HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review)
This article reviews the development of the asymmetric synthesis of tailor-made amino acids conducted at Hamari Chemicals during the 10-year period 2013–2022.The discussion is based on strategies such as direct chiral modification of unprotected amino acids via intermediate formation of Ni(II) compl...
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| author | Han, Jianlin Liu, Hong Wang, Jiang Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Moriwaki, Hiroki Sato, Tatsunori Kunisuke , Izawa Konno, Hiroyuki Soloshonok, Vadim |
| author_facet | Han, Jianlin Liu, Hong Wang, Jiang Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Moriwaki, Hiroki Sato, Tatsunori Kunisuke , Izawa Konno, Hiroyuki Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"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": "Hong Liu",
"institution": "State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"
},
{
"author": "Jiang Wang",
"institution": "State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"
},
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Alexander Sorochinsky",
"institution": "Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences of Ukraine, 1 Murmanska str., Kyiv 02094, Ukraine"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Hiroki Moriwaki",
"institution": "Hamari Chemical Ltd., Osaka, Japan"
},
{
"author": "Tatsunori Sato",
"institution": "Hamari Chemical Ltd., Osaka, Japan"
},
{
"author": "Izawa Kunisuke ",
"institution": "Hamari Chemical Ltd., Osaka, Japan"
},
{
"author": "Hiroyuki Konno",
"institution": "Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, 992-8510 Yonezawa, Yamagata, Japan"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Han, Jianlin |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:55Z |
| description | This article reviews the development of the asymmetric synthesis of tailor-made amino acids conducted at Hamari Chemicals during the 10-year period 2013–2022.The discussion is based on strategies such as direct chiral modification of unprotected amino acids via intermediate formation of Ni(II) complexes and elaboration of chiral nucleophilic or electrophilic glycine equivalents. The former approach includes, for example, second-order asymmetric transformation, dynamic kinetic resolution, and inversion of chirality while the latter approach involves construction of the desired amino acid architecture using, for example, alkylation, aldol, Mannich, or Michael addition reactions as well as multistep procedures. Operational convenience, scalability, and practicality of the developed methods are emphasized. |
| doi_str_mv | 10.33609/2708-129X.90.10.2024.88-134 |
| first_indexed | 2025-09-24T17:43:58Z |
| format | Article |
| fulltext |
88 ISSN 2708-129X. Укр. хім. журн., 2024
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.90.10.2024.88-134
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS
OF TAILOR-MADE AMINO ACIDS.
Jianlin Han1*, Hong Liu2, Jiang Wang2*, Alicja Wzorek3, Alexander E. Sorochinsky4*,
Karel D. Klika5, Taizo Ono6, Hiroki Moriwaki7*, Tatsunori Sato7, Kunisuke Izawa7,
Hiroyuki Konno8*, Vadim A. Soloshonok9,10*
1Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of
Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai 201203, China;
3 Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25–406 Kielce, Poland;
4 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences
of Ukraine, Kyiv 02094, Ukraine;
5 Molecular Structure Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280,
69120 Heidelberg, Germany;
6 National Institute of Advanced Industrial Science and Technology, 463–8560, Nagoya, Japan.
7 Hamari Chemical Ltd., Osaka, Japan;
8 Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering,
Yamagata University, 992–8510 Yonezawa, Yamagata, Japan;
9 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/
EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain;
10 IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao,
Spain
email: vadimsoloshonok@gmail.com
This article reviews the development of the asymmetric synthesis of tailor-made amino
acids conducted at Hamari Chemicals during the 10-year period 2013–2022.The discussion
is based on strategies such as direct chiral modification of unprotected amino acids via inter-
mediate formation of Ni(II) complexes and elaboration of chiral nucleophilic or electrophilic
glycine equivalents. The former approach includes, for example, second-order asymmetric
transformation, dynamic kinetic resolution, and inversion of chirality while the latter ap-
proach involves construction of the desired amino acid architecture using, for example, alky-
lation, aldol, Mannich, or Michael addition reactions as well as multistep procedures. Oper-
ational convenience, scalability, and practicality of the developed methods are emphasized.
Keywords: tailor-made amino acids; drug design and development; second-order asym-
metric transformation; dynamic kinetic resolution; inversion of chirality.
89https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
extensive structural diversity of AAs, workers have used several classifications. These include
distinctions such as proteinogenic vs. non-proteinogenic, genetically coded vs. non-coded, natural vs.
synthetic, common vs. uncommon, and usual vs. unusual. These terms are frequently used in the
literature [34] and while these definitions provide some sense of structural identity, they can be
somewhat ambiguous and perplexing. In this article, we have chosen to use the term ‘tailor-made
AAs’, a definition proposed by Hruby et al. [35]. This term emphasizes the intended purpose of the
AAs rather than their assumed origin or perceived distinction.
Beyond fundamental scientific investigation, the primary objective of medicinal chemistry
research in the realm of tailor-made AAs is to engineer more selective and efficacious
pharmaceuticals. From a structural perspective, AAs exemplify a form of molecular dichotomy,
facilitating the step-by-step synthesis of polymers with unique, non-repeating sequences of
monomers. These polymers, known as peptides for short length chains and proteins for longer chains,
perform numerous vital roles in living organisms, including catalysis (enzymes), signaling
(hormones), and mechano-structural functions [36–38]. In the context of contemporary drug
discovery paradigms, tailor-made AAs are essential components with their derivatives increasingly
appearing in newly marketed pharmaceuticals [39–45]. In fact, over 30% of smallmolecule drugs
contain residues of tailor-made AAs or their derivatives, such as amino-alcohols and di-amines
[46–60].
The asymmetric synthesis of AAs is a well-established field that provides a plethora of varied
methodologies [17–33]. However, the challenges of cost-effectiveness, operational ease, and
environmental impact continue to evolve necessitating corresponding advancements in synthetic
techniques. A review of the literature reveals that the synthesis of both general and tailor-made AAs
via Ni(II) complex intermediates, as shown in Scheme 1, has emerged as the most prevalent and
methodologically superior approach [61–65].
Scheme 1. General concept of the preparation of tailor-made AAs in enantiomerically pure form via
intermediate Ni(II) complex formation.
A particularly attractive feature of this methodology is its practicality for the large-scale
preparations of pharmacologically important AAs. At the outset, we envisioned two general strategic
approaches:1. direct chiral modification of unprotected AAs by way of means such as second-order
asymmetric transformation (SOAT), dynamic kinetic resolution (DKR), or inversion of chirality; and
2. elaboration of chiral nucleophilic/electrophilic glycine equivalents, which involves constructing
the desired AA architecture starting from glycine using, for example, alkylation, aldol, Mannich, or
Michael addition reactions as well as multistep procedures. Both approaches have their advantages
and shortcomings which will be noted in the following sections for the particular subsets of the
strategies described herein.
INTRODUCTION. Amino acids (AAs) are
a fundamental class of compounds that are in-
trinsically linked to the origin and evolution of
all recognized life forms. Since their structural
elucidation in the early 19th Century, AAs have
maintained a crucial role in advancing vari-
ous fields of health sciences and technology
[1]. A myriad of AAs have been obtained from
natural sources [2–16] while synthetic variants
have been engineered in research laboratories
[17–33]. To manage the extensive structural
diversity of AAs, workers have used several
classifications. These include distinctions such
as proteinogenic vs. non-proteinogenic, ge-
netically coded vs. non-coded, natural vs. syn-
thetic, common vs. uncommon, and usual vs.
unusual. These terms are frequently used in the
literature [34] and while these definitions pro-
vide some sense of structural identity, they can
be somewhat ambiguous and perplexing. In
this article, we have chosen to use the term ‘tai-
lor-made AAs’, a definition proposed by Hruby
et al. [35]. This term emphasizes the intended
purpose of the AAs rather than their assumed
origin or perceived distinction.
Beyond fundamental scientific investigation,
the primary objective of medicinal chemistry
research in the realm of tailor-made AAs is to
engineer more selective and efficacious phar-
maceuticals. From a structural perspective,
AAs exemplify a form of molecular dichotomy,
facilitating the step-by-step synthesis of poly-
mers with unique, non-repeating sequences of
monomers. These polymers, known as peptides
for short length chains and proteins for longer
chains, perform numerous vital roles in living
organisms, including catalysis (enzymes), sig-
naling (hormones), and mechano-structural
functions [36–38]. In the context of contem-
porary drug discovery paradigms, tailor-made
AAs are essential components with their deriv-
atives increasingly appearing in newly marke
ted pharmaceuticals [39–45]. In fact, over 30%
of small molecule drugs contain residues of tai-
lor-made AAs or their derivatives, such as ami-
no-alcohols and di-amines [46–60].
The asymmetric synthesis of AAs is a
well-established field that provides a plethora
of varied methodologies [17–33]. However, the
challenges of cost-effectiveness, operational
ease, and environmental impact continue to
evolve necessitating corresponding advance-
ments in synthetic techniques. A review of
the literature reveals that the synthesis of both
general and tailor-made AAs via Ni(II) comp
lex intermediates, as shown in Scheme 1, has
emerged as the most prevalent and methodo-
logically superior approach [61–65].
Scheme 1. General concept of
the preparation of tailor-made AAs
in enantiomerically pure form via
intermediate Ni(II) complex for-
mation.
90 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
A particularly attractive feature of this me
thodology is its practicality for the large-scale
preparations of pharmacologically important
AAs. At the outset, we envisioned two general
strategic approaches: 1. direct chiral modifica-
tion of unprotected AAs by way of means such
as second-order asymmetric transformation
(SOAT), dynamic kinetic resolution (DKR),
or inversion of chirality; and 2. elaboration of
chiral nucleophilic/electrophilic glycine equi
valents, which involves constructing the de-
sired AA architecture starting from glycine us-
ing, for example, alkylation, aldol, Mannich, or
Michael addition reactions as well as multistep
procedures. Both approaches have their advan-
tages and shortcomings which will be noted in
the following sections for the particular sub-
sets of the strategies described herein.
Chiral tridentate ligands.
Hamari ligand.
From the standpoint of recyclability, hav-
ing a recoverable source of asymmetric infor-
mation of “indestructible” chirality is of great
interest. Among obvious candidates possessing
stable chirality, we considered (3Z,5Z)-2,7-di-
hydro-1H-azepine-derived axially chiral tri
dentate ligand – the Hamari ligand – 13 (Sche
me 2) [66] as a potential system.
Chiral tridentate ligands.
Hamari ligand.
From the standpoint of recyclability, having a recoverable source of asymmetric information
of “indestructible” chirality is of great interest. Among obvious candidates possessing stable chirality,
we considered (3Z, 5Z)-2,7-dihydro-1H-azepine-derived axially chiral tridentate ligand – the Hamari
ligand – 13 (Scheme 2) [66] as a potential system.
Scheme 2. Synthesis of Hamari ligand 13.
Commercially available enantiomerically pure binaphthol 5 was converted to dimethyl
compound 7 via intermediate ditriflate 6 using Kumadacoupling of 6 with a Grignard reagent.
Subsequentbromination of 7 with 1,3-dibromo-5,5-dimethylhydantoin in ethyl acetate afforded
dibromide 8. This procedure reliably afforded key compound 8 in 71% yield.
Taking advantage of the previously developed strategy of modular approach to the design of
chiral tridentate ligands [67–69], weenvisionedthe use of modules 11 and 12 for assembly of Hamari
ligand 13. Formation of the requisite azepine 9 by dialkylationof allyl amine [70] with dibromide 8
and subsequent removal of the allyl group to provide secondary amine 10 was accomplishedin
moderate yield. Alkylation of 10 with aminobenzophenone module 11 proceeded quantitatively
affording Hamari ligand 13 after three steps in atotal yield of 57%. The procedurewas found to have
somedisadvantages, though, notably being a multistep reaction sequence and thenecessity for silica
gel column purification, thus rendering thisapproach less attractive for large-scale manufacturing.The
alternative solution, with application of module 12, turned out to be significantly more attractive. The
procedure was carefully optimized and was able to be reproduced on a 500 g scale.
Soloshonok – Liu ligand.
Scheme 2. Synthesis of Hamari ligand 13.
91https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Commercially available enantiomerically
pure binaphthol 5 was converted to dimethyl
compound 7 via intermediate ditriflate 6 using
Kumada coupling of 6 with a Grignard rea-
gent. Subsequent bromination of 7 with 1,3-di-
bromo-5,5-dimethylhydantoin in ethyl acetate
afforded dibromide 8. This procedure reliably
afforded key compound 8 in 71% yield.
Taking advantage of the previously deve
loped strategy of modular approach to the
design of chiral tridentate ligands [67–69], we
envisioned the use of modules 11 and 12 for
assembly of Hamari ligand 13. Formation of
the requisite azepine 9 by dialkylationof allyl
amine [70] with dibromide 8 and subsequent
removal of the allyl group to provide secondary
amine 10 was accomplished in moderate yield.
Alkylation of 10 with aminobenzophenone
module 11 proceeded quantitatively affording
Hamari ligand 13 after three steps in atotal
yield of 57%. The procedure was found to have
some disadvantages, though, notably being a
multistep reaction sequence and the necessity
for silica gel column purification, thus render-
ing this approach less attractive for large-scale
manufacturing.The alternative solution, with
application of module 12, turned out to be sig-
nificantly more attractive. The procedure was
carefully optimized and was able to be repro-
duced on a 500 g scale.
Soloshonok–Liu ligand.
The proline-derived ligand 14 (Scheme
3) – the Soloshonok–Liu ligand – bearing
three chlorine atoms in strategic positions
was developed in a collaboration between the
laboratories of Prof.s Soloshonok and Liu in
2014 [71,72]. It’s phenomenal success for the
asymmetric synthesis of tailor-made AAs can
be attributed to its very high stereochemical
preference. The strategic positioning of the
three chlorine atoms in 14 were rationally de-
duced based on critical analysis of numerous
crystallographic structures of the correspond-
ing Ni(II) complexes of various types of AAs
[73]. In particular, the aromatic stacking, par-
allel-displaced type of interactions between the
o-aminobenzophenone and the Pro-N-benzyl
rings was found to be of primary importance
in shaping the spatial arrangements of the cor-
responding Ni(II) complexes. The influence
of these aromatic interactions is very sensitive
to the position and nature of the substituents,
thereby determining the degree of parallel ori-
entation of the interacting aromatic rings [73].
A large-scale synthesis of ligand 14 has been
developed by Hamari [74].
The challenges of selectively alkylating a
zwitterionic substance, such as proline 15,
are 3-fold: first, selective alkylation on nitro-
gen; second, forming the zwitterionic product
under appropriate pH conditions; and third,
separating and isolating the product from the
large amount of potassium chloride formed in
the reaction. A thorough examination of vari
ous conditions allowed us to determine that
isopropanol using 85% potassium hydroxide
pellets as the baseis an ideal system for the
N-benzylation of proline 15 with benzyl chlo-
ride 16. Upon completion of the alkylation
reaction, the addition of concentrated HCl
causes precipitation of KCl from the solution,
simplifying the isolation and purification of
the product 17 in greater than 90% yield. Simi-
lar to the previous step, the zwitterionic nature
of 17 significantly complicates the activation
of the carboxylic acid and subsequent amide
formation. Furthermore, aromatic amine 18 is
considerably electron deficient and requires a
highly activated electrophile to effect reaction.
92 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
The proline-derived ligand 14 (Scheme 3) – the Soloshonok – Liu ligand – bearing three
chlorine atoms in strategic positions was developed in a collaboration between the laboratories of
Prof.s Soloshonok and Liu in 2014 [71,72]. It’s phenomenal success for the asymmetric synthesis of
tailor-made AAs can be attributed toitsvery high stereochemical preference. The strategic positioning
of the three chlorine atoms in 14 were rationally deduced based on critical analysis of numerous
crystallographic structures of the corresponding Ni(II) complexes of various types of AAs [73]. In
particular, the aromatic stacking, parallel-displaced type ofinteractions between the
o-aminobenzophenone and the Pro-N-benzyl rings was found to be of primary importance inshaping
the spatial arrangements of the corresponding Ni(II) complexes.The influence of these aromatic
interactions is very sensitive to the position and nature of the substituents, thereby determining the
degree of parallel orientation of the interacting aromaticrings [73]. A large-scale synthesis of ligand
14 has been developed by Hamari [74].
Scheme 3. Synthesis of the Soloshonok – Liu ligand 14.
The challenges of selectively alkylating a zwitterionicsubstance, such as proline 15, are 3-fold:
first, selective alkylation on nitrogen; second, forming the zwitterionicproduct under appropriate pH
conditions; and third, separating and isolating the product from the large amount ofpotassium
chloride formed in the reaction.A thorough examination of various conditions allowed us to
determine that isopropanol using 85% potassium hydroxide pellets as the baseis an ideal system for
the N-benzylationof proline 15 with benzyl chloride 16. Upon completion of the alkylation reaction,
the addition of concentrated HCl causes precipitation of KCl from the solution, simplifying the
isolation and purificationof the product 17 in greater than 90% yield. Similar to the previous step, the
zwitterionic nature of 17 significantly complicates the activation of the carboxylic acid and
subsequent amide formation. Furthermore, aromatic amine 18 is considerably electrondeficient and
requires a highly activated electrophile to effect reaction. Previously, we reported [75,76] the use of
methanesulfonyl chloride and 1-methylimidazole/DMAP to form the acid chloride/mixed anhydride,
but the process proved to be problematic upon scalingup the reaction. Even though proline has a low
intrinsic tendency for epimerization [77], we focusedon finding asingle reagent that would serve to
activate the carboxylic acidwithout the addition of base. After an extensivesearch for reaction
Previously, we reported [75,76] the use of
methanesulfonyl chloride and 1-methylimida-
zole/DMAP to form the acid chloride/mixed
anhydride, but the process proved to be prob-
lematic upon scaling up the reaction. Even
though proline has a low intrinsic tendency for
epimerization [77], we focused on finding as-
ingle reagent that would serve to activate the
carboxylic acidwithout the addition of base.
After an extensive search for reaction condi-
tions utilizing thionyl chloride orphosphorus
(V) chloride, we settled on the latter reagent
as it gave more consistent and reproducible re-
sults. Initial experiment susing dichlorometh-
ane as the solvent showed that wecould in-
deed prepare the desired product 14 using one
equivalent of PCl5 without the addition of base.
Once again, this process allowed isolation
of ligand 14 via simple filtration in over 80%
yield. Our next goal was to establish a meth-
od for the satisfactory preparation of Ni(II)
complex 19 on an industrial scale. The major
finding of our work was the application of the
relatively strong, but hindered, base 1,8-diaz-
abicyclo-[5.4.0]-undec-7-ene (DBU) which
met two important criteria, viz. chiral integrity
of the product and simplicity of isolation. In
particular, upon completion of the reaction,
the addition of aqueous acetic acid simulta-
neously neutralizes the reaction mixture and
causes precipitation of the enantiomerically
pure product 19 in near-quantitative yield and
in high purity. This procedure offered a prac-
tical advancement of the synthesis of Ni(II)
complexes (S)- and (R)-19 from bench scale to
multikilogram scale [78].
Scheme 3. Synthesis of the Soloshonok–Liu ligand 14.
93https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
conditions utilizing thionyl chloride orphosphorus (V) chloride, we settled on the latter reagent as
itgave more consistent and reproducible results. Initial experimentsusing dichloromethane as the
solvent showed that wecould indeed prepare the desired product 14 using oneequivalent of PCl5
without the addition of base. Once again, this process allowed isolation of ligand 14 via simple
filtration in over 80% yield. Our next goal was to establish a method for the satisfactory preparation
of Ni(II) complex 19 on an industrial scale. The major finding of our work was the application of the
relatively strong, but hindered, base 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) which met two
important criteria, viz. chiral integrity of the product and simplicity of isolation. In particular, upon
completion of the reaction, the addition of aqueous acetic acid simultaneously neutralizes the reaction
mixture and causes precipitation of the enantiomerically pure product 19 in near-quantitative yield
and in high purity. This procedure offered a practical advancement of the synthesis of Ni(II)
complexes (S)- and (R)-19 from bench scale to multikilogram scale [78].
Fig. 1. Structures of novel axial chiral and Nchiral (*) metal (II) complexes.
Our work on chiral HPLC resolution and the kinetics of racemization of various novel Ni(II)
complexes was conducted in collaboration with the group of Prof. Christian Roussel. In particular, we
successfully developed innovative structural models of Ni(II) complexes of type 20 (Figure 1) to
probe and quantify the rotational barriers about the Ar–Cq bond of the benzophenone moiety. We
demonstrated that axially chiral ortho‐fluoro derivatives 20 are configurationally unstable due to
relatively unhindered rotation about the Ar–Cqbond. By contrast, the configuration of
theortho‐chloro‐substituted analogs 20 are effectively indefinitely stable under ambient conditions
(t½ from 4 to 216 centuries) [79]. In another study, we described the design of a model Ni(II) complex
of a glycine Schiff base possessing a nitrogen stereogenic center 21. Measurement of its
configurational stability using HPLC revealed that the configurational stability of the
Ni(II)-coordinated nitrogen depends heavily on the solvent, ranging from very unstable in polar
solvents with t½s < 5 minutes to highly stable in apolar solvents with t½s of the order ofa century [80].
We also investigated configurational stability of a series of Nchiral complexes 22 as a function of the
substituents as well as the nature of coordinating metal(II). In general, electron-withdrawing
substituents led to decreased configurational stability. With respect to the coordinating metal, the
configurational stability was found to increase from Cu to Ni with Pd complexes the most stable
witht½s of 1.25 minutes, 7 hours, and 10 hours, respectively [81]. The data is of great of theoretical
and synthetic value suggesting avenues for the rational design of a new generation of complexes for
the asymmetric synthesis of tailor‐made α‐AAs [82].
Fig. 1. Structures of novel axial chiral and N chiral (*) metal (II) complexes.
Our work on chiral HPLC resolution and
the kinetics of racemization of various novel
Ni(II) complexes was conducted in collabora-
tion with the group of Prof. Christian Roussel.
In particular, we successfully developed inno-
vative structural models of Ni(II) complexes of
type 20 (Figure 1) to probe and quantify the
rotational barriers about the Ar–Cq bond of
the benzophenone moiety. We demonstrated
that axially chiral ortho‐fluoro derivatives 20
are configurationally unstable due to relative-
ly unhindered rotation about the Ar–Cqbond.
By contrast, the configuration of the ortho‐
chloro‐substituted analogs 20 are effectively
indefinitely stable under ambient conditions
(t½ from 4 to 216 centuries) [79]. In anoth-
er study, we described the design of a model
Ni(II) complex of a glycine Schiff base pos-
sessing a nitrogen stereogenic center 21. Meas-
urement of its configurational stability using
HPLC revealed that the configurational stabil-
ity of the Ni(II)-coordinated nitrogen depends
heavily on the solvent, ranging from very un-
stable in polar solvents with t½s < 5 minutes to
highly stable in apolar solvents with t½s of the
order of a century [80]. We also investigated
configurational stability of a series of N chiral
complexes 22 as a function of the substituents
as well as the nature of coordinating metal(II).
In general, electron-withdrawing substituents
led to decreased configurational stability. With
respect to the coordinating metal, the configu
rational stability was found to increase from
Cu to Ni with Pd complexes the most stable
with t½s of 1.25 minutes, 7 hours, and 10 hours,
respectively [81]. The data is of great of theo-
retical and synthetic value suggesting avenues
for the rational design of a new generation of
complexes for the asymmetric synthesis of tai-
lor‐made α‐AAs [82].
Direct chiral modification of unprotected AAs.
SOAT.
SOAT is defined as a crystallization-in-
duced asymmetric transformation during
which the racemic mixture is converted into a
pure, less-soluble diastereomer [83–89]. This
approach has tremendous practical appeal for
large-scale synthesis as the target product can
be isolated and purified simply by filtration.
However, the major challenge associated with
SOAT is that diastereomers usually do not show
such dramatically distinct differences in pro
perties such as crystallinity and solubility and
94 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Direct chiral modification of unprotected AAs.
SOAT
SOAT is defined as a crystallization-induced asymmetric transformation during which the
racemic mixture is converted into a pure, less-soluble diastereomer [83–89]. This approach has
tremendous practical appeal for large-scale synthesis as the target product can be isolated and purified
simply by filtration. However, the major challenge associated with SOAT is that diastereomersusually
do not show such dramatically distinct differences in properties such as crystallinity and solubility
and furthermore, which, for organic compounds at least, are rather unpredictable.
Rimantadine (24) (Scheme 4) was approved for medical use in 1993 as an orally administered
antiviral drug. It is the most clinically advanced compound among adamantane-based
chemotherapeutics developed for viral infections including influenza A, herpes simplex, hepatitis C,
and HIV [90–92]. It is relatively inexpensive and readily commercially available as a racemate as
well as in both enantiomeric forms [93–96].
Scheme 4. Synthesis and application of adamantyl-containing ligand 25 for the preparation of enantiomerically
pure, tailor-made-AAs via SOAT.
The therapeutic success of Rimantadine (24) is attributed to the presence of the adamantyl
moiety – dubbed a “lipophilic bullet” – providing its derivatives with exceptional lipophilicity
allowing them to penetrate lipophilic domains, including the blood–brainbarrier [97]. Taking into
account the unique lipophilicity of adamantane, we assumed that this group can be used to modify the
physicochemical properties of the corresponding Ni(II) complexes to conduct SOAT-controlled
preparation of diastereomerically pure products. Drawing on previous experience with various N–H
type ligands [98, 99], we designed and prepared adamantly-containing ligand 25 as presented in
Scheme 4 [100]. Amide bond formation between benzophenone 18 and bromoacetyl bromide was
accomplished cleanly in acetonitrile in the presence of K2CO3 to obtain 23 in quantitative yield. The
subsequent alkylation of (S)-24 with 23 was conducted using K2CO3 giving rise to ligand (S)-25in >
95% yield.
furthermore, which, for organic compounds at
least, are rather unpredictable.
Rimantadine (24) (Scheme 4) was approved
for medical use in 1993 as an orally adminis-
tered antiviral drug. It is the most clinically ad-
vanced compound among adamantane-based
chemotherapeutics developed for viral infec-
tions including influenza A, herpes simplex,
hepatitis C, and HIV [90–92]. It is relatively in-
expensive and readily commercially available
as a racemate as well as in both enantiomeric
forms [93–96].
Scheme 4. Synthesis and application of adamantyl-containing ligand 25 for the preparation
of enantiomerically pure, tailor-made-AAs via SOAT.
The therapeutic success of Rimantadine (24)
is attributed to the presence of the adamantyl
moiety – dubbed a “lipophilic bullet” – provid-
ing its derivatives with exceptional lipophilicity
allowing them to penetrate lipophilic domains,
including the blood–brainbarrier [97]. Taking
into account the unique lipophilicity of adaman-
tane, we assumed that this group can be used
to modify the physicochemical properties of
the corresponding Ni(II) complexes to conduct
SOAT-controlled preparation of diastereomeri-
cally pure products. Drawing on previous expe-
rience with various N–H type ligands [98,99],
we designed and prepared adamant ly-contain-
ing ligand 25 as presented in Scheme 4 [100].
Amide bond formation between benzophenone
18 and bromoacetyl bromide was accomplished
cleanly in acetonitrile in the presence of K2CO3
to obtain 23 in quantitative yield. The subse-
quent alkylation of (S)-24 with 23 was conduct-
ed using K2CO3 giving rise to ligand (S)-25 in >
95% yield.
As presented in Scheme 5, the reactions of
Rimantadine ligand (S)-25 and racemic AA 26
were conducted in methanol using 1.1 equiv-
alents of both 26 and Ni(NO3)2·6H2O and 4
equivalents of K2CO3. After heating the reac-
tion mixture for about 2 hours at 70 °C, all four
possible diastereomers 27–30 were observed in
the reaction mixture. However, diastereomer
(SCRNRC)-30 was formed in noticeable excess
(∼9:1:1:1). An important feature of this me
thod is that under the basic conditions, all di-
astereomers 27–30 are interconvertible by the
step-wise inversion of the two labile stereoge
nic centers. Therefore, under SOAT conditions,
one of the diastereomers can potentially arise
as the predominant entity. Depending on the
nature of AA 26, the precipitation of the major
diastereomer can occur either spontaneously
or it can be initiated by a gradual addition of
water. After precipitation, the diastereomeri-
cally pure product is usually obtained simply
by filtration in 60–90% yield [100].
95https://ucj.org.ua
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Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Scheme 5. SOAT approach for the preparation of enantiomerically pure tailor-made AAs.
As presented in Scheme 5, the reactions of Rimantadine ligand (S)-25 and racemic AA 26were
conducted in methanol using 1.1 equivalents of both 26 and Ni(NO3)2·6H2O and 4 equivalents of
K2CO3. After heating the reaction mixture for about 2 hours at 70 °C, all four possible diastereomers
27–30 were observed in the reaction mixture. However, diastereomer (SCRNRC)-30 was formed in
noticeable excess (∼9:1:1:1). An important feature of this method is that under the basic conditions,
all diastereomers 27–30 are interconvertible by the step-wise inversion of the two labile stereogenic
centers. Therefore, under SOAT conditions, one of the diastereomers can potentiallyarise as the
predominant entity. Depending on the nature of AA 26, the precipitation of the major diastereomer
can occur either spontaneously or it can be initiated by a gradual addition of water. After precipitation,
the diastereomerically pure product is usually obtained simply by filtration in 60–90% yield [100].
Our next goal in the area of SOAT was the development of an advanced general process for
the preparation of tailor-made α-AAs via tandem alkylation–SOAT. As presented in Scheme 6,
Rimantadine-containing ligand 25 was reacted with glycine and a Ni(II)salt to assemble complex 32.
For the first step of the alkylation of 32, very mild phase-transfer conditions were used [101] allowing
the introduction of a sidechainto the target α-AA. The second step utilized SOAT
methodologyaffording nearly complete precipitation of the corresponding (SC, RN, RC)-configured
diastereomer 33. Disassembly of 33 provided the target AA 34 as well as recovery of the starting
Rimantadine ligand 25 for reuse [102]. Due to the very mild conditions of the first step, this approach
is limited to the preparation of aromatic AAs, such as phenylalanine and its various derivatives.
Nevertheless, this method is exceptionally practical and of high synthetic value.
Scheme 6.Tandem alkylation–SOAT protocol for the preparation of phenylalanine-type tailor-made α‑AAs.
DKR
Another approach for the direct chiral modification of unprotected AAs is DKR [103–115].
Like SOAT, DKR requires efficient, unimpeded interconverison of diastereomeric species in the
reaction mixture. However, in contrast to SOAT, DKR is based on the thermodynamic stability of
products. Our research in DKR began withthe design of ligands 35 (Scheme 7) derived from
phenylethylamine, one of the most inexpensive and readily available chiral compounds [116–118].
Scheme 7. Phenylethylamine-derived ligands for the DKR of unprotected tailor-made AAs.
As presented in Scheme 7, the reaction of ligand 35 with rac-phenylalanine, Ni(II), and base
resulted in almost quantitative formation of diastereomers 36 and 37 in a ratio of about 2 to 1.
Compounds 36 and 37 can be isolated by precipitation from the reaction mixture and are separableby
column chromatography. Then either 36 or 37 can be disassembled to yieldthe enantiomerically pure
AA as well allowing for the recovery of ligand 35. Additionally, the undesired diastereomer can be
treated in a methanol solution with base to convert it to the desired diastereomer, e.g. 36 into 37 or
vice versa, followed by the chromatographic separation. The process can be repeated until all of the
product is converted into the desired diastereomer to yield the desired (S)- or (R)-AA.
Scheme 5. SOAT approach for the preparation of enantiomerically pure tailor-made AAs.
Scheme 6.Tandem alkylation–SOAT protocol for the preparation
of phenylalanine-type tailor-made α‑AAs.
96 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Scheme 6.Tandem alkylation–SOAT protocol for the preparation of phenylalanine-type tailor-made α‑AAs.
DKR
Another approach for the direct chiral modification of unprotected AAs is DKR [103–115].
Like SOAT, DKR requires efficient, unimpeded interconverison of diastereomeric species in the
reaction mixture. However, in contrast to SOAT, DKR is based on the thermodynamic stability of
products. Our research in DKR began withthe design of ligands 35 (Scheme 7) derived from
phenylethylamine, one of the most inexpensive and readily available chiral compounds [116–118].
Scheme 7. Phenylethylamine-derived ligands for the DKR of unprotected tailor-made AAs.
As presented in Scheme 7, the reaction of ligand 35 with rac-phenylalanine, Ni(II), and base
resulted in almost quantitative formation of diastereomers 36 and 37 in a ratio of about 2 to 1.
Compounds 36 and 37 can be isolated by precipitation from the reaction mixture and are separableby
column chromatography. Then either 36 or 37 can be disassembled to yieldthe enantiomerically pure
AA as well allowing for the recovery of ligand 35. Additionally, the undesired diastereomer can be
treated in a methanol solution with base to convert it to the desired diastereomer, e.g. 36 into 37 or
vice versa, followed by the chromatographic separation. The process can be repeated until all of the
product is converted into the desired diastereomer to yield the desired (S)- or (R)-AA.
Our next goal in the area of SOAT was the
development of an advanced general process
for the preparation of tailor-made α-AAs via
tandem alkylation–SOAT. As presented in
Scheme 6, Rimantadine-containing ligand 25
was reacted with glycine and a Ni(II) salt to
assemble complex 32. For the first step of the
alkylation of 32, very mild phase-transfer con-
ditions were used [101] allowing the introduc-
tion of a side chain to the target α-AA. The se
cond step utilized SOAT methodology afford-
ing nearly complete precipitation of the corre-
sponding (SC,RN,RC)-configured diastereomer
33. Disassembly of 33 provided the target AA
34 as well as recovery of the starting Rimanta-
dine ligand 25 for reuse [102]. Due to the very
mild conditions of the first step, this approach
is limited to the preparation of aromatic AAs,
such as phenylalanine and its various deriva-
tives. Nevertheless, this method is exceptional-
ly practical and of high synthetic value.
DKR
Another approach for the direct chiral
modification of unprotected AAs is DKR
[103–115]. Like SOAT, DKR requires efficient,
unimpeded interconverison of diastereomeric
species in the reaction mixture. However, in
contrast to SOAT, DKR is based on the ther-
modynamic stability of products. Our research
in DKR began with the design of ligands 35
(Scheme 7) derived from phenylethylamine,
one of the most inexpensive and readily availa-
ble chiral compounds [116–118].
Scheme 7. Phenylethylamine-derived ligands for the DKR of unprotected tailor-made AAs.
As presented in Scheme 7, the reaction of
ligand 35 with rac-phenylalanine, Ni(II), and
base resulted in almost quantitative formation
of diastereomers 36 and 37 in a ratio of about
2 to 1. Compounds 36 and 37 can be isolated
by precipitation from the reaction mixture and
are separableby column chromatography. Then
either 36 or 37 can be disassembled to yield
the enantiomerically pure AA as well allow-
ing for the recovery of ligand 35. Additionally,
the undesired diastereomer can be treated in
a methanol solution with base to convert it to
the desired diastereomer, e.g. 36 into 37 or vice
versa, followed by the chromatographic separa-
tion. The process can be repeated until all of the
product is converted into the desired diastere-
97https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Diastereoselectivityin this method can be improved by adding some structural rigidity to the ligand
design. For example, ligand 38 was successfullyused for the DKR of various AAs [119], including
fluorinated tailor-made derivatives [120].
The conceptual breakthrough inthe DKR of unprotected AAs was made with the design of
Soloshonok – Liu ligand 14 (Scheme 3). As shown in Scheme 8, ligand 14 reacts with various AAs
under very mild conditions to produce the corresponding Ni(II) complexes 39 with
diastereoselectivity > 97: 3 [121–125].
Scheme 8. DKR of unprotected tailor-made AAs using Soloshonok – Liu ligand 14.
Precipitation of the major product from the reaction mixture affords virtually
diastereomerically pure 39 which can be disassembled under standard acidic conditions to release the
target AA along with recovery of the chiral ligand 14. The process is very clean as virtually no
byproducts are formed allowing the isolation of complex 39 in yields >90%. DKR can be applied to a
great variety of tailor-made AAs differing of structural types. The limitations, however, include AAs
containing functional groups such as aliphatic CO2H, NH2, SH, or OH.
Similar results for the DKR of unprotected AAs were also obtained usingthe Hamari ligand 13.
As shown in Scheme 9, ligand 13 readilyreacted with racemic AAs forming complex 39 as the major
diastereomer (>95:5) [126,127].
omer to yield the desired (S)- or (R)-AA. Dias-
tereoselectivity in this method can be improved
by adding some structural rigidity to the ligand
design. For example, ligand 38 was successfully
used for the DKR of various AAs [119], includ-
ing fluorinated tailor-made derivatives [120].
The conceptual breakthrough inthe DKR
of unprotected AAs was made with the design
of Soloshonok–Liu ligand 14 (Scheme 3). As
shown in Scheme 8, ligand 14 reacts with va
rious AAs under very mild conditions to pro-
duce the corresponding Ni(II) complexes 39
with diastereoselectivity>97:3 [121–125].
Scheme 8. DKR of unprotected tailor-made AAs using Soloshonok–Liu ligand 14.
Precipitation of the major product from
the reaction mixture affords virtually diastere-
omerically pure 39 which can be disassembled
under standard acidic conditions to release the
target AA along with recovery of the chiral li-
gand 14. The process is very clean as virtually
no byproducts are formed allowing the isola-
tion of complex 39 in yields >90%. DKR can be
applied to a great variety of tailor-made AAs
differing of structural types. The limitations,
however, include AAs containing ω functio
nal groups such as aliphatic CO2H, NH2, SH,
or OH.
Similar results for the DKR of unprotec
ted AAs were also obtained using the Hamari
ligand 13. As shown in Scheme 9, ligand 13
readily reacted with racemic AAs forming
complex 39 as the major diastereomer (>95:5)
[126,127].
The stereochemical outcome of DKR and
reaction limitations for ligands 13 and 14 are
very similar rendering these two chiral ligands
of high synthetic value for the preparation of
enantiomerically pure tailor-made AAs on a
large scale. It should be noted that proline-de-
rived ligand 14 is significantly less expensive in
comparison to 13. On the other hand, the chi-
rality of ligand 13 is resistant under the applied
conditions and therefore its recycling is amena-
ble without requiring additional purification.
98 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Diastereoselectivityin this method can be improved by adding some structural rigidity to the ligand
design. For example, ligand 38 was successfullyused for the DKR of various AAs [119], including
fluorinated tailor-made derivatives [120].
The conceptual breakthrough inthe DKR of unprotected AAs was made with the design of
Soloshonok – Liu ligand 14 (Scheme 3). As shown in Scheme 8, ligand 14 reacts with various AAs
under very mild conditions to produce the corresponding Ni(II) complexes 39 with
diastereoselectivity > 97: 3 [121–125].
Scheme 8. DKR of unprotected tailor-made AAs using Soloshonok – Liu ligand 14.
Precipitation of the major product from the reaction mixture affords virtually
diastereomerically pure 39 which can be disassembled under standard acidic conditions to release the
target AA along with recovery of the chiral ligand 14. The process is very clean as virtually no
byproducts are formed allowing the isolation of complex 39 in yields >90%. DKR can be applied to a
great variety of tailor-made AAs differing of structural types. The limitations, however, include AAs
containing functional groups such as aliphatic CO2H, NH2, SH, or OH.
Similar results for the DKR of unprotected AAs were also obtained usingthe Hamari ligand 13.
As shown in Scheme 9, ligand 13 readilyreacted with racemic AAs forming complex 39 as the major
diastereomer (>95:5) [126,127].
Scheme 9. DKR of unprotected tailor-made AAs using Hamari ligand 13.
The stereochemical outcome of DKR and reaction limitations for ligands 13 and 14are very
similar rendering these two chiral ligands of high synthetic value for the preparation of
enantiomerically pure tailor-made AAs on a large scale. It should be noted that proline-derived ligand
14 is significantly less expensivein comparison to 13. On the other hand, the chirality of ligand 13 is
resistant under the applied conditions and therefore its recycling is amenable without requiring
additional purification.
DKR has an additional synthetic advantage for the preparation of α-deutereo-AAs [128] as a
special class of isotopically labeled compounds. Though the market forα-deutereo-AAs is relatively
small, they have numerous applications in the mechanistic studies of various enzymes and
biochemical processes[129–138]. Furthermore, tailor-made α-deutereo-AAs play an indispensable
role in the emerging area of clinical functional metabolomics for obtainingessential data on in vivo
AA metabolism and protein turnover [139–140].While the asymmetric synthesis of α-deutereo-AAs
has received due attention [141–151], optimal solutions with regards to the problems of selectivity,
level of deuterium incorporation, and enantiomeric purity of the target AAshave not yet been found.
In this respect, the protocol developed by us represents the most advanced procedure reported to date.
As presented in Scheme 10, conducting DKR under the standard conditions in deuterated methanol
affords product 40 in quantitative yield with 98.8% diastereomeric excess (de) and 96% deuterium
incorporation at the α position. For most applications of α-deutereo-AA this is an acceptable level and
thus complex 40 can be disassembled under the usual acidic conditions to produce the target
α-deutereo-AA. However, if a very high level of deuterium incorporation is required, for example for
mechanistic kinetic studies, an additional exposure of 40 to deuterated methanol in the presence of a
stronger base can be performed to produce 40 of ~99% deuterium incorporation at the α position.
Scheme 10. Synthesis of tailor-made α-deutereo-AAs via DKR.
Elaboration of chiral nucleophilic or electrophilic glycine equivalents.
Alkylation.
The alkylation of chiral glycine equivalents is one of the most widely used approaches for the
asymmetric synthesis of tailor-made AAs [152–154]. Both the Hamari ligand 13 and the Soloshonok
– Liu ligand 14 have been successfully used in our laboratories for the large-scale preparation of
tailor-made AAs. As already pointed out above, one of the most rapidly growing areas inmodern drug
design is the application offluorinated residues as bioisosteres of naturally occurring molecular
entities. Based onconsiderations of the biologically relevant size, as cumulatively defined by van der
Scheme 9. DKR of unprotected tailor-made AAs using Hamari ligand 13.
Scheme 10. Synthesis of tailor-made α-deutereo-AAs via DKR.
DKR has an additional synthetic advan-
tage for the preparation of α-deutereo-AAs
[128] as a special class of isotopically labeled
compounds. Though the market for α-deute-
reo-AAs is relatively small, they have nume
rous applications in the mechanistic studies
of various enzymes and biochemical processes
[129–138]. Furthermore, tailor-made α-deu-
tereo-AAs play an indispensable role in the
emerging area of clinical functional metabolo-
mics for obtaining essential data on in vivo AA
metabolism and protein turnover [139–140].
While the asymmetric synthesis of α-deute-
reo-AAs has received due attention [141–151],
optimal solutions with regards to the problems
of selectivity, level of deuterium incorporation,
and enantiomeric purity of the target AA shave
not yet been found. In this respect, the protocol
developed by us represents the most advanced
procedure reported to date. As presented in
99https://ucj.org.ua
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Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Waals (vdW) volume, A values, Taft Es values, and biphenyl rotational interference values [155–159],
a trifluoromethyl group hasoften been considered to be isosteric with an isopropyl substituent.
Although – CF3 and –iPr groups areclearly of different shape, they are sterically much closer than to
–Me, –Et, and –tBu groups. Asshown in Figure 2, the differences projected by several biphenyl
rotational interference values are relativelymodest, suggesting steric mimicry between these two
groups and thereby fueling interest in the synthesis of trifluoromethyl containing α- and β-AAs [160].
Thus, 2‐amino‐4,4,4‐trifluorobutanoic acid (41) can be used as a substitute for leucine (42) in the de
novo design of biologically active peptides and peptidomimetics [161–171].
Fig. 2. Bioisosteric relationships between –CF3 and –iPr groups in the context of using
2-amino-4,4,4-trifluorobutanoic acid (41) as a substitute for leucine (42) in drug design.
Responding to thehigh interest in trifluoro-AA 41, we selected this molecule as one of our
research targets. As shown in Scheme 11, chiral glycine equivalent 19 was alkylated with CF3CH2I to
produce the target complex (S)(2S)-43 as the major diastereomer with 97% de [172,173]. Of note,
usually the alkylation of glycine Schiff base complexes derived from ligands of type 14 is performed
in the presence of a large excess of a base, usually 5–10 equivalents [174–177]. Consequently, it was
an important finding that for large-scale synthesis, the optimized conditions only required a quite
smallexcess of base (5 mol%). The same stoichiometry was found to be optimalfor the alkylating
reagent. Thus, only a 5 mol% excess of the trifluoroethyl iodide was sufficient for optimal yields and
stereochemical outcome. Similar to trifluoro-AA 41, we prepared
(S)-2-amino-6,6,6-trifluorohexanoic acid 44 [178,179] and α-(octyl)glycine 45 [180].
Scheme 10, conducting DKR under the standard
conditions in deuterated methanol affords
product 40 in quantitative yield with 98.8%
diastereomeric excess (de) and 96% deuterium
incorporation at the α position. For most ap-
plications of α-deutereo-AA this is an accep
table level and thus complex 40 can be disas-
sembled under the usual acidic conditions to
produce the target α-deutereo-AA. However, if
a very high level of deuterium incorporation is
required, for example for mechanistic kinetic
studies, an additional exposure of 40 to deu-
terated methanol in the presence of a stronger
base can be performed to produce 40 of ~99%
deuterium incorporation at the α position.
Elaboration of chiral nucleophilic or electro-
philic glycine equivalents.
Alkylation.
The alkylation of chiral glycine equivalents
is one of the most widely used approaches
for the asymmetric synthesis of tailor-made
AAs [152–154]. Both the Hamari ligand 13
and the Soloshonok–Liu ligand 14 have been
successfully used in our laboratories for the
large-scale preparation of tailor-made AAs.
As already pointed out above, one of the most
rapidly growing areas inmodern drug design is
the application of fluorinated residues as bio
isosteres of naturally occurring molecular en-
tities. Based on considerations of the biologi
cally relevant size, as cumulatively defined by
van der Waals (vdW) volume, A values, Taft
Es values, and biphenyl rotational interference
values [155–159], a trifluoromethyl group has
often been considered to be isosteric with an
isopropyl substituent. Although – CF3 and –
iPr groups are clearly of different shape, they
are sterically much closer than to –Me, –Et,
and –tBu groups. As shown in Figure 2, the
differences projected by several biphenyl ro-
tational interference values are relatively mo
dest, suggesting steric mimicry between these
two groups and thereby fueling interest in the
synthesis of trifluoromethyl containing α- and
β-AAs [160]. Thus, 2‐amino‐4,4,4‐trifluoro-
butanoic acid (41) can be used as a substitute
for leucine (42) in the de novo design of bio-
logically active peptides and peptidomimetics
[161–171].
Fig. 2. Bioisosteric relationships between –CF3
and –iPr groups in the context of using 2-amino-
4,4,4-trifluorobutanoic acid (41) as a substitute for
leucine (42) in drug design.
Responding to the high interest in triflu
oro-AA 41, we selected this molecule as one of
our research targets. As shown in Scheme 11,
chiral glycine equivalent 19 was alkylated
with CF3CH2I to produce the target complex
(S2S)-43 as the major diastereomer with 97%
de [172,173]. Of note, usually the alkylation
of glycine Schiff base complexes derived from
ligands of type 14 is performed in the pre
sence of a large excess of a base, usually 5–10
equivalents [174–177]. Consequently, it was an
100 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
important finding that for large-scale synthe-
sis, the optimized conditions only required a
quite small excess of base (5 mol%). The same
stoichiometry was found to be optimal for the
alkylating reagent. Thus, only a 5 mol% ex-
cess of the trifluoroethyl iodide was sufficient
for optimal yields and stereochemical out-
come. Similar to trifluoro-AA 41, we prepared
(S)-2-amino-6,6,6-trifluorohexanoic acid 44
[178,179] and α-(octyl)glycine 45 [180].
Scheme 11. Asymmetric synthesis of tailor-made AA via alkylation of a glycine complex.
Close attention to all aspects of the reaction process and thorough examination of the
chemical entities in the reaction mixture allowed us to isolate not only the usual dialkylation products
46, but also the previously undetermined byproducts 47 and 48. Characterizing these byproducts was
instrumental in gaining a more complete understanding of the reaction chemistry and in formulating
more conducive reaction conditions [181,182].
The installationof sterically constrained tailor-madeα-AAs into strategic positions of peptide
chains brings about noticeable conformationalrestrictions of the corresponding , ψ, andangles inthe
folded biologically active three-dimensional structure [183–190]. In this regard, the synthesisand
applications of α,α-disubstituted AAs havereceived widespread consideration [191,192]. Among the
highly interesting targets isα-(methyl)cysteine (51) (Scheme 12), a quite rare, naturally occurring
quaternary AA isolated from blue-green algae [193,194]. In particular, several natural products that
contain anα-(methyl)cysteine (51) fragment, such as mirabzoles [195,196], tantazoles [197], and
thiangazoles [198,199], were found to possess promising antitumor and anti-HIV-1 activities which
provide considerable motivationfor the development of asymmetric synthesis and in-depth
biologicalinvestigation of α-(methyl)cysteine (51).
Scheme 11. Asymmetric synthesis of tailor-made AA via alkylation of a glycine complex.
Close attention to all aspects of the reac-
tion process and thorough examination of the
chemical entities in the reaction mixture al-
lowed us to isolate not only the usual dialky-
lation products 46, but also the previously
undetermined byproducts 47 and 48. Charac-
terizing these byproducts was instrumental in
gaining a more complete understanding of the
reaction chemistry and in formulating more
conducive reaction conditions [181,182].
The installation of sterically constrained
tailor-madeα-AAs into strategic positions of
peptide chains brings about noticeable confor-
mational restrictions of the corresponding φ,
101https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Scheme 12. Asymmetric synthesis of α-(methyl)cysteine (51).
As presented in Scheme 12, the synthesis of 51 was accomplished by the alkylation of alanine
complexes 49 and 50 derived from Hamari 13 and Soloshonok – Liu 14 ligands, respectively [200]. It
should be noted that the alanine residue in complexes 49 and 50 can be racemic as the reaction
proceeds via formation of the achiral intermediate enolate. Proline derived complex 49 exhibited
better stereochemical preferenceallowing the preparation of the major diastereomer in 77% yield with
80% de. The major product can be purified by column chromatography and disassembled to provide
the target AA 51. Both enantiomers of 51 were prepared with the same stereochemical outcome.
Another interesting example of tailor-made AAs is 7-azatryptophan 52. AA 52 has been
widely used as a biological fluorescent probe [201–204], an antiplasmodial compound [205], and an
inhibitorof checkpoint kinase 1[206–208]. Although there have been several reports on the synthesis
of azatryptophanes [209–215], the synthesis of 7-azatryptophan 52 has remained less developed, in
particular, by asymmetric synthesis. We demonstrated that the synthesis of AA 52 can be effectively
realized via alkylation of a glycine complex (Scheme 13).
Scheme 13. Asymmetric synthesis of 7-azatryptophan via alkylation of glycine–Ni(II)complex.
As shown in Scheme 13, N-protected chloride 53 reacted with glycine complex 19 in the
presence of a strong base in DMSO affording alkylated product 54 as a single diastereomer in 74%
yield. Disassembly of 54 under acidic conditions took place with simultaneous removal of the Boc
protecting groupproviding the target AA 52 in 95% yield [216]. It should be noted that chiral ligand
14 was also collected with 97% recovery for re-use.
Scheme 14 illustrates various AAs synthesized using Hamari ligand 13. The glycine-derived
complex 55 can be prepared quantitatively by treating ligand 13 with glycine and a source of Ni(II),
e.g. NiCl₂, in methanolin the presence of base. Any alkylating reagent compatible with the reaction
conditions can be used to alkylate the glycine moiety in 55. For instance, mono-, di-, or
ψ, and χ angles in the folded biologically ac-
tive three-dimensional structure [183–190].
In this regard, the synthesis and applications
of α,α-disubstituted AAs have received wide-
spread consideration [191,192]. Among the
highly interesting targets is α-(methyl)cysteine
(51) (Scheme 12), a quite rare, naturally occur-
ring quaternary AA isolated from blue-green
algae [193,194]. In particular, several natural
products that contain anα-(methyl)cysteine
(51) fragment, such as mirabzoles [195, 196],
tantazoles [197], and thiangazoles [198, 199],
were found to possess promising antitumor
and anti-HIV-1 activities which provide con-
siderable motivationfor the development of
asymmetric synthesis and in-depth biological-
investigation of α-(methyl)cysteine (51).
Scheme 12. Asymmetric synthesis of α-(methyl)cysteine (51).
As presented in Scheme 12, the synthe-
sis of 51 was accomplished by the alkylation
of alanine complexes 49 and 50 derived from
Hamari 13 and Soloshonok–Liu 14 ligands,
respectively [200]. It should be noted that the
alanine residue in complexes 49 and 50 can be
racemic as the reaction proceeds via formation
of the achiral intermediate enolate. Proline de-
rived complex 49 exhibited better stereochemi
cal preference allowing the preparation of the
major diastereomer in 77% yield with 80% de.
The major product can be purified by column
chromatography and disassembled to provide
the target AA 51. Both enantiomers of 51 were
prepared with the same stereochemical out-
come.
Another interesting example of tailor-made
AAs is 7-azatryptophan 52. AA 52 has been
widely used as a biological fluorescent probe
[201–204], an antiplasmodial compound
[205], and an inhibitorof checkpoint kinase 1
[206–208]. Although there have been several
reports on the synthesis of azatryptophanes
[209–215], the synthesis of 7-azatryptophan
52 has remained less developed, in particular,
by asymmetric synthesis. We demonstrated
that the synthesis of AA 52 can be effective-
ly realized via alkylation of a glycine complex
(Scheme 13).
As shown in Scheme 13, N-protected chlo-
ride 53 reacted with glycine complex 19 in the
presence of a strong base in DMSO affording
102 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
alkylated product 54 as a single diastereomer
in 74% yield. Disassembly of 54 under aci
dic conditions took place with simultaneous
removal of the Boc protecting groupproviding
the target AA 52 in 95% yield [216]. It should
be noted that chiral ligand 14 was also collec
ted with 97% recovery for re-use.
Scheme 13. Asymmetric synthesis of 7-azatryptophan
via alkylation of glycine–Ni(II)complex.
Scheme 14 illustrates various AAs synthe-
sized using Hamari ligand 13. The glycine-de-
rived complex 55 can be prepared quantita-
tively by treating ligand 13 with glycine and
a source of Ni(II), e.g. NiCl₂, in methanol in
the presence of base. Any alkylating reagent
compatible with the reaction conditions can
be used to alkylate the glycine moiety in 55.
For instance, mono-, di-, or polysubstituted
benzyl chlorides/bromides provide excellent
alkylations. The substituents on the phenyl
ring only have a negligible effect on the ste-
reochemical outcome. Similarly, variously
substituted naphthyl derivatives and some
heterocyclic derivatives also produce excel-
lent results. Although inactivated alkyl hali
des react more slowly, they still achieve the
same high stereochemical outcome, typically
around 95% de, with chemical yields exceed-
ing 90%. The alkylation products 56 can be
conveniently disassembled to yield the cor-
responding AA and chiral ligand 13 which
can be easily recovered with uncompromised
enantiomeric purity [217].
Chiral glycine alkylation methodology
can also be used for the synthesis of bis-AA
(Scheme 15) [218, 219]. This particular class of
tailor-made AAs is frequently found in natu-
rally occurring peptides. For example, bis-AAs
play an important role in the structure of the
peptidoglycan cell walls of fungi and bacteria
and can act ascross linking elements to allow
for efficient control of thepeptide secondary
structure. Representative examples of natural-
ly occurring bis-AAs include diaminopimelic
acid [220,221] and dityrosine [222]. Further-
more, bis-AAs serve as a key structural unitin
the design of antibiotics that disrupt microbial
cell wall synthesis [223]. Due to their useful
biological properties and bio structural func-
tions, the synthesis of bis-AAs has received sig-
nificant interest [224–231].
Scheme 12. Asymmetric synthesis of α-(methyl)cysteine (51).
As presented in Scheme 12, the synthesis of 51 was accomplished by the alkylation of alanine
complexes 49 and 50 derived from Hamari 13 and Soloshonok – Liu 14 ligands, respectively [200]. It
should be noted that the alanine residue in complexes 49 and 50 can be racemic as the reaction
proceeds via formation of the achiral intermediate enolate. Proline derived complex 49 exhibited
better stereochemical preferenceallowing the preparation of the major diastereomer in 77% yield with
80% de. The major product can be purified by column chromatography and disassembled to provide
the target AA 51. Both enantiomers of 51 were prepared with the same stereochemical outcome.
Another interesting example of tailor-made AAs is 7-azatryptophan 52. AA 52 has been
widely used as a biological fluorescent probe [201–204], an antiplasmodial compound [205], and an
inhibitorof checkpoint kinase 1[206–208]. Although there have been several reports on the synthesis
of azatryptophanes [209–215], the synthesis of 7-azatryptophan 52 has remained less developed, in
particular, by asymmetric synthesis. We demonstrated that the synthesis of AA 52 can be effectively
realized via alkylation of a glycine complex (Scheme 13).
Scheme 13. Asymmetric synthesis of 7-azatryptophan via alkylation of glycine–Ni(II)complex.
As shown in Scheme 13, N-protected chloride 53 reacted with glycine complex 19 in the
presence of a strong base in DMSO affording alkylated product 54 as a single diastereomer in 74%
yield. Disassembly of 54 under acidic conditions took place with simultaneous removal of the Boc
protecting groupproviding the target AA 52 in 95% yield [216]. It should be noted that chiral ligand
14 was also collected with 97% recovery for re-use.
Scheme 14 illustrates various AAs synthesized using Hamari ligand 13. The glycine-derived
complex 55 can be prepared quantitatively by treating ligand 13 with glycine and a source of Ni(II),
e.g. NiCl₂, in methanolin the presence of base. Any alkylating reagent compatible with the reaction
conditions can be used to alkylate the glycine moiety in 55. For instance, mono-, di-, or
(S2S)
103https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
polysubstituted benzyl chlorides/bromides provide excellent alkylations. The substituents on the
phenyl ring only have a negligible effect on the stereochemical outcome. Similarly, variously
substituted naphthyl derivatives and some heterocyclic derivatives also produce excellent results.
Although inactivated alkyl halides react more slowly, they still achieve the same high stereochemical
outcome, typically around 95% de, with chemical yields exceeding 90%. The alkylation products 56
can be conveniently disassembled to yield the corresponding AA and chiral ligand 13 which can be
easily recovered with uncompromised enantiomeric purity [217].
Scheme 14. Asymmetric synthesis of various tailor-made AAs via alkylation of glycine Ni(II) complex derived
from Hamari ligand13.
Chiral glycine alkylation methodology can also be used for the synthesis of bis-AA (Scheme
15) [218, 219]. This particular class of tailor-made AAs is frequentlyfound in naturally
occurringpeptides. For example, bis-AAs play an important role in the structure ofthe peptidoglycan
cell walls of fungi and bacteria and can act ascross-linking elements to allow for efficient control of
thepeptide secondary structure. Representative examples of naturallyoccurring bis-AAs include
diaminopimelic acid [220, 221] anddityrosine [222]. Furthermore, bis-AAs serve as a key structural
unitin the design of antibiotics that disrupt microbial cell wall synthesis [223]. Due to their useful
biological properties and bio-structuralfunctions, the synthesis of bis-AAs has received
significantinterest [224–231].
Scheme 15. Asymmetric synthesis of tailor-made bis-AAs via alkylation of a glycine Ni(II) complex.
As illustrated in Scheme 15, dibromides 58 can react with two equivalents of
glycine–Ni(II)complex 19 to afford di-alkylated 59. Despite some complexity of this process, the
chemical yields of 59 are usually above 90% with diastereoselectivity >97:3. As expected, the
reaction proceeds via intermediate monoalkylated derivatives which can be determined by TLC and,
if necessary, isolated. This approach, though, is limited to activated dibromides 58 such as benzyl or
allyl derivatives [232]. Attempts to useinactivated alkyl halides require forcing conditions leading to
significant decomposition and loss of stereochemical integrity. Disassembly of 59 under acidic
conditions permits the isolation of the target bis-AAs 60 as well as the recovery of chiral ligand 14.
Aldol addition reactions.
Aldol addition to glycine equivalents is the most convenient approach for the preparation of
α-amino-β-hydroxy AAs [233–237]. For example, glycine Ni(II) complex 19 was shown to react with
various aldehydes and activated ketones [238–240]. The aldol reactions of 19 can be conducted under
either kinetic control using a weak base or under thermodynamic controlusing a strong base [241,
242]. While the latter affords the corresponding aldol addition products with excellent levels of
diastereoselectivity at the α- and β-positions (> 98:2), the former proceeds onlysluggishly and with
only a low degree of stereochemical preference(~60:40) at the β-stereogenic carbon. Considering
these inherently challenging synthetic limitations, we were interested to know whether the
stereochemical preference could be improved when the aldol addition is followed by transformation
to irreversible products (Scheme 16) [243].
Scheme 14. Asymmetric synthesis of various tailor-made AAs via alkylation
of glycine Ni(II) complex derived from Hamari ligand13.
Scheme 15. Asymmetric synthesis of tailor-made bis-AAs via alkylation of a glycine Ni(II) complex.
As illustrated in Scheme 15, dibromides 58
can react with two equivalents of glycine–Ni(II)
complex 19 to afford di-alkylated 59. Despite
some complexity of this process, the chemical
yields of 59 are usually above 90% with diaste-
reoselectivity >97:3. As expected, the reaction
proceeds via intermediate monoalkylated de-
rivatives which can be determined by TLC and,
(S2R)
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HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
if necessary, isolated. This approach, though, is
limited to activated dibromides 58 such as ben-
zyl or allyl derivatives [232]. Attempts to use
inactivated alkyl halides require forcing condi-
tions leading to significant decomposition and
loss of stereochemical integrity. Disassembly of
59 under acidic conditions permits the isolation
of the target bis-AAs 60 as well as the recovery
of chiral ligand 14.
Aldol addition reactions.
Aldol addition to glycine equivalents is the
most convenient approach for the preparation
of α-amino-β-hydroxy AAs [233–237]. For ex-
ample, glycine Ni(II) complex 19 was shown
to react with various aldehydes and activated
ketones [238–240]. The aldol reactions of 19
can be conducted under either kinetic con-
trol using a weak base or under thermody-
namic control using a strong base [241,242].
While the latter affords the corresponding al-
dol addition products with excellent levels of
diastereoselectivity at the α- and β-positions
(> 98:2), the former proceeds only sluggishly
and with only a low degree of stereochemical
preference(~60:40) at the β-stereogenic car-
bon. Considering these inherently challeng-
ing synthetic limitations, we were interested to
know whether the stereochemical preference
could be improved when the aldol addition is
followed by transformation to irreversible pro
ducts (Scheme 16) [243].
Scheme 16. Methodological study of the aldol addition–cyclization reaction cascade.Scheme 16. Methodological study of the aldol addition–cyclization reaction cascade.
As presented in Scheme 16, using the chiral Ni(II) complex of glycine Schiff base 19 we
designed an addition–cyclization reaction cascade to explore aspects of the kinetic
triethylamine-catalyzed formation of the corresponding (S)(2S,3S)-63 and (S)(2S, 3R)-64
diastereomers [243]. It was found that the final lactone products rather reflected thermodynamic
stereocontrol due to much greater rates of the reversible aldol addition, products 61 and 62, vs. a
subsequent and irreversible cyclization step. The observed 80:20diastereoselectivity for
(S)(2S,3S)-63 and (S)(2S, 3R)-64 in the reaction of Ni(II) complex 19 constitutes an improvement
over the previously reported 60:40 ratio.
Mannich additions
Mannich additions of chiral glycine equivalents represent the most direct approach for the
preparation of α, β-bis-AAs [244–247]. In the chemistry of Ni(II) complexes of glycine Schiff bases,
Mannich additions are one of the least studied reactions [248]. Nevertheless, α, β-bis-AAs constitute
an important class of tailor-made AAs found in nature as structural motifs of biologically important
molecules [249, 250].
As illustrated in Scheme 17, we designed a Mannich addition to investigate the case of
matching vs. mismatching diastereomeric preferences between chiral complex 19 and chiral Mannich
acceptor 65 [251].
(S2S,3S)
(S2S,3S) (S2S,3S)
(S2S,3S)
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Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
As presented in Scheme 16, using the chi-
ral Ni(II) complex of glycine Schiff base 19 we
designed an addition–cyclization reaction cas-
cade to explore aspects of the kinetic triethyl-
amine-catalyzed formation of the correspond-
ing (S2S,3S)-63 and (S)(2S,3R)-64 diastereo
mers [243]. It was found that the final lactone
products rather reflected thermodynamic ste-
reocontrol due to much greater rates of the re-
versible aldol addition, products 61 and 62, vs.
a subsequent and irreversible cyclization step.
The observed 80:20 diastereoselectivity for (S)
(2S,3S)-63 and (S)(2S,3R)-64 in the reaction of
Ni(II) complex 19 constitutes an improvement
over the previously reported 60:40 ratio.
Mannich additions.
Mannich additions of chiral glycine equiva
lents represent the most direct approach for
the preparation of α,β-bis-AAs [244–247]. In
the chemistry of Ni(II) complexes of glycine
Schiff bases, Mannich additions are one of the
least studied reactions [248]. Nevertheless,
α,β-bis-AAs constitute an important class of
tailor-made AAs found in nature as structu
ral motifs of biologically important molecules
[249, 250].
As illustrated in Scheme 17, we designed
a Mannich addition to investigate the case
of matching vs. mismatching diastereomeric
preferences between chiral complex 19 and
chiral Mannich acceptor 65 [251].
Scheme 17. Mannich additions of the chiral Ni(II) complex of glycine Schiff base 19
with a chiral Mannich acceptor 65.
Scheme 17. Mannich additions of the chiral Ni(II) complex of glycine Schiff base 19 with a chiral Mannich
acceptor 65.
It was intriguing to find that S-configured Ni(II) complex 19 and
N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine 65 with an (S) configuration have matching
stereochemical preferences resulting in the formation of product 66 with virtually complete
diastereoselectivity. The reaction of (S)-19 with (R)-65 is a case of mismatching stereochemical
preferences and affords amixture of diastereomers 67 and 68 in a ratio of 37:63. These results suggest
that the stereocontrol of the Ni(II) complex 19 prevails over the stereoselectivity provided by imine
65. It is worth noting that N-tert-butylsulfiny l-3,3,3-trifluoroacetaldimine (65) is one of the most
widely used and exceptionally highstereocontrolling chiral reagent for the asymmetric synthesis of
amines and AAs [252–256].
Michael additions.
Michael additions are of great synthetic value for the preparation of various types of
tailor-made AAs containing five carbon atoms in their skeleton. Theseinclude, but are not limited to,
glutamic acid, glutamine, pyroglutamic acid, pyroglutamine, and proline [257–260]. The Michael
addition of Ni(II)complexes with various α, β-unsaturated carboxylic acid derivatives has been one of
the most prolific avenues of this research area [261–264]. We chose Michael addition for the synthesis
of (2S, 3S)‑3‑methylglutamine, one the key compounds used in the total synthesis of cytotoxic marine
peptides callipeltin O and Q [265]. As presented in Scheme 18, glycine Ni(II) complex 19 was reacted
with Michael acceptor 69 under specially designed conditions to keep intact the allyl ester moiety
[266].
(S2R,3RRS)
(S2S,3RRS)
(S2S,3SSS)
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HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
It was intriguing to find that S-configured
Ni(II) complex 19 and N-tert-butylsulfi-
nyl-3,3,3-trifluoroacetaldimine 65 with an (S)
configuration have matching stereochemical
preferences resulting in the formation of pro
duct 66 with virtually complete diastereose-
lectivity. The reaction of (S)-19 with (R)-65 is
a case of mismatching stereochemical prefe
rences and affords amixture of diastereomers
67 and 68 in a ratio of 37:63. These results
suggest that the stereocontrol of the Ni(II)
complex 19 prevails over the stereoselecti
vity provided by imine 65. It is worth noting
that N-tert-butylsulfiny l-3,3,3-trifluoroac-
etaldimine (65) is one of the most widely used
and exceptionally high stereocontrolling chiral
reagent for the asymmetric synthesis of amines
and AAs [252–256].
Michael additions.
Michael additions are of great synthetic va
lue for the preparation of various types of tai-
lor-made AAs containing five carbon atoms in
their skeleton. These include, but are not limi
ted to, glutamic acid, glutamine, pyroglutamic
acid, pyroglutamine, and proline [257–260].
The Michael addition of Ni(II)complexes
with various α,β-unsaturated carboxylic acid
derivatives has been one of the most prolific
avenues of this research area [261–264]. We
chose Michael addition for the synthesis of
(2S,3S)‑3‑methylglutamine, one the key com-
pounds used in the total synthesis of cytotoxic
marine peptides callipeltin O and Q [265]. As
presented in Scheme 18, glycine Ni(II) com-
plex 19 was reacted with Michael acceptor 69
under specially designed conditions to keep
intact the allyl ester moiety [266].
Scheme 18. Asymmetric synthesis of (2S,3S)‑3‑methylglutamine via Michael addition.
The acidic disassembly of the major dia
stereomeric product (S2S3S)-70 was also per-
formed under strictly controlled conditions
using THF as a solvent. Allyl ester hydrochlo-
ride 71 was subsequently transformed into the
target glutamine derivative 72 in five steps in-
volving protection–deprotection procedures.
The substitution of phenylalanine (73, Fi
gure 3) in endogenous peptides with a bulki-
er and more lipophilic β-phenylphenylalanine
(diphenylalanine, DPA, 74) usually leads to im-
proved binding to the apolarsite of the targeted
receptors. DPA-modified peptides were found
to possess some encouraging biological pro-
Scheme 18. Asymmetric synthesis of (2S, 3S)‑3‑methylglutamine via Michael addition.
The acidic disassembly of the major diastereomeric product (S)(2S3S)-70 was also performed
under strictly controlled conditions using THF as a solvent. Allyl ester hydrochloride 71 was
subsequently transformed into the target glutamine derivative 72 in five steps involving
protection–deprotection procedures.
The substitution of phenylalanine (73, Figure 3) in endogenous peptides with a bulkier and more
lipophilicβ-phenylphenylalanine (diphenylalanine, DPA, 74) usually leads to improved binding to the
apolarsite of the targeted receptors. DPA-modified peptides were found to possess some encouraging
biological profiles in the areas of thrombin inhibitors [267, 268], angiotensin-converting enzyme
(ACE) inhibitors [269], HIV proteaseinhibitors [270], pain-related norepinephrine
transporterinhibitors [271], μ and δ opioid receptors [272], and othertypes of
peptidicsubstrate–receptor interactions [273–279].
Fig. 3. Phenylalanine (73) and its more lipophilic analogs.
Numerous advanced in silico studies have generated structural profiles for hundreds of
tailor-made AAs with rationally designed size control and vdW and electrostatic interactions that
influence peptide ligand binding affinity with endogenous receptors [280–283].
2-Amino-4,4-bis-(phenylsulfonyl)butanoic acid (75) is one of the promising structuresfeaturing
enhanced steric bulk and lipophilicity. We envisioned that this molecule could be assembled via
Michael addition between glycine–Ni(II) complex 19 and the specially designed vinyl–disulfonyl
Michael acceptor 76 (Scheme 19) [284–287].
(S2S,3S)
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Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Scheme 18. Asymmetric synthesis of (2S, 3S)‑3‑methylglutamine via Michael addition.
The acidic disassembly of the major diastereomeric product (S)(2S3S)-70 was also performed
under strictly controlled conditions using THF as a solvent. Allyl ester hydrochloride 71 was
subsequently transformed into the target glutamine derivative 72 in five steps involving
protection–deprotection procedures.
The substitution of phenylalanine (73, Figure 3) in endogenous peptides with a bulkier and more
lipophilicβ-phenylphenylalanine (diphenylalanine, DPA, 74) usually leads to improved binding to the
apolarsite of the targeted receptors. DPA-modified peptides were found to possess some encouraging
biological profiles in the areas of thrombin inhibitors [267, 268], angiotensin-converting enzyme
(ACE) inhibitors [269], HIV proteaseinhibitors [270], pain-related norepinephrine
transporterinhibitors [271], μ and δ opioid receptors [272], and othertypes of
peptidicsubstrate–receptor interactions [273–279].
Fig. 3. Phenylalanine (73) and its more lipophilic analogs.
Numerous advanced in silico studies have generated structural profiles for hundreds of
tailor-made AAs with rationally designed size control and vdW and electrostatic interactions that
influence peptide ligand binding affinity with endogenous receptors [280–283].
2-Amino-4,4-bis-(phenylsulfonyl)butanoic acid (75) is one of the promising structuresfeaturing
enhanced steric bulk and lipophilicity. We envisioned that this molecule could be assembled via
Michael addition between glycine–Ni(II) complex 19 and the specially designed vinyl–disulfonyl
Michael acceptor 76 (Scheme 19) [284–287].
Scheme 19. Asymmetric synthesis of 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid (75).
It was interesting to find that due to the high electrophilicity of acceptor 76, the corresponding
Michael addition with glycine complex 19 can be conveniently conducted using triethylamine as base.
Optimization of the reaction conditions allowed for preparation of the diastereomeric products with
an excellent yield of 99% andhigh diastereomeric ratio (dr) of 93:7. The major diastereomer 77 was
transformed into the corresponding Fmoc derivative 78 of 2-amino-4,4-bis-(phenylsulfonyl)butanoic
acid (75) under standard conditions. As usual, chiral ligand (S)-14 is able to be recovered and purified
for future applications [288].
3-Methyleneglutamic acid (79, Figure 4) wasreported as a racemic compound and tested as a
potential suicide inhibitor of pig heart glutamate–aspartate transaminase [289, 290]. Interestingly,
(S)-4-methyleneglutamic acid (80) is a naturally occurring compound [291, 292] and was prepared in
enantiomerically pure form [293, 294].
Fig. 4. Structures of (S)-3-methyleneglutamic acid (79) and (S)-4-methyleneglutamic acid (80).
We also examined the Michael addition between glycine Ni(II) complex 19 and Michael
acceptor 81 bearinga tosylate leaving group (Scheme 20) [95]. Our goal was to prepare addition
product 82 containing the corresponding β-methyl-unsaturated AA. Quite unexpectedly, we isolated
compound 83 as the major product. This outcome was very welcome as it allowed for the asymmetric
synthesis of (S)-3-methyleneglutamic acid (79) which was previously unknown in enantiomerically
pure form.We reasoned that compound 82 underwentbase-catalyzed isomerization to 83 via transition
state 84. This mechanistic rational is supported by the fact that using the same method we were able to
prepare fluoro-AA85 via the expected addition–elimination sequence [295].
files in the areas of thrombin inhibitors [267,
268], angiotensin-converting enzyme (ACE)
inhibitors [269], HIV protease inhibitors [270],
pain-related norepinephrine transporterinhi
bitors [271], μ and δ opioid receptors [272],
and other types of peptidic substrate–receptor
interactions [273–279].
Fig. 3. Phenylalanine (73) and its more lipophilic analogs.
Numerous advanced in silico studies have
generated structural profiles for hundreds of
tailor-made AAs with rationally designed size
control and vdW and electrostatic interactions
that influence peptide ligand binding affinity
with endogenous receptors [280–283]. 2-Ami-
no-4,4-bis-(phenylsulfonyl)butanoic acid (75)
is one of the promising structures featuring
enhanced steric bulk and lipophilicity. We en-
visioned that this molecule could be assembled
via Michael addition between glycine–Ni(II)
complex 19 and the specially designed vinyl–
disulfonyl Michael acceptor 76 (Scheme 19)
[284–287].
Scheme 19. Asymmetric synthesis of 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid (75).
It was interesting to find that due to the high
electrophilicity of acceptor 76, the correspond-
ing Michael addition with glycine complex 19
can be conveniently conducted using triethyl
amine as base. Optimization of the reaction
conditions allowed for preparation of the dia
stereomeric products with an excellent yield of
99% and high diastereomeric ratio (dr) of 93:7.
The major diastereomer 77 was transformed
into the corresponding Fmoc derivative 78
(S2S)
108 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Scheme 19. Asymmetric synthesis of 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid (75).
It was interesting to find that due to the high electrophilicity of acceptor 76, the corresponding
Michael addition with glycine complex 19 can be conveniently conducted using triethylamine as base.
Optimization of the reaction conditions allowed for preparation of the diastereomeric products with
an excellent yield of 99% andhigh diastereomeric ratio (dr) of 93:7. The major diastereomer 77 was
transformed into the corresponding Fmoc derivative 78 of 2-amino-4,4-bis-(phenylsulfonyl)butanoic
acid (75) under standard conditions. As usual, chiral ligand (S)-14 is able to be recovered and purified
for future applications [288].
3-Methyleneglutamic acid (79, Figure 4) wasreported as a racemic compound and tested as a
potential suicide inhibitor of pig heart glutamate–aspartate transaminase [289, 290]. Interestingly,
(S)-4-methyleneglutamic acid (80) is a naturally occurring compound [291, 292] and was prepared in
enantiomerically pure form [293, 294].
Fig. 4. Structures of (S)-3-methyleneglutamic acid (79) and (S)-4-methyleneglutamic acid (80).
We also examined the Michael addition between glycine Ni(II) complex 19 and Michael
acceptor 81 bearinga tosylate leaving group (Scheme 20) [95]. Our goal was to prepare addition
product 82 containing the corresponding β-methyl-unsaturated AA. Quite unexpectedly, we isolated
compound 83 as the major product. This outcome was very welcome as it allowed for the asymmetric
synthesis of (S)-3-methyleneglutamic acid (79) which was previously unknown in enantiomerically
pure form.We reasoned that compound 82 underwentbase-catalyzed isomerization to 83 via transition
state 84. This mechanistic rational is supported by the fact that using the same method we were able to
prepare fluoro-AA85 via the expected addition–elimination sequence [295].
of 2-amino-4,4-bis-(phenylsulfonyl)butanoic
acid (75) under standard conditions. As usual,
chiral ligand (S)-14 is able to be recovered and
purified for future applications [288].
3-Methyleneglutamic acid (79, Figure 4)
was reported as a racemic compound and test-
ed as a potential suicide inhibitor of pig heart
glutamate–aspartate transaminase [289,290].
Interestingly, (S)-4-methyleneglutamic acid
(80) is a naturally occurring compound
[291,292] and was prepared in enantiomerical-
ly pure form [293,294].
Fig. 4. Structures of (S)-3-methyleneglutamic
acid (79) and (S)-4-methyleneglutamic acid (80).
We also examined the Michael addition be-
tween glycine Ni(II) complex 19 and Michael
acceptor 81 bearing a tosylate leaving group
(Scheme 20) [95]. Our goal was to prepare ad-
dition product 82 containing the correspond-
ing β-methyl-unsaturated AA. Quite unex-
pectedly, we isolated compound 83 as the ma-
jor product. This outcome was very welcome
as it allowed for the asymmetric synthesis of
(S)-3-methyleneglutamic acid (79) which was
previously unknown in enantiomerically pure
form.We reasoned that compound 82 under-
went base-catalyzed isomerization to 83 via
transition state 84. This mechanistic rational
is supported by the fact that using the same
method we were able to prepare fluoro-AA
85 via the expected addition–elimination se-
quence [295].
Scheme 20. Michael addition of glycine–Ni(II)complex with Michael acceptors
containing tosylate leaving groups.
Scheme 20. Michael addition of glycine–Ni(II)complex with Michael acceptors containing tosylate leaving
groups.
Organophosphorus derivatives are widely found in natural products, pharmaceuticals, chiral
ligands, and functional materials [296–305]. Phosphorus-containingα-AAs are an important class of
tailor-made AAs that have gained considerable attention in peptide design strategies as they enhance
stability towards protease degradation and permit bioactivity to be modulated [306–314]. Previously,
using Ni(II) complex chemistry,-phosphorus analogs of dicarboxylic AAs were prepared by
alkylation of a glycine chiral Schiff base complex with the corresponding phosphorus alkyl halides
[315]. We envisioned a different approach based on the Michael addition of dehydroalanine chiral
Schiff base complex 86 (Scheme 21).
Scheme 21. Asymmetric synthesis of phosphorus analogs of AAs via Michael addition.
In sharp contrast to the previously discussed Ni(II) complexes representing nucleophilic
glycine equivalents, dehydroalanine derivative 86 [316, 317] represents an electrophilic alanine
equivalent allowing homologation at the corresponding βposition. The addition reactions of
Ni(II)complex 86 with nucleophiles 87 were conducted under the usual nucleophilic conditions using
methanol as a solvent and K2CO3 as base [318]. The Michael addition between dehydroalanine Ni(II)
complex 86 and phosphorous nucleophiles 87occurred very cleanly furnishing products 88 in good
(SS) (SS)
109https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Organophosphorus derivatives are wide-
ly found in natural products, pharmaceuti-
cals, chiral ligands, and functional materials
[296–305]. Phosphorus-containing α-AAs are
an important class of tailor-made AAs that
have gained considerable attention in peptide
design strategies as they enhance stability to-
wards protease degradation and permit bioac-
tivity to be modulated [306–314]. Previously,
using Ni(II) complex chemistry, ω-phosphorus
analogs of dicarboxylic AAs were prepared
by alkylation of a glycine chiral Schiff base
complex with the corresponding phosphorus
alkyl halides [315]. We envisioned a different
approach based on the Michael addition of
dehydroalanine chiral Schiff base complex 86
(Scheme 21).
Scheme 21. Asymmetric synthesis of phosphorus analogs of AAs via Michael addition.
In sharp contrast to the previously dis-
cussed Ni(II) complexes representing nu-
cleophilic glycine equivalents, dehydroala-
nine derivative 86 [316,317] represents an
electrophilic alanine equivalent allowing ho-
mologation at the corresponding β position.
The addition reactions of Ni(II)complex 86
with nucleophiles 87 were conducted under
the usual nucleophilic conditions using me
thanol as a solvent and K2CO3 as base [318].
The Michael addition between dehydroala-
nine Ni(II) complex 86 and phosphorous nu-
cleophiles 87occurred very cleanly furnishing
products 88 in good yields and with excellent
diastereoselectivity. It should be noted that
the α configuration of the addition products
88 appears to be of an unusual (SR) config-
uration, but this is simply due to the CIP
priority rules favoring the phosphorus atom
over the –CO2H group [319,320]. Complexes
88 were disassembled under the usual acid-
ic conditions and the target AAs were in situ
converted to the corresponding N–Boc deri
vatives 89 along with the recovery of the chi-
ral ligand (S)-14.
Multistep procedures.
Described above are general methodolo
gical approaches requiring one key step before
acquiring the target AA. In this section we
provide examples of multiple synthetic trans-
formations for the preparation of structurally
complex tailor-made AAs as exemplified by
the structures in Figure 5.
Scheme 20. Michael addition of glycine–Ni(II)complex with Michael acceptors containing tosylate leaving
groups.
Organophosphorus derivatives are widely found in natural products, pharmaceuticals, chiral
ligands, and functional materials [296–305]. Phosphorus-containingα-AAs are an important class of
tailor-made AAs that have gained considerable attention in peptide design strategies as they enhance
stability towards protease degradation and permit bioactivity to be modulated [306–314]. Previously,
using Ni(II) complex chemistry,-phosphorus analogs of dicarboxylic AAs were prepared by
alkylation of a glycine chiral Schiff base complex with the corresponding phosphorus alkyl halides
[315]. We envisioned a different approach based on the Michael addition of dehydroalanine chiral
Schiff base complex 86 (Scheme 21).
Scheme 21. Asymmetric synthesis of phosphorus analogs of AAs via Michael addition.
In sharp contrast to the previously discussed Ni(II) complexes representing nucleophilic
glycine equivalents, dehydroalanine derivative 86 [316, 317] represents an electrophilic alanine
equivalent allowing homologation at the corresponding βposition. The addition reactions of
Ni(II)complex 86 with nucleophiles 87 were conducted under the usual nucleophilic conditions using
methanol as a solvent and K2CO3 as base [318]. The Michael addition between dehydroalanine Ni(II)
complex 86 and phosphorous nucleophiles 87occurred very cleanly furnishing products 88 in good
(SR)
110 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
yields and with excellent diastereoselectivity. It should be noted that the αconfiguration of the
addition products 88 appears to beof an unusual (S)(R) configuration, but this is simplydue to the CIP
priority rules favoring the phosphorus atom over the –CO2H group [319, 320]. Complexes 88 were
disassembled under the usual acidic conditions and the target AAs were insitu converted to the
corresponding N–Boc derivatives 89 along with the recovery of the chiral ligand (S)-14.
Multistep procedures.
Described above are general methodological approaches requiring one key step before
acquiring the target AA. In this section we provide examples of multiple synthetic transformationsfor
the preparation of structurally complex tailor-made AAs as exemplified by the structures in Figure 5.
Fig. 5. Examples of products prepared using Ni(II)complex methodology.
Thalidomide is a notorious drug due to the monumental socio-scientific impact it had
onnearly every sector of the healthcare industry [321–324]. Nevertheless, in 1998 and 1999 the US
Food and Drug Administration approved thalidomide for use in the treatment of erythema nodosum
leprosum and multiple myeloma, respectively [325]. Moreover, the clinical success of thalidomide
led to the development and marketing of several of its structural analogs [326–328]. The Michael
addition of glycine–Ni(II)complexes were used as a key step in the asymmetric synthesis of novel
4-substituted enantiomerically stable analogs of thalidomide 90 [329, 330]. Oxazolomycin A,
isolated from the fermentation broth of Streptomyces sp., exhibits potent antibiotic properties against
various gram-positive bacteria and Agrobacteriumtumefaciens, strong anticancer activity, as well as
various other antiviralactivities [331–339]. It was envisioned that the pyroglutamatecore unit, such as
compound 91 which possesses appropriate functionalgroups at C-2 and C-3, can be viewed as a
synthetic intermediatein the total synthesis of Oxazolomycin-type natural products.The first step in
this process included the Michael addition of achiral glycine Schiff base with a chiral
αβ-disubstituted acrylate derivativefor the preparation of the enantiomerically pure α,
β-disubstituted pyroglutamic acid core. Atotal of twelve reactions were utilized in the synthesis of 91
with an overallyield of 10% [340].
α, β-Methano-AAs, or methanologs of α-AAs, represent an extreme case of compounds
containing a severelyconformationally restricted cyclopropane ring [341, 342]. Remarkably, several
cyclopropylgroup-containing AAs, such as 92–94 (Figure 6), are naturallyoccurring compounds and
have been isolated from various higherplants [343–351].
92 (2R,3S)-
CO2H
H2N
CO2H
H2N
Me
CO2H
H2N
CO2H
H2N
93 94 95
Fig. 6. Naturally occurring and tailor-made α,β-methano-α-AAs.
yields and with excellent diastereoselectivity. It should be noted that the αconfiguration of the
addition products 88 appears to beof an unusual (S)(R) configuration, but this is simplydue to the CIP
priority rules favoring the phosphorus atom over the –CO2H group [319, 320]. Complexes 88 were
disassembled under the usual acidic conditions and the target AAs were insitu converted to the
corresponding N–Boc derivatives 89 along with the recovery of the chiral ligand (S)-14.
Multistep procedures.
Described above are general methodological approaches requiring one key step before
acquiring the target AA. In this section we provide examples of multiple synthetic transformationsfor
the preparation of structurally complex tailor-made AAs as exemplified by the structures in Figure 5.
Fig. 5. Examples of products prepared using Ni(II)complex methodology.
Thalidomide is a notorious drug due to the monumental socio-scientific impact it had
onnearly every sector of the healthcare industry [321–324]. Nevertheless, in 1998 and 1999 the US
Food and Drug Administration approved thalidomide for use in the treatment of erythema nodosum
leprosum and multiple myeloma, respectively [325]. Moreover, the clinical success of thalidomide
led to the development and marketing of several of its structural analogs [326–328]. The Michael
addition of glycine–Ni(II)complexes were used as a key step in the asymmetric synthesis of novel
4-substituted enantiomerically stable analogs of thalidomide 90 [329, 330]. Oxazolomycin A,
isolated from the fermentation broth of Streptomyces sp., exhibits potent antibiotic properties against
various gram-positive bacteria and Agrobacteriumtumefaciens, strong anticancer activity, as well as
various other antiviralactivities [331–339]. It was envisioned that the pyroglutamatecore unit, such as
compound 91 which possesses appropriate functionalgroups at C-2 and C-3, can be viewed as a
synthetic intermediatein the total synthesis of Oxazolomycin-type natural products.The first step in
this process included the Michael addition of achiral glycine Schiff base with a chiral
αβ-disubstituted acrylate derivativefor the preparation of the enantiomerically pure α,
β-disubstituted pyroglutamic acid core. Atotal of twelve reactions were utilized in the synthesis of 91
with an overallyield of 10% [340].
α, β-Methano-AAs, or methanologs of α-AAs, represent an extreme case of compounds
containing a severelyconformationally restricted cyclopropane ring [341, 342]. Remarkably, several
cyclopropylgroup-containing AAs, such as 92–94 (Figure 6), are naturallyoccurring compounds and
have been isolated from various higherplants [343–351].
92 (2R,3S)-
CO2H
H2N
CO2H
H2N
Me
CO2H
H2N
CO2H
H2N
93 94 95
Fig. 6. Naturally occurring and tailor-made α,β-methano-α-AAs.
Fig. 5. Examples of products prepared using
Ni(II) complex methodology.
Thalidomide is a notorious drug due to the
monumental socio-scientific impact it had on-
nearly every sector of the healthcare industry
[321–324]. Nevertheless, in 1998 and 1999 the
US Food and Drug Administration approved
thalidomide for use in the treatment of erythe-
ma nodosum leprosum and multiple myeloma
[325]. Moreover, the clinical success of thalido-
mide led to the development and marketing of
several of its structural analogs [326–328]. The
Michael addition of glycine–Ni(II) complexes
were used as a key step in the asymmetric syn-
thesis of novel 4-substituted enantiomerically
stable analogs of thalidomide 90 [329,330].
Oxazolomycin A, isolated from the fermenta-
tion broth of Streptomyces sp., exhibits potent
antibiotic properties against various Gram-po
sitive bacteria and Agrobacteriumtume faciens,
strong anticancer activity, as well as various
other antiviralactivities [331–339]. It was envi-
sioned that the pyroglutamate core unit, such
as compound 91 which possesses appropri-
ate functional groups at C-2 and C-3, can be
viewed as a synthetic intermediate in the total
synthesis of Oxazolomycin-type natural prod-
ucts.The first step in this process included the
Michael addition of achiral glycine Schiff base
with a chiral α,β-disubstituted acrylate deriva-
tive for the preparation of the enantiomerically
pure α,β-disubstituted pyroglutamic acid core.
A total of twelve reactions were utilized in the
synthesis of 91 with an overall yield of 10%
[340].
α, β-Methano-AAs, or methanologs of α-AAs,
represent an extreme case of compounds con-
taining a severely conformationally restricted
cyclopropane ring [341, 342]. Remarkably, se
veral cyclopropyl group-containing AAs, such
as 92–94 (Figure 6), are naturally occurring
compounds and have been isolated from va
rious higher plants [343–351].
Fig. 6. Naturally occurring and tailor-made α,β-
methano-α-AAs.
The interest in methanologs of AAs results
from the discovery of a novel and very potent
class of hepatitis C virus NS3/4A protease in-
hibitors [352] containing (1R,2S)-1-amino-
2-vinylcyclopropanecarboxylic acid (95) as
a key structural feature. Thus, at least sixdif-
ferent drugs containing AA 95 are currently
being developed for the treatment of hepati-
tis C. For example, Simeprevir [353], Dano-
previr [354], Asunaprevir [355], Faldaprevir
[356], Ciluprevir, and Grazoprevir [357] all
have a fragment of acid 95 as a sulfonamide
derivative.
Given this profound interest in the phar-
maceutical applications of acid 95, we exami
ned Ni(II) complex chemistry for the asym-
metric synthesis of this compound. The me
thod developed by us is illustrated in Scheme
22 [358].
111https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Scheme 22. Asymmetric synthesis of Boc-protected
(1S,2R)-1-amino-2-vinylcyclopropanecarboxylic acid (99).
The synthetic sequence began with the se-
lective alkylation of glycine complex 19 with
dibromide 96. We found that the first mo-
no-alkylation reaction needed to be conduct-
ed under very mild phase-transfer conditions
using dichloroethane as the solvent at am-
bient temperature. The diastereoselectivity
of the first alkylation step is kinetically con-
trolled and affords product 97 as a mixture of
diastereomers in a ratio of 80:20, but unfor-
tunately it is not high yielding. However, the
ratio of diastereomers 97 is of no concern as
the next alkylation step occurs via deprotona-
tion of the α-stereogenic center. The second
intramolecular, alkylation–cyclization requires
very strong basic conditions giving rise to the
targeted, highly sterically constrained, cyclic
architecture. Product 98 was isolated in 75%
yield as a mixture of diastereomers 90:10. The
major compound with (1S,2R) configuration
was obtained diastereomerically pure by col-
umn chromatography. Disassembly of com-
pound 98 followed by four additional steps
afforded the Boc-protected (1S,2R)-1-amino-
2-vinylcyclopropanecarboxylic acid (99) [358].
A similar reaction sequence was used for the
preparation of the (1S,2R) and (1R,2S) enantio
mers of 1-amino-2-vinylcyclopropanecarbo
xylic acid starting from the glycine complex
derived from the Hamari ligand 13 [359]. Both
approaches provide for reliable access to this
pharmacologically important tailor-made AA.
3-Amino-2-hydroxyoctadecanoic acid (Ahod
100, Figure 7) is a common structural unit of
naturally occurring peptides Ralstonin A and
Ralstoamide A possessing chlamydospore-in-
ducing activity in fungus and moderatephyto-
toxicity in plants [360]. The total synthesis of
Ralstonin A and Ralstoamide A has not been
reported and synthetic work on these mole-
cules has been limited for a long time by the
preparation of selected fragments, in particu-
lar the 3-hydroxy-tyrosine fragment with var-
ious stereochemistries and functional group
protections [361–363]. Planning for the high-
ly anticipated structural confirmation and a
The interest in methanologs of AAs results from the discovery of a novel and very potent
classof hepatitis C virus NS3/4A protease inhibitors [352] containing (1R,
2S)-1-amino-2-vinylcyclopropanecarboxylic acid (95) as a key structural feature. Thus, at least
sixdifferent drugs containing AA 95 are currently beingdeveloped for the treatment of hepatitis C. For
example, Simeprevir [353], Danoprevir [354], Asunaprevir [355], Faldaprevir [356], Ciluprevir, and
Grazoprevir [357] all have a fragment of acid 95 as a sulfonamidederivative.
Given this profound interest in the pharmaceutical applications of acid 95, we examined
Ni(II)complex chemistry for the asymmetric synthesis of this compound. The method developed by
us is illustrated in Scheme 22 [358].
Scheme 22. Asymmetric synthesis of Boc-protected (1S,2R)-1-amino-2-vinylcyclopropanecarboxylic acid
(99).
The synthetic sequence began with the selective alkylation of glycine complex 19 with
dibromide 96. We found that the first mono-alkylation reaction needed to be conducted under very
mild phase-transfer conditions using dichloroethane as the solvent at ambient temperature. The
diastereoselectivity of the first alkylation step is kinetically controlled and affords product 97 as a
mixture of diastereomers in a ratio of 80:20, but unfortunately it is not high yielding. However, the
ratio of diastereomers 97 is of no concern as the next alkylation step occurs via deprotonation of the
α-stereogenic center. The second intramolecular, alkylation–cyclization requires very strong basic
conditions giving rise to the targeted, highly sterically constrained, cyclic architecture. Product 98
was isolated in 75% yield as a mixture of diastereomers 90:10. The major compound with 1S, 2R
configuration was obtained diastereomerically pure by column chromatography. Disassembly of
compound 98 followed by four additional steps afforded the Boc-protected (1S,
2R)-1-amino-2-vinylcyclopropanecarboxylic acid (99) [358]. A similar reaction sequence was used
for the preparation of the 1S,2R and 1R, 2S enantiomers of 1-amino-2-vinylcyclopropanecarboxylic
acid starting from the glycine complex derived from the Hamari ligand 13 [359]. Both approaches
provide for reliable access to this pharmacologically important tailor-made AA.
3-Amino-2-hydroxyoctadecanoic acid (Ahod 100, Figure7) is a common structural unit of
naturally occurring peptides Ralstonin A and Ralstoamide A possessing chlamydospore-inducing
activity in fungus and moderatephytotoxicity in plants [360].The total synthesis of Ralstonin A and
Ralstoamide A has not been reported and synthetic work on these molecules has been limited for a
(S1S,2R)(SS) + (SR)
(S1S,2S)
112 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
long time by the preparation of selected fragments, in particular the 3-hydroxy-tyrosine fragment
with various stereochemistries and functional group protections [361–363]. Planning for the highly
anticipated structural confirmation and a structure–activity relationship study, we decided to focus on
the preparation of Ahod AA 100 which is critically responsible for the lipophilic properties of these
naturally occurring peptides.
Fig. 7. The common structural fragment of Ralstonin A and Ralstoamide A.
As presented in Scheme 23 [364], the synthesis started with the alkylation of chiral glycine
equivalent 19 with alkyl iodide 101. The reaction was conducted under the usual strongly basic
conditions at ambient temperature affording alkylation product 102 in high chemical yield and with
high diastereoselectivity. Disassembly of diastereomerically pure 102 was followed by the
esterification and protection of the amino group. The ester group in 103 was hydrolyzed using NaOH
to yield 104, which was reacted with reagent 105 to produce intermediate 106. Compound 106 was
treated with oxone in THF–methanol to provide keto–ester 107 in moderate yield. Finally, reduction
of the keto group in 107 gave rise to two diastereomeric products, (2S, 3S)-108 and (2R, 3S)-108,
obtained in yields of 39% and 29%, respectively [120]. While the diastereoselectivity of this step was
low, the preparation of both compounds fits well with the current research goals of confirming the
stereochemistries of Ralstonin A and Ralstoamide A.
Scheme 23. Asymmetric synthesis of the lipophilic AA found in Ralstonin A and Ralstoamide A.
CONCLUSIONS. In the field of the asymmetric synthesis of AAs, only a few approaches possess
the practical characteristics attractive to industry for large-scale pharmaceutical production. The
chemistry of Ni(II) complexes is undoubtedly one of these promising methods. As emphasized in this
review, the simplicity of the reaction conditions plays a crucial role in the overall cost structure and
commercial success of chemical processes.
Depending on the structure of the target AA, one may choose either direct chiral modification
of unprotected AAs or the elaboration of chiral glycine equivalents. Of particular commercial interest
are the methods we have developed, which include SOAT, DKR, and inversion of chirality.In the
homologation approach, construction of the desired AA architecture can be efficiently achieved
through alkylation, aldol, Mannich, and Michael addition reactions.
We believe that Hamari’s contributions to this field will be highly valued by practitioners in
both industrial and academic laboratories and will be instrumental in future applications of our
methods for the preparation of commercially marketed pharmaceuticals.
ACKNOWLEDGMENTS. We gratefully acknowledge the financial support from the National
Natural Science Foundation of China (No. 21761132021) and the Qing-Lan Project of Jiangsu
Province (for Han) and IKERBASQUE, Basque Foundation for Science (for Soloshonok).
ВНЕСОК ХАМАРІ В АСИМЕТРИЧНИЙ СИНТЕЗ СПЕЦІАЛЬНО СТВОРЕНИХ АМІНОКИСЛОТ
Цзяньлінь Хань, Хонг Лю, Цзян Ван, Аліція Взорек, Олександр Е. Сорочинський, Карел Д. Кліка, Тайзо
Оно, Хіроїкі Морівакі, Тацунорі Сато, Кунісуке Ізава, Хіройукі Конно, Вадим А. Солошонок
structure–activity relationship study, we decid-
ed to focus on the preparation of Ahod AA 100
which is critically responsible for the lipophilic
properties of these naturally occurring peptides.
Fig. 7. The common structural fragment of
Ralstonin A and Ralstoamide A.
As presented in Scheme 23 [364], the syn-
thesis started with the alkylation of chiral
glycine equivalent 19 with alkyl iodide 101.
The reaction was conducted under the usual
strongly basic conditions at ambient tempera-
ture affording alkylation product 102 in high
chemical yield and with high diastereoselec-
tivity. Disassembly of diastereomerically pure
102 was followed by the esterification and pro-
tection of the amino group. The ester group in
103 was hydrolyzed using NaOH to yield 104,
which was reacted with reagent 105 to pro-
duce intermediate 106. Compound 106 was
treated with oxone in THF–methanol to pro-
vide keto–ester 107 in moderate yield. Finally,
reduction of the keto group in 107 gave rise to
two diastereomeric products, (2S,3S)-108 and
(2R,3S)-108, obtained in yields of 39% and 29%,
respectively [120]. While the diastereoselecti
vity of this step was low, the preparation of
both compounds fits well with the current re-
search goals of confirming the stereochemis-
tries of Ralstonin A and Ralstoamide A.
Scheme 23. Asymmetric synthesis of
the lipophilic AA found in Ralstonin A
and Ralstoamide A.
113https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
CONCLUSIONS. In the field of the asym-
metric synthesis of AAs, only a few approaches
possess the practical characteristics attractive
to industry for large-scale pharmaceutical pro-
duction. The chemistry of Ni(II) complexes is
undoubtedly one of these promising methods.
As emphasized in this review, the simplicity of
the reaction conditions plays a crucial role in
the overall cost structure and commercial suc-
cess of chemical processes.
Depending on the structure of the target
AA, one may choose either direct chiral modi
fication of unprotected AAs or the elaboration
of chiral glycine equivalents. Of particular
commercial interest are the methods we have
developed, which include SOAT, DKR, and
inversion of chirality. In the homologation
approach, construction of the desired AA ar-
chitecture can be efficiently achieved through
alkylation, aldol, Mannich, and Michael addi-
tion reactions.
We believe that Hamari’s contributions to
this field will be highly valued by practitioners
in both industrial and academic laboratories
and will be instrumental in future applications
of our methods for the preparation of com-
mercially marketed pharmaceuticals.
We gratefully acknowledge the finan-
cial support from the National Natu-
ral Science Foundation of China (No.
21761132021) and the Qing-Lan Pro-
ject of Jiangsu Province (for Han) and
IKERBASQUE, Basque Foundation
for Science (for Soloshonok).
ВНЕСОК ХАМАРІ В АСИМЕТРИЧНИЙ СИНТЕЗ
СПЕЦІАЛЬНО СТВОРЕНИХ АМІНОКИСЛОТ
Цзяньлінь Хань, Хонг Лю, Цзян Ван,
Аліція Взорек, Олександр Е. Сорочинський,
Карел Д. Кліка, Тайзо Оно,
Хіроїкі Морівакі, Тацунорі Сато,
Кунісуке Ізава, Хіройукі Конно,
Вадим А. Солошонок
1 Цзянсу-Центр спільних інновацій для ефек-
тивного перероблення та використання лісо-
вих ресурсів, Коледж хімічної інженерії, Нанкін-
ський лісотехнічний університет,
Нанкін 210037, Китай;
2 Державна Ключова лабораторія дослідження
ліків, Шанхайський Інститут медичних мате-
ріалів, Китайська Академія наук,
Шанхай 201203, Китай;
3 Інститут хімії, Університет Яна Коханов-
ського у Кельце, Університетська 7, 25–406
Кельце, Польща;
4 Інститут біоорганічної хімії та нафтохімії
ім. В. П. Кухаря, Національна Академія наук
України, Київ 02094, Україна;
5 Німецький Центр дослідження раку (DKFZ),
Нойенхаймер Фельд 280, 69120 Гейдельберг, Ні-
меччина;
6 Національний Інститут передових промисло-
вих наук і технологій, 463–8560, Нагоя, Японія;
7 Хамарі Кемікал Лтд.., Осака, Японія;
8 Департамент хімії та біологічної інженерії,
Аспірантура наук та інженерії, Університет
Ямагата, 992–8510 Йонедзава, Ямагата, Японія;
9 Департамент органічної хімії, факультет хі-
мії, Університет Країни Басків UPV/EHU,
Пасео Мануель Лардизабал 3, 20018 Сан-Се-
бастьян, Іспанія;
10 ІКЕРБАСКЕ, Баскський Фонд науки, Марія
Діас де Харо 3, плаза Бізкая, 48013 Більбао,
Іспанія.
email: vadimsoloshonok@gmail.com
114 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
У цій статті розглянуто розвиток аси-
метричного синтезу спеціально створених
амінокислот, проведений в компанії Hamari
Chemicals за 10-річний період з 2013 по
2022 рік. Обговорення базується на страте-
гіях, таких як пряма хіральна модифікація
незахищених амінокислот через проміжне
утворення комплексів Ni(II) і розроблення
хіральних нуклеофільних або електрофіль-
них еквівалентів гліцину. Перший підхід
включає, наприклад, асиметричну транс
формацію другого порядку, динамічну кі-
нетичну роздільність та інверсію хірально-
сті, тоді як другий підхід включає побудову
бажаної архітектури амінокислот за допо-
могою, наприклад, реакцій алкілування,
альдольних, Манніха чи Міхаеля, а також
багатоступінчастих процедур. Наголошу-
ється на зручності в експлуатації, масш-
табованості та практичності розроблених
методів.
Ключові слова: спеціально створені амі-
нокислоти; дизайн і розроблення ліків; аси-
метрична трансформація другого порядку;
динамічна кінетична роздільність; інверсія
хіральності.
REFERENCES
1. Vickery H.B., Schmidt C.L.A. The history of
the discovery of the amino acids. Chem. Rev.
1931. 9:169–318.
2. Fowden, L., Lea P.J., Bell E. A. The non-protein
amino acids of plants. In Advances in Enzymol-
ogy, Meister, A. Ed., John Wiley & Sons, New
York, USA, 1979. Vol. 50. 117–175.
3. Lea P.J., Wallsgrove R.M., Miflin B.J. The bio-
synthesis of amino acids in plants. In The Che
mistry and Biochemistry of Amino Acids, Bar-
rett, G. C. Ed.; Chapman and Hall, London,
UK, 1985. 197–226.
4. Bryan J.K. Advances in the biochemistry of
amino acid biosynthesis. In The Biochemistry of
Plants, Stump, P. K., Conn, E. E. Eds. In Inter-
mediary nitrogen metabolism, Miflin B. J., Lea
P. J. Eds.. 1990, Vol. 16. 169–195.
5. Bella A.E., Alison A., NashR. J. Non-Protein
Amino Acids: A Review of the Biosynthesis
and Taxonomic Significance. Nat. Prod. Com-
mun. 2008. 3: 93–110.
6. Frisch D.M., Dunnill P.M., Smith A., Fowden L.
The specificity of amino acid biosynthesis in
the Cucurbitaceae. Phytochemistry. 1967. 6:
921–931.
7. Peterson P.J., Fowden L. The biosynthesis of
γ-substituted glutamic acids in Gleditsia tria-
canthos. Phytochemistry. 1972. 11: 663–673.
8. Murakoshi I., Kuramoto H., Haginiwa J., Fow
den L. The enzymic synthesis of b-substituted
alanines. Phytochemistry. 1972. 11: 177–182.
9. Dunnill P.M., Fowden L. The biosynthesis of
b-pyrazol-1-ylalanine.J. Exp. Bot.1963. 14:
237–248.
10. Dunnill P.M., Fowden L. The amino acids of
the genus Astragalus. Phytochemistry. 1967. 6:
1659–1663.
11. Pilbeam D.J., Bell E.A. Free amino acids of
Crotalaria seeds. Phytochemistry. 1979.18:
973–985.
12. Pilbeam D.J., Polhill R. M., Bell E.A. Free ami-
no acids and alkaloids of South American,
Asian and Australian Crotalaria species Bot. J.
Linn. Soc.1979. 79: 259–266.
13. Evans S.V., Fellows L.E., Bell E.A. Distribution
and systematic significance of basic non-pro-
tein amino acids and amines in the Tephrosie-
ae. Biochem. Syst. Ecol.1985. 13: 271–302.
14. Watson R., Fowden L. Amino acids of Caesal-
pinia tinctoria and some allied species. Phyto-
chemistry. 1973. 12: 617–622.
15. Evans C.S., Bell E.A. Uncommon amino acids
in the seeds of 64 species of Caesalpinieae.
Phytochemistry. 1978. 17: 1127–1129.
16. Soloshonok V. A., Kirilenko A. G., Kukhar
115https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
V. P., Resnati, G. Transamination of Fluorina
ted b-Keto Carboxylic Esters. A Biomimetic
Approach to b-Polyfluoroalkyl-b-Amino Ac-
ids. Tetrahedron Lett.1993. 34: 3621–3624.
17. Xue Y., Cao C., Zheng Y. Enzymatic asymmet-
ric synthesis of chiral amino acids. Chem. Soc.
Rev. 2018. 47: 1516.
18. Roche S.P. In the Pursuit of (Ald) Imine Sur-
rogates for the Direct Asymmetric Synthesis of
Non-Proteinogenic a-Amino Acids. Synthesis.
2021. 53: 2767–2776.
19. Soloshonok V. A., Sorochinsky A. E. Practical
Methods for the Synthesis of Symmetrically
a,a-Disubstituted-a-Amino Acids, Synthesis.
2010. 14: 2319–2344.
20. Han J., Sorochinsky A. E., Ono T. et al. Biomi-
metic Transamination – a Metal-Free Alterna-
tive to the Reductive Amination. Application
for Generalized Preparation of Fluorine-Con-
taining Amines and Amino Acids. Cur. Org.
Synthesis. 2011. 8: 281–294.
21. Mikami K., Fustero S., Sánchez-Roselló M. et
al. Synthesis of Fluorine Containing b-Amino
Acids. Synthesis. 2011. 19: 3045–3079.
22. Molinaro C., Scott J. P., Shevlin M. et al. Ca
talytic, Asymmetric, and Stereodivergent Syn-
thesis of Non-Symmetric b,b-Diaryl-b-Amino
Acids. J. Am. Chem. Soc. 2015. 137: 999–1006.
23. Xue Y. P., Cao C. H., Zheng Y. G. Enzymatic
asymmetric synthesis of chiral amino acids.
Chem. Soc. Rev. 2018. 47: 1516–1561.
24. Leonard D. J., Ward J. W., Clayden J. Asym-
metric a-arylation of amino acids. Nature.
2018. 562: 105–109.
25. He F. S., Jin J. H., Yang Z. T. et al. Direct Asym-
metric Synthesis of b-bis-Aryl-a-Amino Acid
Eesters via Enantioselective Copper-Catalyzed
Addition of p-Quinone Methides. ACS Cataly-
sis. 2016. 6: 652–656.
26. Wei L., Zhu Q., Xu S. M. et al. Stereodivergent
Synthesis of a,a-Disubstituted a-Amino Acids
via Synergistic Cu/Ir Catalysis. J. Am. Chem.
Soc. 2018. 140: 1508–1513.
27. Metz A. E., Kozlowski M. C. Recent Advances
in Asymmetric Catalytic Methods for the For-
mation of Acyclic a, a-Disubstituted a-Amino
Acids. J. Org. Chem. 2015. 80: 1–7.
28. He G., Wang B., Nack W. A., Chen, G. Synthe-
ses and Transformations of a-Amino Acids via
Palladium-Catalyzed Auxiliary-Directed sp3
C–H Functionalization. Acc.Chem. Res. 2016.
49: 635–645.
29. Wei L., Xiao L., Hu Y. et al. Recent Advances in
Metallated Azomethine Ylides for the Synthe-
sis of Chiral Unnatural a-Amino Aacids. Chin.
J. Org. Chem. 2019. 39: 2119–2130.
30. Wzorek A., Han J., Lyutenko N. V. et al. Dis-
covery of biomimetic transamination as a ge
neral synthetic method for preparation of flu-
orine-containing amines and amino acids.Ukr.
Bioorg. Acta. 2023. 18(2): 3–15.
https://doi.org/10.15407/bioorganica2023.
01.010
31. Lyutenko N. V., Sorochinsky A. E., Soloshonok
V. A. Applications of chiral sulfinyl auxiliaries
in the asymmetric synthesis of fluorinated
amines and amino acids.Ukr. Bioorg. Acta.
2023. 18(1): 10–21.
32. Soloshonok V. A., Ono T. The Effect of Substitu-
ents on the Feasibility of Azomethine-Azome-
thine Isomerization: New Synthetic Opportu-
nities for Biomimetic Transamination. Tetra-
hedron. 1996. 52: 14701–14712.
33. Ohkura H., Berbasov D. O., Soloshonok V. A.
Chemo- and Regioselectivity in the Reactions
between Highly Electrophilic Fluorine Con-
taining Dicarbonyl Compounds and Amines.
Improved Synthesis of the Corresponding
Imines/Enamines. Tetrahedron. 2003. 59:
1647–1656.
34. Wagner I., Musso H. New naturally occurring
amino acids.Angew. Chem., Int.Ed. 1983. 22:
816–828.
35. Soloshonok V. A., Cai C., Hruby V. J. et al. Ste-
reochemically Defined C-Substituted Glutam-
ic Acids and their Derivatives. 1. An Efficient
116 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Asymmetric Synthesis of (2S,3S)-3-Methyl-
and -3-Trifluoromethylpyroglutamic Acids.
Tetrahedron. 1999. 55: 12031–12044.
36. Hamley I. W. Introduction to Peptide Science.
John Wiley & Sons, New York, USA. 2020.
ISBN: 9781119698173.
37. Saladin K. Anatomy and Physiology: The Unity
of Form and Function, sixth ed., McGraw-Hill,
2011.
38. Asymmetric Synthesis and Application of
α-Amino Acids. ACS Symposium Series #1009;
Soloshonok V. A., Izawa K., Eds., Oxford Uni-
versity Press, 2009.
39. Blaskovich M.A.T. Unusual amino acids in
medicinal chemistry. J. Med. Chem. 2016. 59:
10807–10836.
40. Hodgson D.R.W., Sanderson J.M. The synthe-
sis of peptides andproteins containing non-
natural amino acids. Chem. Soc. Rev. 2004. 33:
422–430.
41. Henninot A., Collins J. C., Nuss J. M. The cur-
rent state of peptidedrug discovery: Back to
the future? J. Med. Chem. 2018. 61:1382–1414.
42. Han J., Lyutenko N. V., Sorochinsky A. E. et
al.Tailor-Made Amino Acids in Pharma-
ceutical Industry: Synthetic Approaches to
Aza-Tryptophan Derivatives.Chem.–Eur.
J. 2021. 27: 17510–17528. doi.org/10.1002/
chem.202102485.
43. Han J., Konno H., SatoT. et al. Peptidomi-
metics and Peptide-Based Blockbuster Drugs.
Curr. Org. Chem. 2021. 25: 1627–1658.
DOI: 10.2174/1385272825666210610155047
44. Craik D.J., Fairlie D.P., Liras S., Price D. The
future of peptidebased drugs. Chem. Biol.
Drug. Des. 2013. 81:136–147.
45. Bravo P., Guidetti M., Viani F. et al.Chiral
Sulfoxide Controlled Asymmetric Additions
to C,N Double Bond. An Efficient Approach
to Stereochemically Defined a-Fluoroalkyl
Amino Compounds. Tetrahedron. 1998. 54:
12789–12806.
46. Han J.,Wzorek A., Dhawan G. et al. New drugs
appearing on the market in 2023: molecules
containing fluorine and fragments of tai-
lor-made amino acids.Ukr. Bioorg. Acta. 2024.
19(1): 3–20.
https://doi.org/10.15407/bioorganica2024.01.
003
47. 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: 3651.
https://doi.org/10.3390/molecules28093651.
48. Wang Q., Han J., Sorochinsky A. E. et al. The
Latest FDA-Approved Pharmaceuticals Con-
taining Fragments of Tailor-Made Amino Ac-
ids and Fluorine. Pharmaceuticals. 2022. 15:
999.
https://doi.org/10.3390/ ph150809991847558.
49. Liu A., Han J., NakanoA. et al. New pharma-
ceuticals approved by FDA in 2020: Small-mo
lecule drugs derived from amino acids and re-
lated compounds. Chirality. 2022. 34: 86–103.
50. Han J., Konno H., Sato T. et al. Tailor-made-
amino acids in the design of small-molecule
blockbusterdrugs. Eur. J. Med. Chem. 2021.
220:113448.
doi.org/10.1016/j.ejmech.2021.113448.
51. Liu J., Han J., Izawa K. et al. Cyclic tailor-made
amino acids inthe design of modern pharma-
ceuticals. Eur. J. Med. Chem. 2020. 208:112736.
Doi:10.1016/j.ejmech.2020.112736.
52. Mei H., Han J., White S. et al. Tailor-made ami-
no acids andfluorinated motifs as prominent
traits in modern pharmaceuticals. Chem. –
Eur. J. 2020. 26:11349–11390.
https://doi.org/10.1002/chem.202000617.
53. Ma J.S. Unnatural amino acids in drug disco
very. Chim. Oggi–Chem. Today. 2003. 21: 65–68.
54. Yin Z., Hu W., Zhang W. et al. Tailor-made
amino acid-derived pharmaceuticals approved
by the FDA in 2019. Amino Acids. 2020. 52:
1227–1261.
DOI: 10.1007/s00726-020-02887-4.
117https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
55. Qiu W., Gu X., Soloshonok V. A. et al. Stereo
selective synthesis of conformationally con-
strainedreverse turn dipeptide mimetics. Tet-
rahedron Lett. 2001. 42:145–148.
56. Fosgerau K., Hoffmann T. Peptide therapeu-
tics: Current statusand future directions. Drug
Discov. Today. 2015. 20: 122–128.
57. Mei H., Han J., Klika K. D. et al. Applications
of fluorinecontainingamino acids for drug de-
sign. Eur. J. Med. Chem. 2020. 186:111826.
https://doi.org/10.1016/j.ejmech.2019.111826.
58. Cai M., Cai C., Mayorov A. V. et al. Biologi-
cal and conformational study of b-substituted
prolines in MT-II template: steric effects lead-
ing to human MC5 receptor selectivity. J. Pept.
Res. 2004. 63: 116–131.
59. Stevenazzi A., Marchini M., Sandrone G. et
al. Amino acidic scaffolds bearing unnatural
sidechains: An old idea generates new and
versatile tools for thelife sciences. Bioorg. Med.
Chem. Lett. 2014. 24: 5349–5356.
60. Soloshonok V. A., Kirilenko A. G., Galushko
S. V., Kukhar V. P. Catalytic Asymmetric Syn-
thesis of b-Fluoroalkyl-b-Amino Acids via
Biomimetic [1,3]-Proton Shift Reaction.Tetra-
hedron Lett.1994. 35: 5063–5064.
61. Zou Y., Han J., Saghyan A. S. et al. Asymmetric
Synthesis of Tailor-Made Amino Acids Using
Chiral Ni(II)-Complexes of Schiff Bases; An
Update of the Recent Literature. Molecules.
2020. 25: 2739.
doi:10.3390/molecules25122739.
62. Wang Y., Song X.,Wang J. et al. Recent ap-
proaches for asymmetric synthesis of a-amino
acids via homologation of Ni(II) complexes.
Amino Acids. 2017. 49: 1487–1520.
DOI: 10.1007/s00726-017-2458-6.
63. Sorochinsky A. E., Aceña J. L., Moriwaki H. et
al. Asymmetric synthesis of a-amino acids via
homologation of Ni(II) complexes of glycine
Schiff bases; Part 1: Alkyl halide alkylations.
Amino Acids. 2013. 45: 691–718.
DOI: 10.1007/s00726-013-1539-4.
64. Sorochinsky A. E., Aceña J. L., Moriwaki H. et
al. Asymmetric synthesis of a-amino acids via
homologation of Ni(II) complexes of glycine
Schiff bases. Part 2: Aldol, Mannich addition
reactions, deracemization and (S) to (R) in-
terconversion of a-amino acids. mino Acids.
2013. 45: 1017–1033.
DOI 10.1007/s00726-013-1580-3.
65. Aceña J. L., Sorochinsky A. E., Soloshonok
V. A. Asymmetric synthesis of a-amino ac-
ids via homologation of Ni(II) complexes of
glycine Schiff bases. Part 3: Michael addition
reactions and miscellaneous transformations.
Amino Acids. 2014. 46: 2047–2073.
DOI: 10.1007/s00726-014-1764-5.
66. Takahashi M., Moriwaki H., Miwa T. et al.
Large scale synthesis of chiral (3Z, 5Z)-2,7-di-
hydro-1H-azepine-derived Hamari ligand for
general asymmetric synthesis of tailor-made
amino acids. Org. Process Res. Dev. 2019. 23:
619–628.
DOI: 10.1021/acs.oprd.8b00406.
67. Ellis T. K., Ueki H., Yamada T. et al. The Design,
Synthesis and Evaluation of a New Generation
ofModular Nucleophilic Glycine Equivalents
for the Efficient Synthesisof Sterically Con-
strained a-Amino Acids. J. Org. Chem. 2006.
71: 8572–8578.
68. Soloshonok V. A., Cai C., Hruby V. J. Toward
Design of a Practical Methodology for Stereo-
controlled Synthesis of c-Constrained Pyro-
glutamic Acids and Related Compounds. Vir-
tually Complete Control of Simple Diastereo-
selectivity in the Michael Addition Reactions
of Glycine Ni(II) Complexes with N-(Enoyl)
oxazolidinones. Tetrahedron Lett. 2000. 41:
135–139.
69. Soloshonok V. A., Ueki H., Ellis T. K. et al.
Application of Modular Nucleophilic Glycine
Equivalentsfor Truly Practical Asymmetric
Synthesis of b-Substituted Pyroglutamic Ac-
ids. Tetrahedron Lett. 2005. 46: 1107–1110.
70. Moore J. L., Taylor S. M., Soloshonok V. A.
118 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
An Efficient and Operationally Convenient
General Synthesis of Tertiary Amines by Di-
rect Alkylation of Secondary Amines with
Alkyl Halides in the Presence of Hünig’s Base.
Arkivoc. 2005. 6: 287–292.
71. Zhou S., Wang J., Chen X. et al. Chemical
Kinetic Resolution of Unprotected b-Substi-
tuted-b-Amino Acids Using Recyclable Chi-
ral Ligands. Angew. Chem., Int. Ed. 2014. 53:
7883–7886.
DOI: 10.1002/anie.201403556.
72. Soloshonok V. A., Kirilenko A. G., Fokina N.
A. et al. Biocatalytic Resolution of b-Fluoro-
alkyl-b-Amino Acids. Tetrahedron: Asymme-
try. 1994. 5: 1119–1126.
73. Nian Y.,Wang J., Moriwaki H. et al. Analysis of
crystallographic structures of Ni(II) complex-
es of a-amino acid Schiff bases; Elucidation of
the substituents effect on stereochemical pre
ferences. Dalton Trans. 2017. 46: 4191–4198.
DOI: 10.1039/C7DT00014F.
74. Romoff T. T., Palmer A. B., Mansour N. et al.
Scale-up Synthesis of (R)- and (S)-N-(2-Ben-
zoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)
pyrrolidine-2-carboxamide Hydrochloride,
a Versatile Reagent for Preparation of Tai-
lor-made a- and b-Amino Acids in Enanti-
omerically Pure Form. Org. Process Res. Dev.
2017. 21: 732–739.
DOI: 10.1021/acs.oprd.7b00055.
75. Ueki H., Ellis T. K., Martin C. H., Soloshonok
V. A. Efficient Large-Scale Synthesis of Picoli
nic Acid Derived Ni(II)-Complexes of Gly-
cine. Eur. J. Org. Chem. 2003. 1954–1957.
76. Ueki H., Ellis T. K., Martin C. H. et al. Improved
Synthesis of Proline Derived Ni(II)-Complex-
es of Glycine, a Versatile Chiral Equivalents of
Nucleophilic Glycine for General Asymmet-
ric Synthesis of a-Amino Acids. J. Org. Chem.
2003. 68: 7104–7107.
77. Romoff T. T., Goodman M. Urethane-protect-
ed N-carboxyanhydrides (UNCAs) as unique
reactants for the study of intrinsic racemiza-
tion tendencies in peptide synthesis. J. Pept.
Res. 1997. 49: 281–292.
78. 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-pyrrolidinecarbo
xamide.Org. Process Res. Dev. 2020. 24: 294–
300.
https://dx.doi.org/10.1021/acs.oprd.9b00399.
79. Zhang W., Eto Ekomo R., Roussel C. et al.
Axially Chiral Ni(II) Complexes of a-Amino
Acids; Separation of Enantiomers and Kinetics
of Racemization. Chirality. 2018. 30: 498–508.
DOI: 10.1002/chir.22815.
80. Han J., Jean M., Roussel C. et al. Chromato-
graphic Approach to Study the Configuratio
nal Stability of Ni(II) Complexes of Amino
Acid Schiff Bases Possessing Stereogenic Nit
rogen. Chirality. 2019. 31: 328–335.
https://doi.org/10.1002/chir.23059.
81. Mei H., Jean M., Albalat M. et al. Effect of Sub-
stituents on the Configurational Stability of
the Stereogenic Nitrogen in Metal(II) Comp
lexes of a-Amino Acid Schiff Bases. Chirality.
2019. 31: 401–409.
DOI:10.1002/chir.23066.
82. Bergagnini M., Fukushi K., Han J. et al. NH-
type of chiral Ni(II) complexes of glycine
Schiff base: design, structural evaluation, reac-
tivity and synthetic applications. Org. Biomol.
Chem. 2014. 12:1278–1291.
DOI:10.1039/C3OB41959B.
83. Jamison M. M., Turner E. E. The Inter-Rela-
tion ofFirst- and Second-Order Asymmetric
Transformations. J. Chem. Soc.1942. 437–440.
84. Busch D. H. High Yield Resolution of Tris-
(ethylenediamine)-cobalt(III) by a Second-
order Asymmetric Process. J. Am. Chem.
Soc.1955. 77: 2747–2748.
85. Faigl F., Mátravölgyi B., Holczbauer T. et
al.Resolution of 1-[2-Carboxy-6-(trifluorome-
thyl)phenyl]-1H-pyrrole-2-carboxylic Acid-
119https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
with Methyl (R)-2-Phenylglycinate, Recipro-
cal Resolution andSecond Order Asymmetric
Transformation. Tetrahedron: Asymmetry.
2011. 22: 1879–1884.
86. Tsubaki K., Miura M., Morikawa H. et al. Syn-
thesis ofOptically Active Oligonaphthalenes
via Second-Order AsymmetricTransforma-
tion. J. Am. Chem. Soc. 2003. 125: 16200–
16201.
87. Yamada K., Ishii R., Nakagawa H., Kawazura
H. A. Second-Order Asymmetric Transforma-
tion of Racemic 2-Hydroxymethyl-[5]-thia-
heterohelicene into a Single Enantiomer upon
Uptake by Bovine Serum Albumin. Tetrahe-
dron: Asymmetry. 1996. 7: 737–746.
88. Donaldson W. A., Shang L., Rogers R. D. Re-
activity ofTricarbonyl(pentadienyl)iron(1+)
Cations: Preparation of an OpticallyPure Tri-
carbonyl(diene)iron Complex via Second-Or-
der Asymmetric Transformation. Organome-
tallics. 1994. 13: 6–7.
89. Smrcina M., Lorenc M., Hanus V. et al. Synthe-
sis of Enantiomerically Pure 2,2′-Dihydroxy-
1,1′-binaphthyl,2,2′-Diamino-1,1′-binaphthyl,
and 2-Amino-2′-hydroxy-1,1′-binaphthyl.
Comparison of Processes Operating as Dia
stereoselective Crystallization and as Second
Order Asymmetric Transformation. J. Org.
Chem. 1992. 57: 1917–1920.
90. Spilovska K., Zemek F., Korabecny J. et al.
Adamantane – A Lead Structure for Drugs in
Clinical Practice. Curr. Med. Chem. 2016. 23:
3245–3266.
91. Ide K., Kawasaki Y., Kawakami K., Yamada
H. Anti-influenza Virus Effects of Catechins:
A Molecular and Clinical Review. Curr. Med.
Chem. 2016. 23: 4773–4783.
92. Das K. Antivirals targeting influenza A virus. J.
Med. Chem. 2012. 55: 6263–6277.
93. Kolocouris N., Kolocouris A., Foscolos G. B. et
al. Synthesis and Antiviral Activity Evaluation
of Some New Aminoadamantane Derivatives.
J. Med. Chem.1996. 39: 3307–3318.
94. Zoidis G., Kolocouris N., Kelly J. M. et al. New
aminoadamantane derivatives with antiproli
ferative activity. Eur. J. Med. Chem. 2010. 45:
5022–5030.
95. Han J., Takeda R., Sato T. H. et al. Optical Re
solution of Rimantadine. Molecules. 2019. 24:
1828.
doi: 10.3390/molecules24091828.
96. Soloshonok V. A., Ono T., Soloshonok I. V.
Enantioselective Biomimetic Transamination
of b-Keto Carboxylic Acid Derivatives. An
Efficient Asymmetric Synthesis of b-Fluoro-
alkyl-b-Amino Acids. J. Org. Chem.1997. 62:
7538–7539.
97. Wanka L., Iqbal K., Schreiner P. R. Discovery
of innovative small molecule therapeutics.
Chem. Rev. 2013. 113: 3516–3604.
98. Soloshonok V. A., Ellis T. K. Design and Syn-
thesis of a New Generation of “NH” Ni(II)
Complexes of Glycine Schiff Bases and Their
Unprecedented C-H vs. N-H Chemoselectivi-
ty in the Alkyl Halide Alkylations and Michael
addition Reactions. Synlett. 2006. 533–538.
99. Soloshonok V. A., Ellis T. K., Ueki H., Ono T.
Resolution/Deracemization of Chiral a-Ami-
no Acids Using Resolving Reagents with Fle
xible Stereogenic Centers. J. Am. Chem. Soc.
2009. 131: 7208–7209.
100. Takeda R., Kawamura A., Kawashima A. et al.
Second-order asymmetric transformation and
its application for the practical synthesis of
α-amino acids. Org. Biomol. Chem. 2018. 16:
4968–4972.
DOI: 10.1039/C8OB00963E.
101. 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: 2672–2679. DOI:
10.1002/hlca.201200536.
102. Takeda R., Kawashima A., Yamamoto J. et al.
Tandem Alkylation–Second-Order Asymmet-
ric Transformation Protocol for Preparation
of Phenylalanine-Type Tailor-Made a-Amino
120 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Acids. ACS Omega 2018. 3: 9729–9737.
DOI: 10.1021/acsomega.8b01424.
103. Pellissier H. Recent developments in dynam-
ic kinetic resolution. Tetrahedron. 2011. 67:
3769–3802.
104. Ward R.S. Dynamic kinetic resolution. Tetra-
hedron: Asymmetry. 1995. 6: 1475–1490.
105. Zhang Y., Zhang Y., Ramström O. Dynamic
covalent kinetic resolution. Cataly. Rev. 2020.
62: 66–95.
106. Kamal A., Azhar M. A., Krishnaji T. et al. Ap-
proaches based on enzyme mediated kinetic to
dynamic kinetic resolutions: A versatile route
for chiral intermediates. Coord. Chem. Rev.
2008. 252: 569–92.
107. Turner N.J. Enzyme catalysed deracemisation
and dynamic kinetic resolution reactions. Curr
.Op. Chem. Biol. 2004. 8: 114–119.
108. De Risi C., Bortolini O., Di Carmine G. et al.
Kinetic resolution, dynamic kinetic resolution
and asymmetric desymmetrization by N-he
terocyclic carbene catalysis. Synthesis. 2019.
1871–1891.
109. Ahn Y., Ko S. B., Kim M. J., Park J. Racemi-
zation catalysts for the dynamic kinetic reso-
lution of alcohols and amines. Coord. Chem.
Rev. 2008. 252: 647–58.
110. Vedej E., Jure M. Efficiency in nonenzyma
tic kinetic resolution. Angew. Chem., Int. Ed.
2005. 44: 3974–4001.
111. Huerta F.F., Minidis A.B., Bäckvall J.E. Race-
misation in asymmetric synthesis. Dynamic
kinetic resolution and related processes in
enzyme and metal catalysis. Chem. Soc. Rev.
2001. 30: 21–331.
112. Lee J.H., Han K., Kim M.J., Park J. Chemoen-
zymatic dynamic kinetic resolution of alcohols
and amines. Eur. J.Org. Chem. 2010. 999–1015.
113. Liu W, Yang X. Recent advances in (dynamic)
kinetic resolution and desymmetrization cata-
lyzed by chiral phosphoric acids. Asian J. Org.
Chem. 2021. 4: 92–710.
114. Kim M.J., Ahn Y., Park J. Dynamic kinetic re
solutions and asymmetric transformations by
enzymes coupled with metal catalysis. Curr
Op. Biotech. 2002. 13: 578–87.
115. Bhat V., Welin E.R., Guo X., Stoltz B.M. Ad-
vances in stereoconvergent catalysis from 2005
to 2015: transition-metal-mediated stereoab-
lative reactions, dynamic kinetic resolutions,
and dynamic kinetic asymmetric transforma-
tions. Chem. Rev. 2017. 117: 4528–4561.
116. Moriwaki H., Resch D., Li, H. et al. Synthesis
and stereochemical assignments of diastereo
meric Ni(II) complexes of glycine Schiff base
with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)
amino]acetyl}amino)benzophenone; a case of
configurationally stable stereogenic nitrogen.
Beilstein J. Org. Chem. 2014. 10: 442–448.
doi:10.3762/bjoc.10.41.
117. Moriwaki H., Resch D., Li, H. et al. Inexpen-
sive chemical method for preparation of enan-
tiomerically pure phenylalanine.Amino Acids.
2014. 46: 945–952.
DOI: 10.1007/s00726-013-1656-0.
118. Takeda R., Kawamura A., Kawashima A. et al.
Design and synthesis of (S)- and (R)-a-(phe-
nyl)-ethylamine-derived NH-type ligands and
their application for the chemical resolution of
a-amino acids.Org. Biomol. Chem. 2014. 12:
6239–6249.
DOI: 10.1039/c4ob00669k.
119. Sorochinsky A. E., Ueki H., Aceña J. L. et al.
Chemical approach for interconversion of (S)-
and (R)-a-amino acids. Org. Biomol. Chem.
2013. 11: 4503–4507.
DOI:10.1039/C3OB40541A.
120. Sorochinsky A. E., Ueki H., Aceña J. L. et al.
Chemical deracemization and (S) to (R) in-
terconversion of some fluorine-containing
a-amino acids. J. Fluor. Chem. 2013. 152: 114–
118.
DOI: 10.1016/j.jfluchem.2013.02.022.
121. Nian Y., Wang J., Zhou S. et al. Recyclable Li
gands for the Non-Enzymatic Dynamic Kine
tic Resolution of Challenging a-Amino Acids.
121https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Angew. Chem., Int. Ed. 2015. 54: 12918–12922.
DOI: 10.1002/anie.201507273.
122. Nian Y., Wang J., Zhou S. et al. Purely Chemi-
cal Approach for Preparation o fD-alpha-ami-
no Acidsvia(S)-to-(R)-interconversion of Un-
protected Tailor-madealpha-aminoAcids. J.
Org. Chem. 2016. 81: 3501–3508.
DOI: 10.1021/acs.joc.5b02707.
123. Mei H., Han J., Takeda R. et al. Practical Meth-
od for Preparation of (S)‑2-Amino-5,5,5-trif-
luoropentanoic Acid via Dynamic Kinetic Res-
olution. ACS Omega. 2019. 4: 11844–11851.
DOI: 10.1021/acsomega.9b01537.
124. Nagaoka K., Nakano A., Han J. et al. Com-
parative Study of Different Chiral Ligands for
Dynamic Kinetic Resolution of Amino Acids.
Chirality. 2021. 33: 685–702.
DOI.10.1002/chir.23350.
125. Nakano A., Hayashi A., Nagaoka K. et al. Dy-
namic Thermodynamic Resolution of Unpro-
tected Amino Acids Using Ni(II) Chiral Schiff
Bases. Eur. J. Org. Chem. 2024. 27: e202400417.
126. Takeda R., Kawamura A., Kawashima A. et
al. Chemical Dynamic Kinetic Resolution
and (S)/(R)-Interconversion of Unprotected
a-Amino Acids.Angew. Chem., Int. Ed. 2014.
53: 12214–12217.
DOI: 10.1002/anie.201407944.
127. Wang S., Zhou S., Wang J. et al. Chemical Dy-
namic Thermodynamic Resolution and S/R
Interconversion of Unprotected Unnatural
Tailor-made a-Amino Acids. J. Org. Chem.
2015. 80: 9817–9830.
DOI: 10.1021/acs.joc.5b01292.
128. TakedaR., AbeH., Shibata N. et al. Asymmet-
ric synthesis of a-deuterated a-amino acids.
Org. Biomol. Chem. 2017. 15: 6978–6983.
DOI: 10.1039/C7OB01720K.
129. Anglister J., Srivastava G., Naider F. NMR
Spectroscopy of Paramagnetic Molecules,
Prog. Nucl. Magn. Reson. Spectrosc. 2016. 97:
40–56.
130. Dubey A., Kadumuri R. V., Jaipuria G. et al.
Crowding interactions perturb structure and
stability by destabilizing the stable core of the
a-subunit of tryptophan synthase. Chem. Bio-
Chem. 2016. 17: 334–340.
131. Dayal P. V., Singh H., Busenlehner L. S.H., El-
lis R. Exposing the Alkanesulfonate Monooxy-
genase Protein–Protein Interaction Sites. Bio-
chemistry. 2015. 54: 7531–7538.
132. Yu Y., Lv X., Li J. et al. De Novo Design of
Chemical Stability Near-Infrared Molecular
Probes for High-Fidelity Hepatotoxicity Eva
luation In Vivo. J. Am. Chem. Soc. 2015. 137:
4594–4597.
133. Wei L., Shen Y., Xu F. et al. I maging complex
protein metabolism in live organisms by sti
mulated Raman scattering microscopy with
isotope labeling. ACS Chem. Biol. 2015. 10:
901–908.
134. Pantoja-Uceda D., Santoro J. Amino-acid-type
identification for deuterated proteins with a
beta-carbon-edited HNCOCACB experiment.
J. Biomol. NMR2012. 54: 145–153.
135. Tonelli M., Singarapu K. K., Makino S. et al.
Ligand-specific structural changes in the
vitamin D receptor in solution. J. Biomol.
NMR2011. 51: 467–476.
136. Miyanoiri Y.,Takeda M., Jee J.G. et al. Ste-
reo-array isotope labeling method for study-
ing protein structure and dynamics. J. Biomol.
NMR2011. 51: 425–435.
137. Torizawa T., Ono A. M., Terauchi T., Kainosho
M. NMR Assignment Methods for the Aro-
matic Ring Resonances of Phenylalanine and
Tyrosine Residues in Proteins.J. Am. Chem.
Soc. 2005. 127: 12620–12626.
138. Yokoyama J., Matsuda T., Koshiba S .et al. Cell-
free protein synthesis system from Escherichia
coli cells cultured at decreased temperatures
improves productivity by decreasing DNA
template degradation. Anal. Biochem. 2011.
411: 223–229.
139. Bornoe A., van Hall G. Quantitative amino
acid profiling and stable isotopically labeled
122 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
amino acid tracer enrichment used for in vivo
human systemic and tissue kinetics measure-
ments. J. Chromatogr. B. 2014. 951–952: 69–
77.
140. Claydon A. J., Thom M. D., Hurst J. L., Beynon
R. J. Protein turnover methods in single-celled
organisms: dynamic SILAC. Proteomics. 2012.
12: 1194–1206.
141. Chatterjee B., Krishnakumar V., Gunanathan
C. Ruthenium Catalyzed Selective Hydrobora-
tion of Carbonyl Compounds. Org. Lett. 2016.
18: 5892–5895.
142. Hutchby M., Sedgwick A. C., Bull S. D. Or-
thogonally Protected Schöllkopf ’s Bis-lactim
Ethers for the Asymmetric Synthesis of a-Ami-
no Acid Derivatives and Dipeptide Esters. Syn-
thesis. 2016. 2036–2049.
143. Oh J.-S., Kim K. I., Song C. E. Enantioselective
synthesis of a-deuterium labelled chiral a-ami-
no acids via dynamic kinetic resolution of
racemic azlactones.Org. Biomol. Chem. 2011.
9: 7983–7985.
144. Zlatopolskiy B. D., Loscha K., Alvermann P. et
al. Final elucidation of the absolute configu-
ration of the signal metabolite hormaomycin.
Chem.–Eur. J. 2004. 10: 4708–4717.
145. Winnicka E., Pająk M., Pałka et al. Enzymatic
Synthesis of Halogen Derivatives of Aroma
tic Amino Acids Labeled with Hydrogen Iso-
topes. J. Chem. Chem. Eng. 2014. 8: 54–60.
146. Mosin O. V., Shvets V. I., Skladnev D. A. Ig-
natov I. Microbiological synthesis of [2H]-ino-
sine with a high degree of isotopic enrichment
by the gram-positive chemoheterotrophic bac-
terium Bacillus subtilis.Appl. Biochem. Micro-
biol.1998. 62: 233–243.
147. Raap J., Nieuwenhuis S., Creemers A. et al.
Synthesis of Isotopically Labelled L‐Phenyla-
lanine and L‐Tyrosine. Eur. J. Org. Chem. 1999.
2609–2621.
148. Lygo B., Humphreys L. D. Enantioselective
synthesis of a-carbon deuterium-labelled
l-a-amino acids. Tetrahedron Lett. 2002. 43:
6677–6679.
149. Taylor P. J. M., Bull S. D. An improved synthe-
sis of deuterated Schöllkopf ’s bis-lactim ether
and its use for the asymmetric synthesis of
(R)-[a-2H]-phenylalanine methyl esters. Tet-
rahedron: Asymmetry. 2006. 17: 1170–1178.
150. Kendall J. T., Preliminary Research of Radio
labeled Atezolizumab for the Noninvasive
Evaluation of TNBC PD‐L1 Expression In
Vivo. J. Labelled Comp. Radiopharm. 2000. 43:
917–924.
151. Moozeh K., So S. M., ChinJ. Catalytic Stereo-
inversion of L-Alanine to Deuterated D-Ala-
nine. Angew. Chem., Int. Ed. 2015. 54: 9381–
9385.
152. Ellis T. K., Martin C. H., Tsai G. M. et al. Effi-
cient Synthesis of Sterically Constrained Sym-
metrically a, a-Disubstituted a-Amino Acids
under Operationally Convenient Conditions.J.
Org. Chem. 2003. 68: 6208–6214.
153. Soloshonok V. A., Tang X., Hruby V. J., Me
ervelt L. V. Asymmetric Synthesis of a,b-Di-
alkyl-a-Phenylalanines via Direct Alkylation
of Chiral Alanine Derivative with Racemic
a-Alkylbenzylbromides. A Case of High Enan-
tiomer Differentiation at Room Temperature.
Org. Lett. 2001. 3: 341–343.
154. Tang X., Soloshonok V. A., Hruby V. J. Con-
venient Asymmetric Synthesis of Enantio
merically Pure 2',6'-Dimethyltyrosine (DMT)
via Alkylation of Chiral Nucleophilic Glycine
Equivalent. Tetrahedron: Asymmetry. 2000. 11:
2917–2925.
155. Bott F., Field L.D., Sternhell S. Steric efects. A
study of a rationally designed system. J. Am.
Chem. Soc. 1980. 102: 5618–5626.
156. Lunazzi L., Mancinelli M., Mazzanti A. et al.
Rotational barriers of biphenyls having heavy
heteroatoms as ortho substituents: Experi-
mental and theoretical determination of steric
effects. Org. Biomol. Chem. 2012. 10: 1847–
1855.
157. de Riggi I., Virgili A., de Moragas M., Jaime C.
123https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Restricted rotation and NOE transfer: A con-
formationalof some substituted (9-anthry1)car-
binol derivatives. J. Org. Chem.1995. 60: 27–31.
158. Belot V., Farran D., Jean M. et al. Steric Scale
of Common Substituentsfrom Rotation-
al Barriers of N-(o-Substituted aryl)thiazo-
line-2-thione Atropisomers. J. Org. Chem.
2017. 82: 10188–10200.
159. Bravo P., Capelli S., Meille S. V. et al. Synthesis
of Optically Pure (R)- and (S)-a-Trifluorome-
thyl-Alanine. Tetrahedron: Asymmetry. 1994.
5: 2009–2018.
160. Jagodzinska M., Huguenot F., Candiani G.,
Zanda M. Assessing the bioisosterism of the
trifluoromethyl group with a protease probe.
Chem. Med. Chem. 2009. 4: 49–51.
161. Walborsky H. M., Baum M. E. Chemical Ef-
fects of the Trifluoromethyl Group: III. Syn-
thesis of 2-Amino-4,4,4-trifluorobutyric Acid.
J. Org. Chem. 1956. 21: 538–539.
162. Steglich W., Heininger H. U., Dworschak H.,
Weygand F. A General Method for the Prepa-
ration of Perfluoroalkylalanines. Angew.
Chem., Int. Ed. 1967. 6: 807–808.
163. Tsushima T., Kawada K., Ishihara S., et al. Flu-
orine containing amino acids and their deri
vatives. 7. Synthesis and antitumor activity of
a-substituted methotrexate analogs. Tetrahe-
dron 1988. 44: 5375–5387.
164. Seebach D., Buerger H. M., Schickli C. P. Ste
reoselektive Umsetzungen von rac-, (R), oder
(S)-5-Alkyliden-2-tbutyl-3-methyl-4-oxo-1-
imidazolidincarbonsäure-t-butylestern (chi-
rale 2,3-Dehydroaminosäure-Derivate) und
Herstellung einiger nichtproteinogener Amin-
osäuren. Ann. Chem. 1991. 7: 669–684.
165. Kondratov I. S., Logvinenko I. G., Tolmacho-
va N. A., et al. Synthesis and physical chemical
properties of 2-amino-4-(trifluoromethoxy)
butanoic acid–CF3O-containing analogue of
natural lipophilic amino acids. Org. Biomol.
Chem. 2017. 15: 672–679.
166. Xin B. T., Huber E. M., de Bruin G., et al.
Structure-Based Design of Inhibitors Selective
for Human Proteasome b2c or b2i Subunits. J.
Med. Chem. 2019. 62: 1626–1642.
167. Franko N., Grammatoglou K., Campanini B.,
et al. Inhibition of O-acetylserine sulfhydry
lase by fluoroalanine derivatives. J. Enzyme
Inhib. Med. Chem. 2018. 33: 1343–1351.
168. Gambini L., Salem A. F., Udompholkul P., et
al. Structure-Based Design of Novel EphA2
Agonistic Agents with Nanomolar Affinity in
Vitro and in Cell. ACS Chem. Biol. 2018. 13:
2633–2644.
169. Soloshonok V. A., Kukhar V. P. Biomimetic
Transamination of a-Keto Perfluorocarboxyl-
ic Esters. An Efficient Preparative Synthesis of
b,b,b-Trifluoroalanine. Tetrahedron 1997. 53:
8307–8314.
170. Soloshonok V. A., Ohkura H., Yasumoto M.
Operationally Convenient Asymmetric Syn-
thesis of (S)- and (R)-3-Amino-4,4,4-trif-
luorobutanoic Acid. Part II: Enantioselective
Biomimetic Transamination of 4,4,4-Trif-
luoro-3-oxo-N-(R)-1-phenylethyl)butana-
mide. J. Fluor. Chem. 2006. 127: 930–935.
171. Soloshonok V. A., Kukhar V. P. Biomimetic
Base-Catalyzed [1,3]-Proton Shift Reaction. A
Practical Synthesis of b-Fluoroalkyl-b-Amino
Acids. Tetrahedron 1996. 52: 6953–6964.
172. Han J., Takeda R., Liu X. et al. Prepara-
tive Method for Asymmetric Synthesis of
(S)-2-Amino-4,4,4-trifluorobutanoic Acid. Mo
lecules 2019. 24: 4521.
doi:10.3390/molecules24244521.
173. Mei H., Hiramatsu T., Takeda R. et al. Expe-
dient Asymmetric Synthesis of (S)-2-Ami-
no-4,4,4-trifluorobutanoic Acid via Alkylation
of Chiral Nucleophilic Glycine Equivalent.
Org. Process Res. Dev. 2019. 23: 629–634.
DOI: 10.1021/acs.oprd.8b00404.
174. Soloshonok V. A., Tang X., Hruby V. J. Large-
Scale Asymmetric Synthesis of Novel Sterical-
ly Constrained 2’,6’-Dimethyl- and a,2’,6’-Tri-
methyltyrosine and –phenylalanine Derivatives
124 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
via Alkylation of Chiral Equivalents of Nu-
cleophilic Glycine and Alanine. Tetrahedron.
2001. 57: 6375–6382.
175. Qiu W., Soloshonok V. A., Cai C. et al. Con-
venient, Large-Scale Asymmetric Synthesis of
Enantiomerically Pure trans-Cinnamylglycine
and -a-Alanine. Tetrahedron 2000. 56: 2577–
2582.
176. Ellis T. K., Hochla V. M., Soloshonok V. A.
Efficient Synthesis of 2-Aminoindane-2-Car-
boxylic Acid via Dialkylation of Nucleophilic
Glycine Equivalent. J. Org. Chem. 2003. 68:
4973–4976.
177. Wang J., Lin D., Zhou S. et al.Asymmetric Syn-
thesis of Sterically Constrained Linear Trifluo-
romethyl Containing Amino Acids via Alky-
lation of Chiral Equivalents of Nucleophilic
Glycine and Alanine. J. Org. Chem. 2011.76:
684–687.
178. Mei H., Yin Z., Miwa T., et al. Convenient
Asymmetric Synthesis of Fmoc-(S)-6,6,6-trif-
luoro-Norleucine. Symmetry. 2019. 11: 578.
doi:10.3390/sym11040578.
179. Yin Z., Moriwaki H., Abe H., et al. Large-Scale
Asymmetric Synthesis of Fmoc-(S)-2-Ami-
no-6,6,6-Trifluorohexanoic Acid. Chemistry-
Open 2019. 8: 701–704.
DOI: 10.1002/open.201900131.
180. Fu B., Takeda R., Zou Y., et al. Asymmetric
Synthesis of (S)-a-(octyl)Glycine via Alky-
lation of Ni(II)-Complex of Chiral Glycine
Schiff Base. Chirality 2020. 32: 1354–1360.
DOI https://doi.org/10.1002/chir.23281.
181. Soloshonok V. A., Ono T., Ueki H., et al. Ridge-
tile-like chiral topology: Synthesis, Resolution
and Complete Chiroptical Characterization
of Enantiomers of Edge-Sharing Binuclear
Square Planar Complexes of Ni(II) Bearing
Achiral Ligands. J. Am. Chem. Soc. 2010. 132:
10477–10483.
182. Soloshonok V. A., Ueki H., Moore J. L., Ellis
T. K. Design and Synthesis of Molecules with
Switchable Chirality via Formation and Clea
vage of Metal-Ligand Coordination Bonds. J.
Am. Chem. Soc. 2007. 129: 3512–3513.
183. Gibson S. E., Guillo N., Tozer M. J. Towards
control of c-space: Conformationally con-
strained analogues of Phe, Tyr, Trp and His.
Tetrahedron 1999. 55: 585–615.
184. Soloshonok V. A. Highly Diastereoselective
Michael Addition Reactions between Nu-
cleophilic Glycine Equivalents and b-substi-
tuted-a,b-Unsaturated Carboxylic acid Deri
vatives a General Approach to the Stereochemi
cally Defined and Sterically c-Constrained
a-Amino Acids. Curr. Org. Chem. 2002. 6:
341–364.
185. Urman S., Gaus K., Yang Y., et al. The Con-
strained Amino Acid b-Acc Confers Potency
and Selectivity to Integrin Ligands. Angew.
Chem., Int. Ed. 2007. 46: 3976–3978.
186. Mikhailiuk P. K., Afonin S., Chernega A. N.,
et al. Conformationally Rigid Trifluorome-
thyl-Substituted a-Amino Acid Designed for
Peptide Structure Analysis by Solid-State 19F
NMR Spectroscopy. Angew. Chem., Int. Ed.
2006. 45: 5659–5661.
187. Ma J. S. Unnatural amino acids in drug dis-
covery. Chim. Oggi–Chem. Today. 2003. 21:
65–68.
188. Kukhar V. P., Sorochinsky A. E., Soloshonok
V. A. Practical synthesis of fluorine-contain-
ing a- and b-amino acids: recipes from Kiev,
Ukraine. Future Med. Chem. 2009. 1. 793–819.
doi.org/10.4155/fmc.09.70.
189. Soloshonok V. A., Kirilenko A. G., Fokina
N. A. et al. Chemo-Enzymatic Approach to
the Synthesis of Each of the Four Isomers of
a-Alkyl-b-Fluoroalkyl-Substituted b-Amino
Acids.Tetrahedron: Asymmetry. 1994. 5: 1225–
1228.
190. Soloshonok V. A., Soloshonok I. V., Kukhar V.
P., Svedas V. K. Biomimetic Transamination of
a-Alkyl-b-keto Carboxylic Esters. Chemo-En-
zymatic Approach to the Stereochemically De-
fined a-Alkyl-b-Fluoroalkyl-b-Amino Acids. J.
125https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Org. Chem.1998. 63: 1878–1884.
191. Aceña J. L., Sorochinsky A. E., Soloshonok V.
A. Recent advances in asymmetric synthesis of
a-(trifluoromethyl)-containing a-amino acids.
Synthesis. 2012. 44: 1591–1602.
DOI: 10.1055/s-0031-1289756.
192. Ellis T. K., Martin C. H., Ueki H., Soloshonok
V. A. Efficient, Practical Synthesis of Symmet-
rically a,a-Disubstituted a-Amino Acids. Tet-
rahedron Lett. 2003. 44: 1063–1066.
193. Jansen R., Kunze B., Reichenbach H. et al.
Antibiotics from Gliding Bacteria. Part 43.
Phenoxan: A Novel Inhibitor of HIV1 Infec-
tion in Cell Cultures from Polyangium sp.,
Strain Pl VO19 (Myxobacteria). Liebigs Ann.
Chem.1992. 357–359.
194. Wipf P., Venkatraman S. Total Synthesis of
(−)-Thiangazole and Structurally Related Pol-
yazoles. Synlett 1997. 1–10.
195. Parsons R. L., Heathcock C. H. Revision of the
stereostructure of mirabazole C. Tetrahedron
Lett. 1994. 35: 1379–1382.
196. Parsons R. L., Heathcock C. H. Total synthe-
sis of mirabazole B. Tetrahedron Lett. 1994. 35:
1383–1384.
197. Carmeli S., Paik S., Moore R. E., et al. Revised
structures and biosynthetic studies of tan-
tazoles A and B. Tetrahedron Lett. 1993. 34:
6680–6684.
198. Parsons R. L., Heathcock C. H. Total synthesis
of mirabazole B. J. Org. Chem. 1994. 59: 4733–
4734.
199. Boyce R. L., Mulqueen G. C., Pattenden G. To-
tal synthesis of thiangazole. a novel inhibitor
of HIV-1 from Polyangium sp. Tetrahedron
Lett. 1994. 35: 5705–5708.
200. Yamamoto J., Kawashima A., Kawamura A.,
et al. Operationally Convenient and Scalable
Asymmetric Synthesis of (2S)- and (2R)-a-
(Methyl)cysteine Derivatives through Alkyla-
tion of Chiral Alanine Schiff Base Ni II Com-
plexes. Eur. J. Org. Chem. 2017. 1931–1939.
DOI: 10.1002/ejoc.201700018.
201. Filippis V. D., Boni S. D., Dea D. E., et al. Pro-
tein engineering by chemical methods: Incor-
poration of nonnatural amino acids as a tool
for studying protein folding, stability, and
function. Protein Sci. 2004. 13: 1489–1502.
202. Chao W. C., Chiang T. H., Chaudhari P. D.,
et al. Highly sensitive metal-insulator-metal
plasmonic refractive index sensor with a cent
rally coupled nanoring containing defects.
Bioorg. Chem. 2018. 81: 504–511.
203. Newton L. D., Pascu S. I., Tyrrell R. M., Eggle-
ston I. M. Development of a peptide-based
fluorescent probe for biological heme moni-
toring. Org. Biomol. Chem. 2019. 17: 467–471.
204. Hoesl M. G., Larregola M., Cui H., Budisa N.
Azatryptophans as tools to study polarity re-
quirements for folding of green fluorescent
protein. J. Pept. Sci. 2010. 16: 589–595.
205. Beghyn T. B., Charton J., Leroux F., et al. Drug
to Genome to Drug: Discovery of New Anti-
plasmodial Compounds. J. Med. Chem. 2011.
54: 3222–3240.
206. Gazzard L., Appleton B., Chapman K., et al.
Antagonists of inhibitor of apoptosis proteins
based on thiazole amide isosteres. Bioorg. Med.
Chem. Lett. 2014. 24: 5704–5709.
207. Katragadda M., Lambris J. D. Expression of
compstatin in Escherichia coli: incorporation
of unnatural amino acids enhances its activity.
Protein Expres. Purif. 2006. 47: 289–295.
208. Broos J., Gabellieri E., Beimans-Oldehinkel E.,
Strambini G. B. Efficient biosynthetic incorpo-
ration of tryptophan and indole analogs in an
integral membrane protein. Protein Sci. 2003.
12: 1991–2000.
209. Crestey F., Collot V., Stiebing S., Rault S. New
practical access to 2-azatryptophans and dehy-
dro derivatives via the Wittig-Horner reaction.
Tetrahedron 2006. 62: 7772–7775.
210. Cretey F., Collot V., Stiebing S., et al. Design and
synthesis of a new indazole library: direct con-
version of N-methoxy-N-methylamides (Wein-
reb amides) to 3-keto and 3-formylindazoles.
126 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Tetrahedron Lett. 2007. 48: 2457–2460.
211. Jeanty M., Suzenet F., Guillaumet G. Synthesis
of C3-Substituted 4-Azaindoles: An Easy Ac-
cess to 4-Azamelatonin and Protected 4-Az-
atryptophan. J. Org. Chem. 2008. 73: 7390–
7393.
212. Sanchez-Obregon R., Fallis A. G. Syntheses of
a potential fluorescence probe, (−)-(R)-7-aza-
tryptophan, via alkylation of the (1R, 4R)-cam-
phor imine of tert-butylgycinate. Can. J. Chem.
1992. 70: 1531–1536.
213. Lecointe L., Rolland-Fulcrand V., Roumestant
M. L., et al. Chemoenzymatic synthesis of the
two enantiomers of 7-azatryptophan. Tetrahe-
dron: Asymmetry 1998. 9: 173–1758.
214. Nakano S., Minamino Y., Hasebe F., Ito S. De-
racemization and Stereoinversion to Aroma
tic D-Amino Acid Derivatives with Ancestral
l-Amino Acid Oxidase. ACS Catal. 2019. 9:
10152–10158.
215. Winn M., Francis D., Micklefield J. De novo
Biosynthesis of “Non-Natural” Thaxtomin
Phytotoxins. Angew. Chem., Int. Ed. 2018. 57:
6830–6833.
216. Zou Y., Takeda R., Han J., et al. Asymmetric
Synthesis of N-Fmoc-(S)-7-azatryptophan
via Alkylation of Chiral Nucleophilic Glycine
Equivalent. Eur. J. Org. Chem. 2021. 2962–
2965. DOI: 10.1002/ejoc.202100485.
217. Li J., Zhou S., Wang J., et al. Asymmetric
Synthesis of Aromatic and Hetero-Aromatic
a-Amino Acids Using Recyclable Axially Chi-
ral Ligand. Eur. J. Org. Chem. 2016. 999–1006.
DOI: 10.1002/ejoc.201501442.
218. Soloshonok V. A., Yamada T., Ueki H., et al.
Operationally Convenient, Efficient Asym-
metric Synthesis of Enantiomerically Pure
4-Aminoglutamic Acids via Direct Methylen-
edimerization of Chiral Glycine Equivalents
with Dichloromethane. Tetrahedron. 2006. 62:
6412–6419.
219. Taylor S. M., Yamada T., Ueki H., Soloshonok
V. A. Asymmetric Synthesis of Enantiomeri-
cally Pure 4-Aminoglutamic Acids via Methyl-
enedimerization of Chiral Glycine Equivalents
with Dichloromethane under Operationally
Convenient Conditions. Tetrahedron Lett.
2004. 45: 9159–9162.
220. Cox R. J. The DAP pathway to lysine as a target
for antimicrobial agents.Nat. Prod.Rep. 1996.
13: 29–43.
221. Cox R. J., Sutherland A., Vederas J. C. Syn-
thesis and Testing of Heterocyclic Analogs
of Diaminopimelic Acid (DAP) as Inhibitors
of DAP Dehydrogenase and DAP Epimerase.
Bioorg. Med. Chem. 2000. 8: 843–871.
222. Andersen S. O. The cross-links in resilin iden-
tified as dityrosine and trityrosine. Biochim.
Biophys. Acta. 1964. 93: 213–215.
223. Hubbard B. K., Walsh C. T. Vancomycin as-
sembly: nature's way.Angew. Chem., Int. Ed.
2003. 42: 730–765.
224. Schafmeister C. E., Po J., Verdine G. L. An
All-Hydrocarbon Cross-Linking System for
Enhancing the Helicity and Metabolic Stabi
lity of Peptides. J. Am. Chem. Soc. 2000. 122:
5891–5892.
225. Feliu L., Planas M. Solid-phase synthesis of
biaryl bicyclic peptides containing a 3-arylty-
rosine or a 4-arylphenylalanine moiety. Int. J.
Pept. Res. Ther. 2005. 11: 53–97.
226. Del Valle J. R., Goodman M. Stereoselective
Synthesis of Boc-Protected cis and trans-4-Tri-
fluoromethylprolines by Asymmetric Hydro-
genation Reactions. J. Org. Chem. 2004. 69:
5946–5948.
227. Skaff O., Jollife K. A., Hutton C. A. Synthesis of
the side chain cross-linked tyrosine oligomers
dityrosine, trityrosine, and pulcherosine. J.
Org. Chem. 2005. 70: 7353–7363.
228. Tadd A. C., Meinander K., Luthman K., Wallén
E. A. A. Pseudopeptides with a centrally po-
sitioned alkene-based disulphide bridge mi-
metic stimulate kallikrein-related peptidase 3
activity. J. Org. Chem. 2011. 76: 673–675.
229. Kastrinsky D. B., Kumar P., Marriner G. A.,
127https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Barry III C. E. A Convergent Synthesis of Chi-
ral Diaminopimelic Acid Derived Substrates
for Mycobacterial l,d-Transpeptidases. Synthe-
sis 2012. 3043–3048.
230. Ritzén A., Basu B., Chattopadhyay S. K., et al.
Phenyltrisalanine: a new, C3-symmetric, tri-
functional amino acid. Tetrahedron: Asymme-
try. 1998. 9: 503–512.
231. Wang W., Xiong C., Yang J., Hruby V. J. Syn-
thesis of specifically deuterated S-benzyl-
cysteines and of oxytocin and related diastere-
omers deuterated in the half-cystine positions.
Synthesis. 2002. 94–98.
232. Wang J., Liu H., Aceña J. L., et al. Synthesis of
bis-a,a-amino acids through diastereoselective
bis-alkylations of chiral Ni(II)-complexes of
glycine. Org. Biomol. Chem. 2013. 11: 4508–
4515.
DOI: 10.1039/C3OB40594J.
233. Soloshonok V. A., Hayashi T. Gold(I)-Catalyz-
ed Asymmetric Aldol Reaction of Fluorinat-
ed Benzaldehydes with a-Isocyanoacetamide.
Tetrahedron: Asymmetry 1994. 5: 1091–1094.
234. Soloshonok V. A., Hayashi T. Gold(I)-Catalyz-
ed Asymmetric Aldol Reaction of Methyl Iso-
cyanoacetate with Fluorinated Benzaldehydes.
Tetrahedron Lett. 1994. 35: 2713–2716.
235. 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:
1055–1058.
236. Soloshonok V. A., Kacharov A. D., Hayashi T.
Gold(I)-Catalyzed Asymmetric Aldol Reac-
tions of Isocyanoacetic Acid Derivatives with
Fluoroaryl Aldehydes. Tetrahedron 1996. 52:
245–254.
237. Soloshonok V. A., Kacharov A. D., Avilov
D. V., et al. Transition Metal/Base-Catalyzed
Aldol Reactions of Methyl a-Isocyanoace-
tate with Prochiral Ketones, a Straightfor-
ward Approach to Stereochemically Defined
b,b-Disubstituted-b-Hydroxy-a-Amino Acids.
Scope and Limitations. J. Org. Chem. 1997. 62:
3470–3479.
238. Soloshonok V. A., Avilov D. V., Kukhar V. P.
Highly Diastereoselective Asymmetric Aldol
Reactions of Chiral Ni(II)-Complex of Glycine
with Trifluoromethyl Ketones. Tetrahedron:
Asymmetry. 1996. 7: 1547–1550.
239. Soloshonok V. A., Kukhar V. P., Galushko S.
V., et al. General method for the synthesis of
enantiomerically pure b-hydroxy-a-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-(trifluorome-
thyl)threonine. J. Chem. Soc., Perkin Trans. 1,
1993. 3143–3155.
240. Soloshonok V. A., Avilov D. V., Kukhar V. P.
Asymmetric Aldol Reactions of Trifluorome-
thyl Ketones with a Chiral Ni(II) Complex of
Glycine: Stereocontrolling Effect of the Tri-
fluoromethyl Group. Tetrahedron 1996. 52:
12433–12442.
241. Li T., Zhou S., Wang J., et al. Asymmetric
synthesis of (2S,3S)-a-(1-oxoisoindolin-3-yl)
glycines under low-basicity “kinetic” control.
J. Org. Chem. 2015. 80: 11275–11280. DOI:
10.1021/acs.joc.5b01730.
242. Li T., Zhou S., Wang J., et al. Asymmetric
synthesis of a-(1-oxoisoindolin-3-yl)glycine:
synthetic and mechanistic challenges. Chem.
Commun. 2015. 51: 1624–1626. DOI: 10.1039/
C4CC05659K.
243. 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. Bioorg. Acta 2021. 16(1): 3–9.
244. Duthaler R. O. Recent developments in the
stereoselective synthesis of a-aminoacids. Tet-
rahedron, 1994. 50: 1539–1560.
245. Maruoka K., Ooi T. Enantioselective Ami-
no Acid Synthesis by Chiral Phase-Transfer
128 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
Catalysis.Chem. Rev. 2003. 103: 3013–3028.
246. Ma J.-A. Recent Developments in the Cataly
tic Asymmetric Synthesis of a- andb-Amino
Acids.Angew. Chem., Int. Ed. 2003. 42: 4290–
4299.
247. Nájera C., Sansano J. M. Catalytic asymmet-
ric synthesis of alpha-amino acids.Chem. Rev.
2007, 107, 4584–4671.
248. Soloshonok V. A., Avilov D. V., Kukhar V. P.,
et al. Highly Diastereoselective aza-Aldol Re-
actions 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: 4671–4674.
249. Gómez Arrayás R., Carretero J. C. Catalytic
asymmetric direct Mannich reaction: a power-
ful tool for the synthesis of a,b-diamino acids.
Chem. Soc. Rev. 2009. 38: 1940–1948.
250. Viso A., Fernández de la Pradilla R., Tortosa
M., García A., Flores A. Update 1 of: a,b-Di-
amino Acids: Biological Significance and
Synthetic Approaches. Chem. Rev. 2011. 111:
PR1–PR42.
251. Kawamura A., Moriwaki H., Röschenthaler
G.-V., et al. Synthesis of (2S,3S)-b-(trifluo-
romethyl)-a,b-diamino acid by Mannich ad-
dition of glycine Schiff base Ni(II) complex-
es to N-tert-butylsulfinyl-3,3,3-trifluoroac-
etaldimine. J. Fluor. Chem. 2015. 171: 67–72.
DOI: 10.1016/j.jfluchem.2014.09.013.
252. Mimura H., Kawada K., Yamashita T., et al. Tri-
fluoroacetaldehyde: A useful industrial bulk
material for the synthesis of trifluoromethyl-
ated amino compounds. J. Fluor. Chem. 2010.
131: 477–486.
253. Robak M. T., Herbage M. A., Ellman J. A. Syn-
thesis and Applications of tert-Butanesulfina-
mide. Chem. Rev. 2010. 110: 3600–3740.
254. Xie C., Wu L., Mei H., et al. Generalized ac-
cess to fluorinated b-keto amino compounds
through asymmetric additions of a,a-difluo-
roenolates to CF3-sulfinylimine. Org. Biomol.
Chem. 2014. 12: 7836–7843.
DOI: 10.1039/C4OB01575D.
255. Mei H., Xie C., Wu L., et al. Asymmetric Man-
nich reactions of imidazo-[2,1-b]-thiazole-de-
rived nucleophiles with (SS)-N-tert-bu-
tanesulfinyl-(3,3,3)-trifluoroacetaldimine.
Org. Biomol. Chem. 2013. 11: 8018–8021.
DOI: 10.1039/c3ob41785a.
256. Shibata N., Nishimine T., Shibata N., et al. Or-
ganic base-catalyzed stereodivergent synthesis
of (R)- and (S)-3-amino-4,4,4-trifluorobuta-
noic acids. Chem. Commun. 2012. 48: 4124–
4126.
DOI: 10.1039/C2CC30627A.
257. Cai C., Soloshonok V. A., Hruby V. J. Michael
Addition Reactions Between Chiral Ni(II)
Complex of Glycine and 3-(trans-enoyl)oxa
zolidin-2-ones. A Case of Electron Donor-Ac-
ceptor Attractive Interactions-Controlled Face
Diastereoselectivity. J. Org. Chem. 2001. 66:
1339–1350.
258. 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-Substi-
tuted Pyroglutamic Acids and Prolines. J. Org.
Chem. 2004. 69: 4984–4990.
259. Soloshonok V. A., Avilov D. V., Kukhar V. P., et
al. An Efficient Asymmetric Synthesis of (2S,
3S)-3-Trifluoromethylpyroglutamic Acid. Tet-
rahedron Lett. 1997. 38: 4903–4904.
260. Soloshonok V. A., Cai C., Hruby V. J. Asym-
metric Michael Addition Reactions of Chiral
Ni(II) Complex of Glycine with N-(Enoyl)
oxazolidinones: Improved Reactivity and Ste-
reochemical Outcome. Tetrahedron: Asymme-
try. 1999. 10: 4265–4269.
261. Soloshonok V. A., Cai C., Hruby V. J. A Unique
Case of Face Diastereoselectivity in the Michael
Addition Reactions Between Ni(II)-Complex-
es of Glycine and Chiral 3-(E-enoyl)-1,3-oxa
129https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
zolidin-2-ones. Tetrahedron Lett. 2000. 41:
9645–9649.
262. Soloshonok V. A., Cai C., Hruby V. J. A Practi-
cal Asymmetric Synthesis of Enantiomerically
Pure 3-Substituted Pyroglutamic Acids and
Related Compounds. Angew. Chem., Int. Ed.
2000. 39: 2172–2175.
263. Soloshonok V. A., Cai C., Hruby V. J. (S)- or
(R)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-
ones: Ideal Michael Acceptors to Afford a Vir-
tually Complete Control of Simple and Face
Diastereoselectivity in Addition Reactions
with Glycine Derivatives. Org. Lett. 2000. 2:
747–750.
264. 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:
15296–15303.
265. Stierhof M., Hansen K. Ø., Sharma M., et al.
New cytotoxic callipeltins from the Solomon
Island marine sponge Asteropus sp. Tetrahe-
dron 2016. 72: 6929–6934.
266. Tokairin Y., Soloshonok V. A., Moriwaki H.,
Konno H. Asymmetric synthesis of (2S,3S)-3-
Me-glutamine and (R)-allo-threonine deriva-
tives proper for solid phase peptide coupling.
Amino Acids 2019. 51: 419–432.
https://doi.org/10.1007/s00726-018-2677-5.
267. Tucker T. J., Lumma W. C., Mulichak A. M.,
et al. Potent noncovalent thrombin inhibitors
that utilize the unique amino acid D-dicy-
clohexylalanine in the P3 position. Implica-
tions on oral bioavailability and antithrombo
tic efficacy. J. Med. Chem. 1997. 40: 1565–1569.
268. Cheng L., Goodwin C. A., Schully M. F., et al.
Synthesis and biological activity of ketome
thylene pseudopeptide analogs as thrombin
inhibitors. J. Med. Chem. 1992. 35: 3364–3369.
269. Pavar M. C., Hanif K., Azam A., et al. Struc-
ture–activity relationship study between or-
nithyl-proline and lysyl-proline based tripep-
tidomimics as angiotensinconverting enzyme
inhibitors. Bioorg. Med. Chem. Lett. 2006. 16:
2117–2121.
270. Stranix B. R., Lavallée J.-F., Sévigny G., et al.
Lysine sulfonamides as novel HIV-protease
inhibitors: Nε-acyl aromatic a-amino acids.
Bioorg. Med. Chem. Lett. 2006. 16: 3459–3462.
271. Brust A., Palant E., Croker D. E., et al. x-Cono-
peptide pharmacophore development: toward
a novel class of norepinephrine transporter
inhibitor (Xen2174) for pain. J. Med. Chem.
2009. 52: 6991–7002.
272. Lee Y. S., Nyberg J., Moye S., et al. Understand-
ing the structural requirements of 4-anilidop-
iperidine analogues for biological activities at
m and s opioid receptors. Bioorg. Med.Chem.
Lett. 2007. 17: 2161–2165.
273. Müller J., Feifel S. C., Schmiederer T., et al. In
vitro Synthesis of New Cyclodepsipeptides of
the PF1022-Type: Probing the a-D-Hydroxy
Acid Tolerance of PF1022 Synthetase. Chem
Bio Chem. 2009. 10: 323–328.
274. Jørgensen M. R., Olsen C. A., Mellor I. R., et
al. The Effects of Conformational Constraints
and Steric Bulk in the Amino Acid Moiety of
Philanthotoxins on AMPAR Antagonism. J.
Med. Chem. 2005. 48: 56–70.
275. Li X., Taylor J. S. General strategy for the
preparation of membrane permeable fluoro-
genic peptide ester conjugates for in vivo
studies of ester prodrug stability. Bioorg. Med.
Chem. 2004. 12: 545–552.
276. Haug B. E., Skar M. L., Svenden J. S. Bulky ar-
omatic amino acids increase the antibacterial
activity of 15-residue bovine lactoferricin de-
rivatives. J. Pept. Sci. 2001. 7: 425–432.
277. Gomez-Catalan J., Perez J. J., Jimenez A. I.,
Cativiela C. Study of the conformational pro-
file of selected unnatural amino acid residues
derived from L-phenylalanine. J. Pept. Sci.
130 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
1999. 5: 251–262.
278. Alvarez R., Valazquez S., San-Felix A., et al.
1,2,3-Triazole–[2',5'-Bis-O-(tert-butyldime
thylsilyl)-β-D-ribofuranosyl]-3'-spiro-5''-(4''-
amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO)
Analogues: Synthesis and Anti-HIV-1 Activi-
ty. J. Med. Chem. 1994. 37: 4185–4194.
279. Sharp R. E., Palmitessa A., Gibney B. R., et al.
Ubiquinone Binding Capacity of the Rhodo-
bacter capsulatus Cytochrome bc1 Complex:
Effect of Diphenylamine, a Weak Binding QO
Site Inhibitor. Biochemistry. 1999. 38: 3440–
3446.
280. Khoury G. A., Smadbeck J., Tamamis P., et al.
Forced_NCAA: ab initio charge parameters to
aid in the discovery and design of therapeutic
proteins and peptides with unnatural amino
acids and their application to complement in-
hibitors of the compstatin family. ACS Synth.
Biol. 2014. 3: 855–869.
281. Mao S., Rui Y., Yunru Z., et al. Predicting the
activity of antimicrobial peptides with ami-
no acid topological information. Med. Chem.
2013. 9: 32–44.
282. Gfeller D., Michielin O., Zoete V. Expand-
ing molecular modeling and design tools to
non-natural sidechains. J. Comput. Chem.
2012. 33: 1525–1535.
283. Tian F., Zhou P., Li Z. T-scale as a novel vector
of topological descriptors for amino acids and
its application in QSARs of peptides. J. Mol.
Struct. 2007. 830: 106–115.
284. Zhu Q., Cheng L., Lu Y. Asymmetric organo-
catalytic Michael addition of ketones to vi-
nylsulfone. Chem. Commun. 2008. 47: 6315–
6317.
285. Dou X., Lu Y. Enantioselective conjugate
addition of 3-fluoro-oxindoles to vinyl sul-
fone: an organocatalytic access to chiral
3-fluoro-3-substituted oxindoles. Org. Biomol.
Chem. 2013. 11: 5217–5221.
286. Zhu Y., Ni Y. F., Soloshonok V. A., et al. Cat-
alytic enantioselective Michael addition reac-
tions between in situ detrifluoroacetylatively
generated 3-fluorooxindole-derived enolates
and 1-(1-(phenylsulfonyl) vinylsulfonyl)ben-
zene. J. Fluor. Chem. 2019. 219: 32–38. https://
doi.org/10.1016/j.jfluchem.2018.12.009.
287. Zhu Y., Zhang W., Mei H., et al. Catalytic enan-
tioselective Michael addition reactions of ter-
tiary enolates generated by detrifluoroacety
lation. Chem. –Eur. J. 2017. 23: 11221–11225.
DOI: 10.1002/chem.201702091.
288. Nagaoka K., Mei H., Guo Y., et al. Michael ad-
dition reactions of chiral glycine Schiff base Ni
(II)‐complex with 1‐(1‐phenylsulfonyl)ben-
zene. Chirality 2020. 32: 885–893. https://doi.
org/10.1002/chir.23203.
289. Cooper A. J. L., Haber M. T., Ginos J. Z., et al.
Interaction of soluble pig heart glutamate-as-
partate transaminase with various b,g-un-
saturated amino acids. Biochem. Biophys. Res.
Commun. 1985. 129: 193–199.
290. Paik Y. H., Dowd P. b-Methyleneglutamic
acid and b-methyleneglutamine. J. Org. Chem.
1986. 51: 2910–2913.
291. Winter H. C., Powel G. K., Dekker E. E.
4-Methyleneglutamic acid and 4-methylene-
glutamine: isolation from extracts of peanut
seedlings and determination by high-perfor-
mance liquid chromatography. Prep. Biochem.
1988. 18: 121–136.
292. Receveur J. M., Roumestant M. L., Viallefont
P. Neuroexcitatory amino acids: 4-methylene
glutamic acid derivative. Amino Acids. 1995. 9:
391–395.
293. Kang S., Shi Q., Ha M. W., et al. Enantioselec-
tive synthesis of (S)-4-methyleneglutamic acid
via tandem conjugate addition–elimination
under phase-transfer catalytic conditions. Tet-
rahedron. 2010. 66: 4326–4329.
294. Eacquerra J., Pedregal C., Micó I., Nájera C.
Efficient synthesis of 4-methylene-L-glutamic
acid and its cyclopropyl analogue. Tetrahe-
dron: Asymmetry.1994. 5: 921–926.
295. Shigeno Y., Han J., Soloshonok V. A., et al.
131https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
Asymmetric synthesis of (S)-3-methylene-
glutamic acid and its N-Fmoc derivative via
Michael addition of chiral glycine Schiff base
Ni(II) complex with enol tosylates. Chirality
2021. 33: 115–123.
296. Babine R. E., Bender S. L. Molecular Recog-
nition of Protein–Ligand Complexes: Appli-
cations to Drug Design. Chem. Rev. 1997. 97:
1359–1472.
297. Tang W., Zhang X. New Chiral Phosphorus
Ligands for Enantioselective Hydrogenation.
Chem. Rev. 2003. 103: 3029–3070.
298. Feng Y., Coward J. K. Prodrug Forms of N-[(4-
Deoxy-4-amino-10-methyl)pteroyl]glutama
te-γ-[wP(O)(OH)]-glutarate, a Potent Inhibi-
tor of Folylpoly-g-glutamate Synthetase: Syn-
thesis and Hydrolytic Stability. J. Med. Chem.
2006. 49: 770–788.
299. Baumgartner T., Réau R. Organophosphorus
π-Conjugated Materials. Chem. Rev. 2006.
106: 4681–4727.
300. Yang Y., Coward J. K. Synthesis of p-Ami-
nophenyl Aryl H-Phosphinic Acids and Esters
via Cross-Coupling Reactions: Elaboration to
Phosphinic Acid Pseudopeptide Analogues of
Pteroyl Glutamic Acid and Related Antifolates.
J. Org. Chem. 2007. 72: 5748–5758.
301. Boëdec A., Sicard H., Dessolin J. G., et al.
Synthesis and Biological Activity of Phospho-
nate Analogues and Geometric Isomers of
the Highly Potent Phosphoantigen (E)-1-Hy-
droxy-2-methylbut-2-enyl 4-Diphosphate. J.
Med. Chem. 2008. 51: 1747–1754.
302. Allen D. W. Phosphines and related C–P bond-
ed compounds. Organophos. Chem. 2016. 45:
1–50.
303. Kukhar V. P., Soloshonok V. A., Solodenko
V. A. Asymmetric Synthesis of Phosphorus
Analogs of Amino Acids. Phosphorus, Sulfur,
and Silicon and the Related Elements. 1994. 92.
239–264.
DOI: 10.1080/10426509408021478.
304. Turcheniuk K. V., Kukhar V. P., Röschenthaler
G.-V., et al. Recent advances in the synthesis of
fluorinated aminophosphonates and amino-
phosphonic acids. RSCAdv. 2013. 3: 6693–6716.
DOI: 10.1039/c3ra22891f.
305. Wzorek A., Han J., Lyutenko N. V., et al. En-
zymatic approaches for preparation of α-ami-
nophosphonic acids and fluorine-containing
β-amino acids. Ukr. Bioorg. Acta. 2024. 19(1):
21–32.
306. Turski L., Klockgether T., Turski W. A., et al.
Blockade of excitatory neurotransmission in
the globus pallidus induces rigidity and akine-
sia in the rat: implications for excitatory neu-
rotransmission in pathogenesis of Parkinson’s
diseases. Brain Res. 1990. 512: 125–131.
307. Yoneda Y., Ogita K. Current topics on gluta-
mate receptors. Yakugaku Zasshi 1991. 111:
329–344.
308. Nadlewska A., Car H., Wiśniewska R., et al.
Behavioral effects of D-AP7 in rats subjected
to experimental hypoxia. Pol. J. Pharmacol.
2003. 55: 337–344.
309. Zhang H.-M., Chen S.-R., Pan H.-L. Effects of
activation of group III metabotropic glutamate
receptors on spinal synaptic transmission in a
rat model of neuropathic pain. Neuroscience.
2009. 158: 875–884.
310. Morris R. G. M. NMDA receptors and memo-
ry encoding.Neuropharmacology. 2013, 74: 32.
311. Lopez S., Turle N., Lorenzo F., et al. Targeting
Group III Metabotropic Glutamate Receptors
Produces Complex Behavioral Effects in Ro-
dent Models of Parkinson’s Disease. J. Neuros-
ci. 2007. 27: 6701–6711.
312. Turcheniuk K. V., Poliashko K. O., Kukhar V.
P., et al. Efficient asymmetric synthesis of tri-
fluoromethylated b-aminophosphonates and
their incorporation into dipeptides. Chem.
Commun. 2012. 48: 11519–11521.
DOI: 10.1039/c2cc36702e.
313. Röschenthaler G.-V., Kukhar V. P., Kulik
I. B., et al. Asymmetric synthesis of phospho-
notrifluoroalanine and its derivatives using
132 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
N-tert-butanesulfinyl imine derived from
fluoral. Tetrahedron Lett. 2012. 53: 539–542.
doi:10.1016/j.tetlet.2011.11.096.
314. Röschenthaler G.-V., Kukhar V. P., Kulik I.
B., et al. Convenient Synthesis of Fluoroalkyl
a- and b-Aminophosphonates. J. Fluor. Chem.
2011. 132: 834–837.
315. Soloshonok V. A., Belokon Y. N., Kuzmina N.
A., et al. Asymmetric Synthesis of Phosphorus
Analogs of Dicarboxylic a-Amino Acids. J.
Chem. Soc., Perkin Trans. 1. 1992. 1525–1529.
316. Tokairin Y., Soloshonok V. A., Konno H., et al.
Convenient synthesis of racemic 4,4-difluoro
glutamic acid derivatives via Michael-type ad-
ditions of Ni(II)-complex of dehydroalanine
Schiff bases. J. Fluor. Chem. 2019. 227: 109376.
doi.org/10.1016/j.jfluchem.2019.109376.
317. Tokairin Y., Shigeno Y., Han J. G., et al. Asym-
metric Synthesis of 4,4-(Difluoro)glutamic
Acid via Chiral Ni(II)-Complexes of Dehy-
droalanine Schiff Bases. Effect of the Chiral
Ligands Structure on the Stereochemical Out-
come. Chemistry Open. 2020. 9: 93–96.
DOI: 10.1002/open.201900343.
318. Tokairin Y., Konno H., Noireau, A. et al.
Asymmetric synthesis of the two enantiomers
of b-phosphorus-containing a-amino acids via
hydrophosphinylation and hydrophosphony-
lation of chiral Ni(II)-complexes.Org. Chem.
Front. 2021. 8: 2190–2195.
https://doi10.1039/D1QO00159K.
319. Cahn R. S., Ingold C. K., Prelog V. Specifica-
tion of Molecular Chirality. Angew. Chem., Int.
Ed. 1966. 5: 385–415.
320. Prelog V., Helmchen G. Basic Principles of the
CIP-System and Proposals for a Revision. An-
gew. Chem., Int. Ed. 1982. 21: 567–58.
321. Diggle G. E. Thalidomide: 40 years on. Int. J.
Clin. Pract. 2001. 55: 627–631.
322. Thomas F. X. C. History and Evolution of Re-
productive and Developmental Toxicology
Guidelines. Curr. Pharm. Des. 2006. 12: 1449–
65.
323. Miller M. T., Stromland K. K. What can we
learn from the thalidomide experience: an
ophthalmologic perspective. Curr. Opin. Oph-
thalmol. 2011. 22: 356–364.
324. Hendrickx A. G., Binkerd P. E. Nonhuman pri-
mates and teratological research. J. Med. Pri-
matol. 1990. 19: 81–108.
325. Powell R. J. Thalidomide: current uses. BioD-
rugs. 1999. 11: 409–416.
326. Guirguis, A. A., Ebert B. L. Lenalidomide: de-
ciphering mechanisms of action in myeloma,
myelodysplastic syndrome and beyond. Curr.
Opin. Cell. Biol. 2015. 37: 61–67.
327. Engelhardt M., Wasch R., Reinhardt H., Kle-
ber M. Pomalidomide. Recent Results. Cancer
Res. 2014. 201: 359–372.
328. Tokunaga E., Akiyama H., Soloshonok V. A., et
al. Biological evaluation of both enantiomers
of fluoro-thalidomide using human myeloma
cell line H929 and others. PLoS ONE 2017. 12:
e0182152.
DOI 10.1371/journal.pone.0182152.
329. Soloshonok V. A., Yamada T., Sakaguchi K.,
Ohfune Y. Concise Asymmetric Synthesis of
Configurationally Stable 4-trifluoromethyl Tha-
lidomide. Future Med. Chem. 2009. 1: 897–908.
doi.org/10.4155/fmc.09.63.
330. Yamada T., Okada T., Sakaguchi K., et al. Effi-
cient Asymmetric Synthesis of Novel 4-Substi-
tuted and Configurationally Stable Analogs of
Thalidomide. Org. Lett. 2006. 8: 5625–5628.
331. Mori T., Takahashi K., Kashiwabara M., Ue-
mura D. Structure of oxazolomycin, a novel
b-lactone antibiotic. Tetrahedron Lett. 1985.
26: 1073–1076.
332. Kanzaki H., Wada K., Nitoda T., Kawazu K.
Novel bioactive oxazolomycin isomers pro-
duced by Streptomyces albus JA3453. Biosci.
Biotechnol. Biochem. 1998. 62: 438–442.
333. Kawazu K., Kanzaki H., Kawabata G., et al.
Oxazolomycin Esters, Specific Inhibitors of
Plant Transformation. Biosci. Biotechnol. Bio-
chem. 1992. 56: 1382–1385.
133https://ucj.org.ua
Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Hiroki Moriwaki,
Tatsunori Sato, Kunisuke Izawa, Hiroyuki Konno, Vadim A. Soloshonok UCJ № 10 / Vol. 90
334. Tonew E., Tonew M., Gräfe U., Zöpel P. Grise-
ochelin methyl ester, a new polyether deriva-
tive with antiviral activity. Acta Virol. 1992. 36:
166–172.
335. Grigorjev P. A., Schegel R., Gräfe U. Formation
of membrane pores by aurantimycins A and B,
new lipopeptide antibiotics from Streptomyces
aurantiacus. Pharmazie. 1992. 47: 707–709.
336. Bullough P. A., Hughson F. M., Skehel J. J.,
Wiley D. C. Structure and topology of the in-
fluenza virus fusion peptide in lipid bilayers.
Nature. 1994. 371: 37–43.
337. Carr C. M., Kim P. S. A spring-loaded mech-
anism for the conformational change of influ-
enza hemagglutinin. Cell. 1993. 73: 823–832.
338. Kawai S., Kawabata G., Kobayashi A., Kawa-
zu K. Inhibitory Effect of Oxazolomycin on
Crown Gall Formation. Agric. Biol. Chem.
1989. 53: 1127–1133.
339. Takahashi K., Kawabata M., Uemura D. et al.
Structure of neooxazolomycin, an antitumor
antibiotic. Tetrahedron Lett. 1985. 26: 1077–
1078.
340. Yamada T., Sakaguchi K., Shinada T., et al.
Efficient asymmetric synthesis of the func-
tionalized pyroglutamate core unit common
to oxazolomycin and neooxazolomycin using
Michael reaction of nucleophilic glycine Schiff
base with a,b-disubstituted acrylate. Tetrahe-
dron: Asymmetry 2008. 19: 2789–2795.
doi.org/10.1016/S0040-4020(98)00779-0.
341. Cativiela C., Ordóñez M. Recent progress on
the stereoselective synthesis of cyclic quater-
nary α-amino acids. Tetrahedron: Asymmetry.
2009. 20: 1–63.
342. Brackmann F., de Meijere A. Natural occur-
rence, syntheses, and applications of cyclo-
propyl-group-containing alpha-amino acids.
1. 1-aminocyclopropanecarboxylic acid and
other 2,3-methanoamino acids. Chem. Rev.
2007. 107: 4493–4537.
343. Burroughs L. F. I-Aminocyclopropane-I-Car-
boxylic Acid: A New Amino-Acid in Perry
Pears and Cider Apples. Nature 1957. 179:
360–361.
344. Adams D. O., Yang S. F. Ethylene biosynthesis:
Identification of 1-aminocyclopropane-1-car-
boxylic acid as an intermediate in the con-
version of methionine to ethylene. Proc. Natl.
Acad.Sci. U. S. A 1979. 76: 170–174.
345. Stammer C. H. Cyclopropane amino acids:
2,3- and 3,4-methanoamino acids. Tetrahe-
dron 1990. 46: 2231–2254.
346. Alami A., Calmes M., Daunis J., Jacqui-
er R. Synthesis of Enantiomerically Pure
(1S,2S)-1-Aminocyclopropanephosphonic
Acids from (2S)-Methylcyclopropanone Ace
tal. Bull. Soc. Chim. Fr. 1993. 130: 5–24.
347. Burgess K., Ho K.-K., Moye-Sherman D.
Asymmetric Syntheses of 2,3-Methanoamino
Acids. Synlett 1994. 575–583.
348. Ichichara A., Shiraishi K., Sato H., et al. The
structure of coronatine. J. Am. Chem. Soc.
1977. 99: 636–637.
349. Mitchell R. E. Norcoronatine and N-corona-
facoyl-L-valine, phytotoxic analogues of coro-
natine produced by a strain of Pseudomonas
syringae pv. glycinea. Phytochemistry 1985. 24:
1485–1487.
350. Hoffman N. E., Yang S. F., Ichihara A., Saka-
mura S. Stereospecific conversion of 1-amin-
ocyclopropanecarboxylic acid to ethylene by
plant tissues: conversion of stereoisomers of
1-amino-2-ethylcyclopropanecarboxylic acid
to 1-butene. Plant Physiol. 1982. 70: 195–199.
351. Pirrung M. C., McGeehan G. M. Asymmet-
ric Synthesis of cis and trans 2-Methyl and
2-Ethyl 1-Amino Cyclopropanecarboxylic
acids. J. Org. Chem. 1986. 51: 2103–2106.
352. Tsantrizos Y. S. A practical and scalable sys-
tem for heteroaryl amino acid synthesis. Acc.
Chem. Res. 2008. 41: 1252–1263.
353. Rosenquist A., Samuelsson B., Johansson P.-O.,
et al. New treatments for genotype 1 chro
nic hepatitis C – focus on simeprevir. J. Med.
Chem. 2014. 57: 1673–1693.
134 ISSN 2708-129X. Укр. хім. журн., 2024
HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS.ORGANIC CHEMISTRY
354. Jiang Y., Andrews S. W., Condroski K. R., et
al. Discovery of a New Class of Macrocyclic
Antagonists to the Human Motilin Receptor. J.
Med. Chem. 2014. 57: 1753–1769.
355. Scola P. M., Sun L.-Q., Wang A. X., et al. Dis-
covery of Hepatitis C Virus NS3-4A Protease
Inhibitors with Improved Barrier to Resis
tance and Favorable Liver Distribution. J. Med.
Chem. 2014. 57: 1730–1752.
356. Llinàs-Brunet M., Bailey M. D., Goudreau N.
P., et al. Discovery of a Potent and Selective
Noncovalent Linear Inhibitor of the Hepati-
tis C Virus NS3 Protease (BI 201335). J. Med.
Chem. 2010. 53: 6466–6476.
357. Llinàs-Brunet M., Bailey M. D., Bolger G., et
al. Structure–Activity Study on a Novel Series
of Macrocyclic Inhibitors of the Hepatitis C
Virus NS3 Protease Leading to the Discovery
of BILN 2061. J. Med. Chem. 2004. 47: 1605–
1608.
358. Kawashima A., Xie C., Mei H., et al. Asym-
metric synthesis of (1R,2S)-1-amino-2-vinyl-
cyclopropanecarboxylic acid by sequential
SN2–SN2’ dialkylation of (R)-N-(benzyl)pro-
line-derived glycine Schiff base Ni(II) comp
lex. RSC Adv. 2015. 5: 1051–1058.
DOI: 10.1039/C4RA12658K.
359. Kawashima A., Shu S., Takeda R., et al. Ad-
vanced asymmetric synthesis of (1R,2S)-1-ami-
no-2-vinylcyclopropanecarboxylic acid by
alkylation/cyclization of newly designed axial-
ly chiral Ni(II) complex of glycine Schiff base.
Amino Acids 2016. 48: 973–986.
DOI: 10.1007/s00726-015-2138-3.
360. Murai Y., Mori S., Konno H., et al. Ralstonins A
and B, Lipopeptides with Chlamydospore-In-
ducing and Phytotoxic Activities from the
Plant Pathogen Ralstonia solanacearum. Org.
Lett. 2017. 19: 4175–4178.
361. Konno H., Sasaki Y., Sato R., et al. Synthesis
of b-Hydroxytyrosine, A Component of Burk-
holdines. Nat. Prod. Commun. 2016. 11: 213–
218.
362. Kato S., Sasaki M., Yano S., Konno H. Synthe-
sis of burkholdine analogue containing the
b-hydroxytyrosine. Biosci. Biotechnol. Bio-
chem. 2019. 83: 1216–1219.
363. Boyle P. H., Davis A. P., Dempsey K. J., Hosken
G. L. Synthesis of (S)-2-Amino-1,1-diphenyl
butan-4-ol; conversion of an a-amino acid into
an a-(diphenylmethyl)amino without loss of
optical purity. Tetrahedron: Asymmetry 1995.
6: 2819–2828.
364. Oyama K., Han J., Moriwaki H., et al. Synthe-
sis of Ahod moiety of ralstonin A using ami-
no acid Schiff base Ni(II)-complex chemistry.
Helv. Chim. Acta. 2020. 103: e2000077.
https://doi.org/10.1002/hlca.202000077.
Cтаття надійшла 05.10.2024.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-693 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:12:21Z |
| publishDate | 2024 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/af/a8e061637e74716418ad245cbe7ab8af.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-6932026-07-22T08:23:55Z HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) Han, Jianlin Liu, Hong Wang, Jiang Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Moriwaki, Hiroki Sato, Tatsunori Kunisuke , Izawa Konno, Hiroyuki Soloshonok, Vadim tailor-made amino acids; drug design and development; second-order asymmetric transformation; dynamic kinetic resolution; inversion of chirality. This article reviews the development of the asymmetric synthesis of tailor-made amino acids conducted at Hamari Chemicals during the 10-year period 2013–2022.The discussion is based on strategies such as direct chiral modification of unprotected amino acids via intermediate formation of Ni(II) complexes and elaboration of chiral nucleophilic or electrophilic glycine equivalents. The former approach includes, for example, second-order asymmetric transformation, dynamic kinetic resolution, and inversion of chirality while the latter approach involves construction of the desired amino acid architecture using, for example, alkylation, aldol, Mannich, or Michael addition reactions as well as multistep procedures. Operational convenience, scalability, and practicality of the developed methods are emphasized. V.I.Vernadsky Institute of General and Inorganic Chemistry 2024-11-29 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/693 10.33609/2708-129X.90.10.2024.88-134 Ukrainian Chemistry Journal; Vol. 90 No. 10 (2024): Ukrainian Chemistry Journal; 88-134 Украинский химический журнал; ##issue.vol## 90 ##issue.no## 10 (2024): Ukrainian Chemistry Journal; 88-134 Український хімічний журнал; Том 90 № 10 (2024): Ukrainian Chemistry Journal; 88-134 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/693/346 Copyright (c) 2024 Jianlin Han, Hong Liu, Jiang Wang, Alicja Wzorek, Alexander Sorochinsky, Karel Klika, Taizo Ono, Hiroki Moriwaki, Tatsunori Sato, Izawa Kunisuke , Hiroyuki Konno, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Han, Jianlin Liu, Hong Wang, Jiang Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Moriwaki, Hiroki Sato, Tatsunori Kunisuke , Izawa Konno, Hiroyuki Soloshonok, Vadim HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title | HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title_full | HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title_fullStr | HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title_full_unstemmed | HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title_short | HAMARI’S CONTRIBUTION TO THE ASYMMETRIC SYNTHESIS OF TAILOR-MADE AMINO ACIDS(Review) |
| title_sort | hamari’s contribution to the asymmetric synthesis of tailor-made amino acids(review) |
| topic_facet | tailor-made amino acids drug design and development second-order asymmetric transformation dynamic kinetic resolution inversion of chirality. |
| url | https://ucj.org.ua/index.php/journal/article/view/693 |
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