivalents, Dehydroamino Acids, Self-Disproportionation of
Enantiomers (SDE).
28 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
INTRODUCTION.
Amino acids represent a pinnacle of mo-
lecular design. Their orthogonal amino and
carboxylic acid functionalities enable virtual-
ly infinite polymeric peptide structures, while
diverse side chains can introduce a vast array
of additional functional groups, facilitating
non-bonding electrostatic or lipophilic/hydro-
philic interactions. Furthermore, the inherent
chiral stereogenic center adds another dimen-
sion of molecular complexity in three-dimen-
sional space. Early pharmaceutical applica-
tions of amino acids primarily involved dietary
supplements and medical nutrition therapy for
conditions such as malnutrition and metabolic
disorders [1–4]. However, with advancements
in biochemical research, amino acids became
central to the development of hormonal the
rapies, exemplified by insulin synthesis, which
revolutionized diabetes treatment. Moreover,
peptide-based drugs, derived from amino acids,
pioneered new classes of antibiotics, enzyme
inhibitors, and vaccines [5–8].
In contemporary pharmaceutical science,
amino acids play a pivotal role in biologic
drugs (biopharmaceuticals), targeted ther-
apies, and synthetic medicinal compounds
(small-molecule pharmaceuticals). A signifi-
cant breakthrough, representing a paradigm
shift in drug design, has been the strategic uti-
lization of modified, tailor-made amino acids
in place of their natural counterparts [9–15].
These custom-engineered amino acids can be
rationally designed to enhance drug stability,
solubility, and absorption, thereby optimizing
biological efficacy and enabling more precise
targeted delivery [15–21].
The asymmetric synthesis of α-amino acids
(α-AAs) remains an exciting and crucial area
of research, fueled by ever-evolving scientific
and practical imperatives [22–41]. Within this
broad field, sterically constrained α-AAs are of
particular pharmaceutical significance, as their
restricted side-chain chi(χ)-dihedral angles af-
ford exquisite control over molecular interac-
tions with biological target receptors [42–51].
A prominent class within this category is the
α,β-methano-α-AAs family (Fig. 1), character-
ized by an α-quaternary carbon atom embed-
ded within a highly rigid cyclopropane ring.
This unique structural motif represents the apex
of steric and conformational constraint among
α-AAs [52, 53]. Notably, certain members of
this family are naturally occurring compounds
(vide infra) [54–58]. For instance, 1-aminocy-
clopropanecarboxylic acid (ACC) (1), along
with its 2-methyl (2, 3) and 2-ethyl (4, 5) de-
rivatives, have been identified as constituents
of plant proteins [59–62]. The intriguing bio-
logical properties of the ethyl derivatives 4 and
5 have spurred the development of even more
conformationally restricted tailor-made 2-vinyl
analogues, such as compound 6. Intriguingly,
despite being stereochemically equivalent to 5,
compound 6 exhibits a (1R,2R) absolute configu
ration as dictated by CIP priority rules [63, 64].
Currently, 1-amino-2-vinylcyclopropane-1-
carboxylic acids have emerged as crucial phar-
macophoric elements in the design of next-ge
neration hepatitis C virus (HCV) NS3/4A pro-
tease inhibitors [65]. As detailed in the corre-
sponding section (vide infra), vinyl derivatives
of 1-aminocyclopropanecarboxylic acids have
profoundly impacted the HCV pharmaceutical
landscape, contributing to the development of
over a dozen therapeutic agents. Given the sig-
nificant and ongoing socioeconomic impact of
1-aminocyclopropanecarboxylic acids on the
pharmaceutical industry, a comprehensive re-
view of the available synthetic methodologies
29https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
is both timely and essential. A critical analysis
of these approaches will facilitate the assess-
ment of their respective advantages and limi-
tations, thereby guiding future advancements
in this important field. Considering the inhe
rently multidisciplinary nature of the chemis-
try, biological properties, and pharmaceutical
applications of cyclopropane-derived α-amino
acids, this review is anticipated to be of broad
interest to graduate students and professionals
across diverse disciplines, including organic,
bioorganic, and medicinal chemistry, bio-
chemistry, pharmacology, virology, and drug
design, as well as process chemists within the
pharmaceutical and chemical industries, and
clinical researchers.
Fig. 1. Family of 1-aminocyclopropane carboxy
lic acids.
Naturally occurring 1-aminocyclopropane-
carboxylic acids and their derivatives.
As discussed in the previous section, ACC 1
(Fig. 1), norcoronamic acid (2), allo-norcoro-
namic acid (3), allo-coronamic acid (4), and
coronamic acid (5) are widely distributed in
the proteins of higher plants, where they play
specific defensive roles [54–62, 66–69]. ACC 1
is particularly notable for its role in the in vivo
production of ethylene, a vital plant hormone
that regulates key processes throughout the
plant’s seasonal life cycle. Ethylene influences
germination, growth, leaf and flower senes-
cence, fruit ripening, and the plant’s response
to various environmental stresses, ensuring
adaptability and survival.
As shown in Fig. 2, ACC 1 serves as a key
structural unit in natural products such as
polycyclic alkaloids, including norcoronatine
(7, R = Me) and coronatine (8, R = Et). These
compounds, isolated from certain pathovars
of Pseudomonas syringae, play a crucial role in
plant-pathogen interactions. Norcoronatine 7
and coronatine 8 exhibit significant biological
activity, primarily as jasmonate mimics. They
can interfere with plant hormone signaling
pathways, contributing to the pathogen’s viru
lence by suppressing plant defense responses
and promoting disease development [70–73].
carboxylic acid functionalities enable virtually infinite polymeric peptide structures, while diverse
side chains can introduce a vast array of additional functional groups, facilitating non-bonding
electrostatic or lipophilic/hydrophilic interactions. Furthermore, the inherent chiral stereogenic
center adds another dimension of molecular complexity in three-dimensional space. Early
pharmaceutical applications of amino acids primarily involved dietary supplements and medical
nutrition therapy for conditions such as malnutrition and metabolic disorders [1–4]. However, with
advancements in biochemical research, amino acids became central to the development of hormonal
therapies, exemplified by insulin synthesis, which revolutionized diabetes treatment. Moreover,
peptide-based drugs, derived from amino acids, pioneered new classes of antibiotics, enzyme
inhibitors, and vaccines [5–8].
In contemporary pharmaceutical science, amino acids play a pivotal role in biologic drugs
(biopharmaceuticals), targeted therapies, and synthetic medicinal compounds (small-molecule
pharmaceuticals). A significant breakthrough, representing a paradigm shift in drug design, has been
the strategic utilization of modified, tailor-made amino acids in place of their natural counterparts
[9–15]. These custom-engineered amino acids can be rationally designed to enhance drug stability,
solubility, and absorption, thereby optimizing biological efficacy and enabling more precise targeted
delivery [15–21].
The asymmetric synthesis of α-amino acids (α-AAs) remains an exciting and crucial area of
research, fueled by ever-evolving scientific and practical imperatives [22–41]. Within this broad
field, sterically constrained α-AAs are of particular pharmaceutical significance, as their restricted
side-chain chi(χ)-dihedral angles afford exquisite control over molecular interactions with
biological target receptors [42–51]. A prominent class within this category is the α,β-methano-α-
AAs family (Fig. 1), characterized by an α-quaternary carbon atom embedded within a highly rigid
cyclopropane ring. This unique structural motif represents the apex of steric and conformational
constraint among α-AAs [52, 53]. Notably, certain members of this family are naturally occurring
compounds (vide infra) [54–58]. For instance, 1-aminocyclopropanecarboxylic acid (ACC) (1),
along with its 2-methyl (2, 3) and 2-ethyl (4, 5) derivatives, have been identified as constituents of
plant proteins [59–62]. The intriguing biological properties of the ethyl derivatives 4 and 5 have
spurred the development of even more conformationally restricted tailor-made 2-vinyl analogues,
such as compound 6. Intriguingly, despite being stereochemically equivalent to 5, compound 6
exhibits a (1R,2R) absolute configuration as dictated by CIP priority rules [63, 64].
Fig. 1. Family of 1-aminocyclopropane carboxylic acids.
Fig. 2. Natural products containing residue of ACC 1.
Currently, 1-amino-2-vinylcyclopropane-1-carboxylic acids have emerged as crucial
pharmacophoric elements in the design of next-generation hepatitis C virus (HCV) NS3/4A protease
inhibitors [65]. As detailed in the corresponding section (vide infra), vinyl derivatives of 1-
aminocyclopropanecarboxylic acids have profoundly impacted the HCV pharmaceutical landscape,
contributing to the development of over a dozen therapeutic agents. Given the significant and
ongoing socioeconomic impact of 1-aminocyclopropanecarboxylic acids on the pharmaceutical
industry, a comprehensive review of the available synthetic methodologies is both timely and
essential. A critical analysis of these approaches will facilitate the assessment of their respective
advantages and limitations, thereby guiding future advancements in this important field.
Considering the inherently multidisciplinary nature of the chemistry, biological properties, and
pharmaceutical applications of cyclopropane-derived α-amino acids, this review is anticipated to be
of broad interest to graduate students and professionals across diverse disciplines, including
organic, bioorganic, and medicinal chemistry, biochemistry, pharmacology, virology, and drug
design, as well as process chemists within the pharmaceutical and chemical industries, and clinical
researchers.
Naturally occurring 1-aminocyclopropanecarboxylic acids and their derivatives.
As discussed in the previous section, ACC 1 (Fig. 1), norcoronamic acid (2), allo-
norcoronamic acid (3), allo-coronamic acid (4), and coronamic acid (5) are widely distributed in the
proteins of higher plants, where they play specific defensive roles [54–62, 66–69]. ACC 1 is
particularly notable for its role in the in vivo production of ethylene, a vital plant hormone that
regulates key processes throughout the plant's seasonal life cycle. Ethylene influences germination,
growth, leaf and flower senescence, fruit ripening, and the plant’s response to various
environmental stresses, ensuring adaptability and survival.
As shown in Fig. 2, ACC 1 serves as a key structural unit in natural products such as
polycyclic alkaloids, including norcoronatine (7, R = Me) and coronatine (8, R = Et). These
compounds, isolated from certain pathovars of Pseudomonas syringae, play a crucial role in plant-
pathogen interactions. Norcoronatine 7 and coronatine 8 exhibit significant biological activity,
primarily as jasmonate mimics. They can interfere with plant hormone signaling pathways,
contributing to the pathogen's virulence by suppressing plant defense responses and promoting
disease development [70–73].
Fig. 2. Natural products containing residue of ACC 1.
Carnosadine 9, a guanidino-substituted derivative of ACC 1, isolated from the red alga
Grateloupia carnosa, represents an interesting divergence from other ACC-derived natural products
like norcoronatine 7 and coronatine 8. This naturally occurring compound is notable for its
30 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Carnosadine 9, a guanidino-substituted de-
rivative of ACC 1, isolated from the red alga
Grateloupia carnosa, represents an interesting
divergence from other ACC-derived natural
products like norcoronatine 7 and corona-
tine 8. This naturally occurring compound is
notable for its structural uniqueness, specifi-
cally the incorporation of a guanidine substi
tuent, which introduces a strongly basic center
and the potential for different types of mole
cular interactions compared to the alkyl-sub-
stituted cyclopropanes. While its full functio
nal profile is still being elucidated, the presence
of a guanidino group suggests its involvement
in various biochemical pathways, potentially
influencing enzyme activity and physiological
regulation in ways distinct from other ACC
derivatives. [74, 75].
Cottoquinazoline D 10, a complex quina-
zoline alkaloid containing a residue of ACC
1, belongs to the fumiquinazoline family, a
significant class of natural products primar-
ily isolated from marine and fungal sources
known for their structural diversity and bio-
logical activities. Cottoquinazoline D 10 itself
has demonstrated promising antimicrobial,
cytotoxic, and enzyme-inhibitory proper-
ties, aligning with the broader pharmaceuti-
cal interest in fumiquinazolines as a source
of bioactive compounds. The presence of the
ACC 1 unit within this polycyclic scaffold un-
derscores the importance of this constrained
amino acid in the biosynthesis of structurally
complex and biologically active natural pro
ducts [76–78].
1-Aminocyclopropanecarboxylic Acid Deriva
tives: Essential Pharmacophores for Next-Gene
ration HCV NS3/4A Protease Inhibitors.
Viral infectious diseases pose significant
challenges to treatment. Recent high-profile
examples include the COVID-19 pandemic
and the Ebola virus epidemic in West Africa
[79–81]. While the hepatitis C virus (HCV)
may not currently dominate alarming head-
lines, its impact on global health remains
significant, causing substantial liver-related
morbidity and mortality. The World Health
Organization estimates that nearly 170 million
individuals worldwide are living with chronic
HCV infection, with approximately 3.5 million
new cases occurring annually and 350,000 to
500,000 deaths each year attributed to HCV-re-
lated liver diseases [82]. A crucial turning point
in HCV treatment was the development of the
first generation of direct-acting antiviral drugs,
including the tailor-made α-amino acid-de-
rived NS3/4A protease inhibitors boceprevir
11 [83] and telaprevir 12 [84] (Figure 2). These
drugs marked a significant step forward in
combating this persistent viral infection. The
first-generation direct-acting antiviral drugs
boceprevir 11 and telaprevir 12, although a
significant step forward in their time, were vo
luntarily withdrawn from the market by Merck
and Vertex in 2015. This decision reflected the
clinical superiority and improved tolerability
of subsequently developed all-oral direct-act-
ing antiviral regimens, which have funda-
mentally altered the landscape of Hepatitis C
treatment.
Boceprevir 11 and telaprevir 12 are all-tai-
lor-made amino acid-based drugs, specifically
a tri- and tetrapeptide, respectively. Interes
tingly, both feature cyclopropane rings, a struc-
tural motif that also connects them to the se
cond-generation direct-acting ACC 1 contain-
ing antiviral drugs asunaprevir 13 (Fig. 4) [85],
simeprevir 14 [86], paritaprevir 15 [87], and
vaniprevir 16 [88], all of which received FDA
approval for HCV treatment around 2015.
31https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Fig. 3. The first-generation direct-acting antiviral drugs boceprevir 11 and telaprevir 12.
Fig. 4. The second-generation ACC 1 derived antiviral drugs.
structural uniqueness, specifically the incorporation of a guanidine substituent, which introduces a
strongly basic center and the potential for different types of molecular interactions compared to the
alkyl-substituted cyclopropanes. While its full functional profile is still being elucidated, the
presence of a guanidino group suggests its involvement in various biochemical pathways,
potentially influencing enzyme activity and physiological regulation in ways distinct from other
ACC derivatives. [74, 75].
Cottoquinazoline D 10, a complex quinazoline alkaloid containing a residue of ACC 1,
belongs to the fumiquinazoline family, a significant class of natural products primarily isolated from
marine and fungal sources known for their structural diversity and biological activities.
Cottoquinazoline D 10 itself has demonstrated promising antimicrobial, cytotoxic, and enzyme-
inhibitory properties, aligning with the broader pharmaceutical interest in fumiquinazolines as a
source of bioactive compounds. The presence of the ACC 1 unit within this polycyclic scaffold
underscores the importance of this constrained amino acid in the biosynthesis of structurally
complex and biologically active natural products [76–78].
1-Aminocyclopropanecarboxylic Acid Derivatives: Essential Pharmacophores for Next-
Generation HCV NS3/4A Protease Inhibitors.
Viral infectious diseases pose significant challenges to treatment. Recent high-profile
examples include the COVID-19 pandemic and the Ebola virus epidemic in West Africa [79–81].
While the hepatitis C virus (HCV) may not currently dominate alarming headlines, its impact on
global health remains significant, causing substantial liver-related morbidity and mortality. The
World Health Organization estimates that nearly 170 million individuals worldwide are living with
chronic HCV infection, with approximately 3.5 million new cases occurring annually and 350,000
to 500,000 deaths each year attributed to HCV-related liver diseases [82]. A crucial turning point in
HCV treatment was the development of the first generation of direct-acting antiviral drugs,
including the tailor-made α-amino acid-derived NS3/4A protease inhibitors boceprevir 11 [83] and
telaprevir 12 [84] (Figure 2). These drugs marked a significant step forward in combating this
persistent viral infection. The first-generation direct-acting antiviral drugs boceprevir 11 and
telaprevir 12, although a significant step forward in their time, were voluntarily withdrawn from the
market by Merck and Vertex in 2015. This decision reflected the clinical superiority and improved
tolerability of subsequently developed all-oral direct-acting antiviral regimens, which have
fundamentally altered the landscape of Hepatitis C treatment.
Fig. 3. The first-generation direct-acting antiviral drugs boceprevir 11 and telaprevir 12.
Boceprevir 11 and telaprevir 12 are all-tailor-made amino acid-based drugs, specifically a
tri- and tetrapeptide, respectively. Interestingly, both feature cyclopropane rings, a structural motif
that also connects them to the second-generation direct-acting ACC 1 containing antiviral drugs
asunaprevir 13 (Fig. 4) [85], simeprevir 14 [86], paritaprevir 15 [87], and vaniprevir 16 [88], all of
which received FDA approval for HCV treatment around 2015.
While these compounds 13-16, being di- or tripeptides, share some structural similarities
with the earlier drugs boceprevir 11 and telaprevir 12, a key distinguishing feature in their design is
the significant conformational constraint imposed by the residue of ACC 1 often integrated within
three distinct types of macrocyclic motifs [89]. The rapid and successful development of these four
drugs 13-16 represents a remarkable achievement in a relatively short timeframe, underscoring the
power of rational drug design. However, the full pharmaceutical potential of ACC 1 and its diverse
array of derivatives remains largely untapped and ripe for further exploration. The unique steric and
conformational properties imparted by the cyclopropane ring in ACC 1 offer a powerful tool for
modulating molecular interactions and pharmacokinetic profiles, suggesting a wealth of
opportunities for the design of novel therapeutics beyond HCV treatment.
Fig. 4. The second-generation ACC 1 derived antiviral drugs.
What is particularly noteworthy is the current development pipeline, featuring numerous
novel drug candidates incorporating the ACC 1 moiety. To illustrate the chemical architecture of
current-generation HCV treatment drugs, we have selected neceprevir 17 [90], danoprevir 18 [91],
glecaprevir 19 [92], and GS-9256 20 [93]. Chemically, these compounds are peptidomimetics that
share a central hydroxyproline core and ACC 1 as key structural elements. Additional steric
constraints, enabling more precise biological interactions, are introduced through macrocyclic
bridges and bulky aromatic groups. Furthermore, these structures are stereochemically complex,
possessing an average of five or more stereogenic centers and existing as single enantiomers [94],
While these compounds 13-16, being di- or
tripeptides, share some structural similarities
with the earlier drugs boceprevir 11 and tela-
previr 12, a key distinguishing feature in their
design is the significant conformational con-
straint imposed by the residue of ACC 1 often
integrated within three distinct types of mac-
rocyclic motifs [89]. The rapid and successful
development of these four drugs 13-16 repre-
sents a remarkable achievement in a relatively
short timeframe, underscoring the power of
rational drug design. However, the full phar-
maceutical potential of ACC 1 and its diverse
array of derivatives remains largely untapped
32 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
and ripe for further exploration. The unique
steric and conformational properties impart-
ed by the cyclopropane ring in ACC 1 offer a
powerful tool for modulating molecular inter-
actions and pharmacokinetic profiles, suggest-
ing a wealth of opportunities for the design of
novel therapeutics beyond HCV treatment.
What is particularly noteworthy is the cur-
rent development pipeline, featuring numerous
novel drug candidates incorporating the ACC 1
moiety. To illustrate the chemical architecture of
current-generation HCV treatment drugs, we
have selected neceprevir 17 [90], danoprevir 18
[91], glecaprevir 19 [92], and GS-9256 20 [93].
Chemically, these compounds are peptidomi-
metics that share a central hydroxyproline core
and ACC 1 as key structural elements. Addi-
tional steric constraints, enabling more precise
biological interactions, are introduced through
macrocyclic bridges and bulky aromatic groups.
Furthermore, these structures are stereochemi-
cally complex, possessing an average of five or
more stereogenic centers and existing as single
enantiomers [94], highlighting the critical im-
portance of the precise three-dimensional posi-
tioning of all functional groups. Notably, these
structures also strategically incorporate fluorine
[95–97] for fine-tuning their biopharmaceutical
properties and metabolic stability, underscoring
the significant role of fluorine in modern phar-
maceutical design [98–100]. Finally, as exempli
fied by GS-9256 20, the application of phos-
phorus analogs of carboxylic acids represents a
growing trend in drug design [101–103].
Fig. 5. Recent antiviral drugs incorporating ACC 1 and fluorine substitution.
highlighting the critical importance of the precise three-dimensional positioning of all functional
groups. Notably, these structures also strategically incorporate fluorine [95–97] for fine-tuning their
biopharmaceutical properties and metabolic stability, underscoring the significant role of fluorine in
modern pharmaceutical design [98–100]. Finally, as exemplified by GS-9256 20, the application of
phosphorus analogs of carboxylic acids represents a growing trend in drug design [101–103].
Fig. 5. Recent antiviral drugs incorporating ACC 1 and fluorine substitution.
Given the widespread occurrence of ACC and its derivatives in natural products, coupled
with the remarkable success of ACC-based compounds in the design of numerous HCV drugs, it is
reasonable to expect that the synthesis of ACC has garnered significant attention. The extensive
body of synthetic methodologies will be classified in the subsequent sections based on the mode of
ACC skeleton construction.
Successive di-alkylation of nucleophilic glycine equivalents
The first synthesis of racemic vinyl-ACC 23 was reported in 1981 by a group of biochemists
studying the biological mechanism of ethylene production in plants [104]. The procedure was based
on the alkylation of the starting Schiff base 21, derived from glycine methyl ester and benzaldehyde
(Scheme 1). The vinyl-cyclopropane ring was formed in a key step, involving an intermolecular SN2
alkylation followed by intramolecular SN2' cyclization of glycine Schiff base 21 with trans-1,4-
dibromo-2-butene. A notable aspect of this approach is the high stereochemical control: the SN2–
SN2' dialkylation of glycine derivative 21 proceeded with complete relative stereochemistry,
yielding the diastereomerically pure intermediate 22, which was then converted to the free amino
acid 23 via acidic hydrolysis. The reactions were conducted under homogeneous conditions using a
33https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Given the widespread occurrence of ACC
and its derivatives in natural products, coupled
with the remarkable success of ACC-based
compounds in the design of numerous HCV
drugs, it is reasonable to expect that the syn-
thesis of ACC has garnered significant atten-
tion. The extensive body of synthetic metho
dologies will be classified in the subsequent
sections based on the mode of ACC skeleton
construction.
Successive di-alkylation of nucleophilic gly-
cine equivalents
The first synthesis of racemic vinyl-ACC 23
was reported in 1981 by a group of biochemists
studying the biological mechanism of ethylene
production in plants [104]. The procedure was
based on the alkylation of the starting Schiff
base 21, derived from glycine methyl ester and
benzaldehyde (Scheme 1). The vinyl-cyclopro-
pane ring was formed in a key step, involving
an intermolecular SN2 alkylation followed by
intramolecular SN2’ cyclization of glycine Schiff
base 21 with trans-1,4-dibromo-2-butene.
A notable aspect of this approach is the high
stereochemical control: the SN2–SN2’ dialkyla
tion of glycine derivative 21 proceeded with
complete relative stereochemistry, yielding the
diastereomerically pure intermediate 22, which
was then converted to the free amino acid 23
via acidic hydrolysis. The reactions were con-
ducted under homogeneous conditions using a
strong base (LDA) in THF at low temperature.
This SN2–SN2’ dialkylation sequence proved to
be a synthetically general and concise route to
the vinyl-ACC skeleton, and has been employed
in many subsequent studies.
strong base (LDA) in THF at low temperature. This SN2–SN2' dialkylation sequence proved to be a
synthetically general and concise route to the vinyl-ACC skeleton, and has been employed in many
subsequent studies.
Scheme 1. Synthesis of vinyl-ACC 23 via SN2–SN2′ dialkylation of Schiff base 21.
This approach was thoughtfully designed for large-scale synthesis, with careful
consideration of the cost structure [105], reaction simplicity, and operational convenience [106–
108]. For the construction of the vinyl-ACC framework, the authors selected the straightforward
SN2–SN2' dialkylation sequence. The reaction of glycine ethyl ester Schiff base 24 (Scheme 2) with
trans-1,4-dibromo-2-butene was systematically studied using a variety of bases and solvents. It was
found that aprotic solvents were essential for high diastereoselectivity. In particular, the reaction
conducted in toluene with lithium tert-butoxide as a base yielded the desired cyclopropane 25 with
virtually complete diastereomeric purity. After Schiff base deprotection and simple purification by
several extractions, diastereomerically pure racemic 26 was converted into Boc-protected vinyl-
ACC ethyl ester 27 in 65–70% overall yield. Enzymatic resolution of diastereomerically pure ethyl
ester 27 using Alcalase proceeded with very high enantioselectivity, producing a mixture of
(1S,2R)-28, as a free acid, and (1R,2S)-29, as an ethyl ester.
Scheme 2. Enzymatic approach for preparation of enantiomerically pure derivatives 28 and 29.
In general, enzymatic resolutions of sterically constrained α-amino acids are challenging
[109–111] as most natural enzymes are sterically sensitive and adapted to the typical structure of α-
unsubstituted amino acids.
Enantioselective adaptation of the SN2–SN2' dialkylation sequence strategy, employing a
chiral phase transfer catalyst (Scheme 3) [112, 113]. Extensive efforts to refine the catalyst’s
structure ultimately led to the breakthrough discovery of the catalyst 32, with the benzylic moiety
substitution proving essential—its unsubstituted benzyl counterpart 31 delivered a mere 2% ee of
30. With catalyst 32, the synthesis of 30 achieved an impressive 77% enantiomeric excess (ee) and
78% yield, marking a significant advancement. However, meticulous control over reaction
Scheme 1. Synthesis of vinyl-ACC 23 via SN2–SN2′ dialkylation of Schiff base 21.
This approach was thoughtfully designed
for large-scale synthesis, with careful conside
ration of the cost structure [105], reaction
simplicity, and operational convenience [106–
108]. For the construction of the vinyl-ACC
framework, the authors selected the straight-
forward SN2–SN2’ dialkylation sequence. The
reaction of glycine ethyl ester Schiff base 24
(Scheme 2) with trans-1,4-dibromo-2-butene
was systematically studied using a variety of
bases and solvents. It was found that aprotic
solvents were essential for high diastereose-
lectivity. In particular, the reaction conducted
in toluene with lithium tert-butoxide as a base
yielded the desired cyclopropane 25 with vir-
tually complete diastereomeric purity. After
Schiff base deprotection and simple purifica-
tion by several extractions, diastereomerically
pure racemic 26 was converted into Boc-pro-
tected vinyl-ACC ethyl ester 27 in 65–70%
overall yield. Enzymatic resolution of diaste
reomerically pure ethyl ester 27 using Alcalase
proceeded with very high enantioselectivity,
producing a mixture of (1S,2R)-28, as a free
acid, and (1R,2S)-29, as an ethyl ester.
34 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 2. Enzymatic approach for preparation of enantiomerically
pure derivatives 28 and 29.
strong base (LDA) in THF at low temperature. This SN2–SN2' dialkylation sequence proved to be a
synthetically general and concise route to the vinyl-ACC skeleton, and has been employed in many
subsequent studies.
Scheme 1. Synthesis of vinyl-ACC 23 via SN2–SN2′ dialkylation of Schiff base 21.
This approach was thoughtfully designed for large-scale synthesis, with careful
consideration of the cost structure [105], reaction simplicity, and operational convenience [106–
108]. For the construction of the vinyl-ACC framework, the authors selected the straightforward
SN2–SN2' dialkylation sequence. The reaction of glycine ethyl ester Schiff base 24 (Scheme 2) with
trans-1,4-dibromo-2-butene was systematically studied using a variety of bases and solvents. It was
found that aprotic solvents were essential for high diastereoselectivity. In particular, the reaction
conducted in toluene with lithium tert-butoxide as a base yielded the desired cyclopropane 25 with
virtually complete diastereomeric purity. After Schiff base deprotection and simple purification by
several extractions, diastereomerically pure racemic 26 was converted into Boc-protected vinyl-
ACC ethyl ester 27 in 65–70% overall yield. Enzymatic resolution of diastereomerically pure ethyl
ester 27 using Alcalase proceeded with very high enantioselectivity, producing a mixture of
(1S,2R)-28, as a free acid, and (1R,2S)-29, as an ethyl ester.
Scheme 2. Enzymatic approach for preparation of enantiomerically pure derivatives 28 and 29.
In general, enzymatic resolutions of sterically constrained α-amino acids are challenging
[109–111] as most natural enzymes are sterically sensitive and adapted to the typical structure of α-
unsubstituted amino acids.
Enantioselective adaptation of the SN2–SN2' dialkylation sequence strategy, employing a
chiral phase transfer catalyst (Scheme 3) [112, 113]. Extensive efforts to refine the catalyst’s
structure ultimately led to the breakthrough discovery of the catalyst 32, with the benzylic moiety
substitution proving essential—its unsubstituted benzyl counterpart 31 delivered a mere 2% ee of
30. With catalyst 32, the synthesis of 30 achieved an impressive 77% enantiomeric excess (ee) and
78% yield, marking a significant advancement. However, meticulous control over reaction
In general, enzymatic resolutions of steri-
cally constrained α-amino acids are challeng-
ing [109–111] as most natural enzymes are
sterically sensitive and adapted to the typical
structure of α-unsubstituted amino acids.
Enantioselective adaptation of the SN2–SN2’
dialkylation sequence strategy, employing a
chiral phase transfer catalyst (Scheme 3) [112,
113]. Extensive efforts to refine the catalyst’s
structure ultimately led to the breakthrough
discovery of the catalyst 32, with the benzylic
moiety substitution proving essential—its un-
substituted benzyl counterpart 31 delivered a
mere 2% ee of 30. With catalyst 32, the syn-
thesis of 30 achieved an impressive 77% enan-
tiomeric excess (ee) and 78% yield, marking a
significant advancement. However, meticulous
control over reaction conditions was crucial—
water content and sodium hydroxide selection
played pivotal roles in minimizing undesirable
byproducts, particularly ester saponification.
Notably, pin-milled NaOH with fine particle
size (~30 μm) ensured complete conversion
within 24 hours at 0°C, whereas commercial
powdered NaOH led to extended reaction
times and diminished yields. These findings
underscored the profound impact of precise
reagent selection and process optimization in
achieving superior synthetic outcomes.
conditions was crucial—water content and sodium hydroxide selection played pivotal roles in
minimizing undesirable byproducts, particularly ester saponification. Notably, pin-milled NaOH
with fine particle size (~30 μm) ensured complete conversion within 24 hours at 0°C, whereas
commercial powdered NaOH led to extended reaction times and diminished yields. These findings
underscored the profound impact of precise reagent selection and process optimization in achieving
superior synthetic outcomes.
Scheme 3. Enantioselective synthesis of vinyl-ACC 30 under PTC conditions.
It is important to note that the isolation and purification of product 30 in this study relies on
column chromatography procedures, which are known to be associated with the phenomenon of
Self-Disproportionation of Enantiomers (SDE)—a widely reported occurrence in chiral amines and
amino acid derivatives subjected to achiral column chromatography [114–116]. As a result, unless a
dedicated SDE study on compound 30 is conducted, the reported stereochemical outcome [112,
113] should be regarded as tentative.
The elegant chemical transformation of glycine ethyl ester Schiff base 21 with alkylating
reagent 33 is illustrated in Scheme 4 [117]. The four-carbon framework of 33 contains three
electrophilic sites with distinct reactivity, enabling a stepwise alkylation cascade. The reaction
proceeds under operationally convenient conditions, employing NaH as the base. The first two
alkylation steps follow a typical SN2–SN2' sequence, yielding intermediate 34. Subsequent
neutralization of the reaction medium, followed by re-exposure to basic conditions using K₂CO₃,
initiates the third and final alkylation, culminating in the formation of the sterically constrained
bicyclic architecture 35. Most notably, the use of enantiomerically pure (S)-33 efficiently transmits
stereochemical information, directing the configuration of two newly formed stereogenic centers.
As a result, the process affords the diastereomerically pure intermediate (2S,3R)-34, ultimately
leading to the final product (2S,3S)-35 with exceptional stereochemical fidelity.
Scheme 4. Asymmetric synthesis of bicyclic ACC derivative 35.
Asymmetric synthesis of α-amino acids via Ni(II) complexes of glycine Schiff bases, such
as those of type 36, represents a well-established and widely used methodology (Scheme 5) [118–
121]. Homologation of the glycine moiety within chiral Schiff base 36 can be achieved through
various reactions, including aldol [122–125], Michael [126–129], and Mannich [130–132]
Scheme 3. Enantioselective synthesis of vinyl-ACC 30 under PTC conditions.
35https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
It is important to note that the isolation and
purification of product 30 in this study relies
on column chromatography procedures, which
are known to be associated with the pheno
menon of Self-Disproportionation of Enanti-
omers (SDE)—a widely reported occurrence
in chiral amines and amino acid derivatives
subjected to achiral column chromatography
[114–116]. As a result, unless a dedicated SDE
study on compound 30 is conducted, the re-
ported stereochemical outcome [112, 113]
should be regarded as tentative.
The elegant chemical transformation of gly-
cine ethyl ester Schiff base 21 with alkylating
reagent 33 is illustrated in Scheme 4 [117]. The
four-carbon framework of 33 contains three
electrophilic sites with distinct reactivity, enab
ling a stepwise alkylation cascade. The reaction
proceeds under operationally convenient con-
ditions, employing NaH as the base. The first
two alkylation steps follow a typical SN2–SN2’
sequence, yielding intermediate 34. Subsequent
neutralization of the reaction medium, followed
by re-exposure to basic conditions using K₂CO₃,
initiates the third and final alkylation, culminat-
ing in the formation of the sterically constrained
bicyclic architecture 35. Most notably, the use of
enantiomerically pure (S)-33 efficiently trans-
mits stereochemical information, directing the
configuration of two newly formed stereogenic
centers. As a result, the process affords the dia
stereomerically pure intermediate (2S,3R)-34,
ultimately leading to the final product (2S,3S)-
35 with exceptional stereochemical fidelity.
conditions was crucial—water content and sodium hydroxide selection played pivotal roles in
minimizing undesirable byproducts, particularly ester saponification. Notably, pin-milled NaOH
with fine particle size (~30 μm) ensured complete conversion within 24 hours at 0°C, whereas
commercial powdered NaOH led to extended reaction times and diminished yields. These findings
underscored the profound impact of precise reagent selection and process optimization in achieving
superior synthetic outcomes.
Scheme 3. Enantioselective synthesis of vinyl-ACC 30 under PTC conditions.
It is important to note that the isolation and purification of product 30 in this study relies on
column chromatography procedures, which are known to be associated with the phenomenon of
Self-Disproportionation of Enantiomers (SDE)—a widely reported occurrence in chiral amines and
amino acid derivatives subjected to achiral column chromatography [114–116]. As a result, unless a
dedicated SDE study on compound 30 is conducted, the reported stereochemical outcome [112,
113] should be regarded as tentative.
The elegant chemical transformation of glycine ethyl ester Schiff base 21 with alkylating
reagent 33 is illustrated in Scheme 4 [117]. The four-carbon framework of 33 contains three
electrophilic sites with distinct reactivity, enabling a stepwise alkylation cascade. The reaction
proceeds under operationally convenient conditions, employing NaH as the base. The first two
alkylation steps follow a typical SN2–SN2' sequence, yielding intermediate 34. Subsequent
neutralization of the reaction medium, followed by re-exposure to basic conditions using K₂CO₃,
initiates the third and final alkylation, culminating in the formation of the sterically constrained
bicyclic architecture 35. Most notably, the use of enantiomerically pure (S)-33 efficiently transmits
stereochemical information, directing the configuration of two newly formed stereogenic centers.
As a result, the process affords the diastereomerically pure intermediate (2S,3R)-34, ultimately
leading to the final product (2S,3S)-35 with exceptional stereochemical fidelity.
Scheme 4. Asymmetric synthesis of bicyclic ACC derivative 35.
Asymmetric synthesis of α-amino acids via Ni(II) complexes of glycine Schiff bases, such
as those of type 36, represents a well-established and widely used methodology (Scheme 5) [118–
121]. Homologation of the glycine moiety within chiral Schiff base 36 can be achieved through
various reactions, including aldol [122–125], Michael [126–129], and Mannich [130–132]
Scheme 4. Asymmetric synthesis of bicyclic ACC derivative 35.
Asymmetric synthesis of α-amino acids via
Ni(II) complexes of glycine Schiff bases, such
as those of type 36, represents a well-estab-
lished and widely used methodology (Sche
me 5) [118–121]. Homologation of the gly-
cine moiety within chiral Schiff base 36 can be
achieved through various reactions, including
aldol [122–125], Michael [126–129], and Man-
nich [130–132] additions, as well as alkyl ha
lide alkylation [133, 134], including reactions
with sterically constrained derivatives [135,
136], dialkylation [137–139], and bisalkylation
[140] reactions. Therefore, the application of
the Ni(II) complex 36 holds significant poten-
tial for the preparation of ACC derivatives. In
this context, the Ni(II) complex of Schiff base
(R)-36, readily prepared from glycine, Ni(II)
acetate or chloride, and an (R)-proline-deri
ved ligand 41 [141, 142], was reacted with
trans-1,4-dibromo-2-butene under solid-li
quid phase-transfer catalysis (PTC) conditions
[143, 144], using solid NaOH in the presence
of tetrabutylammonium iodide (TBAI). This
PTC alkylation yielded a mixture of mono
alkylated products 37 and 38 in a 4:1 ratio,
with an overall yield of 79% [145, 146].
36 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 5. Asymmetric synthesis of vinyl-ACC 42 via proline-derived chiral Schiff base 36.
additions, as well as alkyl halide alkylation [133, 134], including reactions with sterically
constrained derivatives [135, 136], dialkylation [137–139], and bisalkylation [140] reactions.
Therefore, the application of the Ni(II) complex 36 holds significant potential for the preparation of
ACC derivatives. In this context, the Ni(II) complex of Schiff base (R)-36, readily prepared from
glycine, Ni(II) acetate or chloride, and an (R)-proline-derived ligand 41 [141, 142], was reacted
with trans-1,4-dibromo-2-butene under solid-liquid phase-transfer catalysis (PTC) conditions [143,
144], using solid NaOH in the presence of tetrabutylammonium iodide (TBAI). This PTC alkylation
yielded a mixture of monoalkylated products 37 and 38 in a 4:1 ratio, with an overall yield of 79%
[145, 146].
Scheme 5. Asymmetric synthesis of vinyl-ACC 42 via proline-derived chiral Schiff base 36.
The relatively low diastereoselectivity at this stage was inconsequential, as both
diastereomers 37 and 38 were utilized in the subsequent intramolecular alkylation. The SN2'
alkylation was accomplished by treating the resulting mixture with sodium tert-butoxide, affording
the target vinylcyclopropanes 39 and 40 in a 9:1 ratio and a 73% yield. Notably, the direct one-pot
sequential SN2–SN2' dialkylation of 36 under homogeneous conditions in N,N-dimethylformamide
(DMF) did not produce the desired products 39 and 40, suggesting that these conditions are too
harsh for the reagents and intermediates, which possess multiple reactive centers. Following
chromatographic separation, the diastereomerically pure major product 39 was treated with 1 N
HCl, resulting in the decomplexation of the Ni(II) complex and the formation of chiral ligand 41,
along with the desired vinyl-ACC 42. The chiral ligand 41 was recycled and used to generate new
batches of the starting glycine Schiff base Ni(II) complex 36. The target vinyl-ACC 42 was isolated
using a cation exchange resin.
Chiral glycine Schiff base Ni(II) complex 36 was also employed in the highly
diastereoselective synthesis of norcoronamic acid (2) (Scheme 6) [147]. A key feature of this
reaction is that both starting compounds—the Ni(II) complex of Schiff base 36 and the
corresponding ester—are chiral and possess matching (S) absolute configurations. This double
asymmetric induction leads to complete diastereoselectivity in the formation of the cyclopropane
ring. Consequently, the product 43 required no additional purification before being disassembled to
yield the target norcoronamic acid (2) and chiral ligand 41. Interestingly, attempts to use the
racemic sulfate resulted in a 1:1 ratio of the corresponding diastereomers, indicating no significant
The relatively low diastereoselectivity at
this stage was inconsequential, as both dia
stereomers 37 and 38 were utilized in the sub-
sequent intramolecular alkylation. The SN2’
alkylation was accomplished by treating the
resulting mixture with sodium tert-butoxide,
affording the target vinylcyclopropanes 39
and 40 in a 9:1 ratio and a 73% yield. Notably,
the direct one-pot sequential SN2–SN2’ dialky
lation of 36 under homogeneous conditions
in N,N-dimethylformamide (DMF) did not
produce the desired products 39 and 40, sug-
gesting that these conditions are too harsh for
the reagents and intermediates, which possess
multiple reactive centers. Following chromato-
graphic separation, the diastereomerically pure
major product 39 was treated with 1 N HCl,
resulting in the decomplexation of the Ni(II)
complex and the formation of chiral ligand 41,
along with the desired vinyl-ACC 42. The chi-
ral ligand 41 was recycled and used to gene
rate new batches of the starting glycine Schiff
base Ni(II) complex 36. The target vinyl-ACC
42 was isolated using a cation exchange resin.
Chiral glycine Schiff base Ni(II) complex
36 was also employed in the highly diastereo
selective synthesis of norcoronamic acid (2)
(Scheme 6) [147]. A key feature of this reaction
is that both starting compounds—the Ni(II)
complex of Schiff base 36 and the correspond-
ing ester—are chiral and possess matching (S)
absolute configurations. This double asymmet-
ric induction leads to complete diastereose-
lectivity in the formation of the cyclopropane
ring. Consequently, the product 43 required
no additional purification before being disas-
sembled to yield the target norcoronamic acid
(2) and chiral ligand 41. Interestingly, attempts
to use the racemic sulfate resulted in a 1:1 ratio
of the corresponding diastereomers, indicating
no significant kinetic resolution in the alkylat-
ing reagent. It should be noted that noticeable
kinetic resolution was observed in the alkyla-
tion of chiral Schiff base Ni(II) complexes of
type 36 with racemic α-alkylbenzyl bromides
[49, 148].
37https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Scheme 6. Asymmetric synthesis of norcoronamic acid (2) via chiral Schiff base 36.
kinetic resolution in the alkylating reagent. It should be noted that noticeable kinetic resolution was
observed in the alkylation of chiral Schiff base Ni(II) complexes of type 36 with racemic α-
alkylbenzyl bromides [49, 148].
Scheme 6. Asymmetric synthesis of norcoronamic acid (2) via chiral Schiff base 36.
The synthetic potential of Ni(II) complexes derived from glycine chiral Schiff bases in the
field of asymmetric AA synthesis has driven the development of next-generation derivatives
designed for large-scale preparation of tailor-made AAs with enhanced efficiency [149–151]. For
example, informed by extensive crystallographic data [152], Ni(II) complex 44 (Fig. 6) was
strategically engineered with chlorine atoms to optimize its performance in asymmetric
transformations [153, 154]. This complex has demonstrated remarkable efficiency in dynamic
kinetic resolution of racemic AAs [155, 156]. Similarly, Ni(II) complex 45, featuring two elements
of chirality, has shown exceptional selectivity in alkylation and aldol addition reactions, benefiting
from double asymmetric induction, where central and axial chirality are stereochemically matched
[121]. Meanwhile, Ni(II) complex 46 [157, 158] has emerged as the most effective catalyst in
processes governed by second-order asymmetric transformation control [159], further expanding
the potential of Ni(II)-based systems in complex synthetic applications.
Fig. 6. New generation Ni(II) complexes of chiral nucleophilic glycine equivalents.
Ni(II) complex 47, derived from C₂-symmetric bis(naphthyl)amine [160–162], holds
significant potential for the asymmetric synthesis of AAs. Its application in the synthesis of vinyl-
ACC derivatives is illustrated in Scheme 7 [163].
After extensive experimentation, it was determined that the two-step SN2–SN2′ dialkylation
of the glycine moiety in 47 was best carried out using a two-step approach. First, the reaction was
performed under phase transfer catalysis (PTC) conditions with the corresponding dibromide,
employing 30% aqueous NaOH in the presence of TBAI, yielding product 48 as the major
diastereomer (70:30 ratio). Without purification, the diastereomeric mixture was then treated with
sodium tert-butoxide, leading to the cyclopropane-cyclized Ni(II) complex 49 with an 83% overall
kinetic resolution in the alkylating reagent. It should be noted that noticeable kinetic resolution was
observed in the alkylation of chiral Schiff base Ni(II) complexes of type 36 with racemic α-
alkylbenzyl bromides [49, 148].
Scheme 6. Asymmetric synthesis of norcoronamic acid (2) via chiral Schiff base 36.
The synthetic potential of Ni(II) complexes derived from glycine chiral Schiff bases in the
field of asymmetric AA synthesis has driven the development of next-generation derivatives
designed for large-scale preparation of tailor-made AAs with enhanced efficiency [149–151]. For
example, informed by extensive crystallographic data [152], Ni(II) complex 44 (Fig. 6) was
strategically engineered with chlorine atoms to optimize its performance in asymmetric
transformations [153, 154]. This complex has demonstrated remarkable efficiency in dynamic
kinetic resolution of racemic AAs [155, 156]. Similarly, Ni(II) complex 45, featuring two elements
of chirality, has shown exceptional selectivity in alkylation and aldol addition reactions, benefiting
from double asymmetric induction, where central and axial chirality are stereochemically matched
[121]. Meanwhile, Ni(II) complex 46 [157, 158] has emerged as the most effective catalyst in
processes governed by second-order asymmetric transformation control [159], further expanding
the potential of Ni(II)-based systems in complex synthetic applications.
Fig. 6. New generation Ni(II) complexes of chiral nucleophilic glycine equivalents.
Ni(II) complex 47, derived from C₂-symmetric bis(naphthyl)amine [160–162], holds
significant potential for the asymmetric synthesis of AAs. Its application in the synthesis of vinyl-
ACC derivatives is illustrated in Scheme 7 [163].
After extensive experimentation, it was determined that the two-step SN2–SN2′ dialkylation
of the glycine moiety in 47 was best carried out using a two-step approach. First, the reaction was
performed under phase transfer catalysis (PTC) conditions with the corresponding dibromide,
employing 30% aqueous NaOH in the presence of TBAI, yielding product 48 as the major
diastereomer (70:30 ratio). Without purification, the diastereomeric mixture was then treated with
sodium tert-butoxide, leading to the cyclopropane-cyclized Ni(II) complex 49 with an 83% overall
The synthetic potential of Ni(II) complex-
es derived from glycine chiral Schiff bases in
the field of asymmetric AA synthesis has dri
ven the development of next-generation de-
rivatives designed for large-scale preparation
of tailor-made AAs with enhanced efficiency
[149–151]. For example, informed by exten-
sive crystallographic data [152], Ni(II) com-
plex 44 (Fig. 6) was strategically engineered
with chlorine atoms to optimize its perfor-
mance in asymmetric transformations [153,
154]. This complex has demonstrated remar
kable efficiency in dynamic kinetic resolution
of racemic AAs [155, 156]. Similarly, Ni(II)
complex 45, featuring two elements of chirali
ty, has shown exceptional selectivity in alky
lation and aldol addition reactions, benefiting
from double asymmetric induction, where
central and axial chirality are stereochemical-
ly matched [121]. Meanwhile, Ni(II) complex
46 [157, 158] has emerged as the most effective
catalyst in processes governed by second-order
asymmetric transformation control [159], fur-
ther expanding the potential of Ni(II)-based
systems in complex synthetic applications.
Fig. 6. New generation Ni(II) complexes of chiral nucleophilic glycine equivalents.
Ni(II) complex 47, derived from C₂-sym-
metric bis(naphthyl)amine [160–162], holds
significant potential for the asymmetric syn-
thesis of AAs. Its application in the synthesis of
vinyl-ACC derivatives is illustrated in Scheme
7 [163].
38 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
After extensive experimentation, it was de-
termined that the two-step SN2–SN2′ dialkyla-
tion of the glycine moiety in 47 was best car-
ried out using a two-step approach. First, the
reaction was performed under phase transfer
catalysis (PTC) conditions with the corre-
sponding dibromide, employing 30% aqueous
NaOH in the presence of TBAI, yielding pro
duct 48 as the major diastereomer (70:30 ra-
tio). Without purification, the diastereomeric
mixture was then treated with sodium tert-bu-
toxide, leading to the cyclopropane-cyclized
Ni(II) complex 49 with an 83% overall yield
and exceptional diastereoselectivity (99.5%
de)—highlighting the superior stereocon-
trolling properties of 47 compared to the pro-
line-derived complex 36.
Product 49, without further purification,
was subsequently disassembled by treatment
with 1N HCl, affording free vinyl-ACC 42 and
chiral ligand 50, which were efficiently sepa-
rated via simple extraction. Vinyl-ACC 42 was
further purified using a cation exchange resin.
Notably, ligand 50 is highly stable and not
prone to racemization under typical organic
synthesis conditions, making it virtually indefi-
nitely recyclable and reusable. In this regard, the
application of ligand 50 presents a more eco-
nomical and practical approach—even surpass-
ing the efficiency of enantioselective catalysis.
yield and exceptional diastereoselectivity (99.5% de)—highlighting the superior stereocontrolling
properties of 47 compared to the proline-derived complex 36.
Product 49, without further purification, was subsequently disassembled by treatment with
1N HCl, affording free vinyl-ACC 42 and chiral ligand 50, which were efficiently separated via
simple extraction. Vinyl-ACC 42 was further purified using a cation exchange resin.
Notably, ligand 50 is highly stable and not prone to racemization under typical organic
synthesis conditions, making it virtually indefinitely recyclable and reusable. In this regard, the
application of ligand 50 presents a more economical and practical approach—even surpassing the
efficiency of enantioselective catalysis.
Scheme 7. Asymmetric synthesis of vinyl ACC 42 via Ni(II) complex of Schiff base derived from axially
chiral ligand 50.
This synthetic sequence was carried out using 33 g of Ni(II) complex 47, yielding 4.5 g of
vinyl-ACC 42. The process demonstrates a virtually complete stereochemical outcome, a fully
recyclable chiral source, and operational simplicity, ensuring convenient and efficient reaction
conditions. Moreover, the proven scalability of Ni(II) complex chemistry further supports its
potential for broad synthetic applications.
(Diphenylmethylene)aminoacetonitrile 51 represents another type of nucleophilic glycine
equivalent, utilized in the synthesis of ACC 1 via a dialkylation sequence. The cyclopropane ring
was efficiently formed under PTC conditions using 1,2-dibromoethane as the electrophilic agent, in
the presence of sodium hydroxide as a base [164–166]. Subsequent acidic hydrolysis removed the
Schiff base and CN protecting groups in 52, yielding the target compound ACC 1. Notably, this
approach is remarkably straightforward and well-suited for large-scale synthesis.
Scheme 7. Asymmetric synthesis of vinyl ACC 42 via Ni(II) complex of Schiff base
derived from axially chiral ligand 50.
This synthetic sequence was carried out
using 33 g of Ni(II) complex 47, yielding 4.5 g
of vinyl-ACC 42. The process demonstrates a
virtually complete stereochemical outcome, a
fully recyclable chiral source, and operational
simplicity, ensuring convenient and efficient
reaction conditions. Moreover, the proven
scalability of Ni(II) complex chemistry further
supports its potential for broad synthetic ap-
plications.
39https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
(Diphenylmethylene)aminoacetonitrile 51
represents another type of nucleophilic glycine
equivalent, utilized in the synthesis of ACC 1
via a dialkylation sequence. The cyclopro-
pane ring was efficiently formed under PTC
conditions using 1,2-dibromoethane as the
electrophilic agent, in the presence of sodium
hydroxide as a base [164–166]. Subsequent
acidic hydrolysis removed the Schiff base and
CN protecting groups in 52, yielding the tar-
get compound ACC 1. Notably, this approach
is remarkably straightforward and well-suited
for large-scale synthesis.
Scheme 8. Preparation of ACC 1 via dialkylation of (diphenylmethylene)aminoacetonitrile 5 and synthesis of
allo-norcoronamic acid 55 via dialkylation of isocyanoacetate 53
Isocyanoacetates are highly versatile reagents in amino acid synthesis, exhibiting unique
reactivity due to their electron-withdrawing isocyanide and ester functional groups. Their ability to
serve as nucleophilic glycine equivalents makes them particularly valuable for the tailored
construction of amino acids via alkyl halide alkylations and various addition reactions [167−171].
For example, the alkylation of isocyanoacetate 53 with propene oxide proceeds efficiently in the
presence of butyl lithium at −78 °C, yielding product 54 with an excellent yield (>90%).
Subsequent mesylation of the hydroxyl group in 54 is followed by a second alkylation step that
induces cyclopropane ring formation. A final hydrolytic cleavage of the isonitrile and ester
protecting groups affords ACC 55 with an overall yield of approximately 50%. Notably, this
cyclization protocol strongly favors the stereochemistry of allo-norcoronamic acid, with the major
diastereomer comprising over 85% of the product [172,173].
An intriguing example of intramolecular alkylation within the proline framework is
illustrated in Scheme 9. Naturally occurring and properly protected hydroxyproline 56 was treated
with CBr₄/PPh₃, facilitating the stereoselective substitution of the hydroxyl group with a bromine
atom. The resulting intermediate 57 was then exposed to harsh reaction conditions, utilizing an
excess of a strong base in THF at −78 °C, forcing the formation of an extremely sterically
constrained bicyclic system 58, consisting of four- and three-membered rings. Remarkably, despite
significant steric strain, the process achieved a respectable yield. Most notably, this cyclization
reaction proceeded in a highly stereoselective manner, converting (S)-configured hydroxyproline 56
into the (2R,3R)-bicyclic system 58 with impressive selectivity [174].
Scheme 9. Preparation of bicyclic ACC 58 from hydroxy proline 56.
Another example of intramolecular cyclization of amino acid derivatives, resulting in the
formation of a cyclopropane ring, is presented in Scheme 10. In this case, the ω-carboxy group in
Scheme 8. Preparation of ACC 1 via dialkylation of (diphenylmethylene)aminoacetonitrile 5
and synthesis of allo-norcoronamic acid 55 via dialkylation of isocyanoacetate 53
Isocyanoacetates are highly versatile re-
agents in amino acid synthesis, exhibiting
unique reactivity due to their electron-with-
drawing isocyanide and ester functional
groups. Their ability to serve as nucleophilic
glycine equivalents makes them particularly
valuable for the tailored construction of amino
acids via alkyl halide alkylations and various
addition reactions [167−171]. For example,
the alkylation of isocyanoacetate 53 with pro-
pene oxide proceeds efficiently in the presence
of butyl lithium at −78 °C, yielding product
54 with an excellent yield (>90%). Subsequent
mesylation of the hydroxyl group in 54 is fol-
lowed by a second alkylation step that induces
cyclopropane ring formation. A final hydroly
tic cleavage of the isonitrile and ester protect-
ing groups affords ACC 55 with an overall yield
of approximately 50%. Notably, this cyclization
protocol strongly favors the stereochemistry of
allo-norcoronamic acid, with the major dia
stereomer comprising over 85% of the product
[172,173].
An intriguing example of intramolecular
alkylation within the proline framework is il-
lustrated in Scheme 9. Naturally occurring
and properly protected hydroxyproline 56 was
treated with CBr₄/PPh₃, facilitating the stereo
selective substitution of the hydroxyl group
with a bromine atom. The resulting interme-
diate 57 was then exposed to harsh reaction
conditions, utilizing an excess of a strong base
in THF at −78 °C, forcing the formation of an
extremely sterically constrained bicyclic sys-
tem 58, consisting of four- and three-mem-
bered rings. Remarkably, despite significant
40 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
steric strain, the process achieved a respectable
yield. Most notably, this cyclization reaction
proceeded in a highly stereoselective manner,
converting (S)-configured hydroxyproline 56
into the (2R,3R)-bicyclic system 58 with im-
pressive selectivity [174].
Scheme 8. Preparation of ACC 1 via dialkylation of (diphenylmethylene)aminoacetonitrile 5 and synthesis of
allo-norcoronamic acid 55 via dialkylation of isocyanoacetate 53
Isocyanoacetates are highly versatile reagents in amino acid synthesis, exhibiting unique
reactivity due to their electron-withdrawing isocyanide and ester functional groups. Their ability to
serve as nucleophilic glycine equivalents makes them particularly valuable for the tailored
construction of amino acids via alkyl halide alkylations and various addition reactions [167−171].
For example, the alkylation of isocyanoacetate 53 with propene oxide proceeds efficiently in the
presence of butyl lithium at −78 °C, yielding product 54 with an excellent yield (>90%).
Subsequent mesylation of the hydroxyl group in 54 is followed by a second alkylation step that
induces cyclopropane ring formation. A final hydrolytic cleavage of the isonitrile and ester
protecting groups affords ACC 55 with an overall yield of approximately 50%. Notably, this
cyclization protocol strongly favors the stereochemistry of allo-norcoronamic acid, with the major
diastereomer comprising over 85% of the product [172,173].
An intriguing example of intramolecular alkylation within the proline framework is
illustrated in Scheme 9. Naturally occurring and properly protected hydroxyproline 56 was treated
with CBr₄/PPh₃, facilitating the stereoselective substitution of the hydroxyl group with a bromine
atom. The resulting intermediate 57 was then exposed to harsh reaction conditions, utilizing an
excess of a strong base in THF at −78 °C, forcing the formation of an extremely sterically
constrained bicyclic system 58, consisting of four- and three-membered rings. Remarkably, despite
significant steric strain, the process achieved a respectable yield. Most notably, this cyclization
reaction proceeded in a highly stereoselective manner, converting (S)-configured hydroxyproline 56
into the (2R,3R)-bicyclic system 58 with impressive selectivity [174].
Scheme 9. Preparation of bicyclic ACC 58 from hydroxy proline 56.
Another example of intramolecular cyclization of amino acid derivatives, resulting in the
formation of a cyclopropane ring, is presented in Scheme 10. In this case, the ω-carboxy group in
Scheme 9. Preparation of bicyclic ACC 58 from hydroxy proline 56.
Another example of intramolecular cycliza-
tion of amino acid derivatives, resulting in the
formation of a cyclopropane ring, is presented
in Scheme 10. In this case, the ω-carboxy group
in properly protected glutamic acid 59 was sub-
stituted with a bromine atom, and the resulting
compound 60 underwent intramolecular cycli-
zation. The formation of the three-membered
ring was achieved using NaH in THF at −78 °C.
It should be noted that the application of two
equivalents of NaH was necessary, as one mole
of the base was used to ionize the N-H bond.
The cyclization proceeded cleanly at the α-car-
bon, with no products of N-alkylation observed.
Following cyclization, hydrolysis of the ester
group and deprotection of CO₂Bn using hydro-
gen over a palladium catalyst afforded the target
compound, ACC 1 [175–178].
Scheme 10. Preparation of ACC 1 via intramolecular cyclization of glutamic acid derivative 60.
properly protected glutamic acid 59 was substituted with a bromine atom, and the resulting
compound 60 underwent intramolecular cyclization. The formation of the three-membered ring was
achieved using NaH in THF at −78 °C. It should be noted that the application of two equivalents of
NaH was necessary, as one mole of the base was used to ionize the N-H bond. The cyclization
proceeded cleanly at the α-carbon, with no products of N-alkylation observed. Following
cyclization, hydrolysis of the ester group and deprotection of CO₂Bn using hydrogen over a
palladium catalyst afforded the target compound, ACC 1 [175–178].
Scheme 10. Preparation of ACC 1 via intramolecular cyclization of glutamic acid derivative 60.
Alkyl 2-nitroacetates as carbenoid glycine equivalents.
Reactions between carbenes and alkenes represent one of the most widely utilized
approaches for constructing cyclopropane rings [179]. In this context, compounds 61 and 62 (Fig.
7), each contributing a single carbon atom to the three-membered ring and carrying amino and
carboxyl groups, can be regarded as suitable carbenoid glycine equivalents for the synthesis of
tailor-made ACC derivatives. However, the precursors of carbenes 61 and 62—such as the
corresponding diazo compounds—are highly unstable, requiring strongly electron-withdrawing or
aromatic substituents directly attached to the carbene carbon. Consequently, nitroacetates 63 may
serve as generalized carbenoid glycine equivalents. The synthesis of ACC derivatives via carbenes
63 will thus necessitate an additional step involving chemo-selective reductive transformation of the
nitro group into the requisite amino group [180, 181].
Fig. 7. Carbenoid glycine equivalents.
For example, the cyclopropanation reaction has been extensively studied using various
diazoesters 64 (Scheme 11). The yields are generally high, while the diastereoselectivity varies
significantly and is strongly influenced by the nature of the alkyl ester group [182]. The formation
of the trans isomer 65 is typically favored over the cis diastereomer 66, though the ratio is clearly
dependent on the steric bulk of the ester alkyl group—highest for methyl and lowest for tert-butyl.
The nitro group was efficiently reduced to the corresponding amino functionality using either zinc
or indium in the presence of hydrochloric acid [183]. Notably, this procedure can be carried out on a
scale exceeding 250 g without any loss in yield or stereoselectivity.
Alkyl 2-nitroacetates as carbenoid glycine
equivalents.
Reactions between carbenes and alkenes
represent one of the most widely utilized ap-
proaches for constructing cyclopropane rings
[179]. In this context, compounds 61 and 62
(Fig. 7), each contributing a single carbon
atom to the three-membered ring and carrying
amino and carboxyl groups, can be regarded
as suitable carbenoid glycine equivalents for
the synthesis of tailor-made ACC derivatives.
However, the precursors of carbenes 61 and
62—such as the corresponding diazo com-
pounds—are highly unstable, requiring strong-
ly electron-withdrawing or aromatic substi
tuents directly attached to the carbene carbon.
Consequently, nitroacetates 63 may serve as
generalized carbenoid glycine equivalents. The
synthesis of ACC derivatives via carbenes 63
will thus necessitate an additional step invol
ving chemo-selective reductive transformation
of the nitro group into the requisite amino
group [180, 181].
41https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Fig. 7. Carbenoid glycine equivalents.
properly protected glutamic acid 59 was substituted with a bromine atom, and the resulting
compound 60 underwent intramolecular cyclization. The formation of the three-membered ring was
achieved using NaH in THF at −78 °C. It should be noted that the application of two equivalents of
NaH was necessary, as one mole of the base was used to ionize the N-H bond. The cyclization
proceeded cleanly at the α-carbon, with no products of N-alkylation observed. Following
cyclization, hydrolysis of the ester group and deprotection of CO₂Bn using hydrogen over a
palladium catalyst afforded the target compound, ACC 1 [175–178].
Scheme 10. Preparation of ACC 1 via intramolecular cyclization of glutamic acid derivative 60.
Alkyl 2-nitroacetates as carbenoid glycine equivalents.
Reactions between carbenes and alkenes represent one of the most widely utilized
approaches for constructing cyclopropane rings [179]. In this context, compounds 61 and 62 (Fig.
7), each contributing a single carbon atom to the three-membered ring and carrying amino and
carboxyl groups, can be regarded as suitable carbenoid glycine equivalents for the synthesis of
tailor-made ACC derivatives. However, the precursors of carbenes 61 and 62—such as the
corresponding diazo compounds—are highly unstable, requiring strongly electron-withdrawing or
aromatic substituents directly attached to the carbene carbon. Consequently, nitroacetates 63 may
serve as generalized carbenoid glycine equivalents. The synthesis of ACC derivatives via carbenes
63 will thus necessitate an additional step involving chemo-selective reductive transformation of the
nitro group into the requisite amino group [180, 181].
Fig. 7. Carbenoid glycine equivalents.
For example, the cyclopropanation reaction has been extensively studied using various
diazoesters 64 (Scheme 11). The yields are generally high, while the diastereoselectivity varies
significantly and is strongly influenced by the nature of the alkyl ester group [182]. The formation
of the trans isomer 65 is typically favored over the cis diastereomer 66, though the ratio is clearly
dependent on the steric bulk of the ester alkyl group—highest for methyl and lowest for tert-butyl.
The nitro group was efficiently reduced to the corresponding amino functionality using either zinc
or indium in the presence of hydrochloric acid [183]. Notably, this procedure can be carried out on a
scale exceeding 250 g without any loss in yield or stereoselectivity.
For example, the cyclopropanation reaction
has been extensively studied using various dia
zoesters 64 (Scheme 11). The yields are gene
rally high, while the diastereoselectivity varies
significantly and is strongly influenced by the
nature of the alkyl ester group [182]. The for-
mation of the trans isomer 65 is typically fa-
vored over the cis diastereomer 66, though the
ratio is clearly dependent on the steric bulk of
the ester alkyl group—highest for methyl and
lowest for tert-butyl. The nitro group was ef-
ficiently reduced to the corresponding amino
functionality using either zinc or indium in the
presence of hydrochloric acid [183]. Notably,
this procedure can be carried out on a scale ex-
ceeding 250 g without any loss in yield or ste-
reoselectivity.
Scheme 11. Rh-catalyzed cyclopropanation of nitrodiazoesters with styrene, followed
by the reduction of the nitro group to an amino group.Scheme 11. Rh-catalyzed cyclopropanation of nitrodiazoesters with styrene, followed by the reduction of the
nitro group to an amino group.
Intramolecular cyclopropanation of molecules containing both unsaturated and α-
nitrodiazoester functionalities has been successfully carried out (Scheme 12) [184]. Rhodium
complexes derived from bulky carboxylate ligands, such as rhodium bis(1-adamantanecarboxylate)
dimer (Rh₂(OCOAd)₄), achieved the highest yields of cyclopropanation products. Treatment of
nitrodiazoester 69, bearing a substituted unsaturated moiety, with a catalytic amount (0.5%) of
rhodium catalyst prepared with adamantyl carboxylate in dichloromethane at mild heating (40°C)
for about four hours resulted in the formation of a bicyclic product 70 with good isolated yields. As
expected, higher yields (95%) were observed for products with minimal steric hindrance and ring
strain (n = 3, R = H). Notably, in all cases studied, only a single diastereomer containing NO₂ and R
in the bridged position was isolated.
Scheme 12. Rh-catalyzed intramolecular cyclopropanations.
Cyclopropanation via nitrodiazoacetate reactions, as precursors to carbenoid glycine
equivalents, can be successfully carried out in a catalytic enantioselective manner. As shown in
Scheme 13, the enantioselective cyclopropanation of ethyl α-nitrodiazoacetate 71 with terminal
olefins is efficiently catalyzed by the chiral porphyrin-based cobalt(II) complex 72 [186−188]. The
reaction proceeds in normal hexane at temperatures ranging from 0 °C to ambient conditions over a
24-hour period. This process enables the enantioselective formation of the corresponding cis isomer
73, wherein the nitro group and R are positioned cis relative to each other. While yields and
enantioselectivities are generally high, the stereochemical outcomes were not confirmed via SDE
tests. Specifically, enantioselectivity data was obtained after product purification by column
chromatography, followed by high-vacuum drying—potentially allowing for SDE effects via achiral
chromatography [189−191] and sublimation [192−194]. Notably, when R is an aryl substituent,
enantioselectivity reaches approximately 90% ee, whereas alkyl and carbonyl derivatives exhibit
Intramolecular cyclopropanation of mole-
cules containing both unsaturated and α-nit
rodiazoester functionalities has been success-
fully carried out (Scheme 12) [184]. Rhodium
complexes derived from bulky carboxylate li-
gands, such as rhodium bis(1-adamantanecar-
boxylate) dimer (Rh₂(OCOAd)₄), achieved the
highest yields of cyclopropanation products.
Treatment of nitrodiazoester 69, bearing a
substituted unsaturated moiety, with a catalytic
amount (0.5%) of rhodium catalyst prepared
with adamantyl carboxylate in dichloromethane
at mild heating (40°C) for about four hours re-
sulted in the formation of a bicyclic product 70
with good isolated yields. As expected, higher
yields (95%) were observed for products with
minimal steric hindrance and ring strain (n =
3, R = H). Notably, in all cases studied, only a
single diastereomer containing NO₂ and R in
the bridged position was isolated.
42 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 12. Rh-catalyzed intramolecular cyclopropanations.
Scheme 11. Rh-catalyzed cyclopropanation of nitrodiazoesters with styrene, followed by the reduction of the
nitro group to an amino group.
Intramolecular cyclopropanation of molecules containing both unsaturated and α-
nitrodiazoester functionalities has been successfully carried out (Scheme 12) [184]. Rhodium
complexes derived from bulky carboxylate ligands, such as rhodium bis(1-adamantanecarboxylate)
dimer (Rh₂(OCOAd)₄), achieved the highest yields of cyclopropanation products. Treatment of
nitrodiazoester 69, bearing a substituted unsaturated moiety, with a catalytic amount (0.5%) of
rhodium catalyst prepared with adamantyl carboxylate in dichloromethane at mild heating (40°C)
for about four hours resulted in the formation of a bicyclic product 70 with good isolated yields. As
expected, higher yields (95%) were observed for products with minimal steric hindrance and ring
strain (n = 3, R = H). Notably, in all cases studied, only a single diastereomer containing NO₂ and R
in the bridged position was isolated.
Scheme 12. Rh-catalyzed intramolecular cyclopropanations.
Cyclopropanation via nitrodiazoacetate reactions, as precursors to carbenoid glycine
equivalents, can be successfully carried out in a catalytic enantioselective manner. As shown in
Scheme 13, the enantioselective cyclopropanation of ethyl α-nitrodiazoacetate 71 with terminal
olefins is efficiently catalyzed by the chiral porphyrin-based cobalt(II) complex 72 [186−188]. The
reaction proceeds in normal hexane at temperatures ranging from 0 °C to ambient conditions over a
24-hour period. This process enables the enantioselective formation of the corresponding cis isomer
73, wherein the nitro group and R are positioned cis relative to each other. While yields and
enantioselectivities are generally high, the stereochemical outcomes were not confirmed via SDE
tests. Specifically, enantioselectivity data was obtained after product purification by column
chromatography, followed by high-vacuum drying—potentially allowing for SDE effects via achiral
chromatography [189−191] and sublimation [192−194]. Notably, when R is an aryl substituent,
enantioselectivity reaches approximately 90% ee, whereas alkyl and carbonyl derivatives exhibit
Cyclopropanation via nitrodiazoacetate
reactions, as precursors to carbenoid glycine
equivalents, can be successfully carried out in
a catalytic enantioselective manner. As shown
in Scheme 13, the enantioselective cyclopro-
panation of ethyl α-nitrodiazoacetate 71 with
terminal olefins is efficiently catalyzed by the
chiral porphyrin-based cobalt(II) complex 72
[186−188]. The reaction proceeds in normal
hexane at temperatures ranging from 0 °C to
ambient conditions over a 24-hour period.
This process enables the enantioselective for-
mation of the corresponding cis isomer 73,
wherein the nitro group and R are positioned
cis relative to each other. While yields and
enantioselectivities are generally high, the ste-
reochemical outcomes were not confirmed via
SDE tests. Specifically, enantioselectivity data
was obtained after product purification by co
lumn chromatography, followed by high-va
cuum drying—potentially allowing for SDE
effects via achiral chromatography [189−191]
and sublimation [192−194]. Notably, when R is
an aryl substituent, enantioselectivity reaches
approximately 90% ee, whereas alkyl and car-
bonyl derivatives exhibit enantioselectivities in
the range of 75–88% ee. Reported yields vary
significantly, ranging from 42% to 92%, high-
lighting the need for a more precise and sys-
tematic study of these cyclopropanation reac-
tions.
Scheme 13. Enantioselective chiral Co-complex catalyzed cyclpropanation reactions.
enantioselectivities in the range of 75–88% ee. Reported yields vary significantly, ranging from
42% to 92%, highlighting the need for a more precise and systematic study of these
cyclopropanation reactions.
Scheme 13. Enantioselective chiral Co-complex catalyzed cyclpropanation reactions.
Another example of enantioselective cyclopropanation, specifically involving (Z)-1,2-
disubstituted olefins and nitrodiazoacetates, is presented in Scheme 14 [195]. The catalyst used in
this synthesis, bis-oxazoline 75, features two distinct substituents (Me and Bn) on the carbon
bridging the two moieties and has been demonstrated as a preferred catalyst for enantioselective
cyclopropanation of disubstituted olefins with diazoesters [196]. Treatment of (Z)-olefins 74 and
ethyl nitrodiazoacetate 71 with copper complexes of bis-oxazoline 75 resulted in the formation of
products 76, with moderate yields and exhibiting excellent diastereoselectivity (>99:1) and
enantioselectivity. Medium-range chemical yields combined with high enantioselectivity often
indicate the manifestation of SDE effects [197–199]. This method is quite versatile, as the
substituent R can be either an aryl group or an olefinic residue and can be further extended to cyclic
alkenes. The only notable limitation of this approach is the requirement for the corresponding (Z)-
olefins.
Scheme 14. Chiral Cu-complex catalyzed enantioselective cyclopropanation using nitrodiazoacetates and
(Z)-1,2-disubstituted olefins.
As noted above (vide supra), diazo compounds rapidly decompose under standard
conditions in the absence of stabilizing electron-withdrawing substituents [200]. As discussed in
this text, nitrodiazoacetates serve as excellent reagents for various cyclopropanation reactions. The
search for alternative approaches led to the discovery of a method utilizing the corresponding
phenyliodonium derivatives [201], which are formed in situ from nitroesters and phenyliodonium
acetate [202−204]. This approach exhibits reactivity remarkably similar to Rh-catalyzed
cyclopropanation with nitrodiazoacetates, suggesting the intermediate formation of identical
43https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Another example of enantioselective cyc
lopropanation, specifically involving (Z)-1,2-
disubstituted olefins and nitrodiazoacetates,
is presented in Scheme 14 [195]. The catalyst
used in this synthesis, bis-oxazoline 75, fea-
tures two distinct substituents (Me and Bn) on
the carbon bridging the two moieties and has
been demonstrated as a preferred catalyst for
enantioselective cyclopropanation of disubsti-
tuted olefins with diazoesters [196]. Treatment
of (Z)-olefins 74 and ethyl nitrodiazoacetate
71 with copper complexes of bis-oxazoline 75
resulted in the formation of products 76, with
moderate yields and exhibiting excellent dia
stereoselectivity (>99:1) and enantioselectivity.
Medium-range chemical yields combined with
high enantioselectivity often indicate the mani
festation of SDE effects [197–199]. This me
thod is quite versatile, as the substituent R can
be either an aryl group or an olefinic residue
and can be further extended to cyclic alkenes.
The only notable limitation of this approach
is the requirement for the corresponding
(Z)-olefins.
enantioselectivities in the range of 75–88% ee. Reported yields vary significantly, ranging from
42% to 92%, highlighting the need for a more precise and systematic study of these
cyclopropanation reactions.
Scheme 13. Enantioselective chiral Co-complex catalyzed cyclpropanation reactions.
Another example of enantioselective cyclopropanation, specifically involving (Z)-1,2-
disubstituted olefins and nitrodiazoacetates, is presented in Scheme 14 [195]. The catalyst used in
this synthesis, bis-oxazoline 75, features two distinct substituents (Me and Bn) on the carbon
bridging the two moieties and has been demonstrated as a preferred catalyst for enantioselective
cyclopropanation of disubstituted olefins with diazoesters [196]. Treatment of (Z)-olefins 74 and
ethyl nitrodiazoacetate 71 with copper complexes of bis-oxazoline 75 resulted in the formation of
products 76, with moderate yields and exhibiting excellent diastereoselectivity (>99:1) and
enantioselectivity. Medium-range chemical yields combined with high enantioselectivity often
indicate the manifestation of SDE effects [197–199]. This method is quite versatile, as the
substituent R can be either an aryl group or an olefinic residue and can be further extended to cyclic
alkenes. The only notable limitation of this approach is the requirement for the corresponding (Z)-
olefins.
Scheme 14. Chiral Cu-complex catalyzed enantioselective cyclopropanation using nitrodiazoacetates and
(Z)-1,2-disubstituted olefins.
As noted above (vide supra), diazo compounds rapidly decompose under standard
conditions in the absence of stabilizing electron-withdrawing substituents [200]. As discussed in
this text, nitrodiazoacetates serve as excellent reagents for various cyclopropanation reactions. The
search for alternative approaches led to the discovery of a method utilizing the corresponding
phenyliodonium derivatives [201], which are formed in situ from nitroesters and phenyliodonium
acetate [202−204]. This approach exhibits reactivity remarkably similar to Rh-catalyzed
cyclopropanation with nitrodiazoacetates, suggesting the intermediate formation of identical
Scheme 14. Chiral Cu-complex catalyzed enantioselective cyclopropanation
using nitrodiazoacetates and (Z)-1,2-disubstituted olefins.
As noted above (vide supra), diazo com-
pounds rapidly decompose under standard
conditions in the absence of stabilizing elec-
tron-withdrawing substituents [200]. As dis-
cussed in this text, nitrodiazoacetates serve
as excellent reagents for various cyclopropa
nation reactions. The search for alternative
approaches led to the discovery of a method
utilizing the corresponding phenyliodonium
derivatives [201], which are formed in situ
from nitroesters and phenyliodonium acetate
[202−204]. This approach exhibits reactivity
remarkably similar to Rh-catalyzed cyclopro-
panation with nitrodiazoacetates, suggesting
the intermediate formation of identical metal−
carbene species. As illustrated in Scheme 15,
ethyl nitroacetate 77 and an excess (5 eq.) of
olefin are treated with PhI(OAc)₂ (1.1 eq.) and
Rh₂(Piv)₄ (0.5 eq.) in dichloromethane at am-
bient temperature, yielding cyclopropanation
products 78 with good yields (>80%). These
reactions are highly robust and can be per-
formed in near-open-air conditions, under-
scoring the practicality of this approach. The
Ar group can be either a substituted phenyl
or a naphthyl moiety, and the methodology
extends to cis-disubstituted and cyclic olefins,
further enhancing its versatility and synthetic
value. It is proposed that the reaction proceeds
via in situ formation of phenyliodonium deri
vatives 79, followed by the generation of ruthe-
nium−carbene species 80.
44 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 15. Rh-Catalyzed approach for cyclopropanation reaction of nitroacetates
and olefines via phenyliodonium derivatives.
metal−carbene species. As illustrated in Scheme 15, ethyl nitroacetate 77 and an excess (5 eq.) of
olefin are treated with PhI(OAc)₂ (1.1 eq.) and Rh₂(Piv)₄ (0.5 eq.) in dichloromethane at ambient
temperature, yielding cyclopropanation products 78 with good yields (>80%). These reactions are
highly robust and can be performed in near-open-air conditions, underscoring the practicality of this
approach. The Ar group can be either a substituted phenyl or a naphthyl moiety, and the
methodology extends to cis-disubstituted and cyclic olefins, further enhancing its versatility and
synthetic value. It is proposed that the reaction proceeds via in situ formation of phenyliodonium
derivatives 79, followed by the generation of ruthenium−carbene species 80.
Scheme 15. Rh-Catalyzed approach for cyclopropanation reaction of nitroacetates and olefines via
phenyliodonium derivatives.
The enantioselective catalytic version of this reaction can be achieved using chiral
bisoxazoline ligands in combination with copper(I) as the metal catalyst. As illustrated in Scheme
16 [205−207], methyl nitroacetate 81 reacts with an excess (5 eq.) of terminal olefin in the presence
of PhI=O (1.1 eq.), AgSbF6 (2.4 mol%), Na2CO3 (2.3 eq.), CuCl (2 mol%), and either chiral
bisoxazoline 82 or 84, leading to the formation of cyclopropanation products 83 or 85, respectively.
The reactions are carried out in benzene at ambient temperature for approximately two hours. The
reported chemical yields and stereochemical outcomes are generally favorable. The substituent R on
the olefin counterpart can be a mono-substituted phenyl or naphthyl ring, or a vinyl group.
Unfortunately, SDE tests were not conducted [208−210], and the enantiomeric purity values were
obtained only after product isolation, purification via column chromatography, and subsequent
drying under high vacuum. Interestingly, the variability in the reported enantioselectivity is difficult
to rationalize based on differences in the electronic or steric properties of substituents such as Me,
MeO, Cl, or even t-Bu groups situated in the remote para-position of the phenyl ring, far from the
reaction center. However, these substituents do contribute to variations in the physicochemical
properties of the products, affecting their SDE profiles under achiral chromatography conditions
and their volatility (sublimation) [211−213].
The enantioselective catalytic version of this
reaction can be achieved using chiral bisoxa
zoline ligands in combination with copper(I) as
the metal catalyst. As illustrated in Scheme 16
[205−207], methyl nitroacetate 81 reacts with an
excess (5 eq.) of terminal olefin in the presence
of PhI=O (1.1 eq.), AgSbF6 (2.4 mol%), Na2CO3
(2.3 eq.), CuCl (2 mol%), and either chiral bi-
soxazoline 82 or 84, leading to the formation
of cyclopropanation products 83 or 85, respec-
tively. The reactions are carried out in benzene
at ambient temperature for approximately two
hours. The reported chemical yields and stereo-
chemical outcomes are generally favorable. The
substituent R on the olefin counterpart can be a
mono-substituted phenyl or naphthyl ring, or a
vinyl group. Unfortunately, SDE tests were not
conducted [208−210], and the enantiomeric
purity values were obtained only after product
isolation, purification via column chromatog-
raphy, and subsequent drying under high vacu-
um. Interestingly, the variability in the reported
enantioselectivity is difficult to rationalize based
on differences in the electronic or steric proper-
ties of substituents such as Me, MeO, Cl, or even
t-Bu groups situated in the remote para-position
of the phenyl ring, far from the reaction center.
However, these substituents do contribute to
variations in the physicochemical properties of
the products, affecting their SDE profiles under
achiral chromatography conditions and their
volatility (sublimation) [211−213].
An alternative approach for generating an
in situ carbenoid glycine equivalent is present-
ed in Scheme 17. In this method, the oxalic
acid-derived compound 86, which contains an
activated carbonyl group, reacts with P(OEt)₃
in chloroform under reflux conditions, yield-
ing cyclopropanation product 89 with mode
rate efficiency and reasonably good diastereo-
selectivity governed by the stereogenic center
of the starting azetidinone 86 [214]. The re-
action proceeds via interaction between the
amide carbonyl of 86 and P(OEt)₃, leading to
the formation of betaine intermediate 87. This
intermediate stabilizes through the elimina-
tion of PO(OEt)₃, generating free carbene 88,
which subsequently undergoes intramolecular
cyclopropanation by reacting with terminal
olefin residues. The resulting diastereome
ric mixture of products can be separated via
column chromatography, affording the major
diastereomer with a yield of 42%. Despite the
relatively low-to-moderate yields, this metho
dology has been employed for the synthesis of
various carbacepham analogs [215].
45https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Scheme 16. Cu-Catalyzed enantioselective catalytic cyclopropanation of nitroacetates
and olefines via phenyliodonium derivatives.
Scheme 17. Cyclopropanation reaction via in situ generation of carbenoid
glycine equivalent using P(OEt)3.
Scheme 16. Cu-Catalyzed enantioselective catalytic cyclopropanation of nitroacetates and olefines via
phenyliodonium derivatives.
An alternative approach for generating an in situ carbenoid glycine equivalent is presented
in Scheme 17. In this method, the oxalic acid-derived compound 86, which contains an activated
carbonyl group, reacts with P(OEt)₃ in chloroform under reflux conditions, yielding
cyclopropanation product 89 with moderate efficiency and reasonably good diastereoselectivity
governed by the stereogenic center of the starting azetidinone 86 [214]. The reaction proceeds via
interaction between the amide carbonyl of 86 and P(OEt)₃, leading to the formation of betaine
intermediate 87. This intermediate stabilizes through the elimination of PO(OEt)₃, generating free
carbene 88, which subsequently undergoes intramolecular cyclopropanation by reacting with
terminal olefin residues. The resulting diastereomeric mixture of products can be separated via
column chromatography, affording the major diastereomer with a yield of 42%. Despite the
relatively low-to-moderate yields, this methodology has been employed for the synthesis of various
carbacepham analogs [215].
Scheme 17. Cyclopropanation reaction via in situ generation of carbenoid glycine equivalent using P(OEt)3.
Fischer dialkylaminocarbenes are known to react with olefins to form cyclopropane rings
[216]. The application of these reagents as carbenoid glycine equivalents for the synthesis of ACC
derivatives is illustrated in Scheme 18 [217]. First, the Fischer dialkylaminocarbene complex 92 is
prepared from alkyl 2-(dimethylamino)acrylate, a dehydroalanine derivative 90, and reagent 91.
Next, the Fischer complex 92 is treated with an excess (4 eq.) of terminal olefin in refluxing
toluene, yielding cyclopropane product 93 with variable efficiency (40–70%) but consistently high
Scheme 16. Cu-Catalyzed enantioselective catalytic cyclopropanation of nitroacetates and olefines via
phenyliodonium derivatives.
An alternative approach for generating an in situ carbenoid glycine equivalent is presented
in Scheme 17. In this method, the oxalic acid-derived compound 86, which contains an activated
carbonyl group, reacts with P(OEt)₃ in chloroform under reflux conditions, yielding
cyclopropanation product 89 with moderate efficiency and reasonably good diastereoselectivity
governed by the stereogenic center of the starting azetidinone 86 [214]. The reaction proceeds via
interaction between the amide carbonyl of 86 and P(OEt)₃, leading to the formation of betaine
intermediate 87. This intermediate stabilizes through the elimination of PO(OEt)₃, generating free
carbene 88, which subsequently undergoes intramolecular cyclopropanation by reacting with
terminal olefin residues. The resulting diastereomeric mixture of products can be separated via
column chromatography, affording the major diastereomer with a yield of 42%. Despite the
relatively low-to-moderate yields, this methodology has been employed for the synthesis of various
carbacepham analogs [215].
Scheme 17. Cyclopropanation reaction via in situ generation of carbenoid glycine equivalent using P(OEt)3.
Fischer dialkylaminocarbenes are known to react with olefins to form cyclopropane rings
[216]. The application of these reagents as carbenoid glycine equivalents for the synthesis of ACC
derivatives is illustrated in Scheme 18 [217]. First, the Fischer dialkylaminocarbene complex 92 is
prepared from alkyl 2-(dimethylamino)acrylate, a dehydroalanine derivative 90, and reagent 91.
Next, the Fischer complex 92 is treated with an excess (4 eq.) of terminal olefin in refluxing
toluene, yielding cyclopropane product 93 with variable efficiency (40–70%) but consistently high
Fischer dialkylaminocarbenes are known to
react with olefins to form cyclopropane rings
[216]. The application of these reagents as car-
benoid glycine equivalents for the synthesis
of ACC derivatives is illustrated in Scheme 18
[217]. First, the Fischer dialkylaminocarbene
complex 92 is prepared from alkyl 2-(dime
thylamino)acrylate, a dehydroalanine deri
vative 90, and reagent 91. Next, the Fischer
complex 92 is treated with an excess (4 eq.) of
terminal olefin in refluxing toluene, yielding
cyclopropane product 93 with variable effi-
ciency (40–70%) but consistently high diaste-
reoselectivity (~95/5). However, the primary
limitation of this approach is that it only allows
for the preparation of ACC derivatives featu
ring a dimethylamino group.
46 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 18. Application of Fisher dialkylaminocarbene complex
in cyclopropanation reactions with olefines.
diastereoselectivity (~95/5). However, the primary limitation of this approach is that it only allows
for the preparation of ACC derivatives featuring a dimethylamino group.
Scheme 18. Application of Fisher dialkylaminocarbene complex in cyclopropanation reactions with olefines.
Cyclopropanation of dehydroamino acids.
As discussed in Scheme 18, dehydroalanine derivatives can be transformed into
corresponding carbenoid glycine equivalents, contributing one carbon atom in cyclopropanation
reactions with alkenes. This strategy can also be reversed, allowing dehydroalanine to act as an
olefin, contributing two carbon atoms in reactions with carbenes [218−220]. A simple example of
this alternative approach is the reaction shown in Scheme 19, where properly protected (Z)-
dehydrotryptophan 94 reacts with diazomethane to yield the spiro cyclopropanation product 95 as a
single diastereomer, albeit with a relatively low yield (34%). The reaction proceeds overnight at
ambient temperature in diethyl ether. The use of (E)-dehydrotryptophan also affords the
corresponding diastereomer of 95 with excellent diastereoselectivity. Cycloaddition product 95 can
be conventionally converted into free amino acid 96 via acidic hydrolysis [221]. Notably, tailor-
made tryptophan derivatives are particularly useful for studying peptide folding and peptide–
peptide interactions [222−224].
Scheme 19. Cyclopropanation of dehydrotryptophane with diazomethane.
This method can be extended to the use of substituted diazomethanes for the synthesis of
ACC derivatives featuring multiple substituents on the cyclopropane ring. One noteworthy example
is illustrated in Scheme 20 [225]. In this approach, trifluoromethyldiazomethane reacts with a series
of dehydroamino acids 97, enabling the preparation of various tailor-made β-amino acids 99
constrained by a trifluoromethylcyclopropane moiety [226]. The reactions of dehydroamino acids
97 with 2,2,2-trifluorodiazoethane are conducted in acetonitrile at 80 °C over two days, yielding
cyclopropanated products 98 with efficiencies ranging from 47% to 87% and excellent
diastereoselectivity (>95/5). The substituent R on the cyclopropane ring can be either an alkyl or
aryl group, highlighting the versatility of this approach. Free amino acids 99 are obtained from
products 98 via simple conventional hydrolysis.
diastereoselectivity (~95/5). However, the primary limitation of this approach is that it only allows
for the preparation of ACC derivatives featuring a dimethylamino group.
Scheme 18. Application of Fisher dialkylaminocarbene complex in cyclopropanation reactions with olefines.
Cyclopropanation of dehydroamino acids.
As discussed in Scheme 18, dehydroalanine derivatives can be transformed into
corresponding carbenoid glycine equivalents, contributing one carbon atom in cyclopropanation
reactions with alkenes. This strategy can also be reversed, allowing dehydroalanine to act as an
olefin, contributing two carbon atoms in reactions with carbenes [218−220]. A simple example of
this alternative approach is the reaction shown in Scheme 19, where properly protected (Z)-
dehydrotryptophan 94 reacts with diazomethane to yield the spiro cyclopropanation product 95 as a
single diastereomer, albeit with a relatively low yield (34%). The reaction proceeds overnight at
ambient temperature in diethyl ether. The use of (E)-dehydrotryptophan also affords the
corresponding diastereomer of 95 with excellent diastereoselectivity. Cycloaddition product 95 can
be conventionally converted into free amino acid 96 via acidic hydrolysis [221]. Notably, tailor-
made tryptophan derivatives are particularly useful for studying peptide folding and peptide–
peptide interactions [222−224].
Scheme 19. Cyclopropanation of dehydrotryptophane with diazomethane.
This method can be extended to the use of substituted diazomethanes for the synthesis of
ACC derivatives featuring multiple substituents on the cyclopropane ring. One noteworthy example
is illustrated in Scheme 20 [225]. In this approach, trifluoromethyldiazomethane reacts with a series
of dehydroamino acids 97, enabling the preparation of various tailor-made β-amino acids 99
constrained by a trifluoromethylcyclopropane moiety [226]. The reactions of dehydroamino acids
97 with 2,2,2-trifluorodiazoethane are conducted in acetonitrile at 80 °C over two days, yielding
cyclopropanated products 98 with efficiencies ranging from 47% to 87% and excellent
diastereoselectivity (>95/5). The substituent R on the cyclopropane ring can be either an alkyl or
aryl group, highlighting the versatility of this approach. Free amino acids 99 are obtained from
products 98 via simple conventional hydrolysis.
Cyclopropanation of dehydroamino acids.
As discussed in Scheme 18, dehydroalanine
derivatives can be transformed into corres
ponding carbenoid glycine equivalents, con-
tributing one carbon atom in cyclopropana-
tion reactions with alkenes. This strategy can
also be reversed, allowing dehydroalanine to
act as an olefin, contributing two carbon atoms
in reactions with carbenes [218−220]. A simp
le example of this alternative approach is the
reaction shown in Scheme 19, where proper-
ly protected (Z)-dehydrotryptophan 94 reacts
with diazomethane to yield the spiro cyclopro-
panation product 95 as a single diastereomer,
albeit with a relatively low yield (34%). The
reaction proceeds overnight at ambient tem-
perature in diethyl ether. The use of (E)-de
hydrotryptophan also affords the correspond-
ing diastereomer of 95 with excellent diaste
reoselectivity. Cycloaddition product 95 can
be conventionally converted into free amino
acid 96 via acidic hydrolysis [221]. Notably,
tailor-made tryptophan derivatives are parti
cularly useful for studying peptide folding and
peptide–peptide interactions [222−224].
Scheme 19. Cyclopropanation of dehydrotryptophane with diazomethane.
This method can be extended to the use of
substituted diazomethanes for the synthesis of
ACC derivatives featuring multiple substitu-
ents on the cyclopropane ring. One notewor-
thy example is illustrated in Scheme 20 [225].
In this approach, trifluoromethyldiazomethane
reacts with a series of dehydroamino acids 97,
enabling the preparation of various tailor-made
β-amino acids 99 constrained by a trifluoro
methylcyclopropane moiety [226]. The reac-
tions of dehydroamino acids 97 with 2,2,2-tri
fluorodiazoethane are conducted in acetonitrile
at 80 °C over two days, yielding cyclopropana-
ted products 98 with efficiencies ranging from
47% to 87% and excellent diastereoselectivity
(>95/5). The substituent R on the cyclopropane
ring can be either an alkyl or aryl group, high-
lighting the versatility of this approach. Free
amino acids 99 are obtained from products 98
via simple conventional hydrolysis.
47https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Scheme 20. Cyclopropanation of dehydroamino acids with 2,2,2-trifluorodiazoethane.
Scheme 20. Cyclopropanation of dehydroamino acids with 2,2,2-trifluorodiazoethane.
Mechanistically, the reactions of dehydroamino acids with diazomethane derivatives proceed
via a [3+2] cycloaddition, resulting in 1-pyrazoline intermediates. The subsequent ring contraction
is facilitated by electron-withdrawing groups and, in some cases, requires heating of the reaction
mixture [227,228].
For example, the cyclopropanation of the phosphorus analog of dehydroalanine 100 with
substituted diazomethanes leads to the formation of unusually stable pyrazoline intermediates 101,
which are reported as solid compounds that can be stored at low temperatures (5 °C) for months
without signs of decomposition [229]. However, upon heating in refluxing toluene, compounds 101
undergo the expected ring contraction, ultimately yielding the target aminocyclopropanephosphonic
acids 102 after subsequent hydrolysis. This approach is broadly applicable, as the substituent R on
the starting diazomethane can be either an alkyl or aryl group. The yields range from 63% to 90%,
with excellent diastereoselectivity (>99/1) for aryl derivatives but low (~55/45) for aliphatic ones.
The synthesis of tailor-made aminophosphonic acids has attracted significant attention due to their
diverse applications in medicinal chemistry, enzyme inhibition, and peptide engineering [230–233].
Scheme 21. Synthesis of aminocyclopropanephosphonic acids.
While diazo compounds are highly effective reagents for cyclopropanation reactions, their
preparation and handling present inherent challenges. This has driven the need for safer and more
efficient alternatives, leading scientists to develop new reagents. One such discovery is
tosylhydrazones, which have proven particularly successful in cycloaddition reactions with
dehydroamino acids [234]. In this approach, properly protected dehydroalanine 103 (Scheme 22)
reacts with metalated tosylhydrazone 104 in the presence of a catalytic amount of a phase-transfer
catalyst [235], yielding cyclopropane 105 with high diastereoselectivity. The major stereoisomer
features aryl and amine groups positioned trans to each other. The reaction is conducted in toluene
at 40 °C for 60 hours with 5 mol% of BnNEt₃Cl as the phase-transfer catalyst, producing 105 with
yields ranging from 50% to 72%. The target ACC 106 is obtained via simple hydrolysis of the
cyclization products 105.
Scheme 20. Cyclopropanation of dehydroamino acids with 2,2,2-trifluorodiazoethane.
Mechanistically, the reactions of dehydroamino acids with diazomethane derivatives proceed
via a [3+2] cycloaddition, resulting in 1-pyrazoline intermediates. The subsequent ring contraction
is facilitated by electron-withdrawing groups and, in some cases, requires heating of the reaction
mixture [227,228].
For example, the cyclopropanation of the phosphorus analog of dehydroalanine 100 with
substituted diazomethanes leads to the formation of unusually stable pyrazoline intermediates 101,
which are reported as solid compounds that can be stored at low temperatures (5 °C) for months
without signs of decomposition [229]. However, upon heating in refluxing toluene, compounds 101
undergo the expected ring contraction, ultimately yielding the target aminocyclopropanephosphonic
acids 102 after subsequent hydrolysis. This approach is broadly applicable, as the substituent R on
the starting diazomethane can be either an alkyl or aryl group. The yields range from 63% to 90%,
with excellent diastereoselectivity (>99/1) for aryl derivatives but low (~55/45) for aliphatic ones.
The synthesis of tailor-made aminophosphonic acids has attracted significant attention due to their
diverse applications in medicinal chemistry, enzyme inhibition, and peptide engineering [230–233].
Scheme 21. Synthesis of aminocyclopropanephosphonic acids.
While diazo compounds are highly effective reagents for cyclopropanation reactions, their
preparation and handling present inherent challenges. This has driven the need for safer and more
efficient alternatives, leading scientists to develop new reagents. One such discovery is
tosylhydrazones, which have proven particularly successful in cycloaddition reactions with
dehydroamino acids [234]. In this approach, properly protected dehydroalanine 103 (Scheme 22)
reacts with metalated tosylhydrazone 104 in the presence of a catalytic amount of a phase-transfer
catalyst [235], yielding cyclopropane 105 with high diastereoselectivity. The major stereoisomer
features aryl and amine groups positioned trans to each other. The reaction is conducted in toluene
at 40 °C for 60 hours with 5 mol% of BnNEt₃Cl as the phase-transfer catalyst, producing 105 with
yields ranging from 50% to 72%. The target ACC 106 is obtained via simple hydrolysis of the
cyclization products 105.
Mechanistically, the reactions of dehydro-
amino acids with diazomethane derivatives
proceed via a [3+2] cycloaddition, resulting
in 1-pyrazoline intermediates. The subsequent
ring contraction is facilitated by electron-with-
drawing groups and, in some cases, requires
heating of the reaction mixture [227,228].
For example, the cyclopropanation of the
phosphorus analog of dehydroalanine 100
with substituted diazomethanes leads to the
formation of unusually stable pyrazoline inter-
mediates 101, which are reported as solid com-
pounds that can be stored at low temperatures
(5 °C) for months without signs of decomposi-
tion [229]. However, upon heating in refluxing
toluene, compounds 101 undergo the expected
ring contraction, ultimately yielding the tar-
get aminocyclopropanephosphonic acids 102
after subsequent hydrolysis. This approach is
broadly applicable, as the substituent R on the
starting diazomethane can be either an alkyl or
aryl group. The yields range from 63% to 90%,
with excellent diastereoselectivity (>99/1) for
aryl derivatives but low (~55/45) for aliphatic
ones. The synthesis of tailor-made aminophos-
phonic acids has attracted significant attention
due to their diverse applications in medicinal
chemistry, enzyme inhibition, and peptide en-
gineering [230–233].
Scheme 21. Synthesis of aminocyclopropanephosphonic acids.
While diazo compounds are highly effective
reagents for cyclopropanation reactions, their
preparation and handling present inherent
challenges. This has driven the need for safer
and more efficient alternatives, leading scien-
tists to develop new reagents. One such dis-
covery is tosylhydrazones, which have proven
particularly successful in cycloaddition reac-
tions with dehydroamino acids [234]. In this
approach, properly protected dehydroalanine
103 (Scheme 22) reacts with metalated to-
sylhydrazone 104 in the presence of a cataly
tic amount of a phase-transfer catalyst [235],
yielding cyclopropane 105 with high diastere-
oselectivity. The major stereoisomer features
aryl and amine groups positioned trans to each
other. The reaction is conducted in toluene at
40 °C for 60 hours with 5 mol% of BnNEt₃Cl
as the phase-transfer catalyst, producing 105
with yields ranging from 50% to 72%. The tar-
get ACC 106 is obtained via simple hydrolysis
of the cyclization products 105.
48 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Scheme 22. Cyclopropanation of dehydroamino acids using diazo compounds
generated from metalated tosylhydrazone.
Scheme 20. Cyclopropanation of dehydroamino acids with 2,2,2-trifluorodiazoethane.
Mechanistically, the reactions of dehydroamino acids with diazomethane derivatives proceed
via a [3+2] cycloaddition, resulting in 1-pyrazoline intermediates. The subsequent ring contraction
is facilitated by electron-withdrawing groups and, in some cases, requires heating of the reaction
mixture [227,228].
For example, the cyclopropanation of the phosphorus analog of dehydroalanine 100 with
substituted diazomethanes leads to the formation of unusually stable pyrazoline intermediates 101,
which are reported as solid compounds that can be stored at low temperatures (5 °C) for months
without signs of decomposition [229]. However, upon heating in refluxing toluene, compounds 101
undergo the expected ring contraction, ultimately yielding the target aminocyclopropanephosphonic
acids 102 after subsequent hydrolysis. This approach is broadly applicable, as the substituent R on
the starting diazomethane can be either an alkyl or aryl group. The yields range from 63% to 90%,
with excellent diastereoselectivity (>99/1) for aryl derivatives but low (~55/45) for aliphatic ones.
The synthesis of tailor-made aminophosphonic acids has attracted significant attention due to their
diverse applications in medicinal chemistry, enzyme inhibition, and peptide engineering [230–233].
Scheme 21. Synthesis of aminocyclopropanephosphonic acids.
While diazo compounds are highly effective reagents for cyclopropanation reactions, their
preparation and handling present inherent challenges. This has driven the need for safer and more
efficient alternatives, leading scientists to develop new reagents. One such discovery is
tosylhydrazones, which have proven particularly successful in cycloaddition reactions with
dehydroamino acids [234]. In this approach, properly protected dehydroalanine 103 (Scheme 22)
reacts with metalated tosylhydrazone 104 in the presence of a catalytic amount of a phase-transfer
catalyst [235], yielding cyclopropane 105 with high diastereoselectivity. The major stereoisomer
features aryl and amine groups positioned trans to each other. The reaction is conducted in toluene
at 40 °C for 60 hours with 5 mol% of BnNEt₃Cl as the phase-transfer catalyst, producing 105 with
yields ranging from 50% to 72%. The target ACC 106 is obtained via simple hydrolysis of the
cyclization products 105.
This approach, initially utilizing metalated
tosylhydrazones as precursors to diazo com-
pounds, was modified to incorporate non-me
talated tosylhydrazones derived from ketones,
as illustrated in Scheme 23. In these reactions,
protected dehydroalanine derivatives 107 are
treated with aromatic ketone-derived tosyl-
hydrazones 108 in the presence of 20 mol%
of a phase-transfer catalyst in toluene. A key
distinction from previous conditions is the re-
quirement for a strong base, Cs₂CO₃ (2 eq.),
and an elevated reaction temperature (90 °C).
The resulting cyclopropanation products 109
are obtained with good yields (~80%) and
high stereoselectivity (~85/15) [236]. Given
the strong interest in synthesizing phosphorus
analogs of tailor-made amino acids [237–239],
this approach was further applied to the prepa-
ration of phosphonate derivatives 110 using
2-aminophosphonates 100 (Scheme 21) and
ketone-derived tosylhydrazones 108. The cor-
responding phosphonates 110 were isolated
with similar yields but of significantly lower
diastereomeric purity 52/48.
Scheme 23. Cyclopropanation reactions using non-metalated ketone-derived tosylhydrazones.
Scheme 22. Cyclopropanation of dehydroamino acids using diazo compounds generated from metalated
tosylhydrazone.
This approach, initially utilizing metalated tosylhydrazones as precursors to diazo
compounds, was modified to incorporate non-metalated tosylhydrazones derived from ketones, as
illustrated in Scheme 23. In these reactions, protected dehydroalanine derivatives 107 are treated
with aromatic ketone-derived tosylhydrazones 108 in the presence of 20 mol% of a phase-transfer
catalyst in toluene. A key distinction from previous conditions is the requirement for a strong base,
Cs₂CO₃ (2 eq.), and an elevated reaction temperature (90 °C). The resulting cyclopropanation
products 109 are obtained with good yields (~80%) and high stereoselectivity (~85/15) [236]. Given
the strong interest in synthesizing phosphorus analogs of tailor-made amino acids [237–239], this
approach was further applied to the preparation of phosphonate derivatives 110 using 2-
aminophosphonates 100 (Scheme 21) and ketone-derived tosylhydrazones 108. The corresponding
phosphonates 110 were isolated with similar yields but of significantly lower diastereomeric purity
52/48.
Scheme 23. Cyclopropanation reactions using non-metalated ketone-derived tosylhydrazones.
This methodology, cyclopropanation of dehydroamino acids using in situ generated diazo
compounds from tosylhydrazones can be applied for catalytic enantioselective synthesis of ACC
derivatives. For example, application of porphyrin-based Co(II) catalyst type of 72 (Scheme 13)
[240]. The reported stereochemical outcome is rather variable with diastereoselectivity in the range
of 70/30 and enantioselectivity being even more disperse between 40 and 90% most likely as a
result of the SDE [241–243].
The application of nonactivated hydrazones for the cyclopropanation of dehydroamino acids
is illustrated in Scheme 24 [244]. In this method, hydrazone 108 is added dropwise to a solution of
PhIO at ambient temperature, generating the corresponding diazo compound in situ. This reactive
intermediate subsequently undergoes cyclopropanation with protected dehydroalanine 111, yielding
ACC derivatives 112 in nearly quantitative amounts.
For unsymmetrical hydrazones 108, the diastereoselectivity of product 112 formation is
moderate, with a ratio ranging between 4:1 and 5:1. Nonetheless, this approach is entirely metal-
free, offering remarkable safety and enhancing its synthetic value as a viable alternative to metal-
mediated methodologies.
Scheme 24. Cyclopropanation of dehydroamino acid derivatives using diazoalkanes generated in situ from
nonactivated hydrazones.
This methodology, cyclopropanation of
dehydroamino acids using in situ generated
diazo compounds from tosylhydrazones can be
applied for catalytic enantioselective synthesis
of ACC derivatives. For example, application
of porphyrin-based Co(II) catalyst type of 72
(Scheme 13) [240]. The reported stereochemi
cal outcome is rather variable with diastereo
selectivity in the range of 70/30 and enantio
selectivity being even more disperse between
40 and 90% most likely as a result of the SDE
[241–243].
The application of nonactivated hydrazones
for the cyclopropanation of dehydroamino
acids is illustrated in Scheme 24 [244]. In this
method, hydrazone 108 is added dropwise to a
solution of PhIO at ambient temperature, ge
nerating the corresponding diazo compound
in situ. This reactive intermediate subsequent-
ly undergoes cyclopropanation with protected
dehydroalanine 111, yielding ACC derivatives
112 in nearly quantitative amounts.
For unsymmetrical hydrazones 108, the dia
stereoselectivity of product 112 formation is
49https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
moderate, with a ratio ranging between 4:1
and 5:1. Nonetheless, this approach is entire-
ly metal-free, offering remarkable safety and
enhancing its synthetic value as a viable alter-
native to metal-mediated methodologies.
Scheme 22. Cyclopropanation of dehydroamino acids using diazo compounds generated from metalated
tosylhydrazone.
This approach, initially utilizing metalated tosylhydrazones as precursors to diazo
compounds, was modified to incorporate non-metalated tosylhydrazones derived from ketones, as
illustrated in Scheme 23. In these reactions, protected dehydroalanine derivatives 107 are treated
with aromatic ketone-derived tosylhydrazones 108 in the presence of 20 mol% of a phase-transfer
catalyst in toluene. A key distinction from previous conditions is the requirement for a strong base,
Cs₂CO₃ (2 eq.), and an elevated reaction temperature (90 °C). The resulting cyclopropanation
products 109 are obtained with good yields (~80%) and high stereoselectivity (~85/15) [236]. Given
the strong interest in synthesizing phosphorus analogs of tailor-made amino acids [237–239], this
approach was further applied to the preparation of phosphonate derivatives 110 using 2-
aminophosphonates 100 (Scheme 21) and ketone-derived tosylhydrazones 108. The corresponding
phosphonates 110 were isolated with similar yields but of significantly lower diastereomeric purity
52/48.
Scheme 23. Cyclopropanation reactions using non-metalated ketone-derived tosylhydrazones.
This methodology, cyclopropanation of dehydroamino acids using in situ generated diazo
compounds from tosylhydrazones can be applied for catalytic enantioselective synthesis of ACC
derivatives. For example, application of porphyrin-based Co(II) catalyst type of 72 (Scheme 13)
[240]. The reported stereochemical outcome is rather variable with diastereoselectivity in the range
of 70/30 and enantioselectivity being even more disperse between 40 and 90% most likely as a
result of the SDE [241–243].
The application of nonactivated hydrazones for the cyclopropanation of dehydroamino acids
is illustrated in Scheme 24 [244]. In this method, hydrazone 108 is added dropwise to a solution of
PhIO at ambient temperature, generating the corresponding diazo compound in situ. This reactive
intermediate subsequently undergoes cyclopropanation with protected dehydroalanine 111, yielding
ACC derivatives 112 in nearly quantitative amounts.
For unsymmetrical hydrazones 108, the diastereoselectivity of product 112 formation is
moderate, with a ratio ranging between 4:1 and 5:1. Nonetheless, this approach is entirely metal-
free, offering remarkable safety and enhancing its synthetic value as a viable alternative to metal-
mediated methodologies.
Scheme 24. Cyclopropanation of dehydroamino acid derivatives using diazoalkanes generated in situ from
nonactivated hydrazones.
Scheme 24. Cyclopropanation of dehydroamino acid derivatives using diazoalkanes
generated in situ from nonactivated hydrazones.
1,1-Dihaloalkanes are well-established as
one-carbon unit donors in the cyclopropana-
tion with dehydroamino acids mediated by
chromium salts [245, 246]. The reactions of
dehydroamino acid derivatives 114, illustrated
in Scheme 25, are typically carried out in ether
using 10 mol% Cr(II) salts and 1.5 eq. Mn,
maintained at 0 to -10 °C for 24 hours. To in-
duce enantioselectivity, chiral diamine ligands
116 capable of metal chelation are employed.
The substituent R can be a para-substituted
phenyl, naphthyl, or alkyl group. When com-
paring dichloroalkanes with dibromo deri
vatives 115, the former exhibit slower reaction
rates but yield products 117 with high efficien-
cy (~90%). Diastereoselectivity strongly favors
the formation of products 117 with R and ami-
no groups positioned cis to each other, achiev-
ing excellent selectivity (>20/1) in most repor
ted cases [247]. The enantioselectivity of these
reactions varies, ranging from 73% to 94% ee.
However, the SDE tests [248–250] have not
been conducted to validate the reported ste
reochemical data.
Scheme 25. Catalytic enantioselective cyclopropanation of dehydroalanine
derivatives with 1,1-dihaloalkanes.
1,1-Dihaloalkanes are well-established as one-carbon unit donors in the cyclopropanation
with dehydroamino acids mediated by chromium salts [245, 246]. The reactions of dehydroamino
acid derivatives 114, illustrated in Scheme 25, are typically carried out in ether using 10 mol%
Cr(II) salts and 1.5 eq. Mn, maintained at 0 to -10 °C for 24 hours. To induce enantioselectivity,
chiral diamine ligands 116 capable of metal chelation are employed. The substituent R can be a
para-substituted phenyl, naphthyl, or alkyl group. When comparing dichloroalkanes with dibromo
derivatives 115, the former exhibit slower reaction rates but yield products 117 with high efficiency
(~90%). Diastereoselectivity strongly favors the formation of products 117 with R and amino
groups positioned cis to each other, achieving excellent selectivity (>20/1) in most reported cases
[247]. The enantioselectivity of these reactions varies, ranging from 73% to 94% ee. However, the
SDE tests [248–250] have not been conducted to validate the reported stereochemical data.
Scheme 25. Catalytic enantioselective cyclopropanation of dehydroalanine derivatives with 1,1-
dihaloalkanes.
Substituted sulfonium ylides can also serve as effective one-carbon unit donors in the
cyclopropanation of dehydroamino acids. As illustrated in Scheme 26, dehydroalanine derivative
118 undergoes reaction with ylides 119 in a highly polar solvent such as acetonitrile or DMF [251].
To generate the reactive species from carbonyl-stabilized ylides 119, potassium carbonate has been
found to provide excellent yields (>90%) and diastereoselectivity (>99/1) for cyclopropanation
products 120. For ylides 119 semi-stabilized by aromatic groups, cesium carbonate proved more
effective, yielding products with a stereochemical outcome similar to that of carbonyl-stabilized
ylides 119. In contrast, ylides 119 stabilized by alkene groups require tBuOK as a base, resulting in
lower yields (79%) and compromised diastereoselectivity (9.3/1). The reaction can also be
conducted using chiral sulfonium ylide 121 in acetonitrile with tBuOK, providing access to
scalemic products 120 with high diastereoselectivity (up to 90%) and yields (80%).
Scheme 26. Application of stabilized sulfonium ylides for cyclopropanation of dehydroalanine derivatives.
An interesting example of the use of bromoacetates as one-carbon unit donors in the
Substituted sulfonium ylides can also serve
as effective one-carbon unit donors in the cyc
lopropanation of dehydroamino acids. As il-
lustrated in Scheme 26, dehydroalanine deri
vative 118 undergoes reaction with ylides 119
in a highly polar solvent such as acetonitrile or
DMF [251]. To generate the reactive species
from carbonyl-stabilized ylides 119, potassium
carbonate has been found to provide excellent
yields (>90%) and diastereoselectivity (>99/1)
50 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
for cyclopropanation products 120. For ylides
119 semi-stabilized by aromatic groups, cesi-
um carbonate proved more effective, yielding
products with a stereochemical outcome simi
lar to that of carbonyl-stabilized ylides 119.
In contrast, ylides 119 stabilized by alkene
groups require tBuOK as a base, resulting in
lower yields (79%) and compromised diaste-
reoselectivity (9.3/1). The reaction can also be
conducted using chiral sulfonium ylide 121 in
acetonitrile with tBuOK, providing access to
scalemic products 120 with high diastereose-
lectivity (up to 90%) and yields (80%).
1,1-Dihaloalkanes are well-established as one-carbon unit donors in the cyclopropanation
with dehydroamino acids mediated by chromium salts [245, 246]. The reactions of dehydroamino
acid derivatives 114, illustrated in Scheme 25, are typically carried out in ether using 10 mol%
Cr(II) salts and 1.5 eq. Mn, maintained at 0 to -10 °C for 24 hours. To induce enantioselectivity,
chiral diamine ligands 116 capable of metal chelation are employed. The substituent R can be a
para-substituted phenyl, naphthyl, or alkyl group. When comparing dichloroalkanes with dibromo
derivatives 115, the former exhibit slower reaction rates but yield products 117 with high efficiency
(~90%). Diastereoselectivity strongly favors the formation of products 117 with R and amino
groups positioned cis to each other, achieving excellent selectivity (>20/1) in most reported cases
[247]. The enantioselectivity of these reactions varies, ranging from 73% to 94% ee. However, the
SDE tests [248–250] have not been conducted to validate the reported stereochemical data.
Scheme 25. Catalytic enantioselective cyclopropanation of dehydroalanine derivatives with 1,1-
dihaloalkanes.
Substituted sulfonium ylides can also serve as effective one-carbon unit donors in the
cyclopropanation of dehydroamino acids. As illustrated in Scheme 26, dehydroalanine derivative
118 undergoes reaction with ylides 119 in a highly polar solvent such as acetonitrile or DMF [251].
To generate the reactive species from carbonyl-stabilized ylides 119, potassium carbonate has been
found to provide excellent yields (>90%) and diastereoselectivity (>99/1) for cyclopropanation
products 120. For ylides 119 semi-stabilized by aromatic groups, cesium carbonate proved more
effective, yielding products with a stereochemical outcome similar to that of carbonyl-stabilized
ylides 119. In contrast, ylides 119 stabilized by alkene groups require tBuOK as a base, resulting in
lower yields (79%) and compromised diastereoselectivity (9.3/1). The reaction can also be
conducted using chiral sulfonium ylide 121 in acetonitrile with tBuOK, providing access to
scalemic products 120 with high diastereoselectivity (up to 90%) and yields (80%).
Scheme 26. Application of stabilized sulfonium ylides for cyclopropanation of dehydroalanine derivatives.
An interesting example of the use of bromoacetates as one-carbon unit donors in the
Scheme 26. Application of stabilized sulfonium ylides for cyclopropanation
of dehydroalanine derivatives.
An interesting example of the use of bro-
moacetates as one-carbon unit donors in the
cyclopropanation of dehydroamino acids is il-
lustrated in Scheme 27 [252, 253]. The process
begins with the quaternization of the tertiary
nitrogen in chiral amine 122 via reaction with
the corresponding bromoacetate. The resul
ting quaternary salt 123 is then treated with
Cs₂CO₃ to remove hydrogen bromide, gene
rating ylide 124, which subsequently engages
in a Michael addition-type reaction with de-
hydroalanine 125 to form the stabilized in-
termediate 126. The ensuing cyclization of
intermediate 126 yields the amino diester 127,
while regenerating chiral amine 122, allow-
ing it to re-enter the reaction cycle. Tertiary
amine is employed in amounts ranging from
1 to 20 mol%. The reactions are conducted in
acetonitrile at 80 °C for 24 hours. The chemical
yields and enantioselectivity of this cyclopro-
panation exceed 90%; however, the SDE tests
were not performed [254].
Scheme 27. Application of bromoacetates as one-carbon unit donors
in the cyclopropanation of dehydroalanine.
cyclopropanation of dehydroamino acids is illustrated in Scheme 27 [252, 253]. The process begins
with the quaternization of the tertiary nitrogen in chiral amine 122 via reaction with the
corresponding bromoacetate. The resulting quaternary salt 123 is then treated with Cs₂CO₃ to
remove hydrogen bromide, generating ylide 124, which subsequently engages in a Michael
addition-type reaction with dehydroalanine 125 to form the stabilized intermediate 126. The
ensuing cyclization of intermediate 126 yields the amino diester 127, while regenerating chiral
amine 122, allowing it to re-enter the reaction cycle. Tertiary amine is employed in amounts ranging
from 1 to 20 mol%. The reactions are conducted in acetonitrile at 80 °C for 24 hours. The chemical
yields and enantioselectivity of this cyclopropanation exceed 90%; however, the SDE tests were not
performed [254].
Scheme 27. Application of bromoacetates as one-carbon unit donors in the cyclopropanation of
dehydroalanine.
Another method for the asymmetric synthesis of fluorinated ACC is illustrated in Scheme 28
[255]. This approach is based on the Reformatsky reaction of fluorodibromoacetate 129 with
properly protected dehydroalanine 128. The reaction is conducted in THF at -20 °C, yielding ACC
derivative 130, with the fluorine atom positioned beta to the amino group. The process begins with
the formation of the Reformatsky reagent [256], where one of the bromine atoms in 129 is
substituted with Zn, stabilizing it as an enolate. This intermediate then undergoes Michael-type
addition to dehydroalanine 128, followed by cyclization, which involves substitution of the second
bromine atom. Chiral oxazolidinones are preferred chiral auxiliaries in asymmetric synthesis,
known for providing exceptional stereocontrol in Michael addition reactions [257–259]. As a result,
the diastereoselectivity of this addition–cyclization sequence is excellent, exceeding 9:1, with
diastereomers readily separable by column chromatography.
Scheme 28. Synthesis of ACC derivatives via Reformatsky-Michael-cyclization sequence.
Finally, an example of photocatalyzed cyclopropanation is illustrated in Scheme 29. This
51https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
Another method for the asymmetric syn-
thesis of fluorinated ACC is illustrated in
Scheme 28 [255]. This approach is based on
the Reformatsky reaction of fluorodibromo-
acetate 129 with properly protected dehydro-
alanine 128. The reaction is conducted in THF
at -20 °C, yielding ACC derivative 130, with
the fluorine atom positioned beta to the ami-
no group. The process begins with the forma-
tion of the Reformatsky reagent [256], where
one of the bromine atoms in 129 is substitu
ted with Zn, stabilizing it as an enolate. This
intermediate then undergoes Michael-type
addition to dehydroalanine 128, followed by
cyclization, which involves substitution of the
second bromine atom. Chiral oxazolidinones
are preferred chiral auxiliaries in asymmetric
synthesis, known for providing exceptional
stereocontrol in Michael addition reactions
[257–259]. As a result, the diastereoselectivity
of this addition–cyclization sequence is excel-
lent, exceeding 9:1, with diastereomers readily
separable by column chromatography.
cyclopropanation of dehydroamino acids is illustrated in Scheme 27 [252, 253]. The process begins
with the quaternization of the tertiary nitrogen in chiral amine 122 via reaction with the
corresponding bromoacetate. The resulting quaternary salt 123 is then treated with Cs₂CO₃ to
remove hydrogen bromide, generating ylide 124, which subsequently engages in a Michael
addition-type reaction with dehydroalanine 125 to form the stabilized intermediate 126. The
ensuing cyclization of intermediate 126 yields the amino diester 127, while regenerating chiral
amine 122, allowing it to re-enter the reaction cycle. Tertiary amine is employed in amounts ranging
from 1 to 20 mol%. The reactions are conducted in acetonitrile at 80 °C for 24 hours. The chemical
yields and enantioselectivity of this cyclopropanation exceed 90%; however, the SDE tests were not
performed [254].
Scheme 27. Application of bromoacetates as one-carbon unit donors in the cyclopropanation of
dehydroalanine.
Another method for the asymmetric synthesis of fluorinated ACC is illustrated in Scheme 28
[255]. This approach is based on the Reformatsky reaction of fluorodibromoacetate 129 with
properly protected dehydroalanine 128. The reaction is conducted in THF at -20 °C, yielding ACC
derivative 130, with the fluorine atom positioned beta to the amino group. The process begins with
the formation of the Reformatsky reagent [256], where one of the bromine atoms in 129 is
substituted with Zn, stabilizing it as an enolate. This intermediate then undergoes Michael-type
addition to dehydroalanine 128, followed by cyclization, which involves substitution of the second
bromine atom. Chiral oxazolidinones are preferred chiral auxiliaries in asymmetric synthesis,
known for providing exceptional stereocontrol in Michael addition reactions [257–259]. As a result,
the diastereoselectivity of this addition–cyclization sequence is excellent, exceeding 9:1, with
diastereomers readily separable by column chromatography.
Scheme 28. Synthesis of ACC derivatives via Reformatsky-Michael-cyclization sequence.
Finally, an example of photocatalyzed cyclopropanation is illustrated in Scheme 29. This
Scheme 28. Synthesis of ACC derivatives via Reformatsky-
Michael-cyclization sequence.
Finally, an example of photocatalyzed cyclo-
propanation is illustrated in Scheme 29. This
photocatalyzed radical addition–ring-closing
sequence of alkyl halide-derived radicals pro-
vides a general method for synthesizing func-
tionalized cyclopropanes [260–262]. To gene
rate the corresponding radical from dichlo-
romethane, the reaction is performed in DMF
under green LED light (525 nm), with zinc
(3 eq.) as the reducing agent, NH₄Cl (1 eq.),
and vitamin B12 as the photocatalyst. Under
these conditions, the dehydroalanine deriva
tive 131 undergoes clean cyclopropanation,
yielding product 132 with 92% efficiency. Sub-
sequent acidic hydrolysis of 132 affords the
target ACC 1 [263].
Scheme 29. Photocatalyzed cyclopropanation of dehydroalanine
with dichloromethane.
photocatalyzed radical addition–ring-closing sequence of alkyl halide-derived radicals provides a
general method for synthesizing functionalized cyclopropanes [260–262]. To generate the
corresponding radical from dichloromethane, the reaction is performed in DMF under green LED
light (525 nm), with zinc (3 eq.) as the reducing agent, NH₄Cl (1 eq.), and vitamin B12 as the
photocatalyst. Under these conditions, the dehydroalanine derivative 131 undergoes clean
cyclopropanation, yielding product 132 with 92% efficiency. Subsequent acidic hydrolysis of 132
affords the target ACC 1 [263].
Scheme 29. Photocatalyzed cyclopropanation of dehydroalanine with dichloromethane.
CONCLUSIONS. The synthesis of α-amino-cyclopropane carboxylic acids (ACC) has
evolved into a well-established and sophisticated field. The extensive body of research offers a
diverse range of methodologies, providing multiple approaches for tailoring ACC derivatives to
meet specific physicochemical, reactivity, and functional versatility requirements. While some of
the methods reviewed here hold historical significance, others represent groundbreaking
advancements in modern synthetic strategies developed over the past decade. Despite this progress,
certain ACC derivatives still pose considerable synthetic challenges. Notably, ACC variants with
multiple substitutions on the cyclopropane ring remain underexplored in existing literature. The
strategies discussed in this work center around the amino acid core and methods for constructing the
cyclopropane ring around it. The key pathways for increasing structural complexity include:
dialkylation of nucleophilic glycine equivalents, cyclopropanation of carbenoid glycine equivalents,
and addition reactions to dehydroamino acids. These routes comprehensively cover all documented
methodologies and are relatively balanced in their representation across published studies.
ACC derivatives are an exceptional subclass of tailor-made amino acids, seamlessly
integrating the unique electronic and steric properties of their highly constrained cyclopropane ring.
Beyond their presence in biologically significant natural compounds, their role in drug design
continues to expand, solidifying their importance in medicinal chemistry. Given that pharmaceutical
applications demand enantiomerically pure derivatives, asymmetric synthesis remains a central
focus in this field. Several promising methodologies—such as chiral auxiliary-assisted asymmetric
synthesis and catalytic enantioselective approaches—offer operational convenience and high
stereochemical fidelity, making them viable for large-scale preparation of enantiomerically pure
ACC derivatives. However, one aspect that remains insufficiently explored is the self-
disproportionation of enantiomers (SDE) in ACC compounds. Based on comparisons with other
amino acids, ACC derivatives are expected to exhibit a significant degree of SDE, particularly
under achiral chromatography conditions. As a result, integrating simulated moving bed (SMB)
chromatography with SDE principles represents the most practical solution for obtaining
enantiomerically pure compounds [94, 264]. Furthermore, given the regulatory importance of chiral
drug characterization, investigating the SDE behavior of biologically active compounds [249, 265–
267] is essential for meeting US FDA requirements for chiral drug submissions [268–270]. Since
sterically constrained amino acids serve as fundamental building blocks in biological, medicinal,
and pharmaceutical sciences, synthetic advancements in ACC derivatives are expected to grow
52 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
CONCLUSIONS. The synthesis of α-amino-
cyclopropane carboxylic acids (ACC) has
evolved into a well-established and sophis-
ticated field. The extensive body of research
offers a diverse range of methodologies, pro-
viding multiple approaches for tailoring ACC
derivatives to meet specific physicochemical,
reactivity, and functional versatility require-
ments. While some of the methods reviewed
here hold historical significance, others repre-
sent groundbreaking advancements in modern
synthetic strategies developed over the past
decade. Despite this progress, certain ACC de-
rivatives still pose considerable synthetic chal-
lenges. Notably, ACC variants with multiple
substitutions on the cyclopropane ring remain
underexplored in existing literature. The stra
tegies discussed in this work center around the
amino acid core and methods for construct-
ing the cyclopropane ring around it. The key
pathways for increasing structural complexity
include: dialkylation of nucleophilic glycine
equivalents, cyclopropanation of carbenoid
glycine equivalents, and addition reactions to
dehydroamino acids. These routes compre-
hensively cover all documented methodologies
and are relatively balanced in their representa-
tion across published studies.
ACC derivatives are an exceptional sub-
class of tailor-made amino acids, seamlessly
integrating the unique electronic and steric
properties of their highly constrained cyclo-
propane ring. Beyond their presence in biolo
gically significant natural compounds, their
role in drug design continues to expand, so-
lidifying their importance in medicinal che
mistry. Given that pharmaceutical applications
demand enantiomerically pure derivatives,
asymmetric synthesis remains a central focus
in this field. Several promising methodolo-
gies—such as chiral auxiliary-assisted asym-
metric synthesis and catalytic enantioselective
approaches—offer operational convenience
and high stereochemical fidelity, making them
viable for large-scale preparation of enantio
merically pure ACC derivatives. However, one
aspect that remains insufficiently explored is
the self-disproportionation of enantiomers
(SDE) in ACC compounds. Based on compari
sons with other amino acids, ACC derivatives
are expected to exhibit a significant degree of
SDE, particularly under achiral chromatogra-
phy conditions. As a result, integrating simu-
lated moving bed (SMB) chromatography with
SDE principles represents the most practical
solution for obtaining enantiomerically pure
compounds [94, 264]. Furthermore, given the
regulatory importance of chiral drug charac-
terization, investigating the SDE behavior of
biologically active compounds [249, 265–267]
is essential for meeting US FDA requirements
for chiral drug submissions [268–270]. Since
sterically constrained amino acids serve as
fundamental building blocks in biological, me-
dicinal, and pharmaceutical sciences, synthetic
advancements in ACC derivatives are expected
to grow substantially in the coming years.
ACKNOWLEDGMENTS:
We gratefully acknowledge the finan-
cial support from ikerbasque, basque
foundation for science (for solosho-
nok). the authors acknowledge the as-
sistance of microsoft copilot and goog-
le gemini with ukrainian translation.
53https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
ПЕРЕДОВІ СТРАТЕГІЇ АСИМЕТРИЧНОГО
СИНТЕЗУ α-АМІНО-ЦИКЛОПРОПАН-
КАРБОНОВИХ КИСЛОТ:
КЛЮЧОВІ СТРУКТУРНІ ЕЛЕМЕНТИ ДЛЯ
РОЗРОБЛЕННЯ ЛІКАРСЬКИХ ПРЕПАРАТІВ.
Аліція Взорек¹, Цзяньлінь Хань²,
Тайзо Оно³, Карел Д. Кліка⁴,
Даніель Беккер5, Вей Чжан6,
Вадим А. Солошонюк7*
¹ Інститут хімії, Університет
імені Яна Кохановського в Кельцях,
вул. Університетська 7, 25-406 Кельце,
Польща;
² Цзянсуський центр спільного
інноваційного ефективного перероблення
та використання лісових ресурсів,
Хіміко-технологічний коледж,
Нанкінський лісотехнічний університет,
Нанкін 210037, Китай;
³ Національний інститут передових
промислових наук і технологій (AIST),
2266-98, Анагахора, Шимошідамі,
Моріяма-ку, Нагоя, 463-8560, Японія;
⁴ Науково-дослідний центр,
Арчер Деніелс Мідленд, вул. Н. Браш Коледж
Рд, 1001, Декейтер, Іллінойс 62521, США.;
5 Відділ фармацевтичної та лікарської хімії,
Фармацевтичний інститут,
Вільний університет Берліна,
Кьоніґін-Луїзе-Штрасе 2+4, 14195 Берлін,
Німеччина;
6 Хімічний факультет, Університет
Массачусетса в Бостоні, Бостон, Массачу
сетс 02125, Сполучені Штати Америкт;
7 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія
α-Аміноциклопропанкарбонова кислота
(ACC) та її похідні широко поширені в рос-
линному царстві, виконуючи різноманітні
функції — від регуляції життєвих циклів рос-
лин до механізмів захисту. Стерично обмеже-
на структура ACC виявилася надзвичайно ко-
рисною у розробленні численних лікарських
засобів, зокрема інгібіторів протеази NS3/4A
вірусу гепатиту C (HCV), і зіграла ключову
роль у створенні кількох поколінь ефектив-
них препаратів проти HCV, із тривалими до-
слідженнями щодо їхнього подальшого вдо-
сконалення. Властиві ACC стеричні обмежен-
ня створюють значні труднощі у їхньому син-
тезі, особливо у енантіомерно чистій формі,
що робить асиметричні методи центральною
темою досліджень. У цій статті представлено
комплексний огляд синтетичних методологій
для отримання ACC та її похідних, згрупова-
них за ключовими перетвореннями, зокре-
ма діалкілування нуклеофільних похідних
гліцину, циклопропанування карбеноїдних
еквівалентів гліцину та реакції приєднання
до дегідроамінокислот. Окремий акцент зро-
блено на енантіоселективних стратегіяx, що
дозволяють отримувати ці специфічні амі-
нокислоти у високій чистоті. Крім того, роз-
глянуто аспекти самодиспропорціонування
енантіомерів (SDE), які відіграють важливу
роль в enantioselective catalysis. Об’єднуючи ці
методології, ми прагнемо надати вичерпний
ресурс для дослідників у синтетичній та ме-
дичній хімії, а також у галузі розроблення лі-
карських препаратів, сприяючи подальшому
прогресу в цій важливій сфері.
Ключові слова: амінокислоти, фарма
цевтика, циклопропан, хіральність, синтез,
нуклеофільні еквіваленти гліцину, карбено-
їдні еквіваленти гліцину, дегідроамінокис
лоти, самодиспропорціонування енантіоме-
рів (SDE).
54 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
REFERENCES
[1] Vickery H.B., Schmidt, C.L.A. The history of
the discovery of the amino acids. Chem. Rev.
1931. 9(2): 169–318.
doi: 10.1021/cr60033a001.
[2] McCoy R.H., Meyer C.E., Rose W.C. Feeding
experiments with mixtures of highly purified
amino acids. VIII. Isolation and identification
of a new essential amino acid. J. Biol. Chem.
1935. 112: 283–302.
[3] Sakami W., Harrington H. Amino acid meta
bolism. Annu. Rev. Biochem. 1963. 32(1): 355–
398.
doi: 10.1146/annurev.bi.32.070163.002035.
[4] Soloshonok V.A., Izawa, K. Eds. Asymmetric
Synthesis and Application of α-Amino Acids.
ACS Symposium Series 1009. Washington,
District of Columbia: American Chemical So-
ciety, 2009. DOI: 10.1021/bk-2009-1009.
[5] Marasco D., Perretta G., Sabatella M., Ruvo
M. Past and future perspectives of synthetic
peptide libraries. Curr. Protein Pept. Sci. 2008.
9(5): 447–467.
doi: 10.2174/138920308785915209.
[6] Han J., Konno H., Sato T. et al. Peptidomi-
metics and Peptide-Based Blockbuster Drugs.
Curr. Org. Chem. 2021. 25(14): 1627–1658.
doi: 10.2174/1385272825666210610155047.
[7] Liu J., Han J., Izawa K. et al. Cyclic tailor-made
amino acids in the design of modern pharma-
ceuticals. Eur. J. Med. Chem. 2020. 208: 112736.
doi: 10.1016/j.ejmech.2020.112736.
[8] Liu A., Han J., Nakano A. et al. New pharma
ceuticals approved by FDA in 2020: Small-
molecule drugs derived from amino acids and
related compounds. Chirality. 2022. 34(1):
86–103.
doi: 10.1002/chir.23376.
[9] Soloshonok V.A., Cai C., Hruby V.J., Meervelt
L.V. Asymmetric synthesis of novel highly
sterically constrained (2S,3S)-3-methyl-3-tri-
fluoromethyl- and (2S,3S,4R)-3-trifluorome-
thyl-4-methylpyroglutamic acids. Tetrahe-
dron. 1999. 55(41): 12045–12058.
doi: 10.1016/S0040-4020(99)00711-5.
[10] Blaskovich M.A.T. Unusual amino acids in
medicinal chemistry. J Med Chem. 2016.
59(24): 10807–10836.
doi: 10.1021/acs.jmedchem.6b00319.
[11] Stevenazzi A., Marchini M., Sandrone G. et
al. Amino acidic scaffolds bearing unnatural
side chains: An old idea generates new and ve
rsatile tools for the life sciences. Bioorg. Med.
Chem. Lett. 2014. 24(23): 5349–5356.
doi: 10.1016/j.bmcl.2014.10.016.
[12] Han J., Konno H., Sato T. et al. Tailor-made
amino acids in the design of small-molecule
blockbuster drugs. Eur. J. Med. Chem. 2021.
220: 113448.
doi: 10.1016/j.ejmech.2021.113448.
[13] Yin Z., Hu W., Zhang W. et al. Tailor-made
amino acid-derived pharmaceuticals approved
by the FDA in 2019. Amino Acids. 2020. 52(9):
1227–1261.
doi: 10.1007/s00726-020-02887-4.
[14] Mei H., Han J., White S. et al. Tailor-made ami-
no acids and fluorinated motifs as prominent
traits in modern pharmaceuticals. Chem.—
Eur. J. 2020. 26(50): 11349–11390.
doi: 10.1002/chem.202000617.
[15] Wang Q., Han J., Sorochinsky A. et al. The La
test FDA-Approved Pharmaceuticals Contain-
ing Fragments of Tailor-Made Amino Acids
and Fluorine. Pharmaceuticals. 2022. 15(8):
999.
doi.org/10.3390/ ph150809991847558.
[16] Han J., Wzorek A. Dhawan G. et al. New drugs
on the pharmaceutical market containing fluo
rine and residues of tailor-made amino acids.
Ukr. Chem. J. 2024. 90(9): 31–56.
doi: 10.33609/2708-129X.90.9.2024.31-56.
[17] Wang N., Mei H., Dhawan G. et al. New Ap-
proved Drugs Appearing in the Pharmaceu-
tical Market in 2022, Featuring Fragments of
Tailor-Made Amino Acids and Fluorine. Mo
lecules. 2023. 28(9): 3651.
doi: 10.3390/molecules28093651.
[18] Han J., Wzorek A., Dhawan G. et al. New
drugs appearing on the market in 2023: mo
lecules containing fluorine and fragments of
55https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
tailor-made amino acids. Ukr. Bioorg. Acta.
2024. 19(1): 3–20.
doi: 10.15407/bioorganica2024.01.003.
[19] Han J., Wzorek A., Dhawan G. et al. Chiral,
fluorine-containing pharmaceuticals, Ukr.
Chem. J. 2025. 91(2): 55–90.
doi.org/10.33609/2708-129X.91.2.2025.55-90.
[20] Jianlin Han, Alicja Wzorek, Taizo Ono, Karel
D. Klika, Vadim A. Soloshonok. Modern phar-
maceutical drugs featuring aliphatic fluorine-
containing groups. Ukr. Chem. J. 2025. 91(6):
15–54.
[21] Soloshonok V.A., Mikami K., Yamazaki T.,
Welch J.T., Honek J.F. Eds. Current fluoroor-
ganic chemistry: new synthetic directions, tech-
nologies, materials, and biological applications.
ACS Symposium Series #949. Oxford Univer-
sity Press. 2007.
doi: 10.1021/bk-2007-0949.
[22] Vogt H., Bräse S. Recent approaches towards
the asymmetric synthesis of α, α-disubstitut-
ed α-amino acids. Org. Biomolec. Chem. 2007.
5(3): 406–430.
doi.org/10.1039/B611091F.
[23] Bera K., Namboothiri I.N. Asymmetric syn-
thesis of quaternary α‐amino acids and their
phosphonate analogues. Asian J. Org. Chem.
2014. 3(12):.1234-1260.
doi.org/10.1002/ajoc.201402178.
[24] Metz A.E., Kozlowski M.C. Recent advances
in asymmetric catalytic methods for the for-
mation of acyclic α, α-disubstituted α-amino
acids. J. Org. Chem. 2015. 80(1): 1-7.
doi.org/10.1021/jo502408z.
[25] Wang Y., Song X., Wang J. et al. Recent ap-
proaches for asymmetric synthesis of α-amino
acids via homologation of Ni (II) complexes.
Amino Acids. 2017. 49: 1487–1520.
doi.org/10.1007/s00726-017-2458-6.
[26] Zou Y., Han J., Saghyan A.S. et al. Asymmet-
ric synthesis of tailor-made amino acids using
chiral Ni (II) complexes of Schiff bases. An up-
date of the recent literature. Molecules. 2020.
25(12): 2739.
doi.org/10.3390/molecules25122739.
[27] Soloshonok V.A. Highly diastereoselective Mi-
chael addition reactions between nucleophilic
glycine equivalents and β-substituted-α,β-un-
saturated carboxylic acid derivatives; a general
approach to the stereochemically defined and
sterically χ-constrained α-amino acids. Curr.
Org. Chem. 2002. 6(4): 341–364.
doi: 10.2174/1385272024605014.
[28] Soloshonok V.A., Sorochinsky A.E. Practical
methods for the synthesis of symmetrically
α,α-disubstituted α-amino acids. Synthesis.
2010. (14): 2319–2344.
doi: 10.1055/s-0029-1220013.
[29] Metrano A.J., Miller S.J. Peptide-catalyzed
conversion of racemic oxazol-5 (4 H)-ones
into enantiomerically enriched α-amino acid
derivatives. J. Org. Chem. 2014. 79(4): 1542–
1554.
doi.org/10.1021/jo402828f.
[30] So S.M., Moozeh K., Lough A.J., Chin J. High-
ly Stereoselective Recognition and Deracemi
zation of Amino Acids by Supramolecular
Self‐Assembly. Angew. Chemi. In. Ed. 2014.
53(3): 829–832.
doi.org/10.1002/anie.201307410.
[31] Zhu H., Wang J., Lu Y. et al. Cu (II) Complex-
es with Proline-Derived Schiff Base Ligand:
Chemical Resolution of N, C-Unprotected
α-Amino Acids and Their Antibacterial Acti
vity. J. Org. Chem. 2022. 87(19): 12900–12908.
doi.org/10.1021/acs.joc.2c01481.
[32] Zhang F., Sun H., Song Z. et al. Stereoselective
synthesis of arylglycine derivatives via palla-
dium-catalyzed α-arylation of a chiral nickel
(II) glycinate. J. Org. Chem. 2015. 80(9): 4459–
4464.
doi.org/10.1021/acs.joc.5b00314.
[33] Fanelli R., Jeanne-Julien L., René A. et al. Ste-
reoselective synthesis of unsaturated α-amino
acids. Amino Acids. 2015. 47: 1107-1115.
doi.org/10.1007/s00726-015-1934-0.
[34] Schwieter K.E., Johnston J.N. Enantioselective
synthesis of D-α-amino amides from alipha
tic aldehydes. Chem. Scien. 2015. 6(4): 2590–
2595.
56 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
DOI: 10.1039/C5SC00064E.
[35] Yamada T., Okada T., Sakaguchi K. et al. Effi-
cient asymmetric synthesis of novel 4-substi-
tuted and configurationally stable analogues
of thalidomide. Org. Lett. 2006. 8(24): 5625–
5628.
doi: 10.1021/ol0623668.
[36] Soloshonok V.A., Ohkura H., Yasumoto M.
Operationally convenient asymmetric synthe-
sis of (S)- and (R)-3-amino-4,4,4-trifluorobu-
tanoic acid: Part II. Enantioselective biomi-
metic transamination of 4,4,4-trifluoro-3-oxo-
N-[(R)-1-phenylethyl)butanamide. J. Fluor.
Chem. 2006. 127(7): 930–935.
doi: 10.1016/j.jfluchem.2006.04.004.
[37] Takeda R., Kawamura A., Kawashima A. et al.
Chemical dynamic kinetic resolution and S/R
interconversion of unprotected α‐amino acids.
Angew. Chem., Int. Ed. 2014. 53(45): 12214–
12217.
doi.org/10.1002/anie.201407944.
[38] Soloshonok V.A., Kirilenko A.G., Fokina N.A.
et al. Biocatalytic resolution of β-fluoroalkyl-
β-amino acids. Tetrahedron: Asymmetry. 1994.
5(6): 1119–1126.
doi.org/10.1016/0957-4166(94)80063-4.
[39] Bravo P., Farina A., Kukhar V. P. et al. Stereo-
selective additions of α-lithiated alkyl-p-tolyl
sulfoxides to N-PMP fluoroalkyl aldimines.
An efficient approach to enantiomerically pure
fluoro amino compounds. J. Org. Chem. 1997.
62(11): 3424–3425.
doi: 10.1021/jo970004v.
[40] Turcheniuk K.V., Poliashko K.O., Kukhar V.P.
et al. Efficient asymmetric synthesis of trifluo-
romethylated β-aminophosphonates and their
incorporation into dipeptides. Chem. Com-
mun. 2012. 48(94): 11519–11521.
doi: 10.1039/C2CC36702E
[41] Nian Y., Wang J., Zhou S. et al. Recyclable li
gands for the non‐enzymatic dynamic kinetic
resolution of challenging α‐amino acids. An-
gew. Chem., Int. Ed. 2015. 54(44): 12918–12922.
doi.org/10.1002/anie.201507273.
[42] Hruby V.J., Li G., Haskell‐Luevano C., Shende
rovich M. Design of peptides, proteins, and
peptidomimetics in chi space. Peptide Scien.
1997. 43(3): 219–266.
doi.org/10.1002/(SICI)1097-0282(1997)43:3
<219::AID-BIP3>3.0.CO;2-Y.
[43] Hruby V.J., Balse P.M. Conformational and
topographical considerations in designing
agonist peptidomimetics from peptide leads.
Curr. Med. Chem. 2000. 7(9): 945–970.
doi.org/10.2174/0929867003374499.
[44] Vagner J., Qu H., Hruby V.J. Peptidomimetics,
a synthetic tool of drug discovery. Curr. Opin.
Chem. Biol. 2008. 12(3): 292–296.
doi.org/10.1016/j.cbpa.2008.03.009.
[45] Cai M., Cai C., Mayorov A.V. et al. Biological
and conformational study of β‐substituted
prolines in MT‐II template: steric effects lead-
ing to human MC5 receptor selectivity. J. Pep.
Res. 2004. 63(2): 116–131.
doi.org/10.1111/j.1399-3011.2003.00105.x.
[46] Qiu W., Gu X., Soloshonok V.A. et al. Stereo
selective synthesis of conformationally con-
strained reverse turn dipeptide mimetics. Tet-
rahedron Lett. 2001. 42(2): 145–148.
doi: 10.1016/S0040-4039(00)01864-5.
[47] Tang X, Soloshonok VA, Hruby VJ. Conveni
ent, asymmetric synthesis of enantiomerically
pure 2′, 6′-dimethyltyrosine (DMT) via alky
lation of chiral equivalent of nucleophilic gly-
cine. Tetrahedron: Asymmetry. 2000. 11(14):
2917–2925.
doi.org/10.1016/S0957-4166(00)00250-0.
[48] Soloshonok V.A., Tang X., Hruby V.J. Large-
scale asymmetric synthesis of novel sterically
constrained 2′, 6′-dimethyl-and α, 2′, 6′-tri-
methyltyrosine and-phenylalanine derivatives
via alkylation of chiral equivalents of nucleo
philic glycine and alanine. Tetrahedron. 2001.
57(30): 6375–6382.
doi.org/10.1016/S0040-4020(01)00504-X.
[49] Soloshonok V.A., Tang X., Hruby V.J., Meer
velt L.V. Asymmetric synthesis of α, β-dialkyl-
α-phenylalanines via direct alkylation of a
chiral alanine derivative with racemic α-alky-
lbenzyl bromides. A case of high enantiomer
57https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
differentiation at room temperature. Org. Lett.
2001. 3(3): 341–343.
doi.org/10.1021/ol000330o.
[50] Soloshonok V.A., Cai C., Hruby V.J. Toward
design of a practical methodology for stereo-
controlled synthesis of χ-constrained pyroglu-
tamic acids and related compounds. Virtually
complete control of simple diastereoselectivity
in the Michael addition reactions of glycine Ni
(II) complexes with N-(enoyl) oxazolidinones.
Tetrahedron Lett. 2000. 41(2): 135–139.
doi.org/10.1016/S0040-4039(99)02018-3.
[51] Afonin S., Mikhailiuk P.K., Komarov I.V.,
Ulrich A.S. Evaluating the amino acid CF3‐
bicyclopentylglycine as a new label for solid‐
state 19F‐NMR structure analysis of mem-
brane‐bound peptides. J. Pept. Scien. 2007.
13(9): 614–623. doi.org/10.1002/psc.854.
[52] Cativiela C., Ordóñez M. Recent progress on
the stereoselective synthesis of cyclic quater-
nary α-amino acids. Tetrahedron: Asymmetry.
2009. 20(1): 1–63.
doi.org/10.1016/j.tetasy.2009.01.002.
[53] Brackmann F., de Meijere A. Natural occur-
rence, syntheses, and applications of cyclo
propyl-group-containing α-amino acids. 1.
1-Aminocyclopropanecarboxylic acid and
other 2, 3-methanoamino acids. Chem. Rev.
2007. 107(11): 4493–4537.
doi.org/10.1021/cr078376j.
[54] Burroughs L.F. 1-aminocyclopropane-l-car-
boxyIic acid: a new amino-acid in perry pears
and cider apples. Nature. 1957. 179: 360–361.
DOI: 10.1038/179360a0.
[55] Adams D.O., Yang S. Ethylene biosynthesis:
identification of 1-aminocyclopropane-1-car-
boxylic acid as an intermediate in the conver-
sion of methionine to ethylene. PNAS. 1979.
76(1): 170–174.
doi.org/10.1073/pnas.76.1.17.
[56] Stammer C.H. Cyclopropane amino acids: 2,3-
and 3,4-Methanoamino acids. Tetrahedron.
1990. 46(7): 2231–2254.
doi.org/10.1016/S0040-4020(01)82005-6.
[57] Dorizon P., Su G., Ludvig G. et al. Stereo-
selective synthesis of highly functionalized
cyclopropanes. Application to the asymmetric
synthesis of (1S,2S)-2,3-methanoamino acids.
J. Org. Chem. 1999. 64(13): 4712–4724.
doi.org/10.1021/jo982528g.
[58] Burgess K., Ho K.K., Moye-Sherman D. Asym-
metric syntheses of 2,3-methanoamino acids.
Synlett. 1994. (08): 575–583.
DOI: 10.1055/s-1994-22933.
[59] Ichihara A., Shiraishi K., Sato H. et al. The
structure of coronatine. J. Am. Chem. Soc. 1977.
99(2): 636–637. doi.org/10.1021/ja00444a067.
[60] Mitchell R.E. Norcoronatine and N-coronafa-
coyl-L-valine, phytotoxic analogues of coro
natine produced by a strain of Pseudomonas
syringae pvglycinea. Phytochem. 1985. 24(7):
1485–1487.
doi.org/10.1016/S0031-9422(00)81049-3.
[61] Hoffmann N.E., Yang S.F., Ichihara A., Saka-
mura S. Stereospecific conversion of 1-amino
cyclopropanecarboxylic acid to ethylene by
plant tissues. Plant Physiol. 1982. 70:195–199.
doi.org/10.1104/pp.70.1.195.
[62] Pirrung M.C., McGeehan G.M. Ethylene bio-
synthesis. 6. Synthesis and evaluation of me
thylaminocyclopropanecarboxylic acid. J. Org.
Chem. 1986. 51(11): 2103-2106.
doi.org/10.1021/jo00361a032.
[63] Prelog V., Helmchen G. Basic principles of the
CIP‐system and proposals for a revision. An-
gew. Chem., Int. Ed. 1982. 21(8): 567–583.
doi.org/10.1002/anie.198205671.
[64] Klika K.D., Wzorek A., Soloshonok V.A. Inter-
nal chirality descriptors iR and iS and ire and
isi. A proposed notation to extend the useful-
ness of the R/S system by retaining the sense
of stereochemistry in cases of ligand ranking
changes. Chirality. 2018. 30(9): 1054–1066.
doi: 10.1002/chir.22982.
[65] Wang S., Wang Y., Wang J. et al. The second-
generation of highly potent hepatitis C virus
(HCV) NS3/4A protease inhibitors: Evolu-
tionary design based on tailor-made amino
acids, synthesis and major features of bio-ac-
tivity. Curr. Pharmaceut. Design. 2017. 23(30):
58 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
4493–4554.
DOI: 10.2174/1381612823666170522122424.
[66] Kakeya H., Zhang H.P., Kobinata K. et al.
Cytotrienin A, a novel apoptosis inducer in
human leukemia HL-60 cells. J. Antibiotics.
1997. 50(4): 370-372.
doi.org/10.7164/antibiotics.50.370.
[67] Cheng Z., Lou L., Liu D. et al. Versiquinazo-
lines A–K, fumiquinazoline-type alkaloids
from the gorgonian-derived fungus Aspergil-
lus versicolor LZD-14-1. J. Nat. Prod. 2016.
79(11): 2941–2952.
doi.org/10.1021/acs.jnatprod.6b00801.
[68] Zhuang Y., Teng X., Wang Y. et al. New quina-
zolinone alkaloids within rare amino acid re
sidue from coral-associated fungus, Aspergil-
lus versicolor LCJ-5-4. Org. Lett. 2011. 13(5):
1130–1133.
doi.org/10.1021/ol103164n.
[69] Cai S., Du L., Gerea A.L. et al. Spiro fused
diterpene–indole alkaloids from a creek-bot-
tom-derived Aspergillus terreus. Org. Lett.
2013. 15(16): 4186–4189.
doi.org/10.1021/ol401891z.
[70] Bender C.L., Alarcón-Chaidez F., Gross D.C.
Pseudomonas syringae phytotoxins: mode of
action, regulation, and biosynthesis by peptide
and polyketide synthetases. Microbiol. Molec.
Biol. Rev. 1999. 63(2): 266–292.
doi.org/10.1128/mmbr.63.2.266-292.1999.
[71] Li Y., Liu J., Díaz-Cruz G. et al. Virulence
mechanisms of plant-pathogenic Strepto-
myces species: an updated review. Microbiol.
2019. 165(10): 1025–1040.
doi.org/10.1099/mic.0.000818.
[72] Bignell D.R., Cheng Z., Bown L. The corona-
facoyl phytotoxins: structure, biosynthesis, re
gulation and biological activities. Antonie Van
Leeuwenhoek. 2018. 111: 649–666.
doi.org/10.1007/s10482-017-1009-1.
[73] Ronald P., Joe A. Molecular mimicry modu-
lates plant host responses to pathogens. Ann.
Bot. 2018. 121(1): 17–23.
doi.org/10.1093/aob/mcx125.
[74] Fernando I.S., Nah J.W., Jeon Y.J. Potential an-
ti-inflammatory natural products from marine
algae. Environmen. Toxicol. Pharmacol. 2016.
48: 22–30.
doi.org/10.1016/j.etap.2016.09.023.
[75] Sharma K.K., Sharma K., Rao K. et al. Unna
tural amino acids: strategies, designs, and ap-
plications in medicinal chemistry and drug
discovery. J. Med. Chem. 2024. 67(22): 19932–
19965.
doi.org/10.1021/acs.jmedchem.4c00110.
[76] Zhang Z., Sun Y., Li Y. et al. The potential of
marine-derived piperazine alkaloids: Sources,
structures and bioactivities. Eur. J. Med. Chem.
2024. 265: 116081.
doi.org/10.1016/j.ejmech.2023.116081.
[77] He D., Wang M., Zhao S. et al. Pharmaceuti-
cal prospects of naturally occurring quina-
zolinone and its derivatives. Fitoterapia. 2017.
119: 136–149.
doi.org/10.1016/j.fitote.2017.05.001.
[78] Zhang S.S., Meng Z.H., Zhao G.Z. et al. Asper-
gillus versicolor as a source of diversified me
tabolic products with pharmacological activi-
ties. Stud. Nat. Prod. Chem. 2022. 74: 225–277.
doi.org/10.1016/B978-0-323-91099-6.00015-3.
[79] Ciotti M., Angeletti S., Minieri M. et al.
COVID-19 outbreak: an overview. Chemo-
therapy. 2020. 64(5–6): 215–223.
doi.org/10.1159/000507423.
[80] Yuan Y., Jiao B., Qu L. et al. The development
of COVID-19 treatment. Front. Immunol.
2023. 14: 1125246.
doi.org/10.3389/fimmu.2023.1125246.
[81] Ohimain E.I., Silas-Olu D. The 2013–2016
Ebola virus disease outbreak in West Africa.
Curr. Opin. Pharmacol. 2021. 60: 360–365.
doi.org/10.1016/j.coph.2021.08.002.
[82] Gentile I., Buonomo A.R., Zappulo E., Bor-
gia G. Discontinued drugs in 2012–2013: he
patitis C virus infection. Expert Opin. Investi-
gat. Drugs. 2015. 24(2): 239–251.
doi.org/10.1517/13543784.2015.982274.
[83] Njoroge F.G., Chen K.X., Shih N.Y., Piwinski
J.J. Challenges in modern drug discovery: a
case study of boceprevir, an HCV protease in-
59https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
hibitor for the treatment of hepatitis C virus
infection. Acc. Chem. Res. 2008. 41(1): 50–59.
doi.org/10.1021/ar700109k.
[84] Revill P., Serradell N., Bolos J., Rosa E. Tela-
previr. Drugs Future. 2007. 32(9): 788–798.
DOI: 10.1358/dof.2007.032.09.1138229.
[85] Eley T., Garimella T., Li W., Bertz R.J. Asuna
previr: a review of preclinical and clinical phar-
macokinetics and drug–drug interactions.
Clin. Pharmacokin. 2015. 54: 1205–1222.
doi.org/10.1007/s40262-015-0299-6.
[86] Izquierdo L., Helle F., François C. et al. Sime-
previr for the treatment of hepatitis C virus in-
fection. Pharmacogenom. Personal. Med. 2014.
241–249.
doi.org/10.2147/PGPM.S52715.
[87] Menon R.M., Polepally A.R., Khatri A. et al.
Clinical pharmacokinetics of paritaprevir.
Clin. Pharmacokin. 2017. ;56: 1125–1137.
doi.org/10.1007/s40262-017-0520-x.
[88] Das D., Pandya M. Recent advancement of
direct-acting antiviral agents (DAAs) in hepa
titis C therapy. Mini Rev. Med. Chem. 2018.
18(7): 584-596.
doi.org/10.2174/138955751766617091311193.
[89] Du Y., Semghouli A., Wang Q. et al. FDA‐ap-
proved drugs featuring macrocycles or me-
dium‐sized rings. Archiv Pharmazie. 2025.
358(1): e2400890.
doi.org/10.1002/ardp.202400890.
[90] Lee H.W., Jung K.S., Ahn S.H. Treatment of
chronic hepatitis C using newly developed
oral antiviral agents. Kor. J. Med. 2015. 88(6):
635-642.
doi.org/10.3904/kjm.2015.88.6.635.
[91] Brennan B.J., Poirier A., Moreira S. et al. Cha
racterization of the transmembrane transport
and absolute bioavailability of the HCV pro-
tease inhibitor danoprevir. Clin. Pharmacokin.
2015. 54: 537–549.
doi.org/10.1007/s40262-014-0222-6.
[92] Cotter T.G., Jensen D.M. Glecaprevir/pibren-
tasvir for the treatment of chronic hepatitis C:
design, development, and place in therapy. Drug
Design Develop. Ther. 2019. 29: 2565–2577.
doi.org/10.2147/DDDT.S172512.
[93] Yang H., Yang C., Wang Y. et al. Preclinical
characterization of the novel HCV NS3 pro-
tease inhibitor GS-9256. Antivir. Ther. 2017.
22(5): 413–420.
doi.org/10.3851/IMP3132.
[94] Wzorek A., Klika K., Han J. et al. Enantiomer
Purification Through Achiral Chromatogra-
phy: Integrating Simulated Moving Bed and
Self-Disproportionation of Enantiomers. Ukr.
Chem. J. 2025. 91(3): 34–48.
doi.org/10.33609/2708-129X.91.3.2025.34-48.
[95] Du Y., Bian Y., Baecker D. et al. Fluorine in
the Pharmaceutical Industry: FDA‐Approved
Fluorine‐Containing Drugs in 2024. Chem.
Eur. J. 2025. 31(25): e202500662.
doi.org/10.1002/chem.202500662.
[96] Wang Q., Bian Y., Dhawan G. et al. FDA ap-
proved fluorine-containing drugs in 2023.
Chin. Chem. Lett. 2024. 35(11): 109780.
doi: 10.1016/j.cclet.2024.109780.
[97] Bravo P., Guidetti M., Viani F. et al. Chiral
sulfoxide controlled asymmetric additions to
C N double bond. An efficient approach to
stereochemically defined α-fluoroalkyl ami-
no compounds. Tetrahedron. 1998. 54(42):
12789–12806.
doi: 10.1016/S0040-4020(98)00779-0.
[98] Wang J., Sánchez-Roselló M., Aceña J.L. et al.
Fluorine in pharmaceutical industry: fluo-
rine-containing drugs introduced to the mar-
ket in the last decade (2001–2011). Chem. Rev.
2014. 114(4): 2432–2506.
doi.org/10.1021/cr4002879.
[99] Zhou Y., Wang J., Gu Z. et al. Next Genera-
tion of Fluorine-Containing Pharmaceuticals,
Compounds Currently in Phase II–III Clinical
Trials of Major Pharmaceutical Companies:
New Structural Trends and Therapeutic Areas.
Chem. Rev. 2016. 116(2): 422–518.
doi: 10.1021/acs.chemrev.5b00392.
[100] Han J., Kiss L., Mei H. et al. Chemical as-
pects of human and environmental over-
load with fluorine. Chem. Rev. 2021. 121(8):
4678–4742.
60 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
doi.org/10.1021/acs.chemrev.0c01263.
[101] Röschenthaler G.V., Kukhar V.P., Kulik I.B.
et al. Asymmetric synthesis of phospho-
notrifluoroalanine and its derivatives using
N-tert-butanesulfinyl imine derived from
fluoral. Tetrahedron Lett. 2012. 53(5): 539–
542.
doi:10.1016/j.tetlet.2011.11.096.
[102] Soloshonok V.A., Belokon Y.N., Kuzmina
N.A. et al. Asymmetric synthesis of phos-
phorus analogues of dicarboxylic α-amino
acids. J. Chem. Soc. Perkin Transac. 1. 1992.
(12): 1525–1529.
doi.org/10.1039/P19920001525.
[103] Turcheniuk K.V., Kukhar V.P., Röschenthaler
G.V. et al. Recent advances in the synthesis
of fluorinated aminophosphonates and ami-
nophosphonic acids. RSC Adv. 2013. 3(19):
6693–6716. DOI: 10.1039/c3ra22891f.
[104] Walsh C., Pascal Jr R.A., Johnston M. et al.
Mechanistic studies on the pyridoxal phos-
phate enzyme 1-aminocyclopropane-1-car-
boxylate deaminase from Pseudomonas sp.
Biochem. 1981. 20(26): 7509–7519.
doi.org/10.1021/bi00529a028.
[105] Beaulieu P.L., Gillard J., Bailey M.D. et al.
Synthesis of (1R,2S)-1-Amino-2-vinylcyclo-
propanecarboxylic Acid Vinyl-ACCA De-
rivatives: Key Intermediates for the Prepa-
ration of Inhibitors of the Hepatitis C Virus
NS3 Protease. J. Org. Chem. 2005. 70(15):
5869–5879.
doi.org/10.1021/jo050468q.
[106] Park N.H., Teverovskiy G., Buchwald S.L.
Development of an air-stable nickel pre-
catalyst for the amination of aryl chlorides,
sulfamates, mesylates, and triflates. Org.
Lett. 2014. 16(1): 220–223.
doi.org/10.1021/ol403209k.
[107] Boyall D., Frantz D.E., Carreira E.M. Effi-
cient enantioselective additions of terminal
alkynes and aldehydes under operational-
ly convenient conditions. Org. Lett. 2002.
4(15): 2605–2606.
doi.org/10.1021/ol026282k.
[108] Moore J.L., Taylor S.M., Soloshonok V.A. An
efficient and operationally convenient ge
neral synthesis of tertiary amines by direct
alkylation of secondary amines with alkyl
halides in the presence of Huenig’s base.
Arkivoc. 2005. 6(iv): 287–292.
doi.org/10.3998/ark.5550190.0006.624.
[109] Soloshonok V.A., Kirilenko A.G., Fokina
N.A. et al. Chemo-enzymatic approach to
the synthesis of each of the four isomers of
α-alkyl-β-fluoroalkyl-substituted β-amino
acids. Tetrahedron: Asymmetry. 1994. 5(7):
1225–1228.
doi.org/10.1016/0957-4166(94)80163-0.
[110] Sorochinsky A.E., Ueki H., Aceña J.L. et al.
Chemical deracemization and (S) to (R) in-
terconversion of some fluorine-containing
α-amino acids. J. Fluor. Chem. 2013. 152:
114–118.
doi.org/10.1016/j.jfluchem.2013.02.022.
[111] Soloshonok V.A., Soloshonok I.V., Kukhar
V.P., Svedas V.K. Biomimetic transamination
of α-alkyl β-keto carboxylic esters. Chemo-
enzymatic approach to the stereochemically
defined α-alkyl β-fluoroalkyl β-amino acids.
J. Org. Chem. 1998. 63(6): 1878–1884.
doi.org/10.1021/jo971777m.
[112] Belyk K.M., Xiang B., Bulger P.G. et al.
Enantioselective synthesis of (1R,2S)-1-
amino-2-vinylcyclopropanecarboxylic acid
ethyl ester (Vinyl-ACCA-OEt) by asymmet-
ric phase-transfer catalyzed cyclopropana-
tion of (E)-N-phenylmethyleneglycine ethyl
ester. Org. Proc. Res. Develop. 2010. 14(3):
692–700.
doi.org/10.1021/op100070d.
[113] Lou S., Cuniere N., Su B.N., Hobson
L.A. Concise asymmetric synthesis of a
(1R,2S)-1-amino-2-vinylcyclopropanecar-
boxylic acid-derived sulfonamide and ethyl
ester. Org. Biomol. Chem. 2013. 11(39):
6796–6805.
doi.org/10.1039/C3OB41394B.
[114] Nakamura T., Tateishi K. Tsukagoshi, S. et
al. Self-Disproportionation of Enantiomers
61https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
of Non-racemic Chiral Amine Derivatives
Through Achiral Chromatography. Tetrahe-
dron. 2012. 68: 4013–4017.
doi:10.1016/j.tet.2012.03.054.
[115] Suzuki Y., Han J., Kitagawa O. et al. A com-
prehensive examination of the self-dispro-
portionation of enantiomers (SDE) of chiral
amides via achiral, laboratory-routine, gra
vity-driven column chromatography. RSC
Adv. 2015. 5: 2988–2993;
DOI: 10.1039/C4RA13928C.
[116] Soloshonok V.A. Remarkable amplification
of the self‐disproportionation of enantio
mers on achiral‐phase chromatography co
lumns. Angew. Chem. Int. Ed. 2006. 45(5):
766–769.
doi.org/10.1002/anie.200503373.
[117] Hercouet A., Bessières B., Le Corre M. First
asymmetric synthesis of (−)-(2S,3R)-metha
noproline. Tetrahedron: Asymmetry. 1996.
7(5): 1267–1268.
doi.org/10.1016/0957-4166(96)00139-5.
[118] Sorochinsky A.E., Ueki H., Aceña J.L. et al.
Chemical approach for interconversion of
(S)-and (R)-α-amino acids. Org. Biomol.
Chem. 2013. 11(27): 4503–4507.
DOI:10.1039/C3OB40541A.
[119] Takeda R., Abe H., Shibata N. et al. Asym-
metric synthesis of α-deuterated α-amino
acids. Org. Biomol. Chem. 2017. 15(33):
6978–6983.
doi.org/10.1039/C7OB01720K.
[120] Joerres M., Aceña J.L., Soloshonok V.A.,
Bolm C. Asymmetric carbon–carbon bond
formation under solventless conditions in
ball mills. ChemCatChem. 2015. 7(8): 1265–
1269.
doi.org/10.1002/cctc.201500102.
[121] Jörres M., Chen X., Aceña J.L. et al. Asym-
metric synthesis of α‐amino acids under op-
erationally convenient conditions. Adv. Syn.
Cat. 2014. 356(10): 2203–2208.
doi.org/10.1002/adsc.201400405.
[122] Li T., Zhou S., Wang J. et al. Asymmetric
synthesis of α-(1-oxoisoindolin-3-yl) gly-
cine: Synthetic and mechanistic challenges.
Chem. Commun. 2015. 51(9): 1624–1626.
DOI: 10.1039/C4CC05659K.
[123] Soloshonok V.A., Kukhar V.P., Galushko S.V.
et al. General method for the synthesis of
enantiomerically pure β-hydroxy-α-amino
acids, containing fluorine atoms in the side
chains. Case of stereochemical distinction
between methyl and trifluoromethyl groups.
X-Ray crystal and molecular structure of
the nickel (II) complex of (2S,3S)-2 (trifluo-
romethyl) threonine. J. Chem. Soc. Perkin
Trans. 1. 1993. (24): 3143–3155.
doi.org/10.1039/P19930003143.
[124] Soloshonok V.A,. Avilov D.V., Kukhar V.P.
Highly diastereoselective asymmetric aldol
reactions of chiral Ni (II)-complex of glycine
with alkyl trifluoromethyl ketones. Tetrahe-
dron: Asymmetry. 1996. 7(6): 1547–1550.
doi.org/10.1016/0957-4166(96)00177-2.
[125] Zou Y., Yin Z., Mei H. et al. Aldol addi-
tion-cyclization reaction cascade on a plat-
form of chiral Ni (II) complex of glycine
schiff base. Ukr. Bioorgan. Acta. 2021. 16(1):
3-9.
doi.org/10.15407/bioorganica2021.01.003.
[126] Yamada T., Sakaguchi K., Shinada T. et al.
Efficient asymmetric synthesis of the func-
tionalized pyroglutamate core unit common
to oxazolomycin and neooxazolomycin us-
ing Michael reaction of nucleophilic glycine
Schiff base with α, β-disubstituted acrylate.
Tetrahedron: Asymmetry. 2008. 19(24):
2789–2795.
doi.org/10.1016/j.tetasy.2008.11.036.
[127] Soloshonok V.A., Cai C., Hruby V.J. Asym-
metric Michael addition reactions of chiral
Ni (II)-complex of glycine with (N-trans-
enoyl) oxazolidines: improved reactivity
and stereochemical outcome. Tetrahedron:
Asymmetry. 1999. 10(22): 4265–4269.
doi.org/10.1016/S0957-4166(99)00483-8.
[128] Soloshonok V.A., Cai C., Hruby V.J.
A unique case of face diastereoselectivity
in the Michael addition reactions between
62 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
Ni (II)-complexes of glycine and chiral
3-(E-enoyl)-1, 3-oxazolidin-2-ones. Tetrahe-
dron Lett. 2000. 41(49): 9645–9649.
doi.org/10.1016/S0040-4039(00)01737-8.
[129] Soloshonok V.A., Avilov D.V., Kukhar V.P.
et al. An efficient asymmetric synthesis of
(2S,3S)-3-trifluoromethylpyroglutamic acid.
Tetrahedron Lett. 1997. 38(27): 4903–4904.
doi: 10.1016/S0040-4039(97)01054-X.
[130] Kawamura A., Moriwaki H., Roeschentha
ler G.V. et al. Synthesis of (2S,3S)-β-(trifluo-
romethyl)-α, β-diamino acid by Mannich
addition of glycine Schiff base Ni (II) com-
plexes to N-tert-butylsulfinyl-3,3,3-trifluo-
roacetaldimine. J. Fluor. Chem. 2015. 171:
67–72.
doi: 10.1016/j.jfluchem.2014.09.013.
[131] Soloshonok V.A., Avilov D.V., Kukhar V.P.
et al. Highly diastereoselective aza-aldol
reactions of a chiral Ni (II) complex of gly-
cine with imines. An efficient asymmetric
approach to 3-perfluoroalkyl-2,3-diamino
acids. Tetrahedron Lett. 1997. 38(26): 4671–
4674.
doi.org/10.1016/S0040-4039(97)00963-5.
[132] Sorochinsky A.E., Aceña J.L., Moriwaki H. et
al. Asymmetric synthesis of α-amino acids
via homologation of Ni(II) complexes of gly-
cine Schiff bases. Part 2: Aldol, Mannich ad-
dition reactions, deracemization and (S) to
(R) interconversion of α-amino acids. Amino
Acids. 2013. 45(5): 1017–1033.
doi: 10.1007/s00726-013-1580-3.
[133] Qiu W., Soloshonok V..A, Cai C. et al. Con-
venient, large-scale asymmetric synthesis of
enantiomerically pure trans-cinnamylgly
cine and -α-alanine. Tetrahedron. 2000.
56(17): 2577–2582.
doi.org/10.1016/S0040-4020(00)00176-9.
[134] Sorochinsky A.E., Aceña J.L., H. Moriwa-
ki H. et al. Asymmetric synthesis of α-amino
acids via homologation of Ni(II) complexes
of glycine Schiff bases; Part 1: alkyl halide
alkylations. Amino Acids. 2013. 45(4): 691–
718.
doi: 10.1007/s00726-013-1539-4.
[135] Aceña J.L., Sorochinsky A.E., Moriwaki H. et
al. Synthesis of fluorine-containing α-amino
acids in enantiomerically pure form via ho-
mologation of Ni(II) complexes of glycine
and alanine Schiff bases. J. Fluor. Chem.
2013. 155: 21–38.
doi: 10.1016/j.jfluchem.2013.06.004.
[136] Wang J., Lin D., Zhou S. et al. Asymmet-
ric synthesis of sterically and electronically
demanding linear ω-trifluoromethyl con-
taining amino acids via alkylation of chiral
equivalents of nucleophilic glycine and ala-
nine. J. Org. Chem. 2011. 76(2): 684–687.
doi.org/10.1021/jo102031b.
[137] Ellis T.K., Hochla V.M., Soloshonok V.A.
Efficient synthesis of 2-aminoindane-2-
carboxylic acid via dialkylation of nucleo
philic glycine equivalent. J. Org. Chem. 2003.
68(12): 4973–4976.
doi.org/10.1021/jo030065v.
[138] Ellis T.K., Martin C.H., Ueki H., Soloshonok
V.A. Efficient, practical synthesis of symmet-
rically α, α-disubstituted α-amino acids. Tet-
rahedron Lett. 2003. 44(5): 1063–1066.
doi.org/10.1016/S0040-4039(02)02719-3.
[139] Ellis T.K., Martin C.H., Tsai G.M. et al. Effi-
cient synthesis of sterically constrained sym-
metrically α, α-disubstituted α-amino acids
under operationally convenient conditions.
J. Org. Chem. 2003. 68(16): 6208–6214.
doi.org/10.1021/jo030075w.
[140] Wang J., Liu H., Aceña J.L. et al. Synthesis
of bis-α,α′-amino acids through diastereose-
lective bis-alkylations of chiral Ni (ii)-comp
lexes of glycine. Org. Biomolec. Chem. 2013.
11(27): 4508–4515.
DOI:10.1039/C3OB40594J.
[141] Ueki H., Ellis T.K., Martin C.H., Soloshonok
V.A. Efficient large‐scale synthesis of pico
linic acid‐derived nickel (II) complexes of
glycine. Eur. J. Org. Chem. 2003. 2003. (10):
1954–1957.
DOI: 10.1002/ejoc.200200688.
[142] Ueki H., Ellis T.K., Martin C.H. et al. Im-
63https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
proved synthesis of proline-derived Ni (II)
complexes of glycine: versatile chiral equi
valents of nucleophilic glycine for general
asymmetric synthesis of α-amino acids. J.
Org. Chem. 2003. 68(18): 7104–7107.
DOI: 10.1021/jo0301494.
[143] Houck D., Aceña J.L., Soloshonok V.A. Alky-
lations of Chiral Nickel (II) Complexes of
Glycine under Phase‐Transfer Conditions.
Helv. Chim. Acta. 2012. 95(12): 2672–2679.
DOI: 10.1002/hlca.201200536.
[144] Taylor S.M., Yamada T., Ueki H., Soloshonok
V.A. Asymmetric synthesis of enantiomeri-
cally pure 4-aminoglutamic acids via methy
lenedimerization of chiral glycine equiva-
lents with dichloromethane under opera-
tionally convenient conditions. Tetrahedron
Lett. 2004. 45(50): 9159–9162.
doi.org/10.1016/j.tetlet.2004.10.111.
[145] Sato T., Izawa K., Aceña J.L. et al. Tailor‐
made α‐amino acids in the pharmaceutical
industry: synthetic approaches to (1R,2S)‐1‐
amino‐2‐vinylcyclopropane‐1‐carboxylic
acid (vinyl‐ACCA). Eur. J. Org. Chem. 2016.
(16): 2757–2774.
doi.org/10.1002/ejoc.201600112.
[146] Kawashima A., Xie C., Mei H. et al. Asym-
metric synthesis of (1R,2S)-1-amino-2-vi-
nylcyclopropanecarboxylic acid by sequen-
tial SN 2–SN 2′ dialkylation of (R)-N-(ben-
zyl) proline-derived glycine Schiff base Ni
(ii) complex. RSC Adv. 2015. 5(2): 1051–
1058.
DOI: 10.1039/C4RA12658K.
[147] Debache A., Collet S., Bauchat P. et al. Be-
lokon’s Ni (II) complex as a chiral masked
glycine for the diastereoselective synthesis of
2-substituted 1-aminocyclopropane carbo
xylic acids. Tetrahedron: Asymmetry. 2001.
12(5): 761–764.
doi.org/10.1016/S0957-4166(01)00106-9.
[148] Soloshonok V.A., Boettiger T.U., Bolene
S.B. Asymmetric synthesis of (2S,3S)-and
(2R,3R)-α,β-dialkyl-α-amino acids via alky-
lation of chiral nickel (II) complexes of ali-
phatic α-amino acids with racemic α-alkyl
benzyl bromides. Synthesis. 2008. (16):
2594–2602.
DOI: 10.1055/s-2008-1067172.
[149] Ellis T.K., Ueki H., Soloshonok V.A. New
generation of nucleophilic glycine equiva-
lents. Tetrahedron Lett. 2005. 46(6): 941–
944.
doi.org/10.1016/j.tetlet.2004.12.050.
[150] Soloshonok V.A., Ueki H., Ellis T.K. New
generation of modular nucleophilic gly-
cine equivalents for the general synthesis of
α-amino acids. Synlett. 2009. (5): 704–715.
DOI: 10.1055/s-0028-1087929.
[151] Soloshonok V.A., Ueki H., Ellis T.K. et al.
Application of modular nucleophilic glycine
equivalents for truly practical asymmet-
ric synthesis of β-substituted pyroglutamic
acids. Tetrahedron Lett. 2005. 46(7): 1107–
1110.
doi.org/10.1016/j.tetlet.2004.12.093.
[152] Nian Y., Wang J., Moriwaki H. et al. Ana
lysis of crystallographic structures of Ni (ii)
complexes of α-amino acid Schiff bases: elu-
cidation of the substituent effect on stereo
chemical preferences. Dalton Trans. 2017.
46(13): 4191–4198.
doi.org/10.1039/C7DT00014F.
[153] Ellis T.K., Ueki H., Yamada T. et al. Design,
synthesis, and evaluation of a new genera-
tion of modular nucleophilic glycine equi
valents for the efficient synthesis of sterically
constrained α-amino acids. J. Org. Chem.
2006. 71(22): 8572–8578.
doi.org/10.1021/jo0616198.
[154] Romoff T.T., Ignacio B.G., Mansour N. et al.
Large-scale synthesis of the glycine Schiff
base Ni (II) complex derived from (S)-and
(R)-N-(2-benzoyl-4-chlorophenyl)-1-[(3,
4-dichlorophenyl) methyl]-2-pyrrolidine
carboxamide. Org. Proc. Res. Develop. 2020.
24(2): 294–300.
doi.org/10.1021/acs.oprd.9b00399.
[155] Nian Y., Wang J., Zhou S. et al. Purely chemi
cal approach for preparation of D-α-amino
64 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
acids via (S)-to-(R)-interconversion of un-
protected tailor-made α-amino acids. J. Org.
Chem. 2016. 81(9): 3501–3508.
DOI: 10.1021/acs.joc.5b02707
[156] Mei H., Han J., Takeda R. et al. Practical
method for preparation of (S)-2-Amino-5, 5,
5-trifluoropentanoic acid via dynamic ki-
netic resolution. ACS Omega. 2019. 4(7):
11844–11851.
DOI: 10.1021/acsomega.9b01537.
[157] Bergagnini M., Fukushi K., Han J. et al. NH-
type of chiral Ni (II) complexes of glycine
Schiff base: design, structural evaluation,
reactivity and synthetic applications. Org.
Biomolec. Chem. 2014. 12(8): 1278–1291.
DOI:10.1039/C3OB41959B.
[158] Ellis T.K., Soloshonok V.A. Design and Syn-
thesis of a New Generation of ‘NH’-Ni (II)
Complexes of Glycine Schiff Bases and their
Unprecedented CH vs. NH Chemoselectivi-
ty in Alkyl Halide Alkylations and Michael
Addition Reactions. Synlett. 2006. (4): 533–
538.
DOI: 10.1055/s-2006-926252.
[159] Takeda R., Kawamura A., Kawashima A. et
al. Second-order asymmetric transforma-
tion and its application for the practical syn-
thesis of α-amino acids. Org. Biomol. Chem.
2018. 16(27): 4968–4972.
DOI: 10.1039/C8OB00963E.
[160] Takahashi M., Moriwaki H., Miwa T. et al.
Large Scale Synthesis of Chiral (3 Z, 5 Z)-
2, 7-Dihydro-1 H-azepine-Derived Hamari
Ligand for General Asymmetric Synthesis
of Tailor-Made Amino Acids. Org. Proc. Res.
Develop. 2019. 23(4): 619–628.
DOI: 10.1021/acs.oprd.8b00406.
[161] Wang S., Zhou S., Wang J. et al. Chemical
dynamic thermodynamic resolution and
S/R interconversion of unprotected unnatu-
ral tailor-made α-amino acids. J. Org. Chem.
2015. 80(20): 9817–9830.
DOI: 10.1021/acs.joc.5b01292.
[162] Han J., Romoff T.T., Moriwaki H. et al. De-
velopment of Hamari ligands for practical
asymmetric synthesis of tailor-made ami-
no acids. ACS Omega. 2019. 4(21): 18942–
18947.
DOI: 10.1021/acsomega.9b02940.
[163] Kawashima A., Shu S., Takeda R. et al. Ad-
vanced asymmetric synthesis of (1R,2S)-1-
amino-2-vinylcyclopropanecarboxylic acid
by alkylation/cyclization of newly designed
axially chiral Ni (II) complex of glycine
Schiff base. Amino Acids. 2016. 48: 973–986.
DOI: 10.1007/s00726-015-2138-3.
[164] O’Donnell M.J., Bruder W.A., Eckrich T.M.
et al. Simple syntheses of the amino acids:
1-aminocyclopropane-1-carboxylic acid,
cycloleucine and 2,6-diaminopimelic acid.
Synthesis. 1984. (2): 127–128.
DOI: 10.1055/s-1984-30749.
[165] Allwein S.P., Secord E.A., Martins A. et al.
Convenient synthesis and isolation of 1-ami-
nocyclopropane-1-carboxylic acid (ACC)
and N-protected ACC derivatives. Synlett.
2004. (14): 2489-2492. DOI: 10.1055/s-
2004-834793.
[166] Vergne F., Aitken D.J., Husson H.P. Synthesis
of 1-amino-1-(aminomethyl) cyclopropane
and its monobenzamides. J. Org. Chem.
1992. 57(22): 6071–6075.
doi.org/10.1021/jo00048a054.
[167] Soloshonok V.A., Hayashi T. Gold (I)-cata-
lyzed asymmetric aldol reactions of fluor-
inated benzaldehydes with an α-isocyano-
acetamide. Tetrahedron: Asymmetry. 1994.
5(6): 1091–1094.
doi.org/10.1016/0957-4166(94)80059-6.
[168] Soloshonok V.A., Hayashi T. Gold (I)-cata-
lyzed asymmetric aldol reaction of methyl
isocyanoacetate with fluorinated benzalde-
hydes. Tetrahedron Lett. 1994. 35(17): 2713–
2716.
doi.org/10.1016/S0040-4039(00)77013-4.
[169] Schöllkopf U., Hoppe D., Jentsch R. Higher
amino acids by alkylation of α‐metalated
isocyano‐acetic or‐propionic esters. Angew.
Chem. Int. Ed. 1971. 10(5): 331–333.
doi.org/10.1002/anie.197103312.
65https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
[170] Soloshonok V.A., Hayashi T., Ishikawa K.,
Nagashima N. Highly diastereoselective al-
dol reaction of fluoroalkyl aryl ketones with
methyl isocyanoacetate catalyzed by silver
(I)/triethylamine. Tetrahedron Lett. 1994.
35(7): 1055–1058.
doi.org/10.1016/S0040-4039(00)79964-3.
[171] Soloshonok V.A., Kacharov A.D., Avilov D.V.
et al. Transition Metal/Base-Catalyzed Aldol
Reactions of Isocyanoacetic Acid Derivatives
with Prochiral Ketones, a Straightforward
Approach to Stereochemically Defined β,
β-Disubstituted-β-hydroxy-α-amino Acids.
1 Scope and Limitations. J. Org. Chem. 1997.
62(11): 3470–3479.
doi.org/10.1021/jo9623402.
[172] Schöllkopf U., Hupfeld B., Gull R. Simple
Synthesis of 1‐Amino‐1‐cyclopropanecar-
boxylic Acids from tert‐Butyl Isocyanoa
cetate and Epoxides; Synthesis of Alkyl 5,6‐
Dihydro‐4H‐1,3‐oxazine‐4‐carboxylates.
Angew. Chem. Int. Ed. 1986. 25(8): 754–755.
doi.org/10.1002/anie.198607541.
[173] Pirrung M., McGeehan G.M. Cyclopropyl‐
Substituted Aminocyclopropane Carboxylic
Acid (Cyclopropyl‐ACC)—an Investigation
of the Mechanism of Ethylene Biosynthesis.
Angew. Chem. Int. Ed. 1985. 24(12): 1044–
1045.
doi.org/10.1002/anie.198510441.
[174] Semeno V.V., Vasylchenko V.O., Vashchenko
B.V. et al. Building the housane: diastereo-
selective synthesis and characterization of
bicyclo [2.1. 0] pentane carboxylic acids. J.
Org. Chem. 2019. 85(4): 2321–2337.
doi.org/10.1021/acs.joc.9b03044.
[175] De Kimpe N., Sulmon P., Stevens C.. Synthe-
sis of 1-amino-2, 2-dialkylcyclopropanecar-
boxylic acids from β-chloroaldimines. Tetra-
hedron. 1991. 47(26): 4723–4738.
doi.org/10.1016/S0040-4020(01)86477-2.
[176] Easton C.J., Tan E.W., Ward C.M. Synthesis
of cyclopropyl amino acid derivatives. Aus-
tral. J. Chem. 1992. 45(2): 395–402.
doi.org/10.1071/CH9920395.
[177] Subramanian P.K., Kalvin D.M., Ramalin
gam K., Woodard R.W. Synthesis of (1S,2R)-
and (1S,2S)-1-amino [2-2H] cyclopropane-
1-carboxylic acids: The total 1H NMR assign-
ment of cyclo [ACC-. alpha.-methyl-Phe].
J. Org. Chem. 1989. 54(2): 270–276.
doi.org/10.1021/jo00263a004.
[178] Lorthiois E., Marek I., Normant J.F. Amino
zinc enolate carbocyclization reactions. New
access to polysubstituted piperidine deriva-
tives. J. Org. Chem. 1998. 63(3): 566–574
doi.org/10.1021/jo971449m.
[179] DeMuynck B.M., Zhang L., Ralph E.K.,
Nagib D.A. Cyclopropanation of unactivated
alkenes with non-stabilized iron carbenes.
Chem. 2024. 10(3): 1015–1027.
DOI: 10.1016/j.chempr.2024.01.006.
[180] Alford JS, Davies HM. Expanding the scope
of donor/acceptor carbenes to N-phthalimi-
do donor groups: diastereoselective synthe-
sis of 1-cyclopropane α-amino acids. Org.
Lett. 2012. 14(23): 6020–6023.
doi.org/10.1021/ol3029127.
[181] Ballini R., Palmieri A., Fiorini D. Synthesis
and use of nitrocyclopropane derivatives.
Arkivoc. 2007(7): 172–194.
[182] Charette A.B., Wurz R.P., Ollevier T. Synthe-
sis of α‐Nitro‐α‐diazocarbonyl Derivatives
and Their Applications in the Cyclopro-
panation of Alkenes and in O H Insertion
Reactions. Helv. Chim. Acta. 2002. 85(12):
4468–4484.
doi.org/10.1002/hlca.200290023.
[183] Moreau B., Alberico D., Lindsay V.N., Cha-
rette A.B. Catalytic asymmetric synthesis
of nitrocyclopropane carboxylates. Tetrahe-
dron. 2012. 68(17): 3487–3496.
doi.org/10.1016/j.tet.2011.05.113.
[184] Vanier S.F., Larouche G., Wurz R.P., Charette
A.B. Formal synthesis of belactosin A and
hormaomycin via a diastereoselective intra-
molecular cyclopropanation of an α-nitro
diazoester. Org. Lett. 2010. 12(4): 672–675.
doi.org/10.1021/ol9026528.
[185] Green S.P., Wheelhouse K.M., Payne A.D. et
66 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
al. Thermal Stability and Explosive Hazard
Assessment of Diazo Compounds and Diazo
Transfer Reagents. Org. Proc. Res. Dev. 2020.
24(1:, 67−84.
DOI: 10.1055/s-0040-1719295.
[186] Zhu S., Perman J.A., Zhang X.P. Acceptor/
acceptor‐substituted diazo reagents for car-
bene transfers: cobalt‐catalyzed asymmetric
Z‐cyclopropanation of alkenes with α‐nitro-
diazoacetates. Angew. Chem. Int. Ed. 2008.
47(44): 8460–8463.
doi.org/10.1002/anie.200803857.
[187] Doyle M.P. Exceptional selectivity in cyclo-
propanation reactions catalyzed by chiral
cobalt (II) porphyrins. Angew. Chem. Int. Ed.
2009. 48(5): 850.
doi: 10.1002/anie.200804940.
[188] Xu X., Lu H., Ruppel J.V et al. Highly asym-
metric intramolecular cyclopropanation of
acceptor-substituted diazoacetates by Co
(II)-based metalloradical catalysis: iterative
approach for development of new-gene
ration catalysts. J. Am. Chem. Soc. 2011.
133(39): 15292–15295.
doi.org/10.1021/ja2062506.
[189] Han J., Wzorek A., Kwiatkowska M. et al.
The self-disproportionation of enantiomers
(SDE) of amino acids and their derivatives.
Amino Acids. 2019. 51(6): 865–889.
DOI: 10.1007/s00726-019-02729-y.
[190] Wzorek A., Klika K.D., Drabowicz J. et al.
The self-disproportionation of the enantio
mers (SDE) of methyl n-pentyl sulfoxide via
achiral, gravity-driven column chromato
graphy: a case study. Org Biomolec Chem.
2014. 12(26): 4738–4746.
DOI: 10.1039/c4ob00831f.
[191] Wzorek A., Sato A., Drabowicz J. et al. Re-
markable magnitude of the self-dispropor-
tionation of enantiomers (SDE) via achiral
chromatography: application to the prac-
tical-scale enantiopurification of β-amino
acid esters. Amino Acids. 2016. 48: 605–613.
DOI: 10.1007/s00726-015-2152-5.
[192] Yasumoto M., Ueki H., Ono T. et al. Self-Dis-
proportionation of Enantiomers via Subli-
mation: Isopropyl 3,3,3-(Trifluoro)-Lactate.
J. Fluor. Chem. 2010. 131: 535–539.
doi.org/10.1016/j.jfluchem.2009.11.026.
[193] Yasumoto M., Ueki H., Soloshonok V.A.
Self-Disproportionation of Enantiomers of
Trifluoro Lactic Acid Amides via Sublima-
tion. J. Fluor. Chem. 2010. 131: 266–269.
doi.org/10.1016/j.jfluchem.2009.10.002.
[194] Albrecht M., Soloshonok V.A., Schrader L.
et al. Chirality-dependent sublimation of
α-(trifluoromethyl)-lactic acid: Relative va-
por pressures of racemic, eutectic, and enan-
tiomerically pure forms, and vibrational
spectroscopy of isolated (S,S) and (S,R) di-
mers. J. Fluor. Chem. 2010. 131(4): 495–504.
doi.org/10.1016/j.jfluchem.2009.11.015.
[195] Feng L.W., Wang P., Wang L., Tang Y. Cop-
per (I)/SaBOX catalyzed highly diaste-
reo-and enantio-selective cyclopropanation
of cis-1,2-disubstituted olefins with α-nitro-
diazoacetates. Scien. Bull. 2015. 60: 210–215.
doi.org/10.1007/s11434-014-0708-5.
[196] Li J., Liao S.H., Xiong H. et al. Highly Diaste-
reo ‐and Enantioselective Cyclopropanation
of 1,2‐Disubstituted Alkenes. Angew. Chem.
Int. Ed. 2012. 51(35): 8838–8841.
DOI: 10.1002/anie.201203218.
[197] Yasumoto M., Ueki H., Soloshonok V.A.
Self-disproportionation of enantiomers of
α-trifluoromethyl lactic acid amides via sub-
limation. J. Fluor. Chem. 2010. 131(4): 540–
544.
doi.org/10.1016/j.jfluchem.2009.11.010.
[198] Sorochinsky A.E., Soloshonok V.A. Self-dis-
proportionation of enantiomers of enantio-
merically enriched compounds. Differentia-
tion of enantiomers II. 2013: 301–339.
doi.org/10.1007/128_2013_434.
[199] Wzorek A., Sato A., Drabowicz J. et al. Enan-
tiomeric Enrichments via the Self‐Dispro-
portionation of Enantiomers (SDE) by Achi-
ral, Gravity‐Driven Column Chromatogra-
phy: a Case Study Using N‐(1‐Phenylethyl)
acetamide for Optimizing the Enantiomeri-
67https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
cally Pure Yield and Magnitude of the SDE.
Helv. Chim. Acta. 2015. 98(8): 1147–1159.
DOI: 10.1002/hlca.201500041.
[200] Lodhi R., Prakash M., Samanta S. Diastereo
selective desymmetrization reactions of
prochiral para-quinamines with cyclopro
penes generated in situ: access to fused
hydroindol-5-one scaffolds. Org. Biomol.
Chem. 2021. 19(33): 7129−7133.
doi.org/10.1039/D1OB01322J.
[201] Müller, P. Asymmetric Transfer of Carbenes
with Phenyliodonium Ylides. Acc. Chem.
Res. 2004. 37(4): 243−251.
doi.org/10.1021/ar0202619.
[202] Wurz R.P., Charette A.B. Hypervalent Iodi
ne(III) Reagents as Safe Alternatives to α-
Nitro-α-Diazocarbonyls. Org. Lett. 2003.
5(13): 2327−2329.
doi.org/10.1021/ol034672g.
[203] Wurz R.P., Charette A.B. An expedient and
practical method for the synthesis of a di-
verse series of cyclopropane α-amino acids
and amines. J. Org. Chem. 2004. 69(4):
1262−1269.
doi.org/10.1021/jo035596y.
[204] Wurz R.P., Charette A.B. Doubly Activated
Cyclopropanes as Synthetic Precursors for
the Preparation of 4-Nitro- and 4-Cyano-Di-
hydropyrroles and Pyrroles. Org. Lett. 2005.
7(12): 2313−2316.
doi.org/10.1021/ol050442l.
[205] Moreau B., Charette A.B. Expedient synthe-
sis of cyclopropane α-amino acids by the
catalytic asymmetric cyclopropanation of
alkenes using iodonium ylides derived from
methyl nitroacetate. J. Am. Chem. Soc. 2005.
127(51): 18014–1815.
doi.org/10.1021/ja056192l.
[206] Moreau B., Alberico D., Lindsay V.N., Cha-
rette A.B. Catalytic asymmetric synthesis
of nitrocyclopropane carboxylates. Tetra
hedron. 2012. 68(17): 3487–3496.
doi.org/10.1016/j.tet.2011.05.113.
[207] Charette A.B., Wurz R. Progress towards
asymmetric intermolecular and intramole
cular cyclopropanations using α-nitro-α-di-
azo carbonyl substrates. J. Mol. Cat. A Chem.
2003. 196(1-2): 83–91. \
doi.org/10.1016/S1381-1169(02)00636-2.
[208] Han J., Wzorek A., Soloshonok V.A., Klika
K.D. The self‐disproportionation of enan-
tiomers (SDE): The effect of scaling down,
potential problems versus prospective appli-
cations, possible new occurrences, and unre-
alized opportunities?. Electrophoresis. 2019.
40(15): 1869–1880.
DOI: 10.1002/elps.201800414.
[209] Wzorek A., Sato A., Drabowicz J., Solosho-
nok V.A. Self‐disproportionation of Enanti-
omers (SDE) of Chiral Nonracemic Amides
via Achiral Chromatography. Isr. J. Chem.
2016. 56(11-12): 977–989.
DOI: 10.1002/ijch.201600077.
[210] Wzorek A., Sato A., Drabowicz J., Solosho-
nok V.A. Self-disproportionation of enan
tiomers via achiral gravity-driven column
chromatography: A case study of N-acyl-α-
phenylethylamines. J. Chrom. A. 2016. 1467:
270–278.
DOI: 10.1016/j.chroma.2016.05.044.
[211] Terada S., Hirai M., Honzawa A. et al. Pos-
sible Case of Halogen Bond‐Driven Self‐
Disproportionation of Enantiomers (SDE)
via Achiral Chromatography. Chem. Eur. J.
2017. 23(58): 14631–14638.
DOI: 10.1002/chem.201703308.
[212] Tateishi K., Tsukagoshi S., Nakamura T. et al.
Chiral initiator-induces self-disproportiona-
tion of enantiomers via achiral chromatog-
raphy: application to enantiomer separation
of racemate. Tetrahedron Lett. 2013. 54(38):
5220–5223.
DOI: 10.1016/j.tetlet.2013.07.061.
[213] Hosaka T., Imai T., Wzorek A. et al. The self-
disproportionation of enantiomers (SDE) of
α-amino acid derivatives: facets of steric and
electronic properties. Amino Acids. 2019. 51:
283–294.
doi.org/10.1007/s00726-018-2664-x.
[214] Afonso A., Hon F., Weinstein J. et al. A new
68 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
synthesis of penems, the oxalimide cycli-
zation reaction. J. Am. Chem. Soc. 1982.
104(22): 6138–6139.
doi.org/10.1021/ja00386a060.
[215] Korda A., Winiarski J. Synthesis of (3,4)
β-Methylenecepham and (3,4) β-Methylene-
carbacepham via intramolecular carbene ad-
dition to double bond. Bioorg. Med. Chem.
2003. 11(9): 1957–1967.
doi.org/10.1016/S0968-0896(03)00084-1.
[216] Merino I., Hegedus L.S. Group 6 Pyrrolocar-
bene Complexes as Alkoxycarbene Comp
lex Analogs. Organometallics. 1995. 14(5):
2522–2531.
doi.org/10.1021/om00005a058.
[217] Barluenga J., Aznar F., Gutiérrez I. et al. First
intermolecular cyclopropanation of Fischer
dialkylaminocarbene complexes. Synthesis
of 1-aminocyclopropanecarboxylic acid de-
rivatives. Org. Lett. 2002. 4(24): 4273–4276.
doi.org/10.1021/ol026896p.
[218] Alcaraz C., Fernández M.D., de Frutos M.P.
et al. Asymmetric syntheses of 1-amino-2-
phenyl (alkyl) cyclopropanecarboxylic acids
by diastereoselective cyclopropanation of
highly functionalized monochiral olefines.
Tetrahedron. 1994. 50(43): 12443–12456.
doi.org/10.1016/S0040-4020(01)89550-8.
[219] Gracia-Vitoria J., Osante I., Cativiela C. et al.
Self-regeneration of chirality with L-cysteine
through 1,3-dipolar cycloadditions between
diazoalkanes and enantiomerically pure
thiazolines: experimental and computation-
al studies. J. Org. Chem. 2018. 83(7): 3960–
3972.
doi.org/10.1021/acs.joc.8b00312.
[220] Switzer F.L., Van Halbeek H., Holt E.M. et
al. Synthesis of (±)-2,3-methanoproline:
A novel inhibitor of ethylene biosynthesis.
Tetrahedron. 1989. 45(19): 6091-6100.
doi.org/10.1016/S0040-4020(01)85122-X.
[221] Donati D., Garzon-Aburbeh A., Nata-
lini B. et al. Conformationally constrained
tryptophan analogs. Synthesis of (±)-(Z)-
and (±)-(E)-2-amino-2, 3-methano-3-(in-
dol-3-yl)-propanoic acids. Tetrahedron.
1996. 52(29): 9901–9908.
doi.org/10.1016/0040-4020(96)00522-4.
[222] Zou Y., Takeda R., Han J. et al. Asymmetric
Synthesis of N‐Fmoc‐(S)‐7‐aza‐tryptophan
via Alkylation of Chiral Nucleophilic Gly-
cine Equivalent. Eur. J. Org. Chem. 2021.
(21): 2962–2965.
DOI: 10.1002/ejoc.202100485.
[223] Han J., Lyutenko N.V., Sorochinsky A.E. et
al. Tailor‐Made Amino Acids in Pharmaceu-
tical Industry: Synthetic Approaches to Aza‐
Tryptophan Derivatives. Chem. Eur. J. 2021.
27: 17510–17528.
doi.org/10.1002/chem.202102485
[224] Monnie C.M., Hernández I., Meléndez‐Pa-
checo R. et al. Synthesis of 4,6‐Difluoro‐
Tryptophan as a Probe for Protein 19F NMR.
Adv. Syn. Cat. 2024. 366(16): 3417–3422.
doi.org/10.1002/adsc.202400031.
[225] Zhu C.L., Yang L.J., Li S. et al. Brine-stabi-
lized 2,2,2-trifluorodiazoethane and its ap-
plication in the synthesis of CF3–substituted
cyclopropane α-amino acids. Org. Lett. 2015.
17(14): 3442–3445.
doi.org/10.1021/acs.orglett.5b01450.
[226] Mikami K., Fustero S., Sánchez-Roselló M.
et al. Synthesis of fluorinated β-amino acids.
Synthesis. 2011. (19): 3045–3079.
doi: 10.1055/s-0030-1260173.
[227] Suzuki M., Gooch E.E., Stammer C.H.
A new synthesis of racemic coronamic acid
and other cyclopropyl amino acids. Tetrahe-
dron Lett. 1983. 24(36): 3839–3840.
doi.org/10.1016/S0040-4039(00)94289-8.
[228] De Kimpe N., Sulmon P., Schamp N. Syn-
thesis of 2,2-dimethyl-1-aminocyclopropa
necarboxylic acid from β-chloroimines. Tet-
rahedron Lett. 1989. 30(37): 5029–5032.
doi.org/10.1016/S0040-4039(01)80573-6.
[229] Minami T., Tokumasu S., Mimasu R., Hi-
rao I. Cycloaddition of diazomethane to
butadienylphosphonates. A new approach
to functionalized pentadienylphosphonates
and pyrazoles. Chem. Lett. 1985. 14(8):
69https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
1099–1102.
doi.org/10.1246/cl.1985.1099.
[230] Tokairin Y., Konno H., Noireau A. et al.
Asymmetric synthesis of the two enantio
mers of β-phosphorus-containing α-amino
acids via hydrophosphinylation and hydro-
phosphonylation of chiral Ni (II)-complexes.
Org. Chem. Front. 2021. 8(10): 2190–2195.
doi.org/10.1039/D1QO00159K.
[231] Röschenthaler G.V., Kukhar V.P., Kulik I.B.
et al. Convenient synthesis of fluoroalkyl α-
and β-aminophosphonates. J. Fluor. Chem.
2011. 132(10): 834–837.
doi.org/10.1016/j.jfluchem.2011.05.005.
[232] Xie C., Zhang L., Mei H. et al. New Chiral
Reagent for Installation of Pharmacophoric
(S)‐or (R)‐2‐(Alkoxyphosphono)‐1‐amino‐
2,2‐difluoroethyl Groups. Chem. Eur. J.
2016. 22(21): 7036–7040.
DOI: 10.1002/chem.201600758.
[233] Wzorek A., Han J., Lyutenko N.V. et al.
Enzymatic approaches for preparation of
α-aminophosphonic acids and fluorine-con-
taining β-amino acids. Ukr. Bioorg. Acta.
2024. 19(1): 21–32.
doi.org/10.15407/bioorganica2024.01.021.
[234] Adams L.A., Aggarwal V.K., Bonnert R.V. et
al. Diastereoselective synthesis of cyclopro-
pane amino acids using diazo compounds
generated in situ. J. Org. Chem. 2003. 68(24):
9433-9440.
doi.org/10.1021/jo035060c.
[235] Houck D., Aceña J.L., Soloshonok V.A. Alky-
lations of Chiral Nickel (II) Complexes of
Glycine under Phase‐Transfer Conditions.
Helv. Chim. Acta. 2012. 95(12): 2672–2679.
DOI: 10.1002/hlca.201200536.
[236] Zhu C., Li J., Chen P. et al. Transition-metal-
free cyclopropanation of 2-aminoacrylates
with N-tosylhydrazones: a general route to
cyclopropane α-amino acid with contiguous
quaternary carbon centers. Org. Lett. 2016.
18(6): 1470–1473.
doi.org/10.1021/acs.orglett.6b00416.
[237] Zhang W., Sha W., Pajkert R. et al. β‐Ami-
no‐γ,γ‐difluoro‐ω‐phosphonoglutamic Acid
Derivatives: An Unexplored, Multifaceted
Structural Type of Tailor‐Made α‐Amino
Acids. Eur. J. Org. Chem. 2017. 3451–3456;
DOI: 10.1002/ejoc.201700570.
[238] Kukhar V.P., Soloshonok V.A., Solodenko
V.A. Asymmetric Synthesis of Phosphorus
Analogs of Amino Acids, Phosph., Sulf., Silic.
Relat. Elem. 1994. 92: 239–264.
DOI: 10.1080/10426509408021478.
[239] Sorochinsky A.E., Soloshonok V.A. Asym-
metric synthesis of fluorine-containing
amines, amino alcohols, α-and β-amino
acids mediated by chiral sulfinyl group. J.
Fluor. Chem. 2010. 131(2): 127–139.
doi.org/10.1016/j.jfluchem.2009.09.015.
[240] Lee W.C., Wang D.S., Zhang C. et al. Asym-
metric radical cyclopropanation of dehydro-
aminocarboxylates: Stereoselective synthesis
of cyclopropyl α-amino acids. Chem. 2021.
7(6): 1588–1601.
DOI: 10.1016/j.chempr.2021.03.002.
[241] Wzorek A., Kamizela A., Sato A., Soloshonok
V.A. Self-Disproportionation of Enantiomers
(SDE) via achiral gravity-driven column
chromatography of N-fluoroacyl-1-phenyle-
thylamines. J. Fluor. Chem. 2017. 196: 37–43.
DOI: 10.1016/j.jfluchem.2016.07.016.
[242] Goto M., Tateishi K., Ebine K. et al. Chiral
additive induced self-disproportionation
of enantiomers under MPLC conditions:
preparation of enantiomerically pure samp
les of 1-(aryl) ethylamines from racemates.
Tetrahedron: Asymmetry. 2016. 27(7-8):
317–321.
DOI: 10.1016/j.tetasy.2016.03.004.
[243] Kwiatkowska M., Marcinkowska M., Wzo
rek A. et al. The self-disproportionation of
enantiomers (SDE) via column chroma-
tography of β-amino-α,α-difluorophospho
nic acid derivatives. Amino Acids. 2019. 51:
1377–1385.
DOI: 10.1007/s00726-019-02774-7.
[244] Allouche E.M., Charette A.B. Non-stabilized
diazoalkane synthesis via the oxidation of
70 ISSN 2708-129X. Укр. хім. журн., 2025
CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS:
ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY.ORGANIC CHEMISTRY
free hydrazones by iodosylbenzene and ap-
plication in in situ MIRC cyclopropanation.
Chem. Scien. 2019. 10(13): 3802–3806.
DOI: 10.1039/C8SC05558K.
[245] Takai K., Toshikawa S., Inoue A., Koku-
mai R. Stereoselective Iodocyclopropanation
of Terminal Alkenes with Iodoform, Chro-
mium (II) Chloride, and N,N,N‘,N‘-Tetra-
ethylethylenediamine. J. Am. Chem. Soc.
2003. 125(43): 12990-12991.
doi.org/10.1021/ja0373061.
[246] Concellón J.M., Rodríguez-Solla H., Méji-
ca C., Blanco E.G. Stereospecific cyclopro-
panation of highly substituted C− C double
bonds promoted by CrCl2. Stereoselective
synthesis of cyclopropanecarboxamides and
cyclopropyl ketones. Org. Lett. 2007. 9(16):
2981–2984.
doi.org/10.1021/ol070896d.
[247] Liu H.L., Wang X., Gao K., Wang Z. Cata-
lytic Diastereo‐and Enantioselective Cyclo-
propanation of gem‐Dihaloalkanes and Ter-
minal Olefins. Angew. Chem. Int. Ed. 2023.
62(28): e202305987.
doi.org/10.1002/anie.202305987.
[248] Soloshonok V.A., Klika K.D. Terminology
Related to the Phenomenon ‘Self-Dispro-
portionation of Enantiomers’ (SDE). Helv.
Chem Acta. 2014. 97: 1583–1589.
DOI: 10.1002/hlca.201400122.
[249] Soloshonok V.A., Wzorek A., Klika K.D.
A question of policy: should tests for the
self-disproportionation of enantiomers
(SDE) be mandatory for reports involving
scalemates? Tetrahedron: Asymmetry. 2017.
28: 1430–1434.
DOI: 10.1016/j.tetasy.2017.08.020.
[250] Sorochinsky A.E., Katagiri T., Ono T. et al.
Optical purifications via Self-Disproportio
nation of Enantiomers by achiral chromato
graphy; Case study of a series of α-CF3-con-
taining secondary alcohols. Chirality. 2013.
25: 365–368.
DOI: 10.1002/chir.22180.
[251] Zhou R., Deng X., Zheng J. et al. Stereose-
lective Synthesis of 1‐Aminocyclopropane-
carboxylic Acid Derivatives via Ylide Cyclo-
propanation of Dehydroamino Acid Deriva-
tives. Chin. J. Chem. 2011. 29(5): 995–1000.
doi.org/10.1002/cjoc.201190202.
[252] Papageorgiou C.D., Cubillo de Dios M.A.,
Ley S.V., Gaunt M.J. Enantioselective or-
ganocatalytic cyclopropanation via ammo-
nium ylides. Angew. Chem. Int. Ed. 2004.
43(35): 4641–4644.
DOI: 10.1002/anie.200460234.
[253] Li J.P., Zhao G.F., Wang H.X. et al. Highly
enantioselective synthesis of chiral cyclo-
propyl nucleosides via catalytic asymmetric
intermolecular cyclopropanation. Org Lett.
2017. 19(24): 6494–6497.
doi.org/10.1021/acs.orglett.7b03110.
[254] Han J., Kitagawa O., Wzorek A. et al. The
self-disproportionation of enantiomers
(SDE): a menace or an opportunity? Chem.
Scien. 2018. 9(7): 1718–1739.
DOI: 10.1039/C7SC05138G.
[255] Ivashkin P., Couve-Bonnaire S., Jubault P.,
Pannecoucke X. Asymmetric Synthesis of
Cyclopropanes with a Monofluorinated
Quaternary Stereocenter. Org Lett. 2012.
14(19): 5130–5133.
doi.org/10.1021/ol3024264.
[256] Sorochinsky A., Voloshin N., Markovsky A.
et al. Convenient asymmetric synthesis of
β-substituted α,α-difluoro-β-amino acids
via Reformatsky reaction between Davis’
N-Sulfinylimines and ethyl bromodifluoro-
acetate. J. Org. Chem. 2003. 68(19): 7448–
7454.
doi.org/10.1021/jo030082k.
[257] Soloshonok V.A., Ueki H., Tiwari R. et al.
Virtually complete control of simple and
face diastereoselectivity in the Michael ad-
dition reactions between achiral equivalents
of a nucleophilic glycine and (S)-or (R)-3-
(E-enoyl)-4-phenyl-1, 3-oxazolidin-2-ones:
practical method for preparation of β-sub-
stituted pyroglutamic acids and prolines. J.
Org. Chem. 2004. 69(15): 4984–4990.
71https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok. UCJ № 10 / Vol. 91
doi.org/10.1021/jo0495438.
[258] Soloshonok V.A., Cai C., Hruby V.J. (S)-or
(R)-3-(E-Enoyl)-4-phenyl-1, 3-oxazolidin-
2-ones: ideal Michael acceptors to afford a
virtually complete control of simple and face
diastereoselectivity in addition reactions
with glycine derivatives. Org. Lett. 2000.
2(6): 747–750.
doi.org/10.1021/ol990402f.
[259] Soloshonok V.A., Cai C., Yamada T. et al.
Michael addition reactions between chiral
equivalents of a nucleophilic glycine and (S)-
or (R)-3-[(E)-enoyl]-4-phenyl-1, 3-oxazoli-
din-2-ones as a general method for efficient
preparation of β-substituted pyroglutamic
acids. Case of topographically controlled
stereoselectivity. J. Am. Chem. Soc. 2005.
127(43): 15296-15303.
doi.org/10.1021/ja0535561.
[260] Guo T., Zhang L., Liu X. et al. Visible‐Light‐
Promoted Redox‐Neutral Cyclopropanation
Reactions of α‐Substituted Vinylphospho-
nates and Other Michael Acceptors with
Chloromethyl Silicate as Methylene Transfer
Reagent. Adv. Syn. Cat. 2018. 360(23): 4459–
4463. doi.org/10.1002/adsc.201800761.
[261] Phelan J.P., Lang S.B., Compton J.S. et al.
Redox-neutral photocatalytic cyclopropa
nation via radical/polar crossover. J. Am.
Chem. Soc. 2018. 140(25): 8037–8047.
doi.org/10.1021/jacs.8b05243.
[262] Liu M., Ouyang X., Xuan C., Shu C. Advanc-
es in photoinduced radical–polar crossover
cyclization (RPCC) of bifunctional alkenes.
Org. Chem. Front. 2024. 11(3): 895–915.
doi.org/10.1039/D3QO01929B.
[263] Teye‐Kau J.H., Ayodele M.J,. Pitre S.P. Vita-
min B12‐Photocatalyzed Cyclopropanation
of Electron‐Deficient Alkenes Using Dichlo-
romethane as the Methylene Source. Angew.
Chem. Int. Ed. 2024. 63(2): e202316064.
doi.org/10.1002/anie.202316064.
[264] Marek W.K., Lee J.W., Seidel-Morgenstern A.,
Antos D. Separation of nonracemic mixtures
of enantiomers by achiral simulated moving
bed chromatography. Separation and Purifi-
cation Technology. 2025. 361: 131497.
doi.org/10.1016/j.seppur.2025.131497.
[265] Ueki H., Yasumoto M., Soloshonok V.A. Ra-
tional application of self-disproportionation
of enantiomers via sublimation—a novel
methodological dimension for enantiome
ric purifications. Tetrahedron: Asymmetry.
2010. 21: 1396–1400.
doi.org/10.1016/j.tetasy.2010.04.040.
[266] Han J., Wzorek A., Klika K.D., Soloshonok
V.A. Recommended Tests for the Self-Dis-
proportionation of Enantiomers (SDE) to
Ensure Accurate Reporting of the Stereo-
chemical Outcome of Enantioselective Re-
actions. Molecules 2021. 26: 2757.
doi.org/10.3390/molecules26092757.
[267] Han J., Dembinski R., Soloshonok V.A., Kli-
ka K.D. A Call for a Change in Policy Re-
garding the Necessity for SDE Tests to Va
lidate the Veracity of the Outcome of Enan-
tioselective Syntheses, the Inherent Chiral
State of Natural Products, and Other Cases
Involving Enantioenriched Samples. Mole-
cules. 2021. 26: 3994.
doi.org/10.3390/molecules26133994.
[268] De Camp W.H. Chiral drugs: the FDA per-
spective on manufacturing and control.
J. Phar. Biomed. Anal. 1993. 11(11-12):
1167–1172.
doi.org/10.1016/0731-7085(93)80100-F.
[269] Daniels J.M., Nestmann E.R., Kerr A. Deve
lopment of stereoisomers (chiral) drugs:
A brief review of scientific and regulatory
considerations. Drug Infor. J. 1997. 31: 639–
646.
doi.org/10.1177/009286159703100303.
[270] Ceramella J., Iacopetta D., Franchini A. et al.
A look at the importance of chirality in drug
activity: Some significative examples. App.
Scien. 2022. 12(21): 10909.
doi.org/10.3390/app122110909.
Стаття надійшла 05.05.2025.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-754 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:13:52Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/26/49188c95acd272b1cd01a089786de626.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7542026-07-22T08:23:56Z CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim Amino Acids, Pharmaceuticals, Cyclopropane, Chirality, Synthesis, Nucleophilic Glycine Equivalents, Carbenoid Glycine Equivalents, Dehydroamino Acids, Self-Disproportionation of Enantiomers (SDE). α-Aminocyclopropanecarboxylic acid (ACC) and its derivatives are widely distributed in the plant kingdom, fulfilling diverse roles ranging from regulation of plant life cycles to defensive mechanisms. The sterically constrained structure of ACC has proven invaluable in the design of numerous drugs, particularly hepatitis C virus (HCV) NS3/4A protease inhibitors. Indeed, ACC has been instrumental in the development of multiple generations of potent HCV treatments, with ongoing efforts focused on further improvements and refinements. The inherent steric constraints of these derivatives present a significant challenge for their synthesis, especially in enantiomerically pure form. This article provides a comprehensive overview of synthetic methodologies reported in the literature for the preparation of ACC and its derivatives. The synthetic strategies discussed herein are organized based on key transformations, including dialkylation of nucleophilic glycine equivalents, cyclopropanation of carbenoid glycine equivalents, and addition reactions to dehydroamino acids. Particular emphasis is placed on asymmetric approaches that enable the preparation of these tailor-made amino acids in enantiomerically pure form. Furthermore, aspects of Self-Disproportionation of Enantiomers (SDE) relevant to enantioselective catalysis are highlighted. By compiling these methodologies, we aim to provide a comprehensive resource and a source of inspiration for researchers in synthetic and medicinal chemistry, as well as drug discovery. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-11-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/754 10.33609/2708-129X.91.10.2025.27-71 Ukrainian Chemistry Journal; Vol. 91 No. 10 (2025): Ukrainian Chemistry Journal; 27-71 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 10 (2025): Ukrainian Chemistry Journal; 27-71 Український хімічний журнал; Том 91 № 10 (2025): Ukrainian Chemistry Journal; 27-71 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/754/389 Copyright (c) 2025 Alicja Wzorek, Jianlin Han, Taizo Ono, Karel Klika, Daniel Baecker, Wei Zhang, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title | CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title_full | CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title_fullStr | CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title_full_unstemmed | CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title_short | CUTTING-EDGE STRATEGIES IN THE ASYMMETRIC SYNTHESIS OF α-AMINOCYCLOPROPANE CARBOXYLIC ACIDS: ESSENTIAL SCAFFOLDS FOR DRUG DISCOVERY(Review) |
| title_sort | cutting-edge strategies in the asymmetric synthesis of α-aminocyclopropane carboxylic acids: essential scaffolds for drug discovery(review) |
| topic_facet | Amino Acids Pharmaceuticals Cyclopropane Chirality Synthesis Nucleophilic Glycine Equivalents Carbenoid Glycine Equivalents Dehydroamino Acids Self-Disproportionation of Enantiomers (SDE). |
| url | https://ucj.org.ua/index.php/journal/article/view/754 |
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