Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук
Dedication: Dedicated with admiration and gratitude to Professor Giuseppe Resnati on his 70th birthday, for his pioneering and enduring contributions to fluorine chemistry and the art of noncovalent bonding. The 1,3-proton shift reaction has emerged as a highly convenient, scalable, and syntheticall...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2025
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Ukrainica Bioorganica Acta| _version_ | 1869381602563325952 |
|---|---|
| author | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim A. |
| author_facet | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim A. |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan"
},
{
"author": "Daniel Baecker",
"institution": "Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany"
},
{
"author": "Wei Zhang",
"institution": "University of Massachusetts Boston, Boston, MA, Unites States"
},
{
"author": "Vadim A. Soloshonok",
"institution": "IKERBASQUE, Basque Foundation for Science, Bilbao, Spain"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-06-29T15:58:57Z |
| description | Dedication: Dedicated with admiration and gratitude to Professor Giuseppe Resnati on his 70th birthday, for his pioneering and enduring contributions to fluorine chemistry and the art of noncovalent bonding.
The 1,3-proton shift reaction has emerged as a highly convenient, scalable, and synthetically practical strategy for accessing fluorinated amines and amino acids - structural motifs that play a pivotal role in the design of contemporary pharmaceuticals and agrochemicals. This transformation typically proceeds via a biomimetic reductive amination of fluorinated carbonyl compounds, wherein a benzylamine derivative functions dually as the nitrogen source and as a formal reducing agent. Over the past decade, substantial progress has been achieved in this domain, particularly through the strategic use of 1,3-azaallylic anion intermediates in reactions with a broad array of electrophiles. A notable advancement involves the adoption of 2,2-diphenylglycine as a synthetically advantageous alternative to the conventionally employed diphenylmethylamine. In this review, we underscore the benefits of this modification and examine its application across reactions with diverse electrophilic partners, including aldehydes, imines, and allyl alcohol-derived species, enabling the synthesis of vicinal amino alcohols, vicinal diamines, homoallylamines, and α-methylene-γ-amino acids |
| doi_str_mv | 10.15407/bioorganica2025.02.003 |
| first_indexed | 2026-02-08T07:59:47Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
UDC 577.112.34 + 547.233/435.1
DOI: https://doi.org/10.15407/bioorganica2025.02.003
3
REVIEW
Decarboxylative 1,3-proton shift: an unorthodox strategy
for synthesizing biologically relevant amino compounds
Alicja Wzorek1, Taizo Ono2, Daniel Baecker3, Wei Zhang4, Vadim A. Soloshonok5*
1 Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland
2 National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan
3 Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
4 University of Massachusetts Boston, Boston, MA, USA
5 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Dedication: Dedicated with admiration and gratitude to Professor Giuseppe Resnati on his 70th birthday, for his pioneering and enduring
contributions to fluorine chemistry and the art of noncovalent bonding.
Abstract: The 1,3-proton shift reaction has emerged as a highly convenient, scalable, and synthetically practical strategy for accessing
fluorinated amines and amino acids - structural motifs that play a pivotal role in the design of contemporary pharmaceuticals and
agrochemicals. This transformation typically proceeds via a biomimetic reductive amination of fluorinated carbonyl compounds, wherein a
benzylamine derivative functions dually as the nitrogen source and as a formal reducing agent. Over the past decade, substantial progress
has been achieved in this domain, particularly through the strategic use of 1,3-azaallylic anion intermediates in reactions with a broad array
of electrophiles. A notable advancement involves the adoption of 2,2-diphenylglycine as a synthetically advantageous alternative to the
conventionally employed diphenylmethylamine. In this review, we underscore the benefits of this modification and examine its application
across reactions with diverse electrophilic partners, including aldehydes, imines, and allyl alcohol-derived species, enabling the synthesis
of vicinal amino alcohols, vicinal diamines, homoallylamines, and α-methylene-γ-amino acids.
Keywords: fluorine; 1,3-proton shift; fluorinated amines and amino acids; reductive decarboxylation; 2,2-diphenylglycine.
Introduction
Biological transamination [1] is a cornerstone of
metabolic chemistry, facilitating the reversible
interconversion between α-keto acids and α-amino acids
(Scheme 1). Mechanistically, the process involves a base-
catalyzed 1,3-proton transfer across an azaallyl anion
intermediate 3, culminating in the formation of Schiff bases
derived from either α-keto acids 2 or α-amino acids 4.
These intermediates serve as pivotal precursors in two
complementary pathways: one leading to α-amino acids and
Received:
Revised:
Accepted:
Published online:
10.09.2025
22.10.2025
29.10.2025
31.12.2025
Corresponding author. Tel.: +34-94-301-5177;
e-mail: vadimsoloshonok@gmail.com (V.A. Soloshonok)
ORCID: 0000-0003-0681-4526
pyridoxal 5, and the other to α-keto carboxylic acids and
pyridoxamine 1 [2-6].
In biological systems, the 1,3-proton transfer is catalyzed
by the ω-amino group of enzymatic lysine, which
orchestrates enantioselective proton delivery. This process
proceeds through the delocalized 2-azaallyl anion
intermediate 3, ultimately yielding either compound 2 or 4,
depending on the direction of the transformation [7].
Numerous research groups - most notably those led by
Breslow [8-11], Cram [12], and Casella [13] - have
extensively explored the mechanism and stereochemical
features of biological transamination, utilizing both native
and model pyridoxal-based systems. Their investigations
highlighted the pivotal influence of metal complexation on
modulating not only the reaction rate but also its
stereochemical course.
Furthermore, it has been shown that the 1,3-proton shift
typically requires a strong base to proceed at a
© Wzorek A. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
4
N
NH2
2-O3PO
OH
R COOH
O
N
N
2-O3PO
O
R
O
O
Mn+
N
N
2-O3PO
O
R
O
O
Mn+
enzyme
NH3
N
O
2-O3PO
OH
R COOH
NH2
N
N
2-O3PO
O
R
O
O
Mn+
1 2
3
45
(Lys)
Scheme 1. Biological transamination.
synthetically useful rate [14]. The equilibrium constants
determined for this transformation exhibit a robust
correlation with the Hammett equation (ρ = 0.94), lending
strong support to the involvement of a delocalized azaallyl
anion intermediate (type 3). This species is notably
stabilized by electron-withdrawing substituents, while
electron-donating groups exert a destabilizing effect [15,
16].
Initial efforts to emulate biological transamination were
reported by Professor Corey’s group, who designed highly
electrophilic carbonyl compounds 6 and 7 (Scheme 2) and
demonstrated their utility in the biomimetic oxidative
deamination of primary amines to the corresponding
ketones, achieving high yields [17]. Subsequently, Calo et
al. showed that aldehyde 8 (Scheme 2) could be effectively
employed for the oxidative deamination of selected amines
[18]. A broader class of reagents (type 9, see Scheme 2)
designed to mimic natural pyridoxal, was developed by the
groups of Ohta [19], Babler [20], and Rapoport [21]. These
reagents proved to have more general synthetic
applicability, enabling the preparation of both aldehydes
and ketones.
NH2
C Otnegaer
O C NH2tnegaer+
R
R
H
O
O
t-Bu
t-Bu NO2
O2N
O
O
O
X
X
O
6 7
8 9
X = C, N
Scheme 2. Biomimetic oxidative deamination of primary amines.
The biomimetic reductive amination of fluorinated
carbonyl compounds was first reported in 1986 [22, 23],
when the Kukhar-Yagupolskii group investigated a
Staudinger reaction between keto-ester 10 and phosphazene
11 (Scheme 3). Unexpectedly, the reaction furnished Schiff
base 13 as the sole product. It is plausible that the initially
formed intermediate 12 underwent irreversible in situ
isomerization to imine 13, which was then readily
hydrolyzed to yield trifluoroalanine 14 in high yield.
10
11F3C COOEt
O
N Ph
P
Ph Ph
Ph
12
F3C COOEt
N Ph
13
F3C COOEt
N Ph
14
F3C COOH
NH2
H
Scheme 3. Staudinger reaction followed by the irreversible
1,3-proton shift.
The 1,3-proton shift reaction has emerged as a
synthetically versatile and broadly applicable
transformation [24], enabling the efficient conversion of
diverse fluorinated carbonyl substrates, including CF₃-alde-
hydes [25, 26], CF₃-ketones [27, 28], and both α- [29] and
β-ketoacids [30, 31] - into biologically relevant amino
derivatives under a wide range of reaction conditions [32-
34]. Remarkably, the transformation can proceed via two
consecutive steps of 1,3-proton shifts, thereby extending its
synthetic utility and granting access to more architecturally
complex molecular frameworks [35, 36]. Although typically
catalyzed by strong bases [37], the reaction can also be
promoted under thermal conditions [38], highlighting its
operational flexibility and adaptability to varied synthetic
contexts.
Moreover, the incorporation of chiral phenylethylamine
introduces a stereochemical dimension to the transfor-
mation, enabling an asymmetric 1,3-proton shift and
furnishing enantiomerically enriched CF₃-amino
A. Wzorek, T. Ono et al.
5
compounds with enantiomeric excesses (ee) of up to 90%
[39-42].
The first catalytic enantioselective 1,3-proton shift
reaction, reported in 1994, is depicted in Scheme 4 [43]. In
this seminal study, N-benzylenamines 15 - generated from
β-polyfluoroalkyl-β-ketocarboxylic esters and benzylamine
- underwent a 1,3-proton shift catalyzed by (-)-cinchonidine
16 (5-13 mol%). The transformation furnished N-benzy-
lidene derivatives 17 in good yields (67-89%) and with
moderate enantioselectivity, reaching up to 36% ee.
17
16
15
N
OH
N
RF
N O
H
OAlk
Ph
RF
N O
OAlk
Ph
Scheme 4. Enantioselective 1,3-proton shift reaction catalyzed by
(-)-cinchonidine 16.
Subsequent hydrolysis of products 17 proceeded
smoothly, affording the corresponding optically active (R)-
β-polyfluoroalkyl-β-amino acids in excellent yields (87-
93%). This study stands as a foundational example of
asymmetric proton shift catalysis and helped to establish a
conceptual framework for future advances in the
enantioselective synthesis of fluorinated amino acid
derivatives [44].
Examples of biomimetic reductive amination of carbonyl
compounds have been reported by Cainelli [45], Kuzuhara
[46], Breslow [47], Zwanenburg [48], Berg [49], and others
[50-55]. In most cases, amines 18 and 19 (Scheme 5),
featuring a relatively acidic proton and additional resonance
stabilization of the resulting imine, were employed as
sources of both hydrogen and nitrogen atoms. Nevertheless,
the use of strong bases such as KOt-Bu was necessary to
facilitate the biomimetic 1,3-proton shift.
NH2
Ar
Ar
O
R
R1
O
Ar
Ar
NH2
R
R1
+
NH2
NH2
S
O O
18 19
Scheme 5. Biomimetic reductive amination of carbonyl
compounds using amines 18 and 19.
In general, traditional conditions such as polar solvents
and strong bases are effective only for the biomimetic
transamination of carbonyl compounds bearing strongly
electron-withdrawing substituents, which restricts both the
synthetic utility and the generality of this approach. An
unconventional solution to this limitation involves the use
of Schiff bases 21 (Scheme 6), generated in situ from a
carbonyl compound and 2,2-diphenylglycine 20. The key
advantage of this strategy is that formation of the
corresponding 1,3-azaallyl anion 22 is irreversible, as it is
accompanied by decarboxylation. The resulting anion 22
exists in equilibrium with its tautomeric form 23, which is
less sterically hindered and kinetically more reactive. This
tautomer readily undergoes reaction with suitable
electrophiles to afford alkylated products 24, completing a
three-step in situ sequence. Subsequent hydrolytic cleavage
of the imines 24 furnishes the target amino compounds 25.
In this review, we summarize and discuss the progress
achieved in this area over the past decade.
NH2
Ar
Ar
O
R
R1
20
COOH
R R1
N Ph
Ph
COOH
21
22
23
- CO2
R R1
N Ph
Ph
R R1
N Ph
Ph
E
25
R R1
N Ph
Ph
E
R R1
NH2
E
H
24
Scheme 6. Decarboxylative approach to generation of 1,3-aza-
allylic anions.
Reactions with aldehydes; synthesis of vic-amino
alcohols.
Vic‑amino alcohols are considered privileged structural
motifs in medicinal chemistry because their dual
functionality, an amine adjacent to a hydroxyl group,
confers unique reactivity and biological activity that has
been widely exploited in drug design [56].
These compounds play a central role in the development
of numerous therapeutic agents. The β‑amino alcohol
framework is found in essential medicines such as
salbutamol (a bronchodilator by β2-adrenoceptor agonism)
[57] and propranolol (a antihypertensive non-selective
β‑receptor antagonist) [58], underscoring its importance in
treating respiratory and cardiovascular diseases. Their
bifunctional nature allows vic‑amino alcohols to engage in
diverse interactions with biological targets, enhancing
binding affinity, selectivity, and pharmacokinetic proper-
ties. Moreover, they serve as versatile intermediates in
synthetic chemistry, enabling the construction of hetero-
cycles (e.g., oxazolidines) and acting as ligands in
asymmetric catalysis. In drug discovery, the presence of
both the amine and hydroxyl groups provides opportunities
for fine‑tuning solubility, hydrogen bonding, and
stereoelectronic effects, which are critical for optimizing
lead compounds. Over the past decade, research has
highlighted their potential in designing antibacterial [59],
cardiovascular [60], and neurological agents [61], making
vic‑amino alcohols indispensable building blocks in modern
medicinal chemistry.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
6
The reaction of 1,3‑azaallylic anions with carbonyl
compounds offers a direct and efficient route to 1,2‑amino
alcohols. The process benefits from the irreversible
generation of the anion, accompanied by decarboxylation,
and its equilibrium with a more reactive tauto-
mer. Importantly, this strategy requires no protecti-
on/deprotection steps, enabling straightforward electrophilic
capture and hydrolysis to yield vicinal amino alcohols in a
single synthetic sequence - an approach that combines
mechanistic simplicity with broad utility in medicinal
chemistry and drug design.
As illustrated in Scheme 7, aromatic aldehyde 26 was
condensed with the tetrabutylammonium salt of 2,2-di-
phenylglycine 27, affording the key Schiff base
intermediate 28 [62]. Subsequent treatment of 28 at room
temperature with a stoichiometric amount of aromatic
aldehyde 29 in tetrahydrofuran (THF) triggered decarbo-
xylation, generating an anion that underwent an aldol
addition with aldehyde 29. This transformation proceeded
in moderate to good yields and exhibited modest
diastereoselectivity (1.2-2.1:1), favoring the formation of
product 30. Finally, hydrolytic removal of the imine
functionality furnished the target vicinal amino alcohol 31.
NH2
Ph
Ph
O
Ar
H
COO
Ar H
N Ph
Ph
COO
29
26
- CO2
28
27
THF
O
Ar1
H
N OH
Ar1Ar
PhPh
H
H2N OH
Ar1Ar
30 31
n-Bu4N
n-Bu4N
Scheme 7. Synthesis of acyclic vic-amino alcohols.
This strategy is broadly applicable, enabling the
synthesis of both symmetric and non-symmetric vicinal
amino alcohols 31 bearing aromatic rings with electron-
withdrawing substituents such as halogen, nitro, and
isocyano groups. Electron-donating substituents are also
tolerated, including dialkylamino, acetoxy, and alkoxy
functionalities. The aryl moieties can range from simple
phenyl and naphthyl groups to heteroaromatic units such as
thiophene and pyridine. Overall, the method is
straightforward, preparatively convenient, scalable, and
practical. Nevertheless, its relatively low diastereoselecti-
vity remains a significant limitation, reducing its broader
synthetic utility.
An intramolecular variant of this approach is illustrated
in Scheme 8 [63]. Dialdehyde 32 (R¹ = H) or keto-aldehyde
32 (R¹ = alkyl, Ph) reacts with one equivalent of 2,2-diphe-
nylglycine 20 in aqueous dimethylformamide (DMF) at
40 °C. The reaction proceeds via in situ formation of the
corresponding Schiff base, followed by a 1,3-proton shift
and subsequent decarboxylation. The resulting azaallylic
anion undergoes intramolecular aldol addition with the
second carbonyl group to furnish product 33 in good to
excellent yields.
For dialdehydes 32 (R¹ = H), the formation of products
33 is highly diastereoselective (≈ 20:1). In contrast,
reactions with keto-aldehydes 32 (R¹ = alkyl, Ph) afford an
approximately 1:1 mixture of the corresponding
diastereomers 33. Hydrolytic cleavage of the Schiff base
moiety in products 33 provides the free cyclic vicinal amino
alcohols 34 in excellent overall yields.
NH2
Ph
Ph
COOH
H
32
H
O
R1
O
R R N
HO R1
Ph
Ph
20
33
H2N
HO R1
34
DMF/H2O
R
R
R
R
Scheme 8. Synthesis of cyclic vic-amino alcohols.
This approach demonstrates broad generality, as
aromatic rings can be represented by mono - or disub-
stituted phenyl groups as well as naphthyl residues.
Moreover, R¹ may be a hydrogen atom, an alkyl group, or a
phenyl substituent, in the latter two cases enabling the
preparation of diverse derivatives bearing a tertiary alcohol
fragment.
Of particular interest is the stereochemical outcome
observed in the formation of 2,2′-difluoro 33, which
proceeds with relatively low diastereoselectivity (≈ 6:1)
compared to the typically observed ≈ 20:1 ratio in most
cases. This deviation is attributed to strong repulsive
electrostatic interactions between the fluorine atoms and the
lone pairs of the nitrogen and oxygen atoms [64-66].
It should also be noted that this strategy has certain
limitations in the synthesis of non-symmetrically substituted
products 33. The reaction of 2,2-diphenylglycine 20 with
dialdehydes 32 is not regioselective, giving rise to two
possible intermediate Schiff bases. For example, in the case
of mono-chloro-substituted compound 32, the correspon-
ding products 33, bearing the chlorine atom on either side
of the bicyclic framework, are obtained in a ratio of 2.6:1.
This modest region-preference can be rationalized by the
activating effect of the chlorine substituent.
An illustrative example of the intramolecular aldol
reaction involving in situ generation of 1,5-azaallylic anions
is presented in Scheme 9 [67]. The non-symmetric
dialdehyde 35 reacts with 2,2-diphenylglycine 20 in
aqueous THF at ambient temperature to afford compound
A. Wzorek, T. Ono et al.
7
NH2
Ph
Ph
COOH
35
H
O
R
20
THF/H2O
OHC
37
H
O
R R1
N
Ph
Ph
36
H
O
R R1
N
Ph
PhHOOC
38
H
O
R R1
N
Ph
Ph
39
H
O
R R1
N
Ph
Ph
HO
N
Ph
Ph
- CO2
R R1
40
R1
Scheme 9. Aldol additions of 1,5-azaallylyc anions.
40, characterized by a cyclic vicinal alcohol and a Schiff
base-protected enamine framework.
The stepwise process begins with the condensation of the
aromatic aldehyde group of 35 with 20, forming Schiff base
36. This intermediate undergoes a decarboxylative 1,3-pro-
ton shift to yield anion 37, an unusual 1,5-azaallylic species
that can be represented in three potentially reactive forms
(37, 38, and 39). Among these, anion 39 is kinetically the
most reactive, being ideally suited to form a six-membered
ring via aldol addition to the neighboring aromatic aldehyde
group, thereby producing the final product 40.
The yields of compounds 40 range from 54-93%,
depending on the substituents present on the starting
dialdehyde 35. Notably, the reaction of 35 with 20 proceeds
with high chemoselectivity: the enal groups are signify-
cantly more reactive than the aromatic aldehyde groups,
enabling the preparation of variously substituted aromatic
derivatives in the final products 40. The synthetic generality
of this approach is underscored by the fact that aromatic
rings can be represented not only by mono- or disubstituted
phenyl groups but also by naphthyl residues.
Furthermore, this aldol reactions displayed an exceptio-
nal level of diastereoselectivity, yielding exclusively the
trans products 40. The outcome underscores the critical
importance of both the six-membered ring framework and
the presence of an aromatic backbone, which together
enable the reaction to proceed efficiently. By contrast,
aliphatic aldehydes prove unsuitable, as they fail to react
under these conditions.
Reactions with imines; synthesis of vic-diamines.
Mannich additions represent a powerful and general
strategy for the preparation of vicinal diamines. In this
approach, an iminium ion - typically generated in situ from
an aldehyde and ammonia or a primary or secondary amine
- undergoes nucleophilic attack by an enolizable substrate,
furnishing β-aminocarbonyl intermediates. Subsequent
functionalization of these adducts, often through reductive
amination or further Mannich sequences, enables the
introduction of a second amino group in close proximity,
thereby constructing vicinal diamine frameworks. The
method is highly versatile, accommodating a wide range of
aldehydes, ketones, and amines, and provides access to
structurally diverse diamines that are valuable motifs in
medicinal chemistry, natural product synthesis, and ligand
design [68-70].
Vicinal diamines, considered as derivatives of amino
acids, have found wide application in modern drug design
owing to their structural versatility and biological relevance.
The presence of two adjacent amino groups enables diverse
modes of interaction with biological targets, including
hydrogen bonding, metal coordination, and modulation of
enzyme active sites.
These frameworks serve as key building blocks in the
synthesis of antiviral, anticancer, and antibacterial agents,
and are frequently employed in the design of enzyme
inhibitors and receptor ligands. Moreover, vicinal diamines
provide valuable scaffolds for the development of chiral
auxiliaries and pharmacophores, enhancing stereochemical
control and potency in therapeutic molecules. Their dual
functionality and resemblance to natural amino acid motifs
make them indispensable in medicinal chemistry, bridging
fundamental organic synthesis with practical applications in
drug discovery [71-73].
NH2
Ph
Ph
COOH
20
41
O
Ar
H Ar H
N Ph
Ph
COOH 42
26
- CO2
MeOH
N
Ar
H
N NHTs
ArAr
PhPh
43
Ts
MeOH
Scheme 10. Mannich addition reactions of 1,3-anions.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
8
As shown in Scheme 10 [74], 1,3-azaallylic anions
generated by decarboxylation can be reacted with suitably
activated imines to furnish the target vicinal diamines 43. In
the first step, aromatic aldehyde 26 condenses with 2,2-di-
phenylglycine 20 to form the in situ Schiff base 41.
Subsequent addition of N-Ts imines 42 to the reaction
mixture triggers a Mannich-type process, leading to the
formation of vicinal diamine products in 60-80% yields.
These reactions exhibit broad tolerance toward
substitution on the aromatic rings and proceed with
reasonably high diastereoselectivity (≈ 10:1).
The asymmetric variant of this methodology is illustrated
in Scheme 11 [75]. Aldehydes 44 react with the lithium salt
of 2,2-diphenylglycine 45 in methanol (MeOH) at room
temperature for 24 hours, followed by treatment with chiral
imine 47 in the presence of m-nitrobenzoic acid (20 mol%)
to afford the target vicinal diamino products 48 in yields of
up to 90%. Notably, these Mannich additions proceed with
exceptionally high diastereoselectivity (>99:1), enabling the
preparation of virtually enantiomerically pure derivatives
48. The scope of this approach extends to both aromatic and
aliphatic aldehydes with comparable ease and efficiency.
Moreover, its broad synthetic utility is underscored by the
significant variability tolerated at the substituent R by the
chiral imines 47, allowing access to extensive libraries of
enantiomerically pure vicinal diamino derivatives.
NH2
Ph
Ph
COOLi
45
46
O
R
H R H
N Ph
Ph
COOLi
47
44
- CO2
N
H
F3C
N HN
CF3R
PhPh
48
S
MeOH
O
S
O
Scheme 11. Asymmetric Mannich addition reactions of
1,3-anions.
It should be emphasized that chiral N-tert-butylsulfinyl-
3,3,3-trifluoroacetaldimine 47 is readily available on a large
scale and serves as an exceptionally useful auxiliary in the
asymmetric synthesis of diverse enantiomerically pure CF₃-
containing derivatives of natural products [76-80]. Of
particular significance, this methodology enables the
preparation of vicinal diamines bearing a CF₃ substituent,
underscoring the relevance of these compounds in drug
design and medicinal chemistry [81-85].
The application of the decarboxylative 1,3-proton shift
strategy to the asymmetric synthesis of cyclic vicinal
diamines is exemplified in Scheme 12 [86]. Aldehydes 49
undergo reaction with 2,2-diphenylglycine 20, followed
sequentially by a 1,3-proton shift, decarboxylation, and
intramolecular Mannich addition, to furnish a series of
derivatives of trans-exocyclic vicinal diamines 50. The
process affords high yields (84-96%) and favorable
trans/cis ratios, although the diastereoselectivity remains
modest (~ 2:1), when conducted in polar solvents in the
presence of K₂CO₃. Overall, this methodology constitutes a
novel one-step approach for the efficient synthesis of chiral
exocyclic vicinal diamines.
Scheme 12. Asymmetric Mannich addition reactions of 1,3-anions
for preparation of cyclic vicinal diamines.
This strategy constitutes a novel one-step approach for
the efficient synthesis of chiral exocyclic vicinal diamines.
Nevertheless, its broader synthetic utility is constrained by
the relatively low diastereoselectivity and the restriction to
aromatic aldehydes.
Reaction with allylalcohols-derived electrophiles;
synthesis of homoallylamines and α-methylene-γ-
amino acids.
Homoallylamines are important scaffolds in medicinal
chemistry because they combine structural versatility with
valuable biological activity. Their unique framework,
consisting of an amine adjacent to an allylic moiety,
provides a reactive handle for further functionalization
while maintaining conformational flexibility. This makes
them excellent intermediates for the synthesis of diverse
nitrogen‑containing heterocycles, which are common motifs
in bioactive compounds. In drug design, homoallylamines
have been exploited as precursors to chiral amines and
diamines, enabling access to enantiomerically enriched
molecules with high pharmacological relevance. Their
ability to serve as chiral inducing frameworks in
asymmetric transformations allows medicinal chemists to
generate libraries of stereochemically defined compounds, a
critical factor in optimizing potency, selectivity, and safety.
Moreover, the allylic functionality can participate in further
C-C or C-N bond‑forming reactions, expanding chemical
diversity and facilitating structure-activity relationship
(SAR) studies. As a result, homoallylamines are not only
synthetic building blocks but also strategic elements in
rational drug design, contributing to the development of
new therapeutic agents across oncology, neurology, and
infectious disease research [87-89].
The application of a decarboxylative 1,3-proton shift
methodology for the preparation of homoallylamines is
illustrated in Scheme 13 [90]. The synthesis begins with the
conversion of aromatic aldehydes 26 into the corresponding
imines 41 by reacting them with 2,2-diphenylglycine 20.
Subsequent decarboxylation of the imines generates the key
intermediate, a 1,3-azallylic anion. Finally, treatment of this
intermediate mixture under Pd-catalyzed allylation
conditions [91] delivers the desired homoallylic amines 52.
A. Wzorek, T. Ono et al.
9
This method is highly effective, affording the products in
high yields (80-98%) and with excellent regioselectivity.
NH2
Ph
Ph
COOH
26
20
52
THF/H2O
Ar H
O
41
Ar H
N
Ph
Ph
HOOC
R
OCO2Me
Ar
N
R
Ph
Ph51
Pd2(dba)3
(2.5 mol%)
- CO2
Scheme 13. Pd-catalyzed allylation of 1,3-azaallylic anions.
This method exhibits remarkable versatility with respect
to both the Ar and R groups. The Ar moiety can encompass
a wide range of substituted phenyl rings, naphthyl systems,
or diverse heterocyclic structures. Similarly, the R group
tolerates nearly any inert substituent, including aromatic
rings, alkyl chains, esters, or unsaturated moieties such as
vinyl, allyl, and related functional groups. Consequently,
despite yielding racemic products, this approach holds
considerable synthetic value for the preparation of allylic
amino compounds.
A special case of this type of reactions allowing
preparation of α-methylene-γ-amino acids is illustrated in
Scheme 14 [92].
NH2
Ph
Ph
COOH
26
20
54
Ar H
O
41
Ar H
N
Ph
Ph
HOOC
CO2Alk
53
- CO2
BocO
R
DABCO
MeCN
Ar
N
R
CO2Alk
Ph
Ph
Scheme 14. Preparation of α-methylene-γ-amino acid dervivatives.
As typical for the decarboxylative 1,3-proton shift
approach, aromatic aldehydes 26 first reacted with 2,2-di-
phenylglycine 20 to generate the intermediate Schiff base
41. The next step involves the generation of carbanion
followed by the decarboxylation and subsequent reaction
with unsaturated ester 53 giving rise to the target
derivatives of α-methylene-γ-amino acids 54. These
reactions are conducted at 0 °C in the presence of 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) as a catalyst (20 mol%).
The approach is rather general as substituents Ar and R can
represent various substituted phenyl rings as well as
aromatic heterocyclic moieties. The products α-methylene-
γ-amino acids 54 represent very interesting class of tailor-
made amino acids finding increasing application in
medicinal and bioorganic chemistry [93, 94].
Conclusions
Vicinal amino alcohols, vicinal diamines,
homoallylamines, and α-methylene-γ-amino acids constitute
a structurally diverse and pharmacologically important class
of compounds. These motifs are increasingly valued in
medicinal chemistry for their ability to enhance bioactivity,
improve metabolic stability, and fine-tune molecular
recognition. Their strategic incorporation into drug
candidates, including kinase inhibitors, metabolic regula-
tors, and protein-protein interaction disruptors, has led to
clinically approved therapeutics and continues to inspire
innovative scaffold design. This review highlights how the
decarboxylative 1,3-proton shift methodology provides
efficient synthetic access to these valuable structural motifs.
The approach is operationally simple, relies on readily
available and inexpensive starting materials, and proceeds
under preparatively convenient conditions. Importantly, it
consistently delivers high chemical yields and excellent
diastereoselectivity across a broad substrate scope,
rendering it highly practical for synthetic applications. The
primary limitation at present is the scarcity of asymmetric
variants capable of delivering enantiomerically enriched or
pure products. It is reasonable to anticipate that future
efforts in this field will focus on the development of
enantioselective, particularly catalytic, versions of this
transformation. Such advances would unlock the full
biological and therapeutic potential of these privileged
compounds.
Notes
Acknowledgments and finances. We thank
IKERBASQUE – Basque Foundation for Science for
financial support (to V.A.S.). The authors acknowledge the
assistance of Microsoft Copilot, Google Gemini, and Grok
(xAI) in preparing the Ukrainian translation of this
manuscript. The authors declare no conflict of interest.
Author contributions. The manuscript was written
through contributions of all authors. All authors have given
approval to the final version of the manuscript.
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
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Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу
біологічно значущих аміносполук
А. Взорек1, Т. Оно2, Д. Беккер3, В. Чжан4, В.A. Солошонок5*
1 Інститут Хімії, Університет імені Яна Кохановського в Кельцях, Кельці, Польща
2 Національний інститут передових промислових наук і технологій (AIST), Анагахора, Шімосідамі, Моріяма-ку, Нагоя, Японія
3 Фармацевтичний інститут, Вільний університет Берліна, Берлін, Німеччина
4 Массачусетській Університет в Бостоні, Бостон, Массачусетс, США
5 ІКЕРБАСК, Баскський фонд науки, Більбао, Іспанія
Присвята: З глибокою повагою та вдячністю присвячуємо цю роботу професору Джузеппе Резнаті з нагоди його 70 -річного ювілею, за
новаторський та тривалий внесок у хімію флуору та мистецтво нековалентного зв'язку.
Резюме: Реакція 1,3-протонного переміщення є надзвичайно зручною, масштабованою та синтетично практичною стратегією для одержання
флуорованих амінів і амінокислот – структурних мотивів, що відіграють ключову роль у проектуванні сучасних фармацевтичних та агрохімічних
препаратів. Ця трансформація зазвичай відбувається шляхом біоміметичного відновного амінування флуорованих карбонільних сполук, де
похідні бензиламіну виконують подвійну функцію – джерела нітрогену та формального відновника. Протягом останнього десятиліття в цій галузі
досягнуто значного прогресу, зокрема завдяки стратегічному використанню проміжних 1,3-азаалільних аніонів у реакціях з широким спектром
електрофілів. Важливим досягненням стало впровадження 2,2-дифенілгліцину, як синтетично вигідної альтернативи більш традиційному
дифенілметиламіну. У цьому огляді ми підкреслюємо переваги такої модифікації та розглядаємо її застосування в реакціях з різноманітними
електрофільними агентами, включно з альдегідами, імінами та похідними алілових спиртів, що уможливлює синтез віцинальних аміноспиртів,
віцинальних діамінів, гомоаліламінів та α-метилен-γ-амінокислот.
Ключові слова: фармацевтичні препарати; амінокислоти; флуоровмісні сполуки; дизайн і розробка ліків.
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| id | oai:ojs2.bioorganica.com.ua:article-102 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-06-30T01:00:21Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/40/283fb92db4c688c67481fd056a2d2340.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-1022026-06-29T15:58:57Z Decarboxylative 1,3-proton shift: an unorthodox strategy for synthesizing biologically relevant amino compounds Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim A. fluorine 1,3-proton shift fluorinated amines and amino acids reductive decarboxylation 2,2-diphenylglycine флуор 1,3-протонне переміщення флуоровані аміни та амінокислоти відновлювальне декарбоксилювання 2,2-дифенілгліцин Dedication: Dedicated with admiration and gratitude to Professor Giuseppe Resnati on his 70th birthday, for his pioneering and enduring contributions to fluorine chemistry and the art of noncovalent bonding. The 1,3-proton shift reaction has emerged as a highly convenient, scalable, and synthetically practical strategy for accessing fluorinated amines and amino acids - structural motifs that play a pivotal role in the design of contemporary pharmaceuticals and agrochemicals. This transformation typically proceeds via a biomimetic reductive amination of fluorinated carbonyl compounds, wherein a benzylamine derivative functions dually as the nitrogen source and as a formal reducing agent. Over the past decade, substantial progress has been achieved in this domain, particularly through the strategic use of 1,3-azaallylic anion intermediates in reactions with a broad array of electrophiles. A notable advancement involves the adoption of 2,2-diphenylglycine as a synthetically advantageous alternative to the conventionally employed diphenylmethylamine. In this review, we underscore the benefits of this modification and examine its application across reactions with diverse electrophilic partners, including aldehydes, imines, and allyl alcohol-derived species, enabling the synthesis of vicinal amino alcohols, vicinal diamines, homoallylamines, and α-methylene-γ-amino acids Присвята: З глибокою повагою та вдячністю присвячуємо цю роботу професору Джузеппе Резнаті з нагоди його 70-річного ювілею, за новаторський та тривалий внесок у хімію фтору та мистецтво нековалентного зв'язку. Реакція 1,3-протонного переміщення є надзвичайно зручною, масштабованою та синтетично практичною стратегією для одержання флуорованих амінів і амінокислот - структурних мотивів, що відіграють ключову роль у проектуванні сучасних фармацевтичних та агрохімічних препаратів. Ця трансформація зазвичай відбувається шляхом біоміметичного відновного амінування флуорованих карбонільних сполук, де похідне бензиламіну виконує подвійну функцію - джерела нітрогену та формального відновника. Протягом останнього десятиліття в цій галузі досягнуто значного прогресу, зокрема завдяки стратегічному використанню проміжних 1,3-азаалільних аніонів у реакціях з широким спектром електрофілів. Важливим досягненням стало впровадження 2,2-дифенілгліцину, як синтетично вигідної альтернативи більш традиційному дифенілметиламіну. У цьому огляді ми підкреслюємо переваги такої модифікації та розглядаємо її застосування в реакціях з різноманітними електрофільними агентами, включно з альдегідами, імінами та похідними алілових спиртів, що уможливлює синтез віцинальних аміноспиртів, віцинальних діамінів, гомоаліламінів та α-метилен-γ-амінокислот  V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-12-31 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/102 10.15407/bioorganica2025.02.003 Ukrainica Bioorganica Acta; Vol. 20 No. 2 (2025): Ukrainica Bioorganica Acta; 3-12 Ukrainica Bioorganica Acta; Том 20 № 2 (2025): Ukrainica Bioorganica Acta; 3-12 1814-9766 1814-9758 10.15407/bioorganica2025.02 en https://bioorganica.com.ua/index.php/journal/article/view/102/99 Copyright (c) 2025 Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | флуор 1,3-протонне переміщення флуоровані аміни та амінокислоти відновлювальне декарбоксилювання 2,2-дифенілгліцин Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim A. Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title | Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title_alt | Decarboxylative 1,3-proton shift: an unorthodox strategy for synthesizing biologically relevant amino compounds |
| title_full | Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title_fullStr | Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title_full_unstemmed | Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title_short | Декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| title_sort | декарбоксилювальне 1,3-протонне переміщення: нетрадиційна стратегія синтезу біологічно значущих аміносполук |
| topic | флуор 1,3-протонне переміщення флуоровані аміни та амінокислоти відновлювальне декарбоксилювання 2,2-дифенілгліцин |
| topic_facet | fluorine 1,3-proton shift fluorinated amines and amino acids reductive decarboxylation 2,2-diphenylglycine флуор 1,3-протонне переміщення флуоровані аміни та амінокислоти відновлювальне декарбоксилювання 2,2-дифенілгліцин |
| url | https://bioorganica.com.ua/index.php/journal/article/view/102 |
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