SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review)
Amino acids are fundamental to virtually every aspect of biological science and healthcare serving as the cornerstone of molecular structure and function. Research has now expanded beyond naturally occurring amino acids to tailor-made derivatives enabling precise control over biological processes...
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| Дата: | 2025 |
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| Автори: | , , , , , , |
| Формат: | Стаття |
| Мова: | Англійська |
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V.I.Vernadsky Institute of General and Inorganic Chemistry
2025
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Репозитарії
Ukrainian Chemistry Journal| _version_ | 1871466163007913984 |
|---|---|
| author | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_facet | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Jianlin Han",
"institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:56Z |
| description | Amino acids are fundamental to virtually every aspect of biological science and healthcare serving as the cornerstone of molecular structure and function. Research has now expanded beyond naturally occurring amino acids to tailor-made derivatives enabling precise control over biological processes and unlocking new functionalities unattainable with standard amino acids and peptides. One of the most exciting advancements is the development of fluorine-containing amino acids which integrate the powerful pharmacological effects of fluorine with the structural adaptability of amino acid frameworks. This review explores the synthesis of fluorinated amino acids bearing unsaturated residues—a highly valuable and distinct subgroup within the broader class of fluorinated amino acids. These specialized molecules feature fluorine directly bonded to sp2-hybridized carbon atoms, effectively replicating the electronic properties of aromatic substitution without relying on an aromatic system. The olefinic placement of fluorine enhances molecular stability and imparts specific steric, geometric, chemical, and biological characteristics critical for drug design and bioactive compound development. The synthetic strategies presented herein are organized around key transformations, including α alkylation of amino acids, side chain elaboration, introduction of amino and/or carboxylic functionalities, and the generation of unsaturation within fluoro-amino acid cores. By compiling these methodologies we aim to provide a comprehensive resource and a source of inspiration for researchers engaged in synthetic and medicinal chemistry, drug discovery, and organofluorine chemistry. |
| doi_str_mv | 10.33609/2708-129X.91.8.2025.36-64 |
| first_indexed | 2025-12-02T15:13:46Z |
| format | Article |
| fulltext |
36 ISSN 2708-129X. Укр. хім. журн., 2025
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.8.2025.36-64
SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING
C(sp2)–F BONDS.
Alicja Wzorek1, Jianlin Han2, Taizo Ono3, Karel D. Klika4,
Daniel Baecker5, Wei Zhang6, Vadim A. Soloshonok7,8*
1 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25-406 Kielce, Poland;
2 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,
College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
3 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
4 Research & Development Center, Archer Daniels Midland,
1001 N Brush College Rd., Decatur, IL 62521, USA;
5 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy,
Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany;
6 Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, USA;
7 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU,
Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain;
8 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain.
e-mail: vadimsoloshonok@gmail.com
Amino acids are fundamental to virtually every aspect of biological science and healthcare ser
ving as the cornerstone of molecular structure and function. Research has now expanded beyond
naturally occurring amino acids to tailor-made derivatives enabling precise control over biological
processes and unlocking new functionalities unattainable with standard amino acids and peptides.
One of the most exciting advancements is the development of fluorine-containing amino acids which
integrate the powerful pharmacological effects of fluorine with the structural adaptability of amino
acid frameworks. This review explores the synthesis of fluorinated amino acids bearing unsaturated
residues—a highly valuable and distinct subgroup within the broader class of fluorinated amino acids.
These specialized molecules feature fluorine directly bonded to sp2-hybridized carbon atoms, effec
tively replicating the electronic properties of aromatic substitution without relying on an aromatic
system. The olefinic placement of fluorine enhances molecular stability and imparts specific steric,
geometric, chemical, and biological characteristics critical for drug design and bioactive compound
development. The synthetic strategies presented herein are organized around key transformations,
including α alkylation of amino acids, side chain elaboration, introduction of amino and/or carboxylic
functionalities, and the generation of unsaturation within fluoro-amino acid cores. By compiling these
methodologies we aim to provide a comprehensive resource and a source of inspiration for researchers
engaged in synthetic and medicinal chemistry, drug discovery, and organofluorine chemistry.
Key words: Fluorine, Amino Acids, Fluorinated Pharmaceuticals, Unsaturated/Olefinic Groups,
Synthesis, Nucleophilic and Electrophilic Glycine Equivalents.
37https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
INTRODUCTION. Amino acids, the funda
mental building blocks of proteins, have played
a crucial role in medicine and drug development
for centuries. Their significance was first recog
nized in the 19th century when scientists began
isolating and identifying individual amino acids
from natural sources. The discovery of essential
amino acids, those that the human body cannot
synthesize, highlighted their importance in nu
trition and metabolic health [1–5].
Early pharmaceutical applications of amino
acids revolved around dietary supplements and
medical nutrition therapy for conditions such
as malnutrition and metabolic disorders. As
biochemical research advanced in the 20th cen
tury, amino acids became central to developing
hormonal therapies, such as insulin synthe
sis, which revolutionized diabetes treatment.
Additionally, peptide-based drugs derived
from amino acids, such as exenatide for dia
betes, enfuvirtide for AIDS, and goserelin for
breast cancer among many others, have paved
the way for new antibiotics, enzyme inhibitors,
and vaccines [6–9].
In modern pharmaceutical science, amino
acids play a pivotal role in biotechnologically
produced drugs (biopharmaceuticals), targe
ted therapies, and synthetic medicinal com
pounds (small molecule pharmaceuticals).
A significant breakthrough—a paradigm shift
in drug design – has emerged with the strate
gic use of modified tailor-made amino acids
[10–17] instead of their natural counterparts.
These custom engineered amino acids can be
rationally designed to enhance drug stability,
solubility, and absorption thereby optimizing
biological efficacy and enabling more precise
targeted delivery [18–22].
The unique combination of fluorine’s bene
ficial properties [23–30] with the inherent
structural versatility of amino acids [31–36]
underscores the significant value of fluo
rine-containing amino acids in drug design.
These tailor-made amino acid derivatives al
low for the precise fine tuning of drug activity
and pharmacokinetic profiles leading to the
development of more targeted and efficient
treatments. As a result, the selective synthesis
of fluorinated α [37–46] and β amino acids
[47–56] has been an area of intense research
activity in the past two decades [57–77]. The
strategic introduction of fluorine into bioactive
molecules has evolved into a well-established
strategy in drug development culminating in
the approval of numerous fluorinated pharma
ceuticals by the US Food and Drug Administra
tion (FDA) [78–80]. Ultimately, the combined
incorporation of fluorine and amino acid scaf
folds into drug design represents a substantial
advancement in medicinal chemistry opening
new possibilities for the development of more
effective and safer therapeutic interventions.
This review covers the synthesis of tai
lor-made amino acids bearing fluorine-con
taining unsaturated residues, a distinct and
valuable subgroup within the broader class of
fluorinated amino acids. These unique ami
no acids feature fluorine directly bonded to
sp2-hybridized carbon atoms mimicking the
electronic effects of aromatic substitution but
without the aromatic framework. The olefinic
positioning of fluorine enhances its stability
and imparts specific steric, geometric, chem
ical, and biological properties. The synthetic
strategies discussed herein are organized by
key transformations: α-alkylation of amino
acids, elaboration of amino acid side chains,
introduction of amino and/or carboxylic func
tionalities, and the generation of unsaturation
on pre-existing fluoro-amino acid cores. We
38 ISSN 2708-129X. Укр. хім. журн., 2025
SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
anticipate that this compilation will serve as a
valuable resource and source of inspiration for
researchers and practitioners across synthetic
and medicinal chemistry, drug design, and the
wider field of organofluorine chemistry.
EXPERIMENT AND DISCUSSION OF
THE RESULTS.
α-Alkylation of glycine and higher α ami-
no acids.
The alkylation of nucleophilic glycine, ala
nine, and other α amino acids represents one
of the most versatile and widely employed
methods for synthesizing tailor-made amino
acids with novel side chains [81–83]. This ap
proach, applied to the synthesis of fluoro-ole
finic amino acids is illustrated in Scheme 1.
The benzophenone Schiff base of glycine es
ter 1, introduced by G. Stork [84] and further
refined by M. O’Donnell [85], was alkylated
with 2-fluorobut-1-ene 2 yielding product 3
in moderate yield. Hydrolysis of intermediate
3 produced 2-amino-5-fluorohex-5-enoic acid
(4) in an overall yield of ca. 20% [86].
side chains [81–83]. This approach, applied to the synthesis of fluoro-olefinic amino acids is
illustrated in Scheme 1. The benzophenone Schiff base of glycine ester 1, introduced by G. Stork
[84] and further refined by M. O’Donnell [85], was alkylated with 2-fluorobut-1-ene 2 yielding
product 3 in moderate yield. Hydrolysis of intermediate 3 produced 2-amino-5-fluorohex-5-enoic
acid (4) in an overall yield of ca. 20% [86].
Scheme 1. Synthesis of unsaturated fluoro-amino acids 4 and 7 via alkyl halide alkylation.
Under identical conditions, the 2-fluoro-allyl alkylating reagent fluoro-allyl tosylate 5 (Scheme
1) was employed to synthesize 2-amino-4-fluoropent-4-enoic acid (7) in a significantly improved
yield of 80–90% [86].
The same research group led by G. Haufe [87] reported the synthesis of lipophilic amino acid
11 (Scheme 2) featuring a fluorovinyl group as part of a C16 side chain. The reaction sequence
begins with commercially available fluoro-olefin 8, which is hydroxylated to alcohol 9 under
oxidative conditions using SeO2 and tert-butyl hydroperoxide. Subsequently, alcohol 9 is coupled
with N-Boc glycine forming ester 10 using condensation reagents N,N’-dicyclohexylcarbodiimide
(DCC) and 4-dimethylaminophenol (DMAP). Finally, ester 10 undergoes treatment with lithium
diisopropylamide (LDA) to initiate the Claisen rearrangement yielding amino acid 11 in an
impressive 86% yield.
Scheme 2. Synthesis of fluorovinyl amino acid 11 via Claisen rearrangement.
It is worth noting that fluorovinyl-containing amino acids 4, 7, and 11 could serve as suitable
substrates for dynamic kinetic resolution (DKR) through the direct formation of chiral Ni(II)
complexes [88–90] enabling their preparation in both enantiomeric forms.
The synthesis of quaternary amino acids through the alkylation of alanine or higher amino acids
presents a significantly greater challenge compared to the alkylation of their glycine derivatives.
Scheme 1. Synthesis of unsaturated fluoro-amino acids 4 and 7 via alkyl halide alkylation.
Under identical conditions, the 2-fluoro-al
lyl alkylating reagent fluoro-allyl tosylate 5
(Scheme 1) was employed to synthesize 2-ami
no-4-fluoropent-4-enoic acid (7) in a signifi
cantly improved yield of 80–90% [86].
The same research group led by G. Haufe
[87] reported the synthesis of lipophilic ami
no acid 11 (Scheme 2) featuring a fluorovinyl
group as part of a C16 side chain. The reaction
sequence begins with commercially available
fluoro-olefin 8, which is hydroxylated to alco
hol 9 under oxidative conditions using SeO2
and tert-butyl hydroperoxide. Subsequent
ly, alcohol 9 is coupled with N-Boc glycine
forming ester 10 using condensation reagents
N,N’-dicyclohexylcarbodiimide (DCC) and
4-dimethylaminophenol (DMAP). Finally, es
ter 10 undergoes treatment with lithium di
isopropylamide (LDA) to initiate the Claisen
rearrangement yielding amino acid 11 in an
impressive 86% yield.
39https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
Scheme 2. Synthesis of fluorovinyl amino acid 11 via Claisen rearrangement.
side chains [81–83]. This approach, applied to the synthesis of fluoro-olefinic amino acids is
illustrated in Scheme 1. The benzophenone Schiff base of glycine ester 1, introduced by G. Stork
[84] and further refined by M. O’Donnell [85], was alkylated with 2-fluorobut-1-ene 2 yielding
product 3 in moderate yield. Hydrolysis of intermediate 3 produced 2-amino-5-fluorohex-5-enoic
acid (4) in an overall yield of ca. 20% [86].
Scheme 1. Synthesis of unsaturated fluoro-amino acids 4 and 7 via alkyl halide alkylation.
Under identical conditions, the 2-fluoro-allyl alkylating reagent fluoro-allyl tosylate 5 (Scheme
1) was employed to synthesize 2-amino-4-fluoropent-4-enoic acid (7) in a significantly improved
yield of 80–90% [86].
The same research group led by G. Haufe [87] reported the synthesis of lipophilic amino acid
11 (Scheme 2) featuring a fluorovinyl group as part of a C16 side chain. The reaction sequence
begins with commercially available fluoro-olefin 8, which is hydroxylated to alcohol 9 under
oxidative conditions using SeO2 and tert-butyl hydroperoxide. Subsequently, alcohol 9 is coupled
with N-Boc glycine forming ester 10 using condensation reagents N,N’-dicyclohexylcarbodiimide
(DCC) and 4-dimethylaminophenol (DMAP). Finally, ester 10 undergoes treatment with lithium
diisopropylamide (LDA) to initiate the Claisen rearrangement yielding amino acid 11 in an
impressive 86% yield.
Scheme 2. Synthesis of fluorovinyl amino acid 11 via Claisen rearrangement.
It is worth noting that fluorovinyl-containing amino acids 4, 7, and 11 could serve as suitable
substrates for dynamic kinetic resolution (DKR) through the direct formation of chiral Ni(II)
complexes [88–90] enabling their preparation in both enantiomeric forms.
The synthesis of quaternary amino acids through the alkylation of alanine or higher amino acids
presents a significantly greater challenge compared to the alkylation of their glycine derivatives.
It is worth noting that fluorovinyl-contain
ing amino acids 4, 7, and 11 could serve as
suitable substrates for dynamic kinetic reso
lution (DKR) through the direct formation of
chiral Ni(II) complexes [88–90] enabling their
preparation in both enantiomeric forms.
The synthesis of quaternary amino acids
through the alkylation of alanine or higher
amino acids presents a significantly greater
challenge compared to the alkylation of their
glycine derivatives.
Scheme 3. Synthesis of α-(1’-fluoro)vinyl amino acid 16.
This is due to the combined impact of steric and electronic factors which necessitate much
more rigorous reaction conditions [91–93]. The vinylation variant of this process closely parallels
alkylation, similarly requiring strong bases and highly controlled reaction environments [94]. For
instance, the benzophenone-derived Schiff base of glycine ester 1 (Scheme 1) is unsuitable for the
synthesis of quaternary amino acids due to its significant steric bulk. Instead, the less sterically
demanding benzaldehyde-derived Schiff base 12 (Scheme 3) is typically employed for
quaternization of alanine and higher amino acids. The process begins with aldimine 12 which is
treated with n-BuLi and 2,2,6,6-tetramethylpiperidine (TMP) to generate the corresponding enolate.
This enolate is then reacted with 1-(2,2-difluorovinylsulfonyl)benzene (13) yielding the vinylated
product 14 in up to 91% yield. Subsequently, the sulfonyl group in 14 is displaced using Bu3SnH in
the presence of azobisisobutyronitrile (AIBN) producing tributylstannane 15 in an excellent yield
exceeding >90%. Finally, intermediate 15 is treated with HCl to remove the SnBu3 group and to
hydrolyze both the Schiff base and ester functional groups resulting in α-(1’-fluoro)vinyl amino
acid 16. This method demonstrates high generality as alanine can be substituted by various other
amino acids featuring aliphatic, aromatic, or side chains containing appropriately protected
carboxylic or amino functionalities [95].
Scheme 3. Synthesis of α-(1’-fluoro)vinyl amino acid 16.
The asymmetric synthesis of (S)-2-amino-4-fluoropent-4-enoic acid (19) is achieved through
the fluoro-allylation of the chiral Schiff base (R)-17 (Scheme 4) [96]. The chiral nucleophilic
glycine equivalent (R)-17, derived from 2-hydroxy-3-pinanone, is reacted with
3-bromo-2-fluoropropene at −78 °C in the presence of LDA and N,N’-dimethylpropyleneurea
(DMPU) yielding the fluoro-allylated product (S)-18 in 73% yield and diastereoselectivity
exceeding 97%. Subsequent acidic hydrolysis of the Schiff base and deprotection of the carboxylic
group results in the formation of amino acid (S)-19.
Scheme 4. Asymmetric synthesis of amino acid (S)-19.
As shown in Scheme 5, this approach can be employed for the synthesis of the fluorinated
quaternary amino acid (S)-22. The necessary Schiff base 20 is derived from
(R,R,R)-2-hydroxy-3-pinanone and racemic alanine or either of its enantiomers. Since the
fluoro-allylation reaction proceeds via the formation of the corresponding enolate, the initial
configuration of the alanine residue does not influence the stereochemical outcome. Under strongly
basic conditions, Schiff base (R)-20 undergoes allylation to yield the product (S)-21 in a moderate
This is due to the combined impact of steric
and electronic factors which necessitate much
more rigorous reaction conditions [91–93]. The
vinylation variant of this process closely para
llels alkylation, similarly requiring strong bases
and highly controlled reaction environments
[94]. For instance, the benzophenone-derived
Schiff base of glycine ester 1 (Scheme 1) is un
suitable for the synthesis of quaternary amino
acids due to its significant steric bulk. Instead,
the less sterically demanding benzaldehyde-de
rived Schiff base 12 (Scheme 3) is typically em
ployed for quaternization of alanine and higher
amino acids. The process begins with aldimine
12 which is treated with n-BuLi and 2,2,6,6-te
tramethylpiperidine (TMP) to generate the cor
responding enolate. This enolate is then react
ed with 1-(2,2-difluorovinylsulfonyl)benzene
(13) yielding the vinylated product 14 in up to
91% yield. Subsequently, the sulfonyl group in
40 ISSN 2708-129X. Укр. хім. журн., 2025
SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
14 is displaced using Bu3SnH in the presence of
azobisisobutyronitrile (AIBN) producing tribu
tylstannane 15 in an excellent yield exceeding
>90%. Finally, intermediate 15 is treated with
HCl to remove the SnBu3 group and to hydro
lyze both the Schiff base and ester functional
groups resulting in α-(1’-fluoro)vinyl amino
acid 16. This method demonstrates high gene
rality as alanine can be substituted by various
other amino acids featuring aliphatic, aromatic,
or side chains containing appropriately protec
ted carboxylic or amino functionalities [95].
The asymmetric synthesis of (S)-2-amino-
4-fluoropent-4-enoic acid (19) is achieved
through the fluoro-allylation of the chiral
Schiff base (R)-17 (Scheme 4) [96]. The chiral
nucleophilic glycine equivalent (R)-17, derived
from 2-hydroxy-3-pinanone, is reacted with
3-bromo-2-fluoropropene at −78 °C in the
presence of LDA and N,N’-dimethylpropyl
eneurea (DMPU) yielding the fluoro-allylated
product (S)-18 in 73% yield and diastereo
selectivity exceeding 97%. Subsequent acidic
hydrolysis of the Schiff base and deprotection
of the carboxylic group results in the forma
tion of amino acid (S)-19.
This is due to the combined impact of steric and electronic factors which necessitate much
more rigorous reaction conditions [91–93]. The vinylation variant of this process closely parallels
alkylation, similarly requiring strong bases and highly controlled reaction environments [94]. For
instance, the benzophenone-derived Schiff base of glycine ester 1 (Scheme 1) is unsuitable for the
synthesis of quaternary amino acids due to its significant steric bulk. Instead, the less sterically
demanding benzaldehyde-derived Schiff base 12 (Scheme 3) is typically employed for
quaternization of alanine and higher amino acids. The process begins with aldimine 12 which is
treated with n-BuLi and 2,2,6,6-tetramethylpiperidine (TMP) to generate the corresponding enolate.
This enolate is then reacted with 1-(2,2-difluorovinylsulfonyl)benzene (13) yielding the vinylated
product 14 in up to 91% yield. Subsequently, the sulfonyl group in 14 is displaced using Bu3SnH in
the presence of azobisisobutyronitrile (AIBN) producing tributylstannane 15 in an excellent yield
exceeding >90%. Finally, intermediate 15 is treated with HCl to remove the SnBu3 group and to
hydrolyze both the Schiff base and ester functional groups resulting in α-(1’-fluoro)vinyl amino
acid 16. This method demonstrates high generality as alanine can be substituted by various other
amino acids featuring aliphatic, aromatic, or side chains containing appropriately protected
carboxylic or amino functionalities [95].
Scheme 3. Synthesis of α-(1’-fluoro)vinyl amino acid 16.
The asymmetric synthesis of (S)-2-amino-4-fluoropent-4-enoic acid (19) is achieved through
the fluoro-allylation of the chiral Schiff base (R)-17 (Scheme 4) [96]. The chiral nucleophilic
glycine equivalent (R)-17, derived from 2-hydroxy-3-pinanone, is reacted with
3-bromo-2-fluoropropene at −78 °C in the presence of LDA and N,N’-dimethylpropyleneurea
(DMPU) yielding the fluoro-allylated product (S)-18 in 73% yield and diastereoselectivity
exceeding 97%. Subsequent acidic hydrolysis of the Schiff base and deprotection of the carboxylic
group results in the formation of amino acid (S)-19.
Scheme 4. Asymmetric synthesis of amino acid (S)-19.
As shown in Scheme 5, this approach can be employed for the synthesis of the fluorinated
quaternary amino acid (S)-22. The necessary Schiff base 20 is derived from
(R,R,R)-2-hydroxy-3-pinanone and racemic alanine or either of its enantiomers. Since the
fluoro-allylation reaction proceeds via the formation of the corresponding enolate, the initial
configuration of the alanine residue does not influence the stereochemical outcome. Under strongly
basic conditions, Schiff base (R)-20 undergoes allylation to yield the product (S)-21 in a moderate
Scheme 4. Asymmetric synthesis of amino acid (S)-19.
As shown in Scheme 5, this approach can be
employed for the synthesis of the fluorinated
quaternary amino acid (S)-22. The necessary
Schiff base 20 is derived from (R,R,R)-2-hy
droxy-3-pinanone and racemic alanine or ei
ther of its enantiomers. Since the fluoro-ally
lation reaction proceeds via the formation of
the corresponding enolate, the initial configu
ration of the alanine residue does not influence
the stereochemical outcome. Under strongly
basic conditions, Schiff base (R)-20 undergoes
allylation to yield the product (S)-21 in a mo
derate yield of 64% but with high diastereose
lectivity that exceeds 97%. Subsequent hydro
lytic deprotection of both the amino and car
boxylic functional groups results in the forma
tion of the fluorinated quaternary amino acid
(S)-22 [97]. It should be noted that the sense of
asymmetric induction observed was consistent
with that seen in similar transformations of
glycine-derived compounds (Scheme 4).
Scheme 5. Asymmetric synthesis of quaternary amino acid (S)-22.
yield of 64% but with high diastereoselectivity that exceeds 97%. Subsequent hydrolytic
deprotection of both the amino and carboxylic functional groups results in the formation of the
fluorinated quaternary amino acid (S)-22 [97]. It should be noted that the sense of asymmetric
induction observed was consistent with that seen in similar transformations of glycine-derived
compounds (Scheme 4).
Scheme 5. Asymmetric synthesis of quaternary amino acid (S)-22.
The same research group led by G. Haufe [98] investigated the application of the chiral glycine
equivalent imidazolidinone (R)-Boc-BMI 23, introduced by D. Seebach [99], for the asymmetric
synthesis of fluoro-amino acids 26 (Scheme 6). The fluoro-allylation of imidazolidinone (R)-23,
derived from glycine (R = H) or alanine (R = Me), was carried out using fluorovinyl tosylate 24 in
the presence of LDA/DMPU. This reaction yielded products 25 in 89% and 84% yields for R = H
and Me, respectively, along with excellent diastereoselectivities exceeding >97%. Functional group
deprotection was performed in two stages: first, the tert-butyl group was removed under acidic
conditions and then subsequently the N-methyl amide group was cleaved using KOH. However, the
latter step caused partial racemization in the case of glycine-derived products due to the presence of
a relatively acidic α hydrogen.
Scheme 6. Asymmetric synthesis of fluoro-amino acid 26.
In all the methods reported above for the asymmetric synthesis of fluoro-allyl amino acids, the
fluorine atom on the allylating reagents was found to exert virtually no influence on the chemical or
stereochemical outcome of the reactions. It can be postulated that utilizing these reagents for the
fluoro-allylation of other, more effective and practical nucleophilic glycine and alanine equivalents
[100–105] may offer a significantly improved pathway for the efficient synthesis of this class of
fluoro-olefinic amino acids.
Finally, application of the electrophilic glycine equivalent 27 (Scheme 7) to the synthesis of
trifluorovinyl amino acid 30 [106] leverages the unique reactivity of electrophilic reagent 27
enabling efficient nucleophilic substitution of the chlorine with various Grignard reagents.
Specifically, the reaction of 27 with the Mg-trifluorovinyl reagent 28 proceeds cleanly in
tetrahydrofuran (THF) at −78 °C providing product 29 in good yield. Subsequent acidic hydrolysis
of 29 yields trifluorovinyl amino acid 30.
41https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
The same research group led by G. Haufe
[98] investigated the application of the chiral
glycine equivalent imidazolidinone (R)-Boc-
BMI 23, introduced by D. Seebach [99], for the
asymmetric synthesis of fluoro-amino acids 26
(Scheme 6). The fluoro-allylation of imidazoli
dinone (R)-23, derived from glycine (R = H) or
alanine (R = Me), was carried out using fluoro
vinyl tosylate 24 in the presence of LDA/DMPU.
This reaction yielded products 25 in 89% and
84% yields for R = H and Me, respectively, along
with excellent diastereoselectivities exceeding
>97%. Functional group deprotection was per
formed in two stages: first, the tert-butyl group
was removed under acidic conditions and then
subsequently the N-methyl amide group was
cleaved using KOH. However, the latter step
caused partial racemization in the case of gly
cine-derived products due to the presence of a
relatively acidic α hydrogen.
yield of 64% but with high diastereoselectivity that exceeds 97%. Subsequent hydrolytic
deprotection of both the amino and carboxylic functional groups results in the formation of the
fluorinated quaternary amino acid (S)-22 [97]. It should be noted that the sense of asymmetric
induction observed was consistent with that seen in similar transformations of glycine-derived
compounds (Scheme 4).
Scheme 5. Asymmetric synthesis of quaternary amino acid (S)-22.
The same research group led by G. Haufe [98] investigated the application of the chiral glycine
equivalent imidazolidinone (R)-Boc-BMI 23, introduced by D. Seebach [99], for the asymmetric
synthesis of fluoro-amino acids 26 (Scheme 6). The fluoro-allylation of imidazolidinone (R)-23,
derived from glycine (R = H) or alanine (R = Me), was carried out using fluorovinyl tosylate 24 in
the presence of LDA/DMPU. This reaction yielded products 25 in 89% and 84% yields for R = H
and Me, respectively, along with excellent diastereoselectivities exceeding >97%. Functional group
deprotection was performed in two stages: first, the tert-butyl group was removed under acidic
conditions and then subsequently the N-methyl amide group was cleaved using KOH. However, the
latter step caused partial racemization in the case of glycine-derived products due to the presence of
a relatively acidic α hydrogen.
Scheme 6. Asymmetric synthesis of fluoro-amino acid 26.
In all the methods reported above for the asymmetric synthesis of fluoro-allyl amino acids, the
fluorine atom on the allylating reagents was found to exert virtually no influence on the chemical or
stereochemical outcome of the reactions. It can be postulated that utilizing these reagents for the
fluoro-allylation of other, more effective and practical nucleophilic glycine and alanine equivalents
[100–105] may offer a significantly improved pathway for the efficient synthesis of this class of
fluoro-olefinic amino acids.
Finally, application of the electrophilic glycine equivalent 27 (Scheme 7) to the synthesis of
trifluorovinyl amino acid 30 [106] leverages the unique reactivity of electrophilic reagent 27
enabling efficient nucleophilic substitution of the chlorine with various Grignard reagents.
Specifically, the reaction of 27 with the Mg-trifluorovinyl reagent 28 proceeds cleanly in
tetrahydrofuran (THF) at −78 °C providing product 29 in good yield. Subsequent acidic hydrolysis
of 29 yields trifluorovinyl amino acid 30.
Scheme 6. Asymmetric synthesis of fluoro-amino acid 26.
In all the methods reported above for the
asymmetric synthesis of fluoro-allyl amino
acids, the fluorine atom on the allylating rea
gents was found to exert virtually no influence
on the chemical or stereochemical outcome of
the reactions. It can be postulated that utiliz
ing these reagents for the fluoro-allylation of
other, more effective and practical nucleophilic
glycine and alanine equivalents [100–105] may
offer a significantly improved pathway for the
efficient synthesis of this class of fluoro-olefinic
amino acids.
Finally, application of the electrophilic gly
cine equivalent 27 (Scheme 7) to the synthesis
of trifluorovinyl amino acid 30 [106] leverages
the unique reactivity of electrophilic reagent
27 enabling efficient nucleophilic substitution
of the chlorine with various Grignard rea
gents. Specifically, the reaction of 27 with the
Mg-trifluorovinyl reagent 28 proceeds cleanly
in tetrahydrofuran (THF) at −78 °C providing
product 29 in good yield. Subsequent acidic
hydrolysis of 29 yields trifluorovinyl amino
acid 30.
Scheme 7. Synthesis of trifluorovinyl amino acid 30.
Scheme 7. Synthesis of trifluorovinyl amino acid 30.
Elaboration of amino acid side chains.
The elaboration of amino acid side chains involves modifying their structures to introduce new
groups or functional groups, thereby expanding their chemical versatility and functionality. The
process typically starts with protecting reactive groups such as amino or carboxylic groups to
prevent unwanted reactions. The side chain can then be selectively transformed using techniques
such as alkylation, acylation, or coupling reactions. These modifications can introduce fluorine
atoms, aromatic groups, hydroxyls, or other functionalities enabling the synthesis of tailor-made
amino acids. Such elaboration is crucial for designing bioactive molecules, catalysts, or advanced
materials as it allows fine tuning of structural and functional properties for specific applications. A
representative transformation of this type is illustrated in Scheme 8.
Scheme 8. Synthesis of amino acid (S)-33.
Methyl N-Boc-(S)-2-amino-5-fluorohex-5-enoate {(S)-33} was synthesized starting from the
alanine iododerivative (S)-31. The reaction, carried out in the presence of activated zinc, results in
the formation of intermediate (S)-32. Subsequent treatment of intermediate (S)-32 with CuBr,
followed by allylation using tosylate 24, yielded product (S)-33 in 61% yield [107]. Notably, the
optical integrity of the compound remains intact throughout this process enabling the preparation of
enantiopure (S)-33.
The preparation of fluorinated γ amino acids 39 and 40 is illustrated in Scheme 9 [108, 109].
The synthesis begins with vinyl pyrrolidone 34 which undergoes fluorination–bromination of the
double bond using a combination of HF/pyridine and N-bromosuccinimide (NBS) yielding a
mixture of products 35 and 36 in a 25:75 ratio, respectively. The elimination of HBr under strongly
basic conditions produces the unsaturated compounds 37 and 38. Following the separation of
isomers 37 and 38, hydrolysis of the amide bond results in γ-fluorovinyl-γ-amino acids 39 and 40.
Elaboration of amino acid side chains.
The elaboration of amino acid side chains
involves modifying their structures to intro
duce new groups or functional groups, thereby
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SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
expanding their chemical versatility and func
tionality. The process typically starts with pro
tecting reactive groups such as amino or car
boxylic groups to prevent unwanted reactions.
The side chain can then be selectively trans
formed using techniques such as alkylation,
acylation, or coupling reactions. These modifi
cations can introduce fluorine atoms, aromatic
groups, hydroxyls, or other functionalities ena
bling the synthesis of tailor-made amino acids.
Such elaboration is crucial for designing bio
active molecules, catalysts, or advanced mate
rials as it allows fine tuning of structural and
functional properties for specific applications.
A representative transformation of this type is
illustrated in Scheme 8.
Scheme 7. Synthesis of trifluorovinyl amino acid 30.
Elaboration of amino acid side chains.
The elaboration of amino acid side chains involves modifying their structures to introduce new
groups or functional groups, thereby expanding their chemical versatility and functionality. The
process typically starts with protecting reactive groups such as amino or carboxylic groups to
prevent unwanted reactions. The side chain can then be selectively transformed using techniques
such as alkylation, acylation, or coupling reactions. These modifications can introduce fluorine
atoms, aromatic groups, hydroxyls, or other functionalities enabling the synthesis of tailor-made
amino acids. Such elaboration is crucial for designing bioactive molecules, catalysts, or advanced
materials as it allows fine tuning of structural and functional properties for specific applications. A
representative transformation of this type is illustrated in Scheme 8.
Scheme 8. Synthesis of amino acid (S)-33.
Methyl N-Boc-(S)-2-amino-5-fluorohex-5-enoate {(S)-33} was synthesized starting from the
alanine iododerivative (S)-31. The reaction, carried out in the presence of activated zinc, results in
the formation of intermediate (S)-32. Subsequent treatment of intermediate (S)-32 with CuBr,
followed by allylation using tosylate 24, yielded product (S)-33 in 61% yield [107]. Notably, the
optical integrity of the compound remains intact throughout this process enabling the preparation of
enantiopure (S)-33.
The preparation of fluorinated γ amino acids 39 and 40 is illustrated in Scheme 9 [108, 109].
The synthesis begins with vinyl pyrrolidone 34 which undergoes fluorination–bromination of the
double bond using a combination of HF/pyridine and N-bromosuccinimide (NBS) yielding a
mixture of products 35 and 36 in a 25:75 ratio, respectively. The elimination of HBr under strongly
basic conditions produces the unsaturated compounds 37 and 38. Following the separation of
isomers 37 and 38, hydrolysis of the amide bond results in γ-fluorovinyl-γ-amino acids 39 and 40.
Scheme 8. Synthesis of amino acid (S)-33.
Methyl N-Boc-(S)-2-amino-5-fluorohex-5-
enoate {(S)-33} was synthesized starting from
the alanine iododerivative (S)-31. The reaction,
carried out in the presence of activated zinc,
results in the formation of intermediate (S)-32.
Subsequent treatment of intermediate (S)-32
with CuBr, followed by allylation using tosylate
24, yielded product (S)-33 in 61% yield [107].
Notably, the optical integrity of the compound
remains intact throughout this process ena
bling the preparation of enantiopure (S)-33.
The preparation of fluorinated γ amino
acids 39 and 40 is illustrated in Scheme 9 [108,
109]. The synthesis begins with vinyl pyrroli
done 34 which undergoes fluorination–bro
mination of the double bond using a combina
tion of HF/pyridine and N-bromosuccinimide
(NBS) yielding a mixture of products 35 and
36 in a 25:75 ratio, respectively. The elimina
tion of HBr under strongly basic conditions
produces the unsaturated compounds 37 and
38. Following the separation of isomers 37
and 38, hydrolysis of the amide bond results in
γ-fluorovinyl-γ-amino acids 39 and 40.
Scheme 9. Preparation of γ amino acids 39 and 40.
Scheme 9. Preparation of amino acids 39 and 40.
Enantiopure 4-formyl-oxazolidine 41 (Scheme 10), derived from natural serine, is extensively
used in organic synthesis as a masked equivalent of generic amino acids featuring an α formyl
group ready for functional elaboration [110]. Compound 41 has been successfully applied in the
preparation of isomeric fluorovinyl amino acids 49 and 50. In the initial step, the formyl group in 41
reacts with diethyl fluoro(phenylsulfonyl)methylphosphonate yielding the corresponding vinyl
sulfone 42. Vinyl sulfone 42 is then treated with Bu3SnH resulting in the formation of isomeric
products 43 and 44. Following separation via column chromatography, each isomer is treated with
strong base to produce the respective fluorovinyl derivatives 45 and 46. Subsequent hydrolytic
opening of the oxazolidine ring in 45 and 46, combined with oxidation of the alcohol functionality
in 47 and 48 using pyridinium dichromate (PDC), and final N-Boc deprotection yields the
fluorovinyl amino acids 49 and 50 in overall yields of ca. 10% [111].
Scheme 10. Synthesis of amino acids 49 and 50.
The reaction sequence described in Scheme 10 can be effectively utilized for the preparation of
fluorovinyl quaternary amino acids [112]. The process begins with compounds 51 (Scheme 11),
which feature appropriately protected amino and carboxyl groups. Compounds 51 react with
α-fluoro-α-(phenylsulfonyl)methyl phosphonate to yield α-fluorovinyl sulfones 52. These reactions
are performed in the presence of lithium hexamethyldisilazide (LiHMDS) as a strong base at
−78 °C depending on the nature of the side chains. Moreover, each compound 52 is obtained as a
single E geometric isomer. The sulfone group in compounds 52 is subsequently converted to
stannane derivative 53. In the final step, acidic hydrolysis leads to the formation of
43https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
Enantiopure 4-formyl-oxazolidine 41
(Scheme 10), derived from natural serine,
is extensively used in organic synthesis as a
masked equivalent of generic amino acids fea
turing an α formyl group ready for functional
elaboration [110]. Compound 41 has been suc
cessfully applied in the preparation of isomeric
fluorovinyl amino acids 49 and 50. In the ini
tial step, the formyl group in 41 reacts with
diethyl fluoro(phenylsulfonyl)methylphos
phonate yielding the corresponding vinyl sul
fone 42. Vinyl sulfone 42 is then treated with
Bu3SnH resulting in the formation of isomeric
products 43 and 44. Following separation via
column chromatography, each isomer is treat
ed with strong base to produce the respective
fluorovinyl derivatives 45 and 46. Subsequent
hydrolytic opening of the oxazolidine ring in
45 and 46, combined with oxidation of the al
cohol functionality in 47 and 48 using pyrid
inium dichromate (PDC), and final N-Boc de
protection yields the fluorovinyl amino acids
49 and 50 in overall yields of ca. 10% [111].
Scheme 10. Synthesis of amino acids 49 and 50.
Scheme 9. Preparation of amino acids 39 and 40.
Enantiopure 4-formyl-oxazolidine 41 (Scheme 10), derived from natural serine, is extensively
used in organic synthesis as a masked equivalent of generic amino acids featuring an α formyl
group ready for functional elaboration [110]. Compound 41 has been successfully applied in the
preparation of isomeric fluorovinyl amino acids 49 and 50. In the initial step, the formyl group in 41
reacts with diethyl fluoro(phenylsulfonyl)methylphosphonate yielding the corresponding vinyl
sulfone 42. Vinyl sulfone 42 is then treated with Bu3SnH resulting in the formation of isomeric
products 43 and 44. Following separation via column chromatography, each isomer is treated with
strong base to produce the respective fluorovinyl derivatives 45 and 46. Subsequent hydrolytic
opening of the oxazolidine ring in 45 and 46, combined with oxidation of the alcohol functionality
in 47 and 48 using pyridinium dichromate (PDC), and final N-Boc deprotection yields the
fluorovinyl amino acids 49 and 50 in overall yields of ca. 10% [111].
Scheme 10. Synthesis of amino acids 49 and 50.
The reaction sequence described in Scheme 10 can be effectively utilized for the preparation of
fluorovinyl quaternary amino acids [112]. The process begins with compounds 51 (Scheme 11),
which feature appropriately protected amino and carboxyl groups. Compounds 51 react with
α-fluoro-α-(phenylsulfonyl)methyl phosphonate to yield α-fluorovinyl sulfones 52. These reactions
are performed in the presence of lithium hexamethyldisilazide (LiHMDS) as a strong base at
−78 °C depending on the nature of the side chains. Moreover, each compound 52 is obtained as a
single E geometric isomer. The sulfone group in compounds 52 is subsequently converted to
stannane derivative 53. In the final step, acidic hydrolysis leads to the formation of
The reaction sequence described in Scheme
10 can be effectively utilized for the prepara
tion of fluorovinyl quaternary amino acids
[112]. The process begins with compounds
51 (Scheme 11), which feature appropriately
protected amino and carboxyl groups. Com
pounds 51 react with α-fluoro-α-(phenylsulfo
nyl)methyl phosphonate to yield α-fluorovinyl
sulfones 52. These reactions are performed in
the presence of lithium hexamethyldisilazide
(LiHMDS) as a strong base at −78 °C depending
on the nature of the side chains. Moreover, each
compound 52 is obtained as a single E geomet
ric isomer. The sulfone group in compounds
52 is subsequently converted to stannane de
rivative 53. In the final step, acidic hydrolysis
leads to the formation of (Z)-α-(2’-fluoro)vinyl
amino acids 54 in yields ranging from 52–93%.
This method demonstrates broad tolerance for
diverse substituents, accommodating both
natural and tailor-made amino acids including
simple alkyl or benzyl-type groups as well as
substituents containing appropriately protect
ed functional groups.
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SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
Scheme 11. Synthesis of (Z)-α-(2’fluoro)vinyl amino acids 54.
(Z)-α-(2’-fluoro)vinyl amino acids 54 in yields ranging from 52–93%. This method demonstrates
broad tolerance for diverse substituents, accommodating both natural and tailor-made amino acids
including simple alkyl or benzyl-type groups as well as substituents containing appropriately
protected functional groups.
Scheme 11. Synthesis of (Z)-α-(2’fluoro)vinyl amino acids 54.
Sterically constrained prolines are highly valued by chemical biologists, molecular
biophysicists, and medicinal chemists for their ability to modulate the conformational landscape of
peptides and drug candidates during the discovery stage [113–116]. An example of the synthesis of
such conformationally constrained prolines is presented in Scheme 12. The procedure involves the
addition of CF2Br2 to the carbonyl group of keto derivative 55, facilitated by zinc and
hexamethylphosphoramide (HMPT), to yield 4-difluoromethyleneproline 56 in 48% yield.
Compound 56 was subsequently utilized for the preparation of the corresponding saturated
4-difluoromethyl-L-proline or, with orthogonal protection, employed in peptide synthesis [117].
Scheme 12. Synthesis of conformationally constrained 4-difluoromethyleneproline 56.
Considering the remarkable biological significance of γ aminobutyric acid (GABA) and its
derivatives, conformationally constrained GABA analogs are highly sought after in biochemistry
and drug design [118–120]. For instance, amino acid 59 (Scheme 13) features two distinct
steric/conformational constraints: a five-membered ring and a C=C double bond. The addition of
two fluorine atoms to the double bond introduces particular effects such as enhanced polarity and
increased lipophilicity, both of which are crucial for interactions with biological receptors. The
synthesis of amino acid 59 begins with the reaction of cyclic amidoketone 57 with diethyl
difluoromethylphosphonate, yielding difluoromethylene derivative 58 [121]. Subsequent
deprotection of the amide nitrogen in 58, followed by hydrolytic cleavage of the amide bond,
completes the reaction sequence producing the cyclic difluoromethylene GABA analog 59.
Scheme 13. Preparation of conformationally constrained cyclic amino acid 59.
The introduction of carboxyl and/or amino groups onto a fluoro-olefinic framework.
The incorporation of carboxyl or amino functionalities onto an existing organic framework
(Z)-α-(2’-fluoro)vinyl amino acids 54 in yields ranging from 52–93%. This method demonstrates
broad tolerance for diverse substituents, accommodating both natural and tailor-made amino acids
including simple alkyl or benzyl-type groups as well as substituents containing appropriately
protected functional groups.
Scheme 11. Synthesis of (Z)-α-(2’fluoro)vinyl amino acids 54.
Sterically constrained prolines are highly valued by chemical biologists, molecular
biophysicists, and medicinal chemists for their ability to modulate the conformational landscape of
peptides and drug candidates during the discovery stage [113–116]. An example of the synthesis of
such conformationally constrained prolines is presented in Scheme 12. The procedure involves the
addition of CF2Br2 to the carbonyl group of keto derivative 55, facilitated by zinc and
hexamethylphosphoramide (HMPT), to yield 4-difluoromethyleneproline 56 in 48% yield.
Compound 56 was subsequently utilized for the preparation of the corresponding saturated
4-difluoromethyl-L-proline or, with orthogonal protection, employed in peptide synthesis [117].
Scheme 12. Synthesis of conformationally constrained 4-difluoromethyleneproline 56.
Considering the remarkable biological significance of γ aminobutyric acid (GABA) and its
derivatives, conformationally constrained GABA analogs are highly sought after in biochemistry
and drug design [118–120]. For instance, amino acid 59 (Scheme 13) features two distinct
steric/conformational constraints: a five-membered ring and a C=C double bond. The addition of
two fluorine atoms to the double bond introduces particular effects such as enhanced polarity and
increased lipophilicity, both of which are crucial for interactions with biological receptors. The
synthesis of amino acid 59 begins with the reaction of cyclic amidoketone 57 with diethyl
difluoromethylphosphonate, yielding difluoromethylene derivative 58 [121]. Subsequent
deprotection of the amide nitrogen in 58, followed by hydrolytic cleavage of the amide bond,
completes the reaction sequence producing the cyclic difluoromethylene GABA analog 59.
Scheme 13. Preparation of conformationally constrained cyclic amino acid 59.
The introduction of carboxyl and/or amino groups onto a fluoro-olefinic framework.
The incorporation of carboxyl or amino functionalities onto an existing organic framework
(Z)-α-(2’-fluoro)vinyl amino acids 54 in yields ranging from 52–93%. This method demonstrates
broad tolerance for diverse substituents, accommodating both natural and tailor-made amino acids
including simple alkyl or benzyl-type groups as well as substituents containing appropriately
protected functional groups.
Scheme 11. Synthesis of (Z)-α-(2’fluoro)vinyl amino acids 54.
Sterically constrained prolines are highly valued by chemical biologists, molecular
biophysicists, and medicinal chemists for their ability to modulate the conformational landscape of
peptides and drug candidates during the discovery stage [113–116]. An example of the synthesis of
such conformationally constrained prolines is presented in Scheme 12. The procedure involves the
addition of CF2Br2 to the carbonyl group of keto derivative 55, facilitated by zinc and
hexamethylphosphoramide (HMPT), to yield 4-difluoromethyleneproline 56 in 48% yield.
Compound 56 was subsequently utilized for the preparation of the corresponding saturated
4-difluoromethyl-L-proline or, with orthogonal protection, employed in peptide synthesis [117].
Scheme 12. Synthesis of conformationally constrained 4-difluoromethyleneproline 56.
Considering the remarkable biological significance of γ aminobutyric acid (GABA) and its
derivatives, conformationally constrained GABA analogs are highly sought after in biochemistry
and drug design [118–120]. For instance, amino acid 59 (Scheme 13) features two distinct
steric/conformational constraints: a five-membered ring and a C=C double bond. The addition of
two fluorine atoms to the double bond introduces particular effects such as enhanced polarity and
increased lipophilicity, both of which are crucial for interactions with biological receptors. The
synthesis of amino acid 59 begins with the reaction of cyclic amidoketone 57 with diethyl
difluoromethylphosphonate, yielding difluoromethylene derivative 58 [121]. Subsequent
deprotection of the amide nitrogen in 58, followed by hydrolytic cleavage of the amide bond,
completes the reaction sequence producing the cyclic difluoromethylene GABA analog 59.
Scheme 13. Preparation of conformationally constrained cyclic amino acid 59.
The introduction of carboxyl and/or amino groups onto a fluoro-olefinic framework.
The incorporation of carboxyl or amino functionalities onto an existing organic framework
Sterically constrained prolines are highly
valued by chemical biologists, molecular bio
physicists, and medicinal chemists for their
ability to modulate the conformational land
scape of peptides and drug candidates during
the discovery stage [113–116]. An example of
the synthesis of such conformationally con
strained prolines is presented in Scheme 12.
The procedure involves the addition of CF2Br2
to the carbonyl group of keto derivative 55,
facilitated by zinc and hexamethylphospho
ramide (HMPT), to yield 4-difluoromethyl
eneproline 56 in 48% yield. Compound 56
was subsequently utilized for the preparation
of the corresponding saturated 4-difluorome
thyl-l-proline or, with orthogonal protection,
employed in peptide synthesis [117].
Scheme 12. Synthesis of conformationally constrained 4-difluoromethyleneproline 56.
Considering the remarkable biological sig
nificance of γ aminobutyric acid (GABA) and
its derivatives, conformationally constrained
GABA analogs are highly sought after in bio
chemistry and drug design [118–120]. For
instance, amino acid 59 (Scheme 13) features
two distinct steric/conformational constraints:
a five-membered ring and a C=C double bond.
The addition of two fluorine atoms to the dou
ble bond introduces particular effects such as
enhanced polarity and increased lipophilicity,
both of which are crucial for interactions with
biological receptors. The synthesis of amino
acid 59 begins with the reaction of cyclic ami
doketone 57 with diethyl difluoromethylphos
phonate, yielding difluoromethylene deriva
tive 58 [121]. Subsequent deprotection of the
amide nitrogen in 58, followed by hydrolytic
cleavage of the amide bond, completes the re
action sequence producing the cyclic difluo
romethylene GABA analog 59.
Scheme 13. Preparation of conformationally constrained cyclic γ amino acid 59.
45https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
The introduction of carboxyl and/or amino
groups onto a fluoro-olefinic framework.
The incorporation of carboxyl or amino
functionalities onto an existing organic frame
work combines standard and well established
approaches from organofluorine and amino acid
chemistry. Due to the stability of the C(sp2)–F
bond, fluoro-olefinic organic compounds typi
cally exhibit resistance to nucleophilic substitu
tion reactions which are commonly employed
to introduce carboxyl or amino groups [122].
A representative example of this approach
(Scheme 14) is the synthesis of (E)-β-(fluo
romethylene)-m-tyrosine (65) [123, 124] which
begins with the bromination of commercially
available methoxy-substituted acetophenone
60 followed by substitution of the bromine
with fluorine using potassium fluoride to yield
fluoro-acyl 61 in 54% yield. Compound 61 is
then treated with triethyl phosphonoacetate in
the presence of NaH producing the unsaturat
ed intermediate 62 as a mixture of Z and E iso
mers in a ratio of 8:1 in 80% yield. Subsequent
bromination of intermediate 62 followed by
the elimination of HBr using piperidine gen
erates the bromo derivative 63. The key step
in this synthesis is the LDA-assisted isomeri
zation of 63 into the thermodynamically more
stable compound 64 which possesses a more
acidic hydrogen at the α position relative to the
ester group. The final steps include the intro
duction of an amino group through treatment
of 64 with ammonia, neutralization, and hy
drolytic deprotection of the carboxylic group
ultimately affording compound (E)-β-(fluo
romethylene)-m-tyrosine (65).
Scheme 14. Synthesis of (E)-β-(fluoromethylene)-m-tyrosine (65).
combines standard and well established approaches from organofluorine and amino acid chemistry.
Due to the stability of the C(sp2)–F bond, fluoro-olefinic organic compounds typically exhibit
resistance to nucleophilic substitution reactions which are commonly employed to introduce
carboxyl or amino groups [122].
A representative example of this approach (Scheme 14) is the synthesis of
(E)-β-(fluoromethylene)-m-tyrosine (65) [123, 124] which begins with the bromination of
commercially available methoxy-substituted acetophenone 60 followed by substitution of the
bromine with fluorine using potassium fluoride to yield fluoro-acyl 61 in 54% yield. Compound 61
is then treated with triethyl phosphonoacetate in the presence of NaH producing the unsaturated
intermediate 62 as a mixture of Z and E isomers in a ratio of 8:1 in 80% yield. Subsequent
bromination of intermediate 62 followed by the elimination of HBr using piperidine generates the
bromo derivative 63. The key step in this synthesis is the LDA-assisted isomerization of 63 into the
thermodynamically more stable compound 64 which possesses a more acidic hydrogen at the α
position relative to the ester group. The final steps include the introduction of an amino group
through treatment of 64 with ammonia, neutralization, and hydrolytic deprotection of the carboxylic
group ultimately affording compound (E)-β-(fluoromethylene)-m-tyrosine (65).
Scheme 14. Synthesis of (E)-β-(fluoromethylene)-m-tyrosine (65).
The reactions of isocyanoacetates with fluorinated carbonyl compounds represent a well
established method for the preparation of fluorinated α-amino-β-hydroxy acids [125–127]. An
intriguing application of this approach for the synthesis of unsaturated derivatives is outlined in
Scheme 15 [123, 124]. The cyclization of bromofluoroacetophenone 66 with isocyanoacetate 67
catalyzed by Cu2O efficiently produces oxazoline intermediate 68 in an excellent 90% yield.
Subsequent treatment of the heterocyclic product 68 with trifluoroacetic acid and activated zinc
results in oxazoline ring opening forming a mixture of geometric isomers 69 and 70 which are
separable by column chromatography. Finally, refluxing 69 and 70 in 47% aqueous HBr removes all
protecting groups yielding the geometric isomers 71 (Z) and 72 (E) of
β-(fluoromethylene)-m-tyrosine in ca. overall yields of 25%.
The reactions of isocyanoacetates with
fluorinated carbonyl compounds represent
a well established method for the prepara
tion of fluorinated α-amino-β-hydroxy acids
[125–127]. An intriguing application of this
approach for the synthesis of unsaturated de
rivatives is outlined in Scheme 15 [123, 124].
The cyclization of bromofluoroacetophenone
66 with isocyanoacetate 67 catalyzed by Cu2O
efficiently produces oxazoline intermediate 68
in an excellent 90% yield. Subsequent treat
ment of the heterocyclic product 68 with tri
fluoroacetic acid and activated zinc results in
oxazoline ring opening forming a mixture of
geometric isomers 69 and 70 which are separa
ble by column chromatography. Finally, reflux
ing 69 and 70 in 47% aqueous HBr removes
all protecting groups yielding the geometric
isomers 71 (Z) and 72 (E) of β-(fluoromethy
lene)-m-tyrosine in ca. overall yields of 25%.
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SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
Scheme 15. Synthesis of the geometric isomers 71 (Z) and 72 (E) of β-(fluoromethylene)-m-tyrosine.
Scheme 15. Synthesis of the geometric isomers 71 (Z) and 72 (E) of β-(fluoromethylene)-m-tyrosine.
During the enzymatic enantioresolution of the geometric isomers 71 (Z) and 72 (E) of
β-(fluoromethylene)-m-tyrosine, it was found [128] that only the E isomer 72 exhibited biological
activity undergoing reactions with α-chymotrypsin, facilitating the preparation of the R and S
enantiomers of (E)-β-(fluoromethylene)-m-tyrosine (72). While it is surprising that the enantiomers
of 71 were unreactive, as a result, enzymatic treatment provides a useful method for separating both
the geometric and optical isomers [128]. Additionally, a compelling avenue for further investigation
would involve chemical deracemization via DKR processes [129–131] to examine the influence of
geometric configuration on the stereochemical outcome.
The Strecker synthesis of amino acids is one of the oldest and most classical chemical reactions
[132]. An example of its application in the synthesis of fluoro-olefinic amino acids is depicted in
Scheme 16 [133]. In this process, 2-fluoroacrolein (73) reacts with
bis(4-methoxyphenyl)methanamine as the amino group source and trimethylsilylcyanide (TMS-CN)
as the carboxylic group source to form intermediate 74. This intermediate is subsequently
hydrolyzed to yield 2-amino-3-fluorobutenoic acid (monofluorovinyl glycine, 75) in an overall
yield of ca. 30%.
Scheme 16. Synthesis of 2-amino-3-fluorobutenoic acid (75).
In addition to α amino acids, the introduction of amino acid functionalities can also be applied
to the preparation of fluoro-olefinic GABA derivatives which not only imparts fluorine effects, but
also strategically restricts the number of accessible conformations. As illustrated in Scheme 17 [123,
124], phthalimide 76 undergoes bromination at the methyl group to yield bromo derivative 77 in
high yield. The bromide in 77 is subsequently substituted with a cyanide group via reaction with
sodium cyanide in dimethyl sulfoxide producing nitrile 78. Finally, treatment of compound 78 with
6 N hydrochloric acid under reflux conditions results in the hydrolysis of the nitrile group and the
removal of the phthalimide protection leading to the formation of amino acid 79.
Scheme 15. Synthesis of the geometric isomers 71 (Z) and 72 (E) of β-(fluoromethylene)-m-tyrosine.
During the enzymatic enantioresolution of the geometric isomers 71 (Z) and 72 (E) of
β-(fluoromethylene)-m-tyrosine, it was found [128] that only the E isomer 72 exhibited biological
activity undergoing reactions with α-chymotrypsin, facilitating the preparation of the R and S
enantiomers of (E)-β-(fluoromethylene)-m-tyrosine (72). While it is surprising that the enantiomers
of 71 were unreactive, as a result, enzymatic treatment provides a useful method for separating both
the geometric and optical isomers [128]. Additionally, a compelling avenue for further investigation
would involve chemical deracemization via DKR processes [129–131] to examine the influence of
geometric configuration on the stereochemical outcome.
The Strecker synthesis of amino acids is one of the oldest and most classical chemical reactions
[132]. An example of its application in the synthesis of fluoro-olefinic amino acids is depicted in
Scheme 16 [133]. In this process, 2-fluoroacrolein (73) reacts with
bis(4-methoxyphenyl)methanamine as the amino group source and trimethylsilylcyanide (TMS-CN)
as the carboxylic group source to form intermediate 74. This intermediate is subsequently
hydrolyzed to yield 2-amino-3-fluorobutenoic acid (monofluorovinyl glycine, 75) in an overall
yield of ca. 30%.
Scheme 16. Synthesis of 2-amino-3-fluorobutenoic acid (75).
In addition to α amino acids, the introduction of amino acid functionalities can also be applied
to the preparation of fluoro-olefinic GABA derivatives which not only imparts fluorine effects, but
also strategically restricts the number of accessible conformations. As illustrated in Scheme 17 [123,
124], phthalimide 76 undergoes bromination at the methyl group to yield bromo derivative 77 in
high yield. The bromide in 77 is subsequently substituted with a cyanide group via reaction with
sodium cyanide in dimethyl sulfoxide producing nitrile 78. Finally, treatment of compound 78 with
6 N hydrochloric acid under reflux conditions results in the hydrolysis of the nitrile group and the
removal of the phthalimide protection leading to the formation of amino acid 79.
During the enzymatic enantioresolution
of the geometric isomers 71 (Z) and 72 (E) of
β-(fluoromethylene)-m-tyrosine, it was found
[128] that only the E isomer 72 exhibited bio
logical activity undergoing reactions with
α-chymotrypsin, facilitating the preparation of
the R and S enantiomers of (E)-β-(fluoromethy
lene)-m-tyrosine (72). While it is surprising
that the enantiomers of 71 were unreactive, as
a result, enzymatic treatment provides a use
ful method for separating both the geometric
and optical isomers [128]. Additionally, a com
pelling avenue for further investigation would
involve chemical deracemization via DKR pro
cesses [129–131] to examine the influence of
geometric configuration on the stereochemical
outcome.
The Strecker synthesis of amino acids is one
of the oldest and most classical chemical reac
tions [132]. An example of its application in
the synthesis of fluoro-olefinic amino acids is
depicted in Scheme 16 [133]. In this process,
2-fluoroacrolein (73) reacts with bis(4-meth
oxyphenyl)methanamine as the amino group
source and trimethylsilylcyanide (TMS-CN)
as the carboxylic group source to form inter
mediate 74. This intermediate is subsequently
hydrolyzed to yield 2-amino-3-fluorobutenoic
acid (monofluorovinyl glycine, 75) in an over
all yield of ca. 30%.
Scheme 16. Synthesis of 2-amino-3-fluorobutenoic acid (75).
In addition to α amino acids, the introduc
tion of amino acid functionalities can also be
applied to the preparation of fluoro-olefinic
GABA derivatives which not only imparts
fluorine effects, but also strategically restricts
the number of accessible conformations. As
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illustrated in Scheme 17 [123, 124], phthali
mide 76 undergoes bromination at the methyl
group to yield bromo derivative 77 in high
yield. The bromide in 77 is subsequently sub
stituted with a cyanide group via reaction with
sodium cyanide in dimethyl sulfoxide produc
ing nitrile 78. Finally, treatment of compound
78 with 6 N hydrochloric acid under reflux
conditions results in the hydrolysis of the nit
rile group and the removal of the phthalimide
protection leading to the formation of γ amino
acid 79.
Scheme 17. Preparation of fluoromethylene GABA derivative 79.
Scheme 17. Preparation of fluoromethylene GABA derivative 79.
Glutamic acid is a crucial amino acid involved in protein synthesis and nitrogen metabolism. It
supports immune function, provides energy for immune cells, and serves as a precursor to amino
acids such as glutamine. Additionally, as glutamate it acts as the primary excitatory neurotransmitter
in the brain playing an essential role in synaptic transmission, learning, and memory [134–138].
The remarkable biological versatility of glutamic acid and its derivatives has inspired significant
synthetic efforts to develop various tailor-made derivatives [139–142].
The synthesis of glutamic acid 87 featuring a fluorine-containing unsaturated moiety is
illustrated in Scheme 18 [123, 124]. The procedure begins with the electrophilic bromination of
inexpensive and commercially available ethyl 3,3-dimethylacrylate (80) using NBS followed by
substitution of the bromine with fluorine via potassium fluoride yielding fluoro-acrylate 81.
Compound 81 is then subjected to radical bromination with bromine followed by
dehydrobromination using 1,4-diazabicyclo[2.2.2]octane (DABCO) producing
α-bromofluoro-acrylate 82. The subsequent isomerization of 82 to 83, facilitated by LDA, is driven
by the greater thermodynamic stability of 83 due to the higher acidity of the proton at the α position
relative to the ester functional group. The bromine in 83 is replaced by an amino group through
treatment with ammonia and the amino group is then protected using phthaloyl dichloride yielding
protected amino acid 84. A second carboxylic function is introduced via electrophilic bromination
of 84 with NBS producing bromo derivative 85. Substitution of bromine with a CN group is
achieved using sodium cyanide generating nitrile 86. The final step involves hydrolysis and
deprotection of compound 86 under acidic conditions to yield (E)-β-fluoromethyleneglutamic acid
(87).
The general method for preparing GABA derivatives featuring di- and trifluorovinyl groups is
outlined in Scheme 19 [108]. The process begins with the oxidation of unsaturated ester 88 to
aldehyde 89 via standard ozonolysis. The addition of 1,1-difluoroethene or 1,1,2-trifluoroethene to
the carbonyl group of 89 is conducted under strictly controlled conditions at −105 °C using
sec-BuLi as base. The resulting alcohols 90 are then reacted with phthalimide in the presence of
PPh3 and diethyl azodicarboxylate (DEAD) yielding protected amino acids 91. The final steps
involve deprotection of the amino group using hydrazine followed by acidic hydrolysis of the ester
group. This procedure yields 4-amino-6,6-difluoro-5-hexenoic acid (92) and
4-amino-5,6,6-trifluoro-5-hexenoic acid (93), both of which are GABA analogs presenting a wide
range of opportunities for exploration in biochemistry and medicinal chemistry.
Glutamic acid is a crucial amino acid in
volved in protein synthesis and nitrogen me
tabolism. It supports immune function, pro
vides energy for immune cells, and serves as
a precursor to amino acids such as glutamine.
Additionally, as glutamate it acts as the primary
excitatory neurotransmitter in the brain play
ing an essential role in synaptic transmission,
learning, and memory [134–138]. The remar
kable biological versatility of glutamic acid and
its derivatives has inspired significant synthetic
efforts to develop various tailor-made deriva
tives [139–142].
The synthesis of glutamic acid 87 featur
ing a fluorine-containing unsaturated moie
ty is illustrated in Scheme 18 [123, 124]. The
procedure begins with the electrophilic bro
mination of inexpensive and commercially
available ethyl 3,3-dimethylacrylate (80) using
NBS followed by substitution of the bromine
with fluorine via potassium fluoride yielding
fluoro-acrylate 81. Compound 81 is then sub
jected to radical bromination with bromine
followed by dehydrobromination using 1,4-di
azabicyclo[2.2.2]octane (DABCO) producing
α-bromofluoro-acrylate 82. The subsequent
isomerization of 82 to 83, facilitated by LDA,
is driven by the greater thermodynamic stabi
lity of 83 due to the higher acidity of the pro
ton at the α position relative to the ester func
tional group. The bromine in 83 is replaced by
an amino group through treatment with am
monia and the amino group is then protected
using phthaloyl dichloride yielding protected
amino acid 84. A second carboxylic function
is introduced via electrophilic bromination of
84 with NBS producing bromo derivative 85.
Substitution of bromine with a CN group is
achieved using sodium cyanide generating ni
trile 86. The final step involves hydrolysis and
deprotection of compound 86 under acidic
conditions to yield (E)-β-fluoromethyleneglu
tamic acid (87).
The general method for preparing GABA de
rivatives featuring di- and trifluorovinyl groups
is outlined in Scheme 19 [108]. The process
begins with the oxidation of unsaturated ester
88 to aldehyde 89 via standard ozonolysis. The
addition of 1,1-difluoroethene or 1,1,2-trifluo
roethene to the carbonyl group of 89 is con
ducted under strictly controlled conditions at
−105 °C using sec-BuLi as base. The resulting
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SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
alcohols 90 are then reacted with phthalimide
in the presence of PPh3 and diethyl azodicar
boxylate (DEAD) yielding protected amino ac
ids 91. The final steps involve deprotection of
the amino group using hydrazine followed by
acidic hydrolysis of the ester group. This proce
dure yields 4-amino-6,6-difluoro-5-hexenoic
acid (92) and 4-amino-5,6,6-trifluoro-5-hexe
noic acid (93), both of which are GABA ana
logs presenting a wide range of opportunities
for exploration in biochemistry and medicinal
chemistry.
Scheme 18. Synthesis of (E)-β-fluoromethyleneglutamic acid (87).
Scheme 18. Synthesis of (E)-β-fluoromethyleneglutamic acid (87).
Scheme 19. Synthesis of GABA analogs 4-amino-6,6-difluoro-5-hexenoic acid (92) and
4-amino-5,6,6-trifluoro-5-hexenoic acid (93).
As shown in Scheme 12, (S)-3-(difluoromethylene)proline can be synthesized from
(S)-3-oxoproline 55 using CF2Br2/Zn [117]. An alternative method for preparing this highly
intriguing conformationally constrained and fluorine-containing proline analog is outlined in
Scheme 20 [143]. This approach begins with the cyclization of a trifluoromethyl-containing and
appropriately protected amino alcohol 94. The reaction requires strong base to deprotonate the NH
group and is conducted in dimethylformamide at 120 °C for 4 hours. Cyclic compound 95 is then
treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to remove the p-methoxybenzyl
(PMB) protecting group. This reaction occurs in a CH2Cl2–MeOH solvent mixture at ambient
temperature but requires ca. two days to complete. The deprotected alcohol 96 is oxidized to a
carboxylic acid using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/NaClO2 under mild
conditions in acetonitrile at ambient temperature. However, this step progresses only slowly, taking
ca. seven days. Despite the extended reaction times, the mild conditions result in excellent yields
exceeding 90% at every step of the process. This method ultimately provides NTs-protected
(S)-3-(difluoromethylene)proline (97) making it a synthetically appealing approach.
Scheme 20. Synthesis of (S)-3-(difluoromethylene)proline 97.
Generation of unsaturation on pre-existing fluoro-amino acid cores.
Scheme 18. Synthesis of (E)-β-fluoromethyleneglutamic acid (87).
Scheme 19. Synthesis of GABA analogs 4-amino-6,6-difluoro-5-hexenoic acid (92) and
4-amino-5,6,6-trifluoro-5-hexenoic acid (93).
As shown in Scheme 12, (S)-3-(difluoromethylene)proline can be synthesized from
(S)-3-oxoproline 55 using CF2Br2/Zn [117]. An alternative method for preparing this highly
intriguing conformationally constrained and fluorine-containing proline analog is outlined in
Scheme 20 [143]. This approach begins with the cyclization of a trifluoromethyl-containing and
appropriately protected amino alcohol 94. The reaction requires strong base to deprotonate the NH
group and is conducted in dimethylformamide at 120 °C for 4 hours. Cyclic compound 95 is then
treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to remove the p-methoxybenzyl
(PMB) protecting group. This reaction occurs in a CH2Cl2–MeOH solvent mixture at ambient
temperature but requires ca. two days to complete. The deprotected alcohol 96 is oxidized to a
carboxylic acid using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/NaClO2 under mild
conditions in acetonitrile at ambient temperature. However, this step progresses only slowly, taking
ca. seven days. Despite the extended reaction times, the mild conditions result in excellent yields
exceeding 90% at every step of the process. This method ultimately provides NTs-protected
(S)-3-(difluoromethylene)proline (97) making it a synthetically appealing approach.
Scheme 20. Synthesis of (S)-3-(difluoromethylene)proline 97.
Generation of unsaturation on pre-existing fluoro-amino acid cores.
Scheme 19. Synthesis of GABA analogs 4-amino-6,6-difluoro-5-hexenoic acid (92)
and 4-amino-5,6,6-trifluoro-5-hexenoic acid (93).
As shown in Scheme 12, (S)-3-(difluo
romethylene)proline can be synthesized from
(S)-3-oxoproline 55 using CF2Br2/Zn [117].
An alternative method for preparing this high
ly intriguing conformationally constrained
and fluorine-containing proline analog is
outlined in Scheme 20 [143]. This approach
begins with the cyclization of a trifluorome
thyl-containing and appropriately protected
amino alcohol 94. The reaction requires strong
base to deprotonate the NH group and is con
ducted in dimethylformamide at 120 °C for
4 hours. Cyclic compound 95 is then treated
with 2,3-dichloro-5,6-dicyano-1,4-benzoqui
none (DDQ) to remove the p-methoxybenzyl
(PMB) protecting group. This reaction occurs
in a CH2Cl2–MeOH solvent mixture at ambi
ent temperature but requires ca. two days to
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complete. The deprotected alcohol 96 is oxi
dized to a carboxylic acid using 2,2,6,6-tetra
methylpiperidine-1-oxyl (TEMPO)/NaClO2
under mild conditions in acetonitrile at am
bient temperature. However, this step progre
sses only slowly, taking ca. seven days. Despite
the extended reaction times, the mild condi
tions result in excellent yields exceeding 90%
at every step of the process. This method ul
timately provides NTs-protected (S)-3-(difluo
romethylene)proline (97) making it a synthe
tically appealing approach.
Scheme 18. Synthesis of (E)-β-fluoromethyleneglutamic acid (87).
Scheme 19. Synthesis of GABA analogs 4-amino-6,6-difluoro-5-hexenoic acid (92) and
4-amino-5,6,6-trifluoro-5-hexenoic acid (93).
As shown in Scheme 12, (S)-3-(difluoromethylene)proline can be synthesized from
(S)-3-oxoproline 55 using CF2Br2/Zn [117]. An alternative method for preparing this highly
intriguing conformationally constrained and fluorine-containing proline analog is outlined in
Scheme 20 [143]. This approach begins with the cyclization of a trifluoromethyl-containing and
appropriately protected amino alcohol 94. The reaction requires strong base to deprotonate the NH
group and is conducted in dimethylformamide at 120 °C for 4 hours. Cyclic compound 95 is then
treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to remove the p-methoxybenzyl
(PMB) protecting group. This reaction occurs in a CH2Cl2–MeOH solvent mixture at ambient
temperature but requires ca. two days to complete. The deprotected alcohol 96 is oxidized to a
carboxylic acid using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/NaClO2 under mild
conditions in acetonitrile at ambient temperature. However, this step progresses only slowly, taking
ca. seven days. Despite the extended reaction times, the mild conditions result in excellent yields
exceeding 90% at every step of the process. This method ultimately provides NTs-protected
(S)-3-(difluoromethylene)proline (97) making it a synthetically appealing approach.
Scheme 20. Synthesis of (S)-3-(difluoromethylene)proline 97.
Generation of unsaturation on pre-existing fluoro-amino acid cores.
Scheme 20. Synthesis of (S)-3-(difluoromethylene)proline 97.
Generation of unsaturation on pre-exist-
ing fluoro-amino acid cores.
Sterically and conformationally constrai
ned pyroglutamic acids are vital in medicinal
chemistry due to their distinct ability to modu
late protein structure and function. These de
rivatives enable the targeted restriction of pep
tide backbone flexibility, stabilizing specific
conformations that enhance binding affinity
and selectivity for biological targets. Conse
quently, the synthesis of substituted pyroglu
tamic acids has garnered considerable atten
tion [144–146]. The synthesis of (S)-4-mono
fluoromethylenylpyroglutamic acid (100)
is outlined in Scheme 21 [147]. The process
begins with 4-difluoromethylpyroglutamate
(98), derived from naturally occurring 4-hy
droxyproline [123, 124]. Treatment of 98 with
triethylamine in acetonitrile induces dehydro
fluorination providing compound 99 in yields
of up to 90%. The final step involves standard
acidic deprotection of the N-Boc and tert-bu
tyl ester groups under mild conditions afford
ing free (S)-4-monofluoromethylenylpyroglu
tamic acid (100).
Scheme 21. Preparation of (S)-4-monofluoromethylenylpyroglutamic acid (100).
Sterically and conformationally constrained pyroglutamic acids are vital in medicinal chemistry
due to their distinct ability to modulate protein structure and function. These derivatives enable the
targeted restriction of peptide backbone flexibility, stabilizing specific conformations that enhance
binding affinity and selectivity for biological targets. Consequently, the synthesis of substituted
pyroglutamic acids has garnered considerable attention [144–146]. The synthesis of
(S)-4-monofluoromethylenylpyroglutamic acid (100) is outlined in Scheme 21 [147]. The process
begins with 4-difluoromethylpyroglutamate (98), derived from naturally occurring
4-hydroxyproline [123, 124]. Treatment of 98 with triethylamine in acetonitrile induces
dehydrofluorination providing compound 99 in yields of up to 90%. The final step involves
standard acidic deprotection of the N-Boc and tert-butyl ester groups under mild conditions
affording free (S)-4-monofluoromethylenylpyroglutamic acid (100).
Scheme 21. Preparation of (S)-4-monofluoromethylenylpyroglutamic acid (100).
The fluoro–Pummerer rearrangement is a variant of the classic Pummerer rearrangement [148]
in which sulfur-containing compounds undergo structural reorganization via an electrophilic
activation process. In this modified reaction, the introduction of fluorine enhances the
electrophilicity of the sulfonium intermediate leading to regioselective rearrangement and
functionalization of adjacent carbon centers [149, 150]. The reaction is valuable in synthetic
chemistry, particularly for constructing fluorinated heterocycles and bioactive molecules with
tailored electronic and steric properties.
An example of the application of the fluoro–Pummerer rearrangement as a key step in the
synthesis of β-fluorodehydroalanine 107 is illustrated in Scheme 22 [151]. The process begins with
the reaction of N-Fmoc-protected serine 101 with 1-(diphenylmethylene)hydrazine in the presence
of iodine and (diacetoxyiodo)benzene yielding compound 102 in 90% yield while installing the
ester protective group. Compound 102 is then converted into the corresponding ester via reaction
with mesyl chloride followed by elimination of methanesulfonic acid using triethylamine affording
dehydroalanine 103 in 82% yield. Addition of 4-methoxybenzenethiol to the double bond in 103
produces derivative 104 in 70% yield which is subsequently oxidized to sulfoxide 105 using
m-chloroperoxybenzoic acid (mCPBA) in 95% yield. The key fluoro–Pummerer rearrangement step
is performed by treating 105 with diethylaminosulfur trifluoride (DAST) in the presence of SbCl3
resulting in fluoro derivative 106 in 70% yield. The final two steps involve oxidation of the sulfur
atom in 106 followed by thermal elimination to regenerate the double bond ultimately producing
fluorodehydroalanine 107 as a 1:1 mixture of Z and E isomers in 47% combined yield.
The fluoro–Pummerer rearrangement is a
variant of the classic Pummerer rearrangement
[148] in which sulfur-containing compounds
undergo structural reorganization via an elec
trophilic activation process. In this modified
reaction, the introduction of fluorine enhan
ces the electrophilicity of the sulfonium inter
mediate leading to regioselective rearrange
ment and functionalization of adjacent carbon
centers [149, 150]. The reaction is valuable in
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SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
synthetic chemistry, particularly for construct
ing fluorinated heterocycles and bioactive
molecules with tailored electronic and steric
properties.
An example of the application of the fluoro–
Pummerer rearrangement as a key step in the
synthesis of β-fluorodehydroalanine 107 is
illustrated in Scheme 22 [151]. The process
begins with the reaction of N-Fmoc-protect
ed serine 101 with 1-(diphenylmethylene)hy
drazine in the presence of iodine and (diace
toxyiodo)benzene yielding compound 102 in
90% yield while installing the ester protec
tive group. Compound 102 is then converted
into the corresponding ester via reaction with
mesyl chloride followed by elimination of
methanesulfonic acid using triethylamine af
fording dehydroalanine 103 in 82% yield. Ad
dition of 4-methoxybenzenethiol to the double
bond in 103 produces derivative 104 in 70%
yield which is subsequently oxidized to sul
foxide 105 using m-chloroperoxybenzoic acid
(mCPBA) in 95% yield. The key fluoro–Pum
merer rearrangement step is performed by
treating 105 with diethylaminosulfur trifluo
ride (DAST) in the presence of SbCl3 resulting
in fluoro derivative 106 in 70% yield. The final
two steps involve oxidation of the sulfur atom
in 106 followed by thermal elimination to re
generate the double bond ultimately producing
fluorodehydroalanine 107 as a 1:1 mixture of Z
and E isomers in 47% combined yield.
Scheme 22. Synthesis of β-fluorodehydroalanine 107.
Scheme 22. Synthesis of -fluorodehydroalanine 107.
An improved strategy for the preparation of (Z)-β-fluorodehydroalanine (110) is outlined in
Scheme 23 [152]. The synthesis begins with the alkylation of glycine Schiff base 108 using CBr2F2
and LiHMDS as base yielding bromodifluoro alanine 109. Compound 109 is then subjected to
selective reduction with Et3SiH in the presence of Pd(OAc)2 resulting in the stereoselective
formation of (Z)-β-fluorodehydroalanine (110) in 60% yield from 108.
Scheme 23. Synthesis of (Z)--fluorodehydroalanine (110).
Bromodifluoro alanine 109 has proven to be a highly versatile starting material for the
generalized synthesis of various β-substituted derivatives of β-fluorodehydroalanine via
Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions (Scheme 24) [152]. For instance,
Schiff base 109 undergoes cross-coupling with p-methoxyphenylboronic acid (111) in the presence
of potassium carbonate, water (150 μL), PdCl2 (5 mol%), and PPh3 (10 mol%) in 1,4-dioxane at
100 °C for 2 hours yielding fluorinated dehydroamino acid 112 in 65% yield. Alternative phosphine
ligands, such as 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)-biphenyl (Davephos),
4,5-bis-(diphenylphosphino)-9,9-dimethylxanthen (Xantphos),
1,1’-bis(diphenylphosphino)ferrocene (dppf), or 1,2-bis(diphenylphosphino)ethane (dppe), as well
as bases such as K3PO4, KHCO3, KOH, Et3N, or Cs2CO3, can be used to optimize the reaction
conditions for different substituents R on boronic acid 111. Using this method, over 50 distinct
derivatives of 112 have been synthesized in yields ranging from 49–93%.
An improved strategy for the preparation of
(Z)-β-fluorodehydroalanine (110) is outlined
in Scheme 23 [152]. The synthesis begins with
the alkylation of glycine Schiff base 108 using
CBr2F2 and LiHMDS as base yielding bromo
difluoro alanine 109. Compound 109 is then
subjected to selective reduction with Et3SiH
in the presence of Pd(OAc)2 resulting in the
stereoselective formation of (Z)-β-fluorode
hydroalanine (110) in 60% yield from 108.
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Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
Scheme 23. Synthesis of (Z)-β-fluorodehydroalanine (110).
Scheme 22. Synthesis of -fluorodehydroalanine 107.
An improved strategy for the preparation of (Z)-β-fluorodehydroalanine (110) is outlined in
Scheme 23 [152]. The synthesis begins with the alkylation of glycine Schiff base 108 using CBr2F2
and LiHMDS as base yielding bromodifluoro alanine 109. Compound 109 is then subjected to
selective reduction with Et3SiH in the presence of Pd(OAc)2 resulting in the stereoselective
formation of (Z)-β-fluorodehydroalanine (110) in 60% yield from 108.
Scheme 23. Synthesis of (Z)--fluorodehydroalanine (110).
Bromodifluoro alanine 109 has proven to be a highly versatile starting material for the
generalized synthesis of various β-substituted derivatives of β-fluorodehydroalanine via
Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions (Scheme 24) [152]. For instance,
Schiff base 109 undergoes cross-coupling with p-methoxyphenylboronic acid (111) in the presence
of potassium carbonate, water (150 μL), PdCl2 (5 mol%), and PPh3 (10 mol%) in 1,4-dioxane at
100 °C for 2 hours yielding fluorinated dehydroamino acid 112 in 65% yield. Alternative phosphine
ligands, such as 2-dicyclohexylphosphino-2’-(N,N-dimethylamino)-biphenyl (Davephos),
4,5-bis-(diphenylphosphino)-9,9-dimethylxanthen (Xantphos),
1,1’-bis(diphenylphosphino)ferrocene (dppf), or 1,2-bis(diphenylphosphino)ethane (dppe), as well
as bases such as K3PO4, KHCO3, KOH, Et3N, or Cs2CO3, can be used to optimize the reaction
conditions for different substituents R on boronic acid 111. Using this method, over 50 distinct
derivatives of 112 have been synthesized in yields ranging from 49–93%.
Bromodifluoro alanine 109 has proven to
be a highly versatile starting material for the
generalized synthesis of various β-substituted
derivatives of β-fluorodehydroalanine via Su
zuki–Miyaura and Mizoroki–Heck cross-cou
pling reactions (Scheme 24) [152]. For in
stance, Schiff base 109 undergoes cross-cou
pling with p-methoxyphenylboronic acid (111)
in the presence of potassium carbonate, water
(150 μL), PdCl2 (5 mol%), and PPh3 (10 mol%)
in 1,4-dioxane at 100 °C for 2 hours yielding
fluorinated dehydroamino acid 112 in 65%
yield. Alternative phosphine ligands, such as
2-dicyclohexylphosphino-2’-(N,N-dimethyl
amino)-biphenyl (Davephos), 4,5-bis-(diphe
nylphosphino)-9,9-dimethylxanthen (Xant
phos), 1,1’-bis(diphenylphosphino)ferrocene
(dppf), or 1,2-bis(diphenylphosphino)ethane
(dppe), as well as bases such as K3PO4, KHCO3,
KOH, Et3N, or Cs2CO3, can be used to optimize
the reaction conditions for different substitu
ents R on boronic acid 111. Using this method,
over 50 distinct derivatives of 112 have been
synthesized in yields ranging from 49–93%.
Scheme 24. Synthesis of β-substituted (Z)-β-fluorodehydroalanine derivatives 112
and 114 via Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions.
Scheme 24. Synthesis of -substituted (Z)--fluorodehydroalanine derivatives 112 and 114 via
Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions.
In the Mizoroki–Heck cross-coupling reaction, Schiff base 109 and styrene 113 are treated in
THF at 100 °C with Pd(PPh3)Cl2 (5 mol%), NaI (3 eq.), and Et3N (5 eq.) yielding diene amino acids
114. Styrenes bearing both electron-donating and electron-withdrawing substituents were well
tolerated (12 examples) affording the desired products in moderate-to-good yields of 45–82%.
Notably, the stereoselectivity was excellent, consistently favoring the (2Z,4E)-isomer irrespective of
the substituents [152].
CONCLUSIONS. As discussed, the current wealth of synthetic methodologies enables access to
a diverse range of tailor-made amino acids featuring mono-, di-, and trifluorovinyl groups as well as
mono- and difluoromethylene functionalities. These fluorinated substituents can be introduced into
both linear and cyclic α amino acids as well as their γ amino acid counterparts. While some
approaches in this review are of primarily historical significance, others represent cutting-edge
advancements in modern synthetic methodology. Despite these developments, fluorine-containing
olefinic amino acids remain comparatively underexplored, particularly when contrasted with amino
acids bearing aromatic or fully aliphatic fluorination. This underdevelopment likely stems from the
inherent challenges of aliphatic fluorination which often results in highly polar fluorinated
unsaturated bonds prone to unwanted addition and isomerization reactions. Consequently, aliphatic
fluorination is largely absent in approved pharmaceutical drugs and agrochemicals. However, this
landscape is poised to change with the growing scientific recognition of dehydroalanine’s role in
naturally occurring peptides. Post-translational modifications of peptides and proteins not only drive
new therapeutic discoveries, but also serve as a catalyst for innovations in synthetic organic
chemistry and chemical biology. Notably, in the past five years, remarkable progress has been
achieved in visible light-driven radical conjugate addition to dehydroalanine enabling site-selective
functionalization of peptides and proteins. These advancements have significantly expanded the
scope of tailor-made amino acid synthesis while furthering the frontiers of bioconjugation and
bioorthogonal chemistry [153–157]. As a result, renewed interest in fluorinated derivatives of
dehydroalanine and other fluoro-olefinic amino acids is expected. Beyond their promising
biological activities, fluorine-containing olefinic amino acids also offer unique opportunities for
investigating the self-disproportionation of enantiomers (SDE) phenomenon [158–160]. Amino
acids are known to exhibit a strong tendency for SDE in achiral chromatography, and due to their
elevated volatility conferred by fluorinated unsaturated groups, these derivatives are particularly
well suited for SDE via sublimation studies [161–163]. Given the regulatory significance of chiral
drug characterization, examining SDE behavior in biologically active compounds [164–167] plays a
crucial role in fulfilling US FDA requirements for chiral drug submissions [168–170]. With
fluorinated compounds continuing to serve as essential tools across the pharmaceutical,
agrochemical, and materials industries, and with increasing recognition of the benefits of
unsaturated fluorine-containing motifs, research in this field is expected to grow substantially in the
coming years.
In the Mizoroki–Heck cross-coupling re
action, Schiff base 109 and styrene 113 are
treated in THF at 100 °C with Pd(PPh3)Cl2 (5
mol%), NaI (3 eq.), and Et3N (5 eq.) yielding
diene amino acids 114. Styrenes bearing both
electron-donating and electron-withdrawing
substituents were well tolerated (12 examples)
affording the desired products in moderate-
to-good yields of 45–82%. Notably, the stere
oselectivity was excellent, consistently favoring
the (2Z,4E)-isomer irrespective of the substit
uents [152].
CONCLUSIONS. As discussed, the current
wealth of synthetic methodologies enables ac
cess to a diverse range of tailor-made amino
acids featuring mono-, di-, and trifluorovinyl
groups as well as mono- and difluoromethy
lene functionalities. These fluorinated substit
uents can be introduced into both linear and
cyclic α amino acids as well as their γ amino
52 ISSN 2708-129X. Укр. хім. журн., 2025
SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
acid counterparts. While some approaches in
this review are of primarily historical signifi
cance, others represent cutting-edge advance
ments in modern synthetic methodology. De
spite these developments, fluorine-containing
olefinic amino acids remain comparatively
underexplored, particularly when contrasted
with amino acids bearing aromatic or fully ali
phatic fluorination. This underdevelopment
likely stems from the inherent challenges of
aliphatic fluorination which often results in
highly polar fluorinated unsaturated bonds
prone to unwanted addition and isomerization
reactions. Consequently, aliphatic fluorination
is largely absent in approved pharmaceutical
drugs and agrochemicals. However, this land
scape is poised to change with the growing
scientific recognition of dehydroalanine’s role
in naturally occurring peptides. Post-transla
tional modifications of peptides and proteins
not only drive new therapeutic discoveries, but
also serve as a catalyst for innovations in syn
thetic organic chemistry and chemical biology.
Notably, in the past five years, remarkable pro
gress has been achieved in visible light-driven
radical conjugate addition to dehydroalanine
enabling site-selective functionalization of
peptides and proteins. These advancements
have significantly expanded the scope of tai
lor-made amino acid synthesis while furthering
the frontiers of bioconjugation and bioortho
gonal chemistry [153–157]. As a result, re
newed interest in fluorinated derivatives of de
hydroalanine and other fluoro-olefinic amino
acids is expected. Beyond their promising bi
ological activities, fluorine-containing olefinic
amino acids also offer unique opportunities
for investigating the self-disproportionation of
enantiomers (SDE) phenomenon [158–160].
Amino acids are known to exhibit a strong
tendency for SDE in achiral chromatography,
and due to their elevated volatility conferred
by fluorinated unsaturated groups, these de
rivatives are particularly well suited for SDE
via sublimation studies [161–163]. Given the
regulatory significance of chiral drug charac
terization, examining SDE behavior in bio
logically active compounds [164–167] plays a
crucial role in fulfilling US FDA requirements
for chiral drug submissions [168–170]. With
fluorinated compounds continuing to serve as
essential tools across the pharmaceutical, agro
chemical, and materials industries, and with
increasing recognition of the benefits of un
saturated fluorine-containing motifs, research
in this field is expected to grow substantially in
the coming years.
ACKNOWLEDGMENTS. We grateful-
ly acknowledge the financial support
from IKERBASQUE, Basque Founda-
tion for Science (for Soloshonok). The
authors acknowledge the assistance of
Microsoft Copilot and Google Gemini
with Ukrainian translation.
СИНТЕЗ СПЕЦІАЛЬНО РОЗРОБЛЕНИХ
АМІНОКИСЛОТ, ЩО МІСТЯТЬ ЗВ'ЯЗКИ
C(sp²)–F
Аліція Взорек¹, Цзяньлінь Хань²,
Тайзо Оно³, Карел Д. Кліка⁴,
Даніель Беккер5, Вей Чжан6,
Вадим А. Солошонюк7,8*
¹ Інститут хімії, Університет імені Яна
Кохановського в Кельцях, вул. Університець-
ка 7, 25–406 Кельце, Польща;
53https://ucj.org.ua
Alicja Wzorek, Jianlin Han, Taizo Ono, Karel D. Klika, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 8 / Vol. 91
² Цзянсуський центр спільного інновацій-
ного ефективного перероблення та вико-
ристання лісових ресурсів, Хіміко-техноло-
гічний коледж, Нанкінський лісотехнічний
університет, Нанкін 210037, Китай;
³ Національний інститут передових про-
мислових наук і технологій (AIST), 2266–98,
Анагахора, Шимошідамі, Моріяма-ку, На-
гоя, 463–8560, Японія;
⁴ Науково-дослідний центр, Archer Daniels
Midland, 1001 N Brush College Rd., Декейтер,
Іллінойс 62521, США;
5 Відділ фармацевтичної та лікарської хі-
мії, Фармацевтичний інститут, Вільний
університет Берліна, Кьоніґін-Луїзе-Штра-
се 2+4, 14195 Берлін, Німеччина;
6 Хімічний факультет, Університет Мас-
сачусетса в Бостоні, Бостон, Массачусетс
02125, Сполучені Штати Америки;
7 Відділ органічної хімії I, Хімічний факуль-
тет, Університет Країни Басків UPV/EHU,
Пасео Мануель Лардізабаль 3, 20018 Сан-Се-
бастьян, Іспанія;
8 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія.
email: vadimsoloshonok@gmail.com
Амінокислоти є фундаментальними
практично для кожного аспекту біологіч
ної науки та охорони здоров'я, слугуючи
наріжним каменем молекулярної струк
тури та функції. Дослідження тепер роз
ширилися за межі природних амінокислот
до спеціально розроблених похідних, що
дало змогу точно контролювати біологічні
процеси та відкривати нові функціональ
ні можливості, недосяжні зі стандартни
ми амінокислотами та пептидами. Одним
із найцікавіших досягнень є розроблення
фторвмісних амінокислот, які поєднують
потужні фармакологічні ефекти фтору зі
структурною адаптивністю амінокислот
них каркасів. Цей огляд досліджує синтез
фторованих амінокислот, що містять не
насичені залишки – надзвичайно цінну та
окрему підгрупу в ширшому класі фторова
них амінокислот. Ці спеціалізовані молеку
ли характеризуються безпосереднім зв'яз
ком фтору з sp²-гібридизованими атомами
вуглецю, ефективно відтворюючи електро
нні властивості ароматичного заміщення
без використання ароматичної системи.
Олефінове розташування фтору підвищує
стабільність молекули та надає специфіч
них стеричних, геометричних, хімічних і
біологічних характеристик, критично важ
ливих для розроблення лікарських засобів
та біологічно активних сполук. Представ
лені тут стратегії синтезу організовано
навколо ключових перетворень, включа
ючи α-алкілування амінокислот, нарощу
вання бічних ланцюгів, введення аміно- та/
або карбоксильних функціональних груп
і створення ненасиченості в межах фто
роамінокислотних ядер. Збираючи ці ме
тодології, ми прагнемо надати вичерпний
ресурс та джерело натхнення для дослід
ників, які працюють у галузях синтетичної
та медичної хімії, розроблення лікарських
засобів та органофторної хімії.
Ключові слова: фтор, амінокислоти,
фторовані фармацевтичні препарати,
ненасичені/олефінові групи, синтез, нук
леофільні та електрофільні еквіваленти
гліцину.
54 ISSN 2708-129X. Укр. хім. журн., 2025
SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS.ORGANIC CHEMISTRY
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Cтаття надійшла 09.05.2025.
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| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-745 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:13:33Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/7d/a29d13cf897469acfb2a5f7a8daef67d.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7452026-07-22T08:23:56Z SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim Fluorine, Amino Acids, Fluorinated Pharmaceuticals, Unsaturated/Olefinic Groups, Synthesis, Nucleophilic and Electrophilic Glycine Equivalents. Amino acids are fundamental to virtually every aspect of biological science and healthcare serving as the cornerstone of molecular structure and function. Research has now expanded beyond naturally occurring amino acids to tailor-made derivatives enabling precise control over biological processes and unlocking new functionalities unattainable with standard amino acids and peptides. One of the most exciting advancements is the development of fluorine-containing amino acids which integrate the powerful pharmacological effects of fluorine with the structural adaptability of amino acid frameworks. This review explores the synthesis of fluorinated amino acids bearing unsaturated residues—a highly valuable and distinct subgroup within the broader class of fluorinated amino acids. These specialized molecules feature fluorine directly bonded to sp2-hybridized carbon atoms, effectively replicating the electronic properties of aromatic substitution without relying on an aromatic system. The olefinic placement of fluorine enhances molecular stability and imparts specific steric, geometric, chemical, and biological characteristics critical for drug design and bioactive compound development. The synthetic strategies presented herein are organized around key transformations, including α alkylation of amino acids, side chain elaboration, introduction of amino and/or carboxylic functionalities, and the generation of unsaturation within fluoro-amino acid cores. By compiling these methodologies we aim to provide a comprehensive resource and a source of inspiration for researchers engaged in synthetic and medicinal chemistry, drug discovery, and organofluorine chemistry. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-09-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/745 10.33609/2708-129X.91.8.2025.36-64 Ukrainian Chemistry Journal; Vol. 91 No. 8 (2025): Ukrainian Chemistry Journal; 36-64 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 8 (2025): Ukrainian Chemistry Journal; 36-64 Український хімічний журнал; Том 91 № 8 (2025): Ukrainian Chemistry Journal; 36-64 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/745/382 Copyright (c) 2025 Alicja Wzorek, Jianlin Han, Taizo Ono, Karel Klika, Daniel Baecker, Wei Zhang, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Wzorek, Alicja Han, Jianlin Ono, Taizo Klika, Karel Baecker, Daniel Zhang, Wei Soloshonok, Vadim SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title | SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title_full | SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title_fullStr | SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title_full_unstemmed | SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title_short | SYNTHESIS OF TAILOR-MADE AMINO ACIDS CONTAINING C(sp2)–F BONDS(Review) |
| title_sort | synthesis of tailor-made amino acids containing c(sp2)–f bonds(review) |
| topic_facet | Fluorine Amino Acids Fluorinated Pharmaceuticals Unsaturated/Olefinic Groups Synthesis Nucleophilic and Electrophilic Glycine Equivalents. |
| url | https://ucj.org.ua/index.php/journal/article/view/745 |
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