Asymmetric synthesis of (S,R)- and (R,R)-methiin stereoisomers

Article abstract of DOI:10.1080/10426507.2020.1755972

An asymmetric synthesis of (+)- and (–)-methiine (S-methyl-(R)-cysteine sulfoxide) diastereomers has been developed. These natural sulfur compounds were isolated from a variety of Brassica vegetables. As the starting compound, (R)-cysteine was used, which was methylated to form (R)-S-methylcysteine. Then the oxidation of S-methylcysteine with tert-butyl hydroperoxide catalyzed by the chiral tetra(isopropylate)titanium/(S)- or (R)-Binol complex led to the formation of (1 R,2S)-(+)- or (1 R,2R)-(–)-methiin stereomers.

Full text of DOI:10.1080/10426507.2020.1755972

Phosphorus, Sulfur, and Silicon and the Related Elements
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Asymmetric synthesis of (S,R)- and (R,R)-methiin
stereoisomers
Anastasy О. Kolodiazhna, Аleksei I. Skliarov, Alena A. Slastennikova & Oleg I.
Kolodiazhnyi
To cite this article: Anastasy О. Kolodiazhna, Аleksei I. Skliarov, Alena A. Slastennikova & Oleg I.
Kolodiazhnyi (2020): Asymmetric synthesis of (S,R)- and (R,R)-methiin stereoisomers, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2020.1755972
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1755972
Asymmetric synthesis of (S,R)- and (R,R)-methiin stereoisomers
Anastasy ꢀ. Kolodiazhna, ffleksei I. Skliarov, Alena A. Slastennikova, and Oleg I. Kolodiazhnyi
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kiev, Ukraine
ABSTRACT
ARTICLE HISTORY
An asymmetric synthesis of (þ)- and (–)-methiine (S-methyl-(R)-cysteine sulfoxide) diastereomers
has been developed. These natural sulfur compounds were isolated from a variety of Brassica veg-
etables. As the starting compound, (R)-cysteine was used, which was methylated to form (R)-S-
methylcysteine. Then the oxidation of S-methylcysteine with tert-butyl hydroperoxide catalyzed by
the chiral tetra(isopropylate)titanium/(S)- or (R)-Binol complex led to the formation of (1 R,2S)-(þ)-
or (1 R,2R)-(–)-methiin stereomers.
Received 3 February 2020
Accepted 26 March 2020
KEYWORDS
Methiine; chiral sulfoxides;
cysteine; asymmet-
ric oxidation
GRAPHICAL ABSTRACT
Introduction
roots (Brassica rapa) and a number of other plants [2]. In
addition, S-methyl-L-cysteine-(S)-sulfoxide [(þ)-Methiin]
and S-allyl-L-cysteine (S)-sulfoxide [(þ)-Alliin] are promis-
ing food additives and medicinal drugs possessing antibiotic
S-Alk(en)yl-cysteine sulfoxides are non-protein sulfur-con-
taining aminoacids found in representatives of the Alliaceae
family and are the precursors of tear and flavoring substan-
ces found in the agronomically important Allium family.
Traditionally, Allium species, especially onions (Allium cepa
L) and garlic (A. sativum), have been used for centuries in
European, Asian and American folk medicines to treat vari-
ous pathologies [1–4]. Examples of chiral sulfoxides include
natural (þ)-S-methyl-L-cysteine sulfoxide (Methiin), (þ)-S-
allyl-cysteine sulfoxide (Alliin), as well as a number of other
amino acid sulfoxides present in some plants, determine
their unique properties (Scheme 1).
Chiral sulfoxides, including S-methylcysteine sulfoxide,
are found among some aminoacids in mammalian metabo-
lites, while L-cysteine sulfoxides have been found in Brassica
plants and a number of other natural sources, some of
which are food products [4, 5]. For example, the natural S-
methyl-(R)-cysteine sulfoxide was isolated from plants such
as Brassica oleracea cabbage, cauliflower, mustard, broccoli,
turnip, etc., which have a number of useful properties [1–3].
S-methyl-(R)-cysteine-(S)-sulfoxide is present in garlic [5],
[
14, 15], cardiovascular and antioxidant [16, 17] properties.
These compounds exhibit anti-inflammatory [9], antidiabetic
18, 19], anti-Alzheimer’s [20] and anticholesterolemic [21]
[
properties. Of particular interest is the antidiabetic efficacy
of (þ)-Methiin [19]. It was found that the optical stereo-
isomers (þ)- and (–)-Methiin, as well as other chiral sulfox-
ides, significantly differ in their biological activity. For
example, in the case of esomeprazole, the activity of one
sulfoxide enantiomer significantly exceeds the activity of its
antipode. Therefore, it is important to develop methods for
the synthesis of methiine stereoisomers and its analogs
Results and discussion
Chiral aminoacid sulfoxides are usually prepared by enzym-
atic oxidation of S-substituted aminoacids, for example
cysteine. Asymmetric oxidation of sulfur-containing L-ami-
noacids was achieved using Fe(II)/a-ketoglutarate-dioxyge-
nase previously found in Bacillus thuringiensis strain 2e2.
onions [6], nuts [7], carrots [8], apples [9, 10], and bananas This enzyme catalyzed the sulfoxidation of S-methyl-L-cyst-
11]. The unique healing properties of garlic are largely eine, S-ethyl-L-cysteine, and S-allyl-L-cysteine into the corre-
[
determined by the presence of aminoacid sulfoxides [1]. sponding (S)-configured sulfoxides such as (þ)-methiin and
Cysteine sulfoxide determines the characteristic smell and (þ)-alliin, which are responsible for valuable physiological
taste of garlic and onions [12, 13]. S-methyl-(R)-cysteine activities in mammals, and have high stereoselectivity
sulfoxide was found in the non-protein fraction of turnip (Scheme 2) [22].
CONTACT Oleg I. Kolodiazhnyi
oikol123@bpci.kiev.ua
V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Kiev, Ukraine.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.175597
ß 2020 Taylor & Francis Group, LLC

2
A. О. KOLODIAZHNA ET AL.
Scheme 3. Sulfoxidation of methionine using isoleucine dioxygenase/hydrogen
peroxide.
Scheme 1. Some natural sulfur-containing aminoacids.
Scheme 4. Biocatalytic oxidation of N-Moc-methylcysteinate with chloroperoxidase
(CPO)/hydrogen peroxide.
Scheme 2. Oxidation of S-substituted aminoacids by Fe(II)/a-ketoglutarate-
dioxygenase.
Oxidation of (R)-1 with hydrogen peroxide led to the for-
mation of racemic S-methyl-(R)-cysteine sulfoxide 2 with a
yield of ꢁ100% without transferring chirality from the chiral
To obtain cysteine-sulfoxide stereoisomers, asymmetric oxi-
dation of sulfides to sulfoxides using Isoleucine dioxygenase
and Chloroperoxidase in combination with hydrogen peroxide
was used [20]. Using this method, methionine sulfoxide, deriva-
tives of (þ) - S-methyl-(R)-cysteine sulfoxide (3) and (þ)-S-
allyl-cysteine sulfoxide were also obtained (Scheme 3).
Treatment of N-methoxycarbonyl derivatives of S-methyl-
L-cysteine with a chloroperoxidase (CPO)/hydrogen perox-
ide resulted in the oxidation at sulfur to produce the (RS)
sulfoxide in good diastereomeric excess. Some other sulfur-
containing amino acids were also obtained by this method
ꢂ
C -NH group to the sulfur atom of the MeS group
2
(Scheme 7). The reaction proceeds similarly in other known
cases of the S-methylcysteine oxidation by achiral oxidizing
agents, in particular, as was shown in the case of publica-
tion [23].
Therefore, we concluded that, in order to achieve the
highest enantioselectivity of oxidation and to obtain optically
pure methylcysteine sulfoxide, it is necessary to use an
asymmetric oxidation reagent effective for this case. To this
end, we investigated several known asymmetric oxidizing
agents, in particular the Sharpless asymmetric oxidation
reagent [24], but without much success. After several
attempts, we drew the conclusion that tert-butyl hydroper-
oxide catalyzed by a chiral complex of titanium tetra(isopro-
pylate) with the optically active (S)- or (R)-binol is the best
reagent for the asymmetric oxidation of S-methylcysteine.
Oxidation with the complex containing (R)-binol led to the
(Scheme 4).
(R,S)-Methionine sulfoxide was obtained with a moderate
diastereomeric excess by kinetically controlled hydrolysis of the
aminoacid ester catalyzed by the enzymes: a-Chymotrypsin,
Aspergillus, sp. Protease, Subtilisin Carlsberg, Aspergillus lipase
(Scheme 5). [20]. It has been reported that stereoselective bioca-
talytic oxidation of sulfides to sulfoxides can be carried out
using Penicillium citreoviride, although no stereochemical
details of this method have been reported [15–17].
(1 R, 2S)-stereoisomer 3 in yield 90% and with optical purity
higher than 80%, which, after purification with crystalliza-
tion or column chromatography, was obtained with a purity
of 95% op (optical purity). Similarly, the oxidation of meth-
ylcysteine (R)-1 with a complex containing (S)-binol led to
the formation of the (1 R, 2 R)-stereoisomer 4 in yield of
The oxidation of methionine and cysteine derivatives to
sulfoxides with chlorine dioxide has also been reported [23].
ꢀ
Oxidation of sulfides with aqueous ClO at 30–40 C led to
2
the formation of corresponding sulfoxides in high yield
5–97%, but with low stereoselectivity.
9
Thus, analyzing the literature data, we drew the conclu- 80% and with 80% de, which was obtained after chromatog-
sion that the existing methods are in most cases rather raphy with an optical purity of 95% (Scheme 8).
experimentally complicated since hard-to-reach enzymes are
The structure of the products was confirmed by NMR
required and do not always give products with high de and and chromatography-mass spectrometry. Chemical shifts
ee. Therefore, the development of a simple stereoselective corresponding to diastereotopic methylene protons (multip-
method for the synthesis of optically active cysteine sulfox- lets at 3.2 and 3.60 ppm), methiine CHN group at 4.4 ppm
þ
ides is undoubtedly interesting.
as well as NH
3
groups of 4.67–4.78, were observed in the
The main strategy, which we have proposed for the NMR spectrum. Protons of the CH
S(O)-group resonated as
3
methiin synthesis, was at first to methylate the aminoacid a singlet at 2.75 ppm, which indicates the formation of
and then to oxidize asymmetrically the sulfide group enantiomerically pure methylcysteine sulfoxides 3 or 4 in
(
Scheme 6). In this work, for this purpose, we used natural the form of two diastereomers, since the chirality on the
cysteine, the thio group of which was methylated to form S- a-C atom was retained, and a new chiral center was formed
methylcysteine, as the initial reagent. Then, the S-methylcys- at the S atom. According to NMR spectroscopy, the ratio of
teine was oxidized to form diastereomers (1 R, 2S)- and (1 R, diastereomers before the purification step was 9:1. In the
13
2
R)-S-methylcysteine sulfoxide.
C NMR spectrum, signals of all five carbon atoms were

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 5. Kinetically controlled hydrolysis of sulfoaminoacid esters.
Scheme 6. Retro synthesis of (þ)- and (–)-methiin.
Scheme 7. Oxidation of S-methylcysteine (R)-1 with hydrogen peroxide.
Scheme 8. Asymmetric oxidation of S-methylcysteine (R)-1.
detected. In particular, the carbon of the carboxyl group is
Thus, we have developed a method to easily obtain the
present at 169 ppm. Purification of the product by silica gel enantiomerically pure chiral cysteine sulfoxides on a preparative
column chromatography, eluent acetonitrile-water in a ratio laboratory scale using tert-butyl hydroperoxide and the chiral
of 2:1, allowed us to obtain optically pure S-methylcysteine catalyst – (S)- or (R)-binol/titanium tetraisopropylate.
sulfoxide stereoisomers with 95% de. The high purity of the
synthesized S-methylcysteine sulfoxide was confirmed by
chromatography–mass spectrometry, which showed the pres-
ence of a single signal in the HPLC as well as the presence
of the expected mass peak ion.
Experimental part
1
13
H NMR and C NMR spectra were recorded in a CDCl3
or D O solvent on a 500 MHz spectrometer at ambient
2

4
A. О. KOLODIAZHNA ET AL.
temperature. Chemical shifts d (ppm) are related to TMS (R)-binaphthol (1 g, 0.0035 mol) in dry toluene (30 mL) at
(
d ¼ 0.00 ppm) as internal standard. Signal multiplicities are room temperature. The reaction mixture was stirred for 1 h,
designated as s, singlet; d, doublet; dd, doublet–doublet; t, then methylcysteine (2.4 g, 0.0178 mol) was added. It was
ꢀ
triplet; m, multiplet; bs, broad singlet. The coupling con- cooled to –50 C and tert-butyl hydroperoxide (4.9 mL
stants J are given in Hertz. Reagents and solvents were used (0.035 mol, 70% aqueous solution) in 10 ml of toluene was
without special purification, unless otherwise indicated. added dropwise. The reaction mixture was stirred overnight
Column chromatography was performed on silica gel 60 at room temperature. Then the mixture was evaporated, the
(
70–230 mesh) using the indicated eluents. Optical rotations residue was dissolved in water and filtered. The solvent was
were measured on a 241 Perkin-Elmer polarimeter (D evaporated in vacuo, the residue was dissolved in methylene
ꢀ
sodium line at 20 C). Melting points were not corrected. chloride and refluxed until the formation of a precipitate.
The reactions were carried out in glassware dried over a fire The precipitate was filtered off, washed on the filter with
or dried in a dry box. The progress of reactions was moni- methylene chloride. It was then purified by column chroma-
tored by analytical thin layer chromatography (TLC) on tography, eluent acetonitrile–water 2:1 to yield solid 3 with
ꢀ
glass plates of silica gel 60 F254 (Merck, Darmstadt, 95% ee. Yield 2.2 g. Mp. 160–165 C (dec). Ref. [24]: m.p.
ꢀ
ꢀ
Germany) and the products were visualized with anisalde- 160–165 C (dec.) Ref.: [22], mp. 171–173 C (decomp). Ref.
ꢀ
20
ꢀ
hyde or UV. The purity of all compounds was checked by [25]: mp. 167–168 C (dec.). [a]
þ 118 (c ¼ 1.0, H
O).
D
2
20
1
thin layer chromatography and NMR measurements. HPLC Ref. [23] [a]
analysis was performed on Chiralpak OD-3 column (hexane: (400 MHz, D
IPA: MeOH 95:2.5:2.5), flow rate
0.6 mL/ 1H), 3.37 (dd, J ¼ 13.93, 5.98 Hz, 1H), 4.18 (dd, J ¼ 7.70,
min, k ¼ 210 nm).
¼ þ125.8 (c ¼ 2.0, H
O). H NMR
D
2
O) d 2.72 (s, 3H), 3.14 (dd, J ¼ 13.87, 7.73 Hz,
2
¼
¼
þ
13
6.05 Hz, 1H). 4.64 bs (NH
þH
O). C NMR (125 MHz,
3
2
D O)
d
33.43, 52.01, 63.93, 168.96. ESI-MS, m/
2
þ
z ¼ 152 [M þ H] .
S-Methyl-L-cysteine (R)-1
L-Cysteine (2.42 g, 0.02 mol) was suspended in absolute
ethanol (60 mL) and sodium metal (1.84 g, 0.08 mol) was
(R,R)-S-Methylcysteine sulfoxide [(2)-methiin] 4
added with cooling. It was stirred for 30 min, and then of (S)-Binaphthol (1 g, 0.0035 mol) was dissolved in 30 ml of
methyl iodide (1.4 mL, 0.022 mol) was added. The tempera- absolute toluene. Then, 0.5 ml of titanium tetraisopropylate
ture was raised to room temperature and the reaction mix- (0.00178 mol) and 0.65 ml of water (0.035 mol) were added
ture was stirred for 30 min. Then water was added until the dropwise at room temperature. The mixture was stirred for
precipitate was dissolved and the solution was acidified to 1 h, then 2.4 g of S-methylcysteine (0.0178 mol) was added.
ꢀ
pH 5. Diethyl ether was added to the mixture, and left in It was cooled to –50 C and a solution of 4.9 ml of 70% tert-
the refrigerator overnight. Precipitated S-methylcysteine was butyl hydroperoxide (0.035 mol) in toluene (10 ml) was
filtered off, washed with ether on a filter. Yield 2.4 g, 90%. added dropwise. It was stirred for 12 h at room temperature,
ꢀ
ꢀ
20
Mp. 245-250 C (Ref. [2] mp. 245 C); [a]
¼ ꢃ34.3 the solvent was evaporated, the residue was dissolved in
D
20
1
(
c ¼ 1, H O), Ref. [2] [a]
¼ ꢃ30.0 (c ¼ 1.5, H O). H water and filtered. The water was evaporated in vacuo, the
2
D
2
NMR (400 MHz, D O) d 1.58 (s, 3H, CH ); 2.46 (m, 1H, residue was dissolved in methylene chloride and refluxed.
2
3
The precipitate was filtered off, washed on the filter with
methylene chloride and recrystallized from aqueous alcohol
or further purified by preparative chromatography (eluent
acetonitrile-water 2:1) to yield crystalline (–)-methiin 4
CH ); 2.51 (m, 1H, CH ); 3.38 (m, 1H, CH); 3.86 (bs, 2H,
2
2
1
3
NH2). C NMR (125.6 MHz, D O) d 14.9, 34.8, 53.5, 173.5.
2
Oxidation of S-methyl-L-cysteine with hydrogen
peroxide to (S 1 R)/(R 1 R)-2
ꢀ
ꢀ
(
70%, 95% ee). M.p. 168–175 C (decomp.); mp. 168–170 C
ꢀ
(decomp.) [Ref. [24] mp. 165–170 C (decomp.)]. Ref. [24]
20
ꢀ
1
[
2
a]D ¼ ꢃ110 (c ¼ 1, H O). H NMR (400 MHz, D O) d
2
2
S-Methyl-L-cysteine 1 (2.7 g) was dissolved in water (6 mL),
.62 (s, 3H), 3.13 (dd, J ¼ 14.0, 8.0 Hz, 1H), 3.22 (dd,
and 30% hydrogen peroxide solution (3 mL) was added drop-
þ 13
ꢀ
J ¼ 14.0, 6.0 Hz, 1H), 4.6 bs (NH
3
þH
O).
2
C-NMR
wise with stirring and the reaction mixture was stirred at 25 C
(125 MHz, D O) d 40.2 (CH ); 53.3 (CH); 56.1 (CH );
2 3 2
for 12 h. Then the reaction mixture was evaporated and the
residue was recrystallized from aqueous ethanol. The HPLC
and NMR showed that the colorless crystalline product is a
mixture of (S,R)- and (R,R)-diastereomers in a 1:1 ratio. Yield
1
75.5 (CO H).
2
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ꢀ ꢀ
1
8
7%; mp 166 C (Ref. [25] 167–168 C). H NMR (500 MHz,
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