Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот
This review article covers the developments made in collaboration by groups of Professors V. P. Kukhar and P. Bravo to the synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino acids. The potential of the sulfinyl chir...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
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|---|---|
| author | Lyutenko, Nataliya V. Sorochinsky, Alexander E. Soloshonok, Vadim A. |
| author_facet | Lyutenko, Nataliya V. Sorochinsky, Alexander E. Soloshonok, Vadim A. |
| author_institution_txt_mv | [
{
"author": "Nataliya V. Lyutenko",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Alexander E. Sorochinsky",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Vadim A. Soloshonok",
"institution": "Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV\/EHU, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain"
}
] |
| author_sort | Lyutenko, Nataliya V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | This review article covers the developments made in collaboration by groups of Professors V. P. Kukhar and P. Bravo to the synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino acids. The potential of the sulfinyl chiral auxiliaries in the field of stereoselective transformations of fluorinated substrates is demonstrated by diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various fluorinated oxirane derivatives, diastereoselective sulfoxide anions addition to fluorinated imines leading to convenient preparation of α-fluoroalkyl α-amino acids, hydroxy amines, and amines, diastereoselective Mannich-type reaction between N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine and protected alkyl glycolates furnishing β-trifluoromethyl isoserine derivatives and diastereoselective additions of phosphite or α-phosphonate anions to N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine using for synthesis of trifluoromethylated α- and β-aminophosphonic acids. Furthermore, diastereoselective additions of Reformatsky reagent derived from bromodifluoroethyl acetate as well as α,α-difluorophosphonate anions to N-p-toluenesulfinyl imines allowing convenient preparation of a,a-difluoro-b-amino acids and α,α-difluoro-β-amino phosphonates in enantiomerically pure form are described. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is briefly discussed. |
| doi_str_mv | 10.15407/bioorganica2023.01.010 |
| first_indexed | 2025-07-17T12:19:48Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
UDC 577.122.34/.345
DOI: https://doi.org/10.15407/bioorganica2023.01.010
10
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
REVIEW
Applications of chiral sulfinyl auxiliaries in the asymmetric synthesis of
fluorinated amines and amino acids
Nataliya V. Lyutenko1*, Alexander E. Sorochinsky1, Vadim A. Soloshonok2,3
1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
2 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, San Sebastián, Spain
3 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Abstract: This review article covers the developments made in collaboration by groups of Professors V.P. Kukhar and P. Bravo to the
synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino
acids. The potential of the sulfinyl chiral auxiliaries in the field of stereoselective transformations of fluorinated substrates is demonstrated
by diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for
preparation of various fluorinated oxirane derivatives, diastereoselective sulfoxide anions addition to fluorinated imines leading to
convenient preparation of α-fluoroalkyl α-amino acids, hydroxy amines, and amines, diastereoselective Mannich-type reaction between
N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine and protected alkyl glycolates furnishing β-trifluoromethyl isoserine derivatives and
diastereoselective additions of phosphite or α-phosphonate anions to N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine using for synthesis
of trifluoromethylated α- and β-aminophosphonic acids. Furthermore, diastereoselective additions of Reformatsky reagent derived from
bromodifluoroethyl acetate as well as α,α-difluorophosphonate anions to N-p-toluenesulfinyl imines allowing convenient preparation of
,-difluoro--amino acids and α,α-difluoro-β-amino phosphonates in enantiomerically pure form are described. Effect of fluorine on the
mechanism and stereochemical outcome of these reactions is briefly discussed.
Keywords: fluorine and compounds; asymmetric synthesis; sulfoxides; N-sulfinyl imines; fluorinated epoxides; α-fluoroalkyl amino
derivatives; α- and β-amino acids; α- and -aminophosphonates.
Introduction
Sulfinyl compounds such as sulfoxides, N-sulfinyl
imines, sulfinamides, sulfoximines, and other derivatives
(Figure 1), are recognized as powerful chiral auxiliaries that
play an important role in the stereoselective preparation of
variety of useful compounds [1]. They are also used in
catalytic stereoselective reactions, both as ligands for
transition metals and as chiral organocatalysts. Recently,
the availability of sulfoximines, sulfonimidamides, and
Received:
Revised:
Accepted:
Published online:
02.03.2023
30.03.2023
20.04.2023
30.06.2023
Corresponding author. Tel.: +380-44-296-0409;
e-mail: nlyutenko@bpci.kiev.ua (N.V. Lyutenko)
ORCID: 0000-0003-3538-2814
sulfonimidates has led to the increased interest in their
application in organic synthesis. Due to tetrahedral
stereogenic sulfur atom connected to electronegative
oxygen atom by a polar, partially dative bond, sulfinyl
auxiliaries are capable to provide high levels of
stereocontrol in various classes of reactions and can be used
as chiral equivalents of alkyl (reductive desulfurization),
vinyl (syn-elimination reaction), hydroxymethyl (Pummerer
rearengement), and amino (hydrolysis of N-sulfinyl imines)
groups.
Figure 1. Examples of chiral sulfinyl compounds.
© Lyutenko N.V. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
mailto:nlyutenko@bpci.kiev.ua
https://orcid.org/0000-0003-3538-2814
N.V. Lyutenko et al.
11
In this review we will discuss the development of
sulfinyl auxiliaries methodology achieved in collaboration
between groups of Professors V.P. Kukhar [2] and P. Bravo
as a part of greater research efforts toward elaboration of
convenient methods for asymmetric preparation of
fluorinated amines and amino acids and investigation of
their biological properties. The transformation of the
sulfinyl chiral auxiliaries was featured with good functional
group tolerance, and the possibility of modifying complex
bioactive scaffolds resulting in augment the diversity and
applications of fluorinated amines and amino acids.
Diastereoselective methylene transfer from
diazomethane to the carbonyl of -keto--fluoro-
alkyl sulfoxides
Our initial investigation in this area was devoted to
exploring asymmetric methylene transfer reactions from
diazomethane to the carbonyl group of β-keto-γ-fluoroalkyl
sulfoxides (R)-2, available by acylation of the α-lithio
derivatives of p-tolyl alkyl sulfoxides (R)-1 with fluorinated
ethyl acetates, giving rise under mild conditions to the
corresponding oxiranes in generally good chemical yields
(Scheme 1). The synthetic opportunities associated with the
epoxide ring and the sulfinyl group make these products
highly promising building blocks for the synthesis of a
variety of enantimerically pure open-chain fluorinated
compounds containing different functional groups [3].
Thus, reactions of -unsubstituted -keto sulfoxides (R)-2a
with diazomethane under optimized conditions in Et2O at
0 °C led to mixtures of oxiranes (RS,2S)-3 and enol ethers
(Z)-4 ranging from 5:1 to 1:2 [4]. Formation of oxiranes
(RS,2S)-3, proceeded in good yield and with high
diastereomeric excess. The diastereoselectivity in favor of
oxiranes (RS,2S)-3 is consistent with ability of the sulfinyl
group to participate in diazomethane coordination resulting
in Re face attack of -keto sulfoxides (R)-2a by
approaching reagent. In addition, high diastereoselectivity is
also associated with the presence of an electron-
withdrawing fluoroalkyl group in β-keto sulfoxides (R)-2a,
since similar results were obtained using the corresponding
bromo and chlorine derivatives. This methodology has been
expanded to α-alkyl/phenyl substituted β-keto sulfoxides
(R)-2b leading under appropriate conditions to mixture of
(RS,1'R,2S)-5 and (RS,l'S,2S)-5 diastereomers in high
chemical yields and synthetically useful levels of
diastereoselectivity [5]. Predominant role of the sulfinyl
group in controlling the configuration of the oxirane ring
was generally observed.
Synthetic application of oxiranes (RS,2S)-3 and
(RS,l'S,2S)-5, isolated in enantiomerically pure form by
fractional crystallization or column chromatography,
including ring opening by oxygen, halogen, and nitrogen
nucleophiles, reduction and elimination reactions were
studied (Scheme 2) [5]. In that context, acid-catalyzed ring-
opening of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5 in
THF/water mixture using perchloric acid as the promotor
cleanly afforded diols (RS,2S)-6 and (RS,2S,3S)-7. Although
p-Tolyl
S
RF
O
(R)-1
R = H, Alk, Ph
RF = CH2F, CHF2, CF2Cl, CF3, C2F5
+
LDA-70 oC, THF
(RS)-2a R = H
+
(RS,3R/3S)-2b R = Alk, Ph
(RS,2S)-3
(RS,1'R,2S)-5
(RS,1'S,2S)-5
H R
1'
2
RFCOOEt
p-Tolyl
S
O
R
p-Toly
S
RF
R
OO
excess of
CH2N2
Et2O, 0 oC
p-Tolyl
S
RF
OO
+
p-Tolyl
S
RF
O OCH3
(Z)-4
R = HR = Alk, Ph
O
p-Tolyl
S
RF
O
H R
1'
2
O
from 88 to >94% de
solvent
Scheme 1. Reactions of β-keto sulfoxides (R)-2 with
diazomethane.
cleanly afforded diols (RS,2S)-6 and (RS,2S,3S)-7. Although
reactions proceeded at room temperature for 3-5 days, the
target products were isolated in high yields (70-91%). Ring
opening of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5 with
benzylamine in THF at room temperature proceeded with
high rates leading to the selective preparation of amino
alcohols (RS,2S)-8 and (RS,2S,3S)-9 in excellent isolated
yields. The reactions of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5
with dibenzyl amine occurred slowly at room temperature
to give N,N-dibenzyl derivatives (RS,2S)-10 and (RS,2S,3S)-
11. Treatment of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5 in
acetone solution with NaI and trifluoroacetic anhydride for
10 min at -20 °C gave sulfenyl derivatives (2S)-12 and
(1'S,2S)-13 without affecting the oxirane ring. It should be
noted that ring-opening reactions proceeded with complete
regioselectivity involving attack of nucleophile exclusively
on the less substituted carbon atom of the epoxide ring and
could be explained based on steric and electronic features.
Sulfur-free epoxy alcohols (S)-15 were synthesized by
Pummerer rearrangement of oxiranes (RS,2S)-3 promoted
by trifluoroacetic anhydride and sym-collidine in
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
12
Scheme 2. Ring-opening and reduction reactions of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5.
Scheme 3. Ring-opening and reduction reactions of oxiranes (RS,2S)-3 and (RS,l'S,2S)-5.
Scheme 4. Pummerer rearrangement of acyclic derivatives (RS,2S)-10 and (RS,2S)-19.
Scheme 5. Addition of α-lithiated alkyl p-tolyl sulfoxides (R)-1 to N-acyl imines of trifluoropyruvate 24.
N.V. Lyutenko et al.
13
Scheme 6. Synthesis of both (S)- and (R)-enantiomers of α-trifluoromethyl α-amino acids 27 and 28.
Table 1. Addition of -lithiated alkyl p-tolyl sulfoxides (R)-1 to N-PMP aldimines 29.
Entry RF R dr yield (%)
1 CF3 H 86/14 88(72)
2 CF2CF3 H 87/13 87(72)
3 CF2CF2H H 85/15 90(70)
4 CF3 Ph 86/14 98(59)
5 CF2CF3 Ph 87/13 97(60)
6 CF2CF2H Ph 87/13 98(59)
a Overall isolated yield. Isolated yield of diastereomerically pure 30 and 31 is given in parentheses.
acetonitrile toward epoxy aldehydes 14 followed by
treatment with sodium borohydride (Scheme 3) [4].
Protection of primary alcohols (S)-15 with benzyl bromide
in the presence of NaH led to (S)-16 in satisfying overall
yield from (RS,2S)-3. Subsequent ring opening of (S)-16
with thymine under base conditions in THF at room
temperature afforded protected acyclic nucleosides 17
which were isolated by flash chromatography [6]. Finally,
reductive debenzylation of 17 employing 10% palladium on
carbon in ethanol allowed to obtain enantiomerically pure
fluorinated acyclic nucleosides 18 in excellent yield.
The Pummerer rearrangement was used to remove the
sulfinyl group in acyclic derivatives (RS,2S)-10 and (RS,2S)-
19 to yield intermediate aldehydes (R)-20 and (R)-21 which
were further transformed into -hydroxy--trifluoromethyl-
-amino acid 22 and -trifluoromethyl-,-dihydroxy acid
23 by oxidation with sodium chlorite (Scheme 4) [4]. It
should be noted that chiral trifluorolactic acid derivatives of
type 23 are very useful compounds in studying the
phenomenon of optical self-purification via preferential
sublimation of racemic or enantiomerically pure forms [7].
Chiral sulfoxide anions addition to fluorinated
imines
The next aim of our study was the development of
diastereoselective addition reactions between sulfoxide
stabilized carboanions and fluoroalkylated imines as
straightforward approach to corresponding enantiomerically
pure -fluoroalkyl -sulfinyl amines and then
demonstration of their transformation into enantiomerically
pure -amino acids bearing fluoroalkyl substituent on the
chiral center. We found that N-acyl imines of methyl
trifluoropyruvate 24, derived by the Staudinger reaction of
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
14
methyl trifluoropyruvate with triphenylphosphazenes under
mild conditions in 70-95% yields [8], were efficient
substrates for addition reactions with lithium anion of alkyl
p-tolyl sulfoxides (R)-1 (Scheme 5) [9]. The nucleophilic
addition in THF at -78 ºC preceded regioselectively at the
iminic carbon affording corresponding products in good
overall yields. However, these reactions were not highly
stereoselective and mixtures of all possible diastereoisomers
were formed according to 1H and 19F NMR analysis of the
crude mixtures. Diastereomerically pure major products 25
and 26 were isolated by flash chromatography and/or
fractional crystallization in moderate yields (30-42%).
Diastereomeric purity was determined to be >98% de for all
isomers by HPLC analyses. Configuration assignments of
the obtained -amino sulfoxides were made by X-ray
crystallography analysis as well as 19F NMR and chemical
correlation.
Resulting diastereomers 25b and 26b could be
transformed into the corresponding free -amino acids (S)-
and (R)-27 in a three-step reaction sequence (Scheme 6).
Well-optimized reduction using sodium iodide and
trifluoroacetic anhydride followed by desulfurization with
Ni-Raney and further deprotection led to series of
-trifluoromethyl -amino acids (S)- and (R)-27 with
excellent enantiomerical purity.
The Pummerer rearrangement of both diastereomers 25a
and 26a with trifluoroacetic anhydride and sym-collidine
followed by hydrolysis of the α-trifluoroacetoxy sulfides, in
situ reduction of the intermediate aldehydes with sodium
borohydride, and subsequent deprotection of amino and
carboxylic functions allowed to extend this strategy to the
first synthesis of both (S)- and (R)-enantiomers of
α-trifluoromethyl serine 28 in enantiomerically pure form
(Scheme 6) [10].
We assumed that high electrophilicity of the N-acyl
imines of methyl trifluoropyruvate [11] resulted in low
stereoselectivity of chiral sulfoxide-stabilised carbanions
additions. To verify this assumption, we explored
nucleophilic additions of chiral sulfoxide-stabilised
carbanions to fluoroalkyl N-p-methoxyphenyl (PMP)
aldimines since PMP protective group provided reasonably
reactivity the C=N double bond, allowed the imine nitrogen
to form coordinated transition states, and was removed by
mild and efficient procedures. The starting N-PMP
aldimines 29 were prepared by direct condensation between
p-anisidine and perfluoroalkyl aldehydes in their
commercially available hydrate or hemi-acetal form
exclusively as (E)-geometric isomers that is critically
important for stereochemical outcome of the addition
reactions (Table 1). N-PMP aldimines 29 bearing
trifluromethyl, pentafluoroethyl and ω-hydrotetra-
fluoroethyl groups were subjected to addition of lithium
anions of Me- and Bn-p-tolyl sulfoxides (R)-1 in THF at
-70 °C. The reactions proceed with a high reaction rate
giving rise to products (RS,2S)-30 and (RS,1S,2S)-31 in high
overall yield [12]. The diastereoselectivities obtained with
different N-PMP aldimines 29 and sulfoxides (R)-1 were
good. Control experiments suggested that additions to
N-PMP aldimines 29 proceeded irreversibly under kinetic
control, which is in sharp contrast to the similar reactions
with nonfluorinated substrates. The nature of the fluoroalkyl
group of the starting N-PMP aldimines 29 had no
significant effect on the stereochemical outcome of the
addition reactions and diastereoselectivity up to 70% de was
achieved even in the case of products (RS,1S,2S)-31 when
two chiral centers were simultaneously created at the
addition stage. α-Fluoroalkyl-β-sulfinyl amines (RS,2S)-30
and (RS,1S,2S)-31 were found to be highly crystalline
compounds that allowing their purification to
enantiomerically pure state by simple crystallization of
crude reaction mixtures and determination of absolute
configuration by X-ray analysis. The six-membered chair-
like transition state where coordination of the metal to the
sulfinyl oxygen and imine nitrogen resulting in preferable
attack of nucleophile to the Re face of the C=N bond in
imine and syn stereoisomeric form of -carbanion of benzyl
p-tolyl sulfoxide dictating configuration of the new C-SO
stereogenic center explains the stereochemical outcome.
The synthetic application of N-PMP protected
α-fluoroalkyl-β-sulfinyl amines (RS,2S)-30 and (RS,1S,2S)-
31 was demonstrated by their conversion into biologically
interesting enantiopure α-fluoroalkyl amines and amino
alcohols without damage to the stereocenters (Scheme 7).
Treatment of (RS,2S)-30 and (RS,1S,2S)-31 with cerium
ammonium nitrate (CAN) in acetonitrile at room
temperature led to selective cleavage of the N-p-methoxy-
phenyl protective group without oxidation of the sulfinyl
moiety even at a larger excess of CAN. This method
allowed for preparation of the N-unsubstituted
α-fluoroalkyl-β-sulfinyl amines (RS,2S)-32 and (RS,1S,2S)-
33 in moderate to good chemical yields which were further
converted into α-fluoroalkyl amines (R)-34 by one-pot
reductive desulfinylation with Raney-Ni/H2 in ethanol.
After reprotection of amines (RS,2S)-32 and (RS,1S,2S)-
33 with benzyl chloroformate, the resulting N-Cbz
derivatives (RS,2S)-35 and (RS,1S,2S)-36 were subjected to
“non-oxidative” Pummerer reaction [13] with
trifluoroacetic anhydride and sym-collidine followed by
treatment with aqueous K2CO3 and NaBH4 to give very
good yields of the corresponding β-amino alcohols (R)-37
and (1R,2R)-38. The asymmetric Pummerer reaction of
sulfoxide (RS,1S,2S)-36 is of significant interest since
SN2-type displacement of the sulfinyl by hydroxy group
occurred with complete inversion of the absolute
configuration at the carbon bearing sulfinyl group yielding
N-Cbz trifluoronorephedrine (1R,2R)-38 with de > 99%.
The method was extended to N-(PMP)-arylimines as an
convenient way to prepare enantiopure α-arylglycinols [14].
Diastereoselective Mannich-type reaction of N-tert-
butanesulfinyl-3,3,3-trifluoroacetaldimine with
protected alkyl glycolates
Chiral fluorinated N-tert-butanesulfinyl imines are
versatile auxiliaries successful employing as electrophiles in
a wide range of reactions [15]. As an example, N-tert-
butylsulfinyl-3,3,3-trifluoroacetaldimine found numerous
applications in the asymmetric synthesis of trifluoromethyl-
N.V. Lyutenko et al.
15
containing amines and amino acids which demonstrated
very interesting biological properties. This aldimine
exhibited high electrophilicity of the C=N bond facilitating
the nucleophilic addition of organometallic compounds
to the iminic carbon as well as high level of
diastereoselectivity provided by combination of stereo-
controlling properties of tert-butanesulfinyl and
trifluoromethyl groups. In addition, N-tert-butylsulfinyl-
Scheme 7. Synthesis of α-fluoroalkyl amines.
S
N
F3C
O
(S)-39
+ OMe
OBoc
O
40
LDA
THF, -78 oC
dr 7:2
F3C OMe
NH
OBoc
O
S
O
(SS,2S,3S)-41
72%
+
F3C OMe
NH
OBoc
O
S
O
(SS,2R,3S)-42
20%
Scheme 8. Mannich-type reaction of imine (S)-39 with lithium enolate derived from Boc-protected methyl glycolate 40.
F3C OMe
NH
OBoc
O
S
O
(SS,2S,3S)-41
F3C OMe
NH3
+
OBoc
O
(2S,3S)-43
86%
HCl/Et2O, rt
F3C OMe
NH
OH
O
S
O
(SS,2S,3S)-44
84%
F3C OH
NH
OH
O
S
O
(SS,2S,3S)-45
75%
HCOOH, rt
LiOH
MeOH/H
2O 3:1
rt
Cl
-
Scheme 9. Manipulations with protection groups of β-trifluoromethyl isoserine (SS,2S,3S)-41.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
16
Scheme 10. Synthesis of β-aminophosphonate (R)-47 and N-Cbz protected β-aminophosphonic dipeptide derivatives (S,R)-48 and
(S,R)-49.
Scheme 11. Addition of dialkyl trimethylsilyl phosphites to imine (S)-39 and deprotection of N-tert-butanesulfinyl-α-aminophosphonates
(SS,S)-50.
3,3,3-trifluoroacetaldimine was readily available in both
enantiomeric forms and free amines could be obtained after
easy removal of the tert-butanesulfinyl group under mild
acidic conditions. We used the reactivity and
stereocontrolling properties of N-tert-butylsulfinyl-3,3,3-
trifluoroacetaldimine (S)-39 in diastereoselective addition
with enolates derived from O-protected α-hydroxyacetates
to synthesize β-trifluoromethyl isoserine derivatives as
structural components of docetaxel analogues (Scheme 8)
[16]. After optimization of reaction conditions imine (S)-39
was treated with excess of lithium enolates of Boc-protected
methyl glycolate 40 generated with LDA as a base in THF
at -78 °C to give mixture of two diastereomeric products
(SS,2S,3S)-41 and (SS,2R,3S)-42 in moderate ratio of 7:2
with high combined yield although theoretically four
isomers could be formed in the addition reaction. It should
be noted complete control over the stereogenic C3 by the
tert-butanesulfinyl/trifluoromethyl groups with no 3R
stereoisomer being observed in the reaction mixture.
Despite the Mannich reaction proceeded with only
moderate diastereoselectivity, the mixture of diastereomeric
products was easily separated by column chromatography
to furnish the enantiomerically pure (Ss,2S,3S)-41 in 72%
yield as well as 20% of enantiomerically pure (Ss,2R,3S)-42
and their absolute configuration was established by X-ray
analysis. In addition, chemoselective manipulation of the
protecting groups in (SS,2S,3S)-41 provided partially
deprotected amino acids (2S,3S)-43, (SS,2S,3S)-44, and
(SS,2S,3S)-45 with no loss of diastereomeric purity allowing
for incorporation of β-trifluoromethyl isoserine residue into
more complex products (Scheme 9).
Diastereoselective additions of α-phosphonate
anions and phosphites to N-tert-butanesulfinyl-
3,3,3-trifluoroacetaldimine
Fluorinated aminophosphonates and aminophosphonic
acids belong to important group of natural amino acid
mimetics exhibited significant influences on the protease
activities with applications ranging from agrochemistry to
medicine [17]. They were intensively used in the design and
development of potent inhibitors for such enzymes as
glutamine synthetase, protein tyrosine phosphatase, HIV
N.V. Lyutenko et al.
17
protease, and human collagenase. In addition, fluorinated
aminophosphonic acid derivatives also hold great promise
as effective starting materials for the preparation of new
phosphapeptides [18]. Therefore, basing on our previous
results, we devised addition of α-phosphonate carbanions to
N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine (S)-39 for
the asymmetric synthesis of trifluoromethylated β-amino-
phosphonates (SS,R)-46 (Scheme 10) [19]. The reactions of
imine (S)-39 with excess of dialkyl methylphosphonates
were carried out using n-BuLi as a base in THF at -78 °C
affording corresponding addition adducts (SS,R)-46 in
moderate to good yield with excellent diastereoselectivity
94-95% de. The diastereoselectivity of the phosphonate
carbanions addition to imine (S)-39 was kinetically
controlled and the stereochemical outcome of reaction was
consistent with the open transition state model. The major
diastereoisomers (Ss,R)-46 were isolated by column
chromatography with diastereomeric purity
96-98% de. After selective desulfinylation of addition
adducts (Ss,R)-46, coupling of β-aminophosphonate (R)-47
with N-Cbz-L-alanine and N-Cbz-L-phenylalanine by using
mixed anhydrides method allowed preparing diastereo-
isomerically pure N-Cbz protected β-aminophos-phonic
dipeptide derivatives (S,R)-48 and (S,R)-49 in good yields.
Next, addition reaction of dialkyl trimethylsilyl
phosphites as efficient phosphorus nucleophiles to imine
(S)-39 was investigated for convenient asymmetric
synthesis of phosphonotrifluoroalanine and its derivatives.
The dialkyl trimethylsilyl phosphites were generated in situ
from corresponding diethyl phosphite in the presence of
TMSCl and Et3N and further reacted with imine (S)-39 in
dichloromethane at 0 °C yielding N-tert-butanesulfinyl
α-aminophosphonates (SS,S)-50 in moderate to high yields
and diastereoselectivity (Scheme 11) [20]. The best result in
term of diastereoselectivity (88% de) was achieved with
diisopropyl trimethylsilyl phosphite. The major
diastereomers were isolated by flash column
chromatography or recrystallization in excellent
diastereomeric purity and their stereochemistry was
determined by X-ray analysis. The formation of the major
diastereomers with (SS,S)-configuration was proposed to
explain by non-chelated transition state model which
provided a rationale for the greater diastereoselectivity
observed for the sterically hindered diisopropyl
trimethylsilyl phosphite relative to other phosphite
derivatives. Partial or complete deprotection of
diastereomeric pure N-tert-butanesulfinyl α-aminophos-
phonates (SS,S)-50 under standard conditions led to
enantiomerically pure phosphonotrifluoromethyl alanine
(S)-52 and its dialkyl esters (S)-51 in excellent yield.
Diastereoselective Reformatsky reaction between
N-p-toluenesulfinyl imines and bromodifluoroethyl
acetate
Traditionally, stereoselective nucleophilic addition of
difluorinated Reformatsky reagent (BrZnCF2CO2Et) to
imines is considered as the most efficient method for the
construction of variety of α,α-difluoro-β-amino acid
derivatives used in the design of peptides and fluoroalkene
dipeptide isosteres [21]. α,α-Difluoro-β-amino acid
derivatives are also components of anticancer, and
antifungal agents as well as protease inhibitors. We
developed stereoselective version of the Reformatsky
reaction between ethyl bromodifluoroacetate and N-p-
toluenesulfinyl imines as a generalized and synthetically
useful approach to enantiomerically pure α,α-difluoro-β-
amino acids. Treatment of the alkyl and aryl N-p-
toluenesulfinyl aldimines (S)-53 with ethyl bromo-
difluoroacetate in the presence of activated Zn powder in
boiling THF provided N-p-toluenesulfinyl protected
α,α-difluoro-β-amino esters 54 with the (SS,3S)-absolute
configuration and good to excellent diastereoselectivities
(72 to >98 de) (Scheme 12) [22]. Optimization experiments
shown that 1/2 ratio of aldimines (S)-53 and ethyl
bromodifluoroacetate was required for complete
transformation of the former to α,α-difluoro-β-amino esters
(SS,3S)-54 isolated in moderate to good yields (59-85%).
The undesired corresponding difluoro--lactams were not
detected in these reactions. The diastereoselectivity of
addition to aryl aldimines (S)-53 was noticeably influenced
by the electron-donating or withdrawing character of the
substituent on the aromatic ring. For example, the very high
diastereoselectivity (>98 de) was observed in the case of
anisaldehyde-derived aldimine (S)-53. In contrast, the
reactions of alkyl aldimines (S)-53 with difluorinated
Reformatsky reagent, conducted under the standard
conditions, proceeded with similar diastereoselectivity (72-
76 de) which is lower compared to the aryl aldimines.
Finally, Reformatsky reaction of ethyl bromodifluoroacetate
with N-p-toluenesulfinyl ketimine (S)-56 derived from
acetophenone was explored to provide the corresponding
quaternary carbon-containing chiral ,-difluoro--amino
acid. After optimization of reaction conditions, treatment of
ketimine (S)-56 with an excess of difluoroorganozinc
reagent freshly preformed from the ethyl bromo-
difluoroacetate and zinc in THF at 20 °C gave the addition
adduct (SS,S)-57 in good yield with excellent
diastereoselectivity (Scheme 12). The isolation of the
α,α-difluoro-β-amino esters (SS,3S)-54 and (SS,S)-57 was
effectively achieved either by crystallization or flash
chromatography and absolute configuration was determined
by X-ray structural analysis. The stereochemical outcome of
the described Reformatsky reactions, regarding the absolute
configuration of the newly formed carbon stereogenic
center, was rationalized by six-membered transition state
where the difluoro ester enolate, assumed to exist as
C-bound tautomer, attack preferably from the Re-face of the
(S)-configured N-p-toluenesulfinyl imine. Esters (SS,3S)-54
and (SS,3S)-57 were hydrolyzed by refluxing with 6 N HCl
to afford, after treatment with propylene oxide, free
α,α-difluoro-β-amino acids (S)-55 and (S)-58 in high
isolated yield with excellent enantiomerical purity
according to chiral HPLC analysis. The only exception was
hydrolysis under standard conditions of the furyl-substituted
product (SS,3S)-54, when the target amino acid could not be
isolated, probably, due to the instability of the furyl ring
under strong acidic conditions. It is worth noting that other
research groups evaluated the influence of the N-tert-
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
18
Scheme 12. Synthesis and acidic hydrolysis of N-p-toluenesulfinyl protected α,α-difluoro-β-amino esters (SS,3S)-54 and (SS,3S)-57.
Scheme 13. Reaction of the diethyl lithiodifluoromethylphosphonate with N-p-toluenesulfinyl imines (S)-53 and (S)-56.
O
P(OEt)2
F F
(SS,R)-59
ONH
S
p-Tolyl
O
R
P(OEt)2
F F
(R)-61
ONH2
R
77-97%R = Ph, 2-thienyl
n-C5H11, i-Pr
TFA
EtOH, 0 oC
1. 10 N HCl
reflux
2.
P(OH)2
F F
(R)-62
ONH2
R
70-86%
Ph
B(OH)2
R1 CO2H
O
for
R = Ph
CH2Cl2, rt
P(OEt)2
F F
ONH
Ph
Ph
CO2HR1
63 R1 = H, S,R/R,R =3:2 (55%)
64 R1 = Me, S,R/R,R =3:1 (49%)
Scheme 14. Deprotection of N-p-toluenesulfinyl α,α-difluoro-β-amino phosphonates (SS,R)-59 and utilization of α,α-difluoro-β-amino
phosphonates (R)-61 in the Petasis boronic acid Mannich reaction.
N.V. Lyutenko et al.
19
butanesulfinyl group on Reformatsky reaction with ethyl
bromodifluoroacetate by examining the addition to
corresponding aldimines [23]. Although the N-tert-
butanesulfinyl protected α,α-difluoro-β-amino esters were
produced with good to excellent diastereoselectivities,
separation of the diastereomeric adducts required
application of chiral HPLC on preparative scale.
Diastereoselective additions of α,α-difluoro-
phosphonate anions to N-p-toluenesulfinyl imines
As bioisosteric, non-hydrolyzable analogues of naturally
occurring phosphates, α-fluorinated phosphonates gained
considerable attention in pharmaceutical and agrochemical
research [24].
Due to the presence of one or two fluorine atoms at the
α-position, α-fluorinated phosphonates closely mimic the
phosphate in terms of pKa2 values as well as potential
hydrogen bonding interactions like the phosphate oxygen
atoms. We explored the use of N-p-toluenesulfinyl imines
as substrates in reaction with phosphonodifluoromethyl
carbanion for stereoselective synthesis of β-amino-α,α-
difluorophosphonates. Structurally diverse enantiomerically
pure alkyl and aryl N-p-toluenesulfinyl aldimines (S)-53
readily undergo nucleophilic addition with 1.3 equiv of
diethyl lithiodifluoromethylphosphonate generated in situ
from diethyl difluoromethylphosphonate and LDA in THF
at -78 °C affording N-p-toluenesulfinyl ,-difluoro--
aminophosphonates (SS,R)-59 (Scheme 13) [25]. Despite
the relatively weak nucleophilicity and poor thermal
stability of diethyl lithiodifluoromethylphosphonate,
N-p-toluenesulfinyl ,-difluoro--aminophosphonates
(SS,R)-59 were obtained from good to high yields (70-92%).
Additional experiments showed that the use of different
bases and solvents did not improve the selectivity of
addition and resulted in incomplete conversion of starting
aldimines (S)-53, as indicated by 1H NMR and TLC
analysis of crude reaction mixtures. Under optimized
reaction conditions the highest diastereoselectivity (90% de)
was observed for the addition of diethyl lithio-
difluoromethylphosphonate to a benzaldehyde-derived
imine (S)-53. The aryl aldimines (S)-53 containing either an
electron-donating group such as methoxy as well as an
electron-withdrawing group such as CF3 at the para-
position of the phenyl ring were well tolerated under
reaction conditions giving the corresponding products
(SS,R)-59 with high diastereoselectivity (88% de). At the
same time the use of heteroaryl and alkyl aldimines (S)-53
as substrates provided lower stereoselectivity (82-84% de).
Moreover, trans-cinnamaldehyde-derived imine (S)-53 was
also compatible affording exclusively 1,2-addition product
(SS,R)-59 with high stereocontrol (88% de). Addition of
diethyl lithiodifluoromethylphosphonate was expanded to
acetophenone-derived N-p-toluenesulfinyl imine (S)-56
providing after 1 h adduct (SS,R)-60 with high
diastereoselectivity (92% de). However, purification by
chromatography allowed the isolation of major
diastereomer (SS,R)-60 in only 40% yield as well as
unreacted starting imine (S)-56 in 51% yield. The
diastereoselectivity and yield remained essentially
unchanged with a longer reaction time. Competitive
deprotonation of the imine (S)-56 under base reaction
conditions was most likely responsible for the observed
moderate yield. The N-p-toluenesulfinyl α,α-difluoro-β-
aminophosphonates (SS,R)-59 and (SS,R)-60 were isolated
by chromatography or crystallization and their
stereochemistry was determined by X-ray analysis. The
stereochemical outcome of the reactions is consistent with
the open transition state model previously proposed for the
addition of dialkyl methylphosphonate carbanions to N-p-
toluenesulfinyl aldimines (S)-53.
A two-step deprotection involving N-desulfinylation of
diastereomerically pure N-p-toluenesulfinyl α,α-difluoro-β-
amino phosphonates (SS,R)-59 with trifluoroacetic acid in
EtOH followed by refluxing of resulting α,α-difluoro-β-
amino phosphonates (R)-61 with 10 N HCl afforded, after
treatment with propylene oxide, free α,α-difluoro-β-amino
phosphonic acids (R)-62 in good to excellent isolated yields
with enantiomerical purity >98% ee (Scheme 14). Thus,
deprotection of N-p-toluenesulfinyl α,α-difluoro-β-amino-
phosphonates (SS,R)-59 proceeded under described
conditions without epimerization at the β-position.
Employing of phenyl-substituted α,α-difluoro-β-amino
phosphonates (R)-61 as amine component in the Petasis
boronic acid Mannich reaction with glyoxylic and pyruvic
acids in the presence of styrylboronic acid provided highly
functionalized N-phosphonomethylglycine analogues 63
and 64 with poor diastereoselectivity [26].
Conclusions
This review highlights several efficient synthetic
approaches using chiral sulfinyl auxiliaries for the
preparation of biologically relevant fluorinated oxiranes,
amines, hydroxy amines, α- and β-amino acids as well as
α- and β- aminophosphonic acids developed in laboratory of
Professor V.P. Kukhar. Currently, the application of chiral
sulfinyl auxiliaries in highly selective asymmetric synthesis
is a reliable methodology and their synthetic versatility is
continuously demonstrated for the preparation of
fluorinated amines and amino acids with various types of
biological activities. In most cases the existing transition
states models facilitate the prediction of the absolute
configuration of major diastereoisomers making this
methodology attractive for synthetic applications. It should
be emphasized that the usefulness of the sulfinyl auxiliaries
comes not only from their ability to produce high
asymmetric inductions but also from their synthetic
versatility allowing construction of enantiopure fluorinated
molecules with wide structural and functional diversities.
We anticipate that the presented potential of the
methodology in which sulfinyl compounds are serving as
chirality source in various preparations of fluorinated
molecules will encourage developing new asymmetric
syntheses of complex natural product analogues for
biomedical applications.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 1
20
Notes
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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Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі
фторованих амінів і амінокислот
Н.В. Лютенко1*, О.Є. Сорочинський1, В.А. Солошонок2,3
1 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря Національної академії наук України, Київ, Україна
2 Університет Країни Басків, Сан-Себастьян, Іспанія
3 ІКЕРБАСК, Баскський фонд науки, Більбао, Іспанія
Резюме: Огляд охоплює розробки, зроблені у співпраці груп професорів В.П. Кухаря та П. Браво щодо синтетичного застосування сульфінільних
сполук як універсальних хіральних ауксиларів для асиметричного отримання фторованих амінів та амінокислот. Потенціал сульфінільних
хіральних ауксиларів у сфері стереоселективних перетворень фторованих субстратів демонструється діастереоселективним перенесенням
метилену від діазометану до карбонілу β-кето-γ-фторалкілсульфоксидів як загального підходу для отримання різних фторованих похідних
оксирану, діастереоселективного сульфоксиду. додавання аніонів до фторованих імінів, що веде до зручного отримання α-фторалкіл
α-амінокислот, гідроксиамінів та амінів, діастереоселективна реакція типу Манніха між N-трет-бутансульфінілом-3,3,3-трифторацетальдиміном і
захищеними алкілгліколятами, що утворюють β-трифторметил використання похідних ізозерину та діастереоселективних приєднань фосфіт- або
α-фосфонат-аніонів до N-трет-бутансульфінілу-3,3,3-трифторацетальдиміну для синтезу трифторметильованих α- та β-амінофосфонових кислот.
Крім того, діастереоселективні додавання реагенту Реформатського, отриманого з бромдифторетилацетату, а також α,α-дифторфосфонат-аніонів
до N-p-толуолсульфінілімінів, дозволяють зручно отримувати ,-дифтор--амінокислоти та α,α-дифтор-β-амінофосфонати в енантіомерно
чистому вигляді описані. Коротко обговорюється вплив фтору на механізм і стереохімічний результат цих реакцій.
Ключові слова: aсиметричний синтез; сульфоксиди; α-фторалкіламінопохідні; α- і β-амінокислоти.
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| id | oai:ojs2.bioorganica.com.ua:article-50 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:06Z |
| publishDate | 2023 |
| 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/b3/2fc6003b1bceb0ad2f835cbc113868b3.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-502026-07-19T14:56:54Z Applications of chiral sulfinyl auxiliaries in the asymmetric synthesis of fluorinated amines and amino acids Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот Lyutenko, Nataliya V. Sorochinsky, Alexander E. Soloshonok, Vadim A. asymmetric synthesis Sulfoxides α-Fluoroalkyl amino derivatives α- and β-Amino acids aсиметричний синтез сульфоксиди α-фторалкіламінопохідні α- і β-амінокислоти This review article covers the developments made in collaboration by groups of Professors V. P. Kukhar and P. Bravo to the synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino acids. The potential of the sulfinyl chiral auxiliaries in the field of stereoselective transformations of fluorinated substrates is demonstrated by diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various fluorinated oxirane derivatives, diastereoselective sulfoxide anions addition to fluorinated imines leading to convenient preparation of α-fluoroalkyl α-amino acids, hydroxy amines, and amines, diastereoselective Mannich-type reaction between N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine and protected alkyl glycolates furnishing β-trifluoromethyl isoserine derivatives and diastereoselective additions of phosphite or α-phosphonate anions to N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine using for synthesis of trifluoromethylated α- and β-aminophosphonic acids. Furthermore, diastereoselective additions of Reformatsky reagent derived from bromodifluoroethyl acetate as well as α,α-difluorophosphonate anions to N-p-toluenesulfinyl imines allowing convenient preparation of a,a-difluoro-b-amino acids and α,α-difluoro-β-amino phosphonates in enantiomerically pure form are described. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is briefly discussed. Огляд охоплює розробки, зроблені у співпраці груп професорів В. П. Кухаря та П. Браво щодо синтетичного застосування сульфінільних сполук як універсальних хіральних ауксиларів для асиметричного отримання фторованих амінів та амінокислот. Потенціал сульфінільних хіральних ауксиларів у сфері стереоселективних перетворень фторованих субстратів демонструється діастереоселективним перенесенням метилену від діазометану до карбонілу β-кето-γ-фторалкілсульфоксидів як загального підходу для отримання різних фторованих похідних оксирану, діастереоселективного сульфоксиду. додавання аніонів до фторованих імінів, що веде до зручного отримання α-фторалкіл α-амінокислот, гідроксиамінів та амінів, діастереоселективна реакція типу Манніха між N-трет-бутансульфінілом 3,3,3-трифторацетальдиміном і захищеними алкілгліколятами, що утворюють β-трифторметил використання похідних ізозерину та діастереоселективних приєднань фосфіт- або α-фосфонат-аніонів до N-трет-бутансульфінілу 3,3,3-трифторацетальдиміну для синтезу трифторметильованих α- та β-амінофосфонових кислот. Крім того, діастереоселективні додавання реагенту Реформатського, отриманого з бромдифторетилацетату, а також α,α-дифторфосфонат-аніонів до N-p-толуолсульфінілімінів, дозволяють зручно отримувати ,-дифтор--амінокислоти та α,α-дифтор-β-амінофосфонати в енантіомерно чистому вигляді описані. Коротко обговорюється вплив фтору на механізм і стереохімічний результат цих реакцій. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/50 10.15407/bioorganica2023.01.010 Ukrainica Bioorganica Acta; Vol. 18 No. 1 (2023): Ukrainica Bioorganica Acta; 10-21 Ukrainica Bioorganica Acta; Том 18 № 1 (2023): Ukrainica Bioorganica Acta; 10-21 1814-9766 1814-9758 10.15407/bioorganica2023.01 en https://bioorganica.com.ua/index.php/journal/article/view/50/61 Copyright (c) 2023 Nataliya V. Lyutenko, Alexander E. Sorochinsky, Vadim A. Soloshonok https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | aсиметричний синтез сульфоксиди α-фторалкіламінопохідні α- і β-амінокислоти Lyutenko, Nataliya V. Sorochinsky, Alexander E. Soloshonok, Vadim A. Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title | Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title_alt | Applications of chiral sulfinyl auxiliaries in the asymmetric synthesis of fluorinated amines and amino acids |
| title_full | Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title_fullStr | Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title_full_unstemmed | Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title_short | Застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| title_sort | застосування хіральних сульфінільних ауксиларів в асиметричному синтезі фторованих амінів і амінокислот |
| topic | aсиметричний синтез сульфоксиди α-фторалкіламінопохідні α- і β-амінокислоти |
| topic_facet | asymmetric synthesis Sulfoxides α-Fluoroalkyl amino derivatives α- and β-Amino acids aсиметричний синтез сульфоксиди α-фторалкіламінопохідні α- і β-амінокислоти |
| url | https://bioorganica.com.ua/index.php/journal/article/view/50 |
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