Synthesis and asymmetric oxidation of thioglycosides derived from neomenthanethiol and α-d-galactose

Article abstract of DOI:10.1134/S1070428013030093

6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-1,2:3, 4-di-O-isopropylidene-α-d-galactopyranose was synthesized in 94% yield from 1,2: 3,4-di-O-isopropylidene-α-d-galactopyranose and neomenthanethiol, and its oxidation gave the correspondin

Full text of DOI:10.1134/S1070428013030093

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 3, pp. 366–373. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © S.V. Pestova, D.V. Sudarikov, S.A. Rubtsova, A.V. Kutchin, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 3,
pp. 379–386.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
Synthesis and Asymmetric Oxidation of Thioglycosides
Derived from Neomenthanethiol and α-D-Galactose
S. V. Pestova, D. V. Sudarikov, S. A. Rubtsova, and A. V. Kutchin
Institute of Chemistry, Komi Research Center, Ural Branch, Russian Academy of Sciences,
ul. Pervomaiskaya 48, Syktyvkar, 167982 Russia
e-mail: pestova-sv@chemi.komisc.ru
Received July 7, 2012
Abstract—6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose was synthesized in 94% yield from 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose and
neomenthanethiol, and its oxidation gave the corresponding diastereoisomeric sulfoxides in up to 84% yield
and de values of up to 52%. The isopropylidene protective groups were removed from the sulfide and
sulfoxides by treatment with trifluoroacetic acid in chloroform.
DOI: 10.1134/S1070428013030093
Thioglycosides rarely occur in nature; they were
found mainly in cruciferous plants. The most com-
monly known thioglycosides are sinigrin and sinalbin
that exhibit a broad spectrum of useful properties [1].
Semisynthetic sulfur-containing monosaccharide
derivatives are used in medicine as antimicrobial and
antiviral drugs, cholagogues, and appetizing agents,
they exhibit anti-inflammatory and antidiabetic ac-
tivity, and are also components of cancer diagnostic
agents [2]. Up to now, a large number of glycomimetics
have been synthesized; these compounds contain a car-
bohydrate fragment and simulate the action of other
substances; they are more resistant to enzymatic
hydrolysis and are characterized by high affinity and
selectivity for some receptors [3].
The most general approach to the synthesis of new
optically active compounds is based on chemical mod-
ification of widely accessible optically pure natural
monoterpenoids and monosaccharides.
In the present article we report on the synthesis of
6-deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcyclo-
hexylsulfanyl]-1,2:3,4-di-O-isopropylidene-α-D-galac-
topyranose (IV) from (1S,2S,5R)-2-isopropyl-5-
methylcyclohexanethiol (I, neomenthanethiol) and
6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (II). The reaction was carried out in
boiling ethanol using Cs2CO3–tetrabutylammonium
iodide (TBAI) as catalytic system, and compound IV
was isolated in 94% yield. Iodo derivative II was
preliminarily prepared by treatment of 1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (III) with iodine
in toluene in the presence of 1H-benzimidazole (BzIm)
and triphenylphosphine. Protected galactose III was
synthesized by reaction of α-D-galactose with acetone
in the presence of concentrated H2SO4 (Scheme 1).
It is known that in some cases introduction of
a small terpene fragment into molecules of biologically
active compounds enhances their biological activity
[4]. Therefore, preparation of hybrid semisynthetic
compounds on the basis of natural monosaccharides
and monoterpenoids attracts interest from the view-
point of further study of their biological properties.
The structure of IV was confirmed by its NMR and
1
IR spectra and elemental analysis. The H and 13C
Numerous data published in recent time showed
that physiological activity of compounds is directly
related to their steric structure [5, 6]. In this connec-
tion, synthesis of enantiomerically or diastereoisomer-
ically pure sulfinyl derivatives is especially important.
NMR spectra of IV contained signals from both ter-
penoid and carbohydrate fragments. Signals from 6-H
in the 1H NMR spectrum of IV were displaced upfield
relative to those of initial iodide II (δ 2.75–2.77 and
3.18–3.35 ppm, respectively), whereas the C6 signal in
366

SYNTHESIS AND ASYMMETRIC OXIDATION OF THIOGLYCOSIDES
367
Scheme 1.
10'
Me
8'
9'
Me
Me
2'
1'
(I)
Me
5'
OH
I
S
11
Me
10
12
Me
7'
Me
O
O
O
Me
Me
Me
Me
6
Me
SH
5
4
O
O
O
O
Ph3P, I2, BzIm, PhMe
Cs2CO3, TBAI, EtOH
O
O
1
2
7
3
O
O
O
9Me
O
O
O
Me
Me
8
Me
Me
Me
III
II
IV
Me
Me
Me
Me
HCl, MeOH
+
S
S
HO
HO
HO
Me
Me
OH
OMe
O
OH
O
OMe
HO
Va, Vb
VI
Me
Me
TFA, CHCl3
S
HO
HO
Me
OH
O
OH
VII
the 13C NMR spectrum of IV appeared in a weaker
field, δC 31.88 ppm against 2.30 ppm in the spectrum
of II. All NOE interactions typical of both terpenoid
and protected carbohydrate fragments were retained.
Compounds Va and Vb are epimeric with respect
to the C1 asymmetric center. The NOESY spectra
revealed interactions between protons in the methoxy
1
group and 1-H. The 1-H signal in the H NMR spec-
trum of Va was a broadened singlet at δ 4.93 ppm,
whereas the 1-H signal of Vb was a doublet at
δ 4.87 ppm with a coupling constant of 4.6 Hz, indicat-
ing increase of the torsion angle H1C1C2H2. These
findings prove that the OMe group in Va appears on
the α-side of the pyranose ring and that the OMe group
in Vb is β-configured.
Removal of the isopropylidene protecting groups
from sulfide IV by the action of HCl in methanol
resulted in the formation of three O-methyl derivatives,
two epimeric methyl galactosides Va (29%) and Vb
(9%) and 2-O-methylgalactopyranose VI (32%); the
ratio of α- and β-anomers was 3:1.
Compounds Va, Vb, and VI were isolated as indi-
vidual substances by column chromatography on silica
gel and were characterized by NMR and IR spectra
and elemental analyses. The IR spectra of Va, Vb, and
VI displayed absorption bands in the region 3300–
3500 cm–1 typical of OH groups. Unlike initial sulfide
1
The H and 13C NMR spectra of VI are superposi-
tions of signals of the α- and β-anomers. In the
NOESY spectrum we observed coupling between the
OCH3 protons and 2-H. The 1-H signal of the
α-anomer appeared as a doublet at δ 4.64 ppm with
a coupling constant of 3.8 Hz, and the corresponding
signal of the β-anomer was located at δ 4.03 ppm
(J = 7.4 Hz).
1
IV, the H and 13C NMR spectra of Va, Vb, and VI
lacked signals assignable to isopropylidene methyl
groups (δ 1.35–1.55, δC 25.85–26.25), and signals
from methoxy group appeared at δ 3.42–3.52 and
δC 54.92–59.99 ppm.
Deprotection of sulfide IV by the action of tri-
fluoroacetic acid (TFA) in chloroform gave 6-deoxy-6-
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PESTOVA et al.
368
Scheme 2.
Me
Me
Me
O
Me
O
S
S(R)
(S)
[O]
O
O
O
O
Me
Me
Me
Me
+
IV
Me
Me
O
O
O
O
O
O
Me
Me
Me
VIII
Me
IX
TFA, CHCl3
TFA, CHCl3
Me
Me
Me
Me
O
O
S
S(R)
(S)
HO
HO
HO
HO
Me
OH
Me
OH
O
O
OH
OH
X
XI
1
β-anomer, at δC 98.00 ppm. In the H NMR spectrum
of VII, the 1-H proton of the α-anomer resonated as
a doublet at 4.91 ppm (J = 2.6 Hz), and the 1-H signal
of the β-anomer was a doublet at δ 4.23 ppm (J =
6.7 Hz); the larger coupling constant corresponds to
increased torsion angle H1C1C2H2 in the β-anomer.
[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-
α,β-D-galactopyranose (VII) as the only product (yield
98%). The IR spectrum of VII characteristically con-
tained OH stretching vibration bands in the region
3300–3500 cm–1. All signals typical of the terpene and
galactopyranose fragments, except for those belonging
to isopropylidene groups (δ 1.35–1.55, δC 25.85–
Sulfide IV was oxidized with m-chloroperoxy-
benzoic acid (m-CPBA), tert-butyl hydroperoxide
(TBHP)–vanadyl acetylacetonate [VO(acac)2], cumyl
hydroperoxide (CHP)–VO(acac)2, and the Bolm chiral
catalytic system [with (S,S)-(+)-N,N′-bis(3,5-di-tert-
butylsalicylidene)cyclohexane-1,2-diamine (L1) and
(1S,2R)-[(3,5-di-tert-butyl-2-hydroxybenzylidene)-
amino]indan-2-ol (L2) as ligands] to obtain sulfoxides
VIII and IX (Scheme 2, see table). Stereoisomeric
sulfoxides VIII and IX were separated by column
1
26.25 ppm), were present in the H and 13C NMR
spectra of VII. According to the NMR data, the ratio of
the α- and β-anomers of VII is 1:1. The largest dif-
ferences in the 13C chemical shifts between the α- and
β-anomers were observed for the galactopyranose ring,
while the neomenthyl fragment was represented by one
set of signals; this suggests that the anomeric center is
distant from the terpene substituent. The C1 signal of
the α-anomer was located at δC 93.14 ppm, and of the
Oxidation of 6-deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylsulfanyl]-1,2:3,4-di-O-isopropylidene-α-D-galacto-
pyranose (IV)
Oxidant
m-CPBA
Ratio (S)-VIII:(R)-IX
Yield,a %
de, a %
32:68
64:36
49:51
24:76
58:42
72
84
20
34
51
37
28
1.5
52
16
TBHP–VO(acac)2
H2O2, L1, VO(acac)2
H2O2, L2, VO(acac)2
CHP–VO(acac)2
a
The yields and de values were calculated for the products isolated by column chromatography.
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SYNTHESIS AND ASYMMETRIC OXIDATION OF THIOGLYCOSIDES
369
chromatography on silica gel and were characterized
by NMR and IR spectra and elemental analyses. Sulf-
oxides VIII and IX displayed in the IR spectra absorp-
tion bands due to S=O group in the region 1036–
1042 cm–1. The appearance of a new chiral center at
the sulfur atom led to increased nonequivalence of
diastereotopic protons on C6, and they appeared in the
1H NMR spectrum as a broadened multiplet, while the
C6 and C1′ signals in the 13C NMR spectra of VIII
(δC 52.14, 57.01 ppm) and IX (δC 53.02, 62.23 ppm)
were displaced downfield relative to the corresponding
signals of IV (δC 31.89, 47.95, respectively). All NOE
interactions observed for initial sulfide IV were
retained in going to sulfoxides VIII and IX.
and 99% yield, respectively. The IR spectra of X and
XI contained absorption bands due to sulfinyl group at
1030–1034 cm–1 and OH groups in the region 3200–
1
3400 cm–1. The H and 13C NMR spectra of X and XI
lacked signals assignable to isopropylidene groups
(δ 1.35–1.55, δC 25.85–26.25 ppm), while those typical
of the terpene and carbohydrate fragments were re-
tained. According to the NMR data, the ratio of the
α- and β-anomers of X and XI was 1:1. Removal of
the isopropylidene protective groups was not accom-
panied by change of the configuration of the terpene
fragment, sulfinyl group, and C2–C5 atoms in the
galactopyranose fragment, as followed from the 1H and
13C NMR spectra and two-dimensional NOESY exper-
iments. Like initial sulfoxide (S)-VIII, its deprotected
derivative X (δC6′ 33.50 ppm) had (S)-configuration
of the sulfur atom; correspondingly, sulfoxide XI
(δC6′ 33.50 ppm) was (R)-isomer with respect to the
sulfinyl group.
We previously found [7] that the configuration of
the sulfinyl group in imidazolyl neomenthyl sulfoxides
affects the chemical shift of C6′ in the neomenthyl
fragment. The C6′ signal of the (R)-diastereoisomer
(δC 35.80 ppm) where the sulfoxide oxygen atom is
oriented opposite to the isopropyl group is located in
a stronger field relative to the corresponding signal of
the (S)-diastereoisomer (δC 37.70 ppm) where the sulf-
oxide oxygen atom is oriented toward the isopropyl
group. Therefore, sulfoxide VIII (δC6′ 34.36 ppm) has
(S)-configuration of the sulfur atom (here, the substit-
uent priority order is the opposite), and sulfoxide IX
has (R)-configuration (δC6′ 37.48 ppm). In addition,
essential similarity in the chemical shifts and coupling
constants for the terpene fragment was observed in the
1H NMR spectra of (S)-neomenthyl imidazolyl sulfox-
ides and sulfoxide VIII, as well as of (R)-neomenthyl
imidazolyl sulfoxides and sulfoxide IX.
Thus we have synthesized new sulfanyl and sulfinyl
derivatives on the basis of neomenthanethiol and
α-D-galactose. Their structure and absolute configura-
tion were determined by elemental analysis and NMR
and IR spectroscopy with account taken of published
data. The use of chiral catalytic systems in the oxida-
tion of sulfides insignificantly increased diastereoiso-
meric excess but considerably reduced the yield of
sulfoxides. It is advisable to use VO(acac)2–hydro-
peroxide to obtain stereoisomeric sulfoxide mixtures
enriched in the (S)-isomer, whereas m-CPBA favors
formation of the (R)-sulfoxide.
EXPERIMENTAL
The best yields of sulfoxides VIII and IX were ob-
tained in the oxidation of IV with TBHP–VO(acac)2.
However, the Bolm system with ligand L2 ensured
higher diastereoselectivity, but the yield of sulfoxides
was poor. This may be due to large size of the substit-
uents attached to the sulfur atom in IV, which hamper
approach of the large chiral complex thereto. The
oxidation of IV with TBHP–VO(acac)2 and CHP–
VO(acac)2 afforded (S)-VIII as the major product,
whereas in the other cases (R)-IX dominated. Presum-
ably, this is related to different mode of oxidant
coordination to the substrate.
The IR spectra were recorded from films or KBr
pellets on a Shimadzu IR Prestige 21 spectrometer
with Fourier transform. The melting points were deter-
mined on a Gallencamp Sanyo melting point appara-
tus. The H and 13C NMR spectra were obtained on
1
a Bruker Avance-300 spectrometer at 300.17 and
75.48 MHz, respectively, from solutions in chloro-
form-d using the solvent or sodium 3-trimethylsilyl-
propane-1-sulfonate as reference. Complete signal
1
assignment in the H and 13C NMR spectra was made
with the aid of two-dimensional homo- (1H–1H COSY,
1H–1H NOESY) and heteronuclear (1H–13C HSQC,
1H–13C HMBC) shift correlation techniques. The
optical rotations were measured on a Kruss P3002RS
automatic digital polarimeter; the optical rotations of
compounds VI, VII, X, and XI were determined at
room temperature in 3 days after mutarotation equilib-
Deprotection of the carbohydrate moiety in sulfox-
ides (S)-VIII and (R)-IX with TFA in CHCl3 gave
6-deoxy-6-{(S)-[(1S,2S,5R)-2-isopropyl-5-methylcy-
clohexyl]sulfinyl}-α,β-D-galactopyranose (X) and
6-deoxy-6-{(R)-[(1S,2S,5R)-2-isopropyl-5-methylcy-
clohexyl]sulfinyl}-α,β-D-galactopyranose (XI) in 91
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PESTOVA et al.
370
rium was achieved. Thin-layer chromatography was
performed using Sorbfil plates. The elemental com-
positions were determined on an EA 1110 CHNS-O
automatic analyzer. All reactions were carried out in
freshly distilled solvents. Silica gel (0.06–0.2 mm;
Alfa Aesar) was used for column chromatography; the
solvent systems were the same as in TLC.
(C8′), 31.88 (C6), 35.45 (C4′), 41.16 (C6′), 47.95 (C1′),
49.11 (C2′), 67.75 (C5), 70.59 (C2), 70.92 (C4), 71.64
(C3), 96.66 (C1), 108.46 (C7), 109.14 (C10). Found, %:
C 63.08; H 9.26; S 7.20. C22H38O5S. Calculated, %:
C 63.73; H 9.24; S 7.73.
Deprotection of compound IV with a solution of
hydrogen chloride in methanol. A flask equipped
with a stirrer was charged with 1 mmol (0.415 g) of
sulfide IV in 3–4 ml of methanol, and 1.5 mmol
(0.44 ml) of a 3.4 M solution of HCl in methanol was
added dropwise under continuous stirring at room tem-
perature. After 96 h, the solvent was distilled off under
reduced pressure, and the products were isolated by
column chromatography on silica gel using chloro-
form–propan-2-ol (10:1) as eluent.
(1S,2S,5R)-2-Isopropyl-5-methylcyclohexane-1-
thiol (I) was synthesized according to the procedure
described in [8]. Yield 58%, [α]D22 = +53.2 (c = 0.83,
EtOH); published data [8]: yield 60%, [α]D20 = +53.0
(c = 0.80, EtOH).
6-Deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (II) [9]. Yield 84%, [α]D22 = –47.6
(c = 0.88, CHCl3); published data: yield 94%, [α]D20
–49.0 (c = 1.00, CHCl3).
=
Methyl 6-deoxy-6-[(1S,2S,5R)-2-isopropyl-5-
methylcyclohexylsulfanyl]-α-D-galactopyranoside
1,2:3,4-Di-O-isopropylidene-α-D-galactopyra-
nose (III) [10]. Yield 85%, [α]D22 = –45.6 (c = 0.35,
(Va). Yield 29%, yellowish viscous liquid, [α]D20
=
acetone); published data [10]: yield 72–90%, [α]D20
–46.0 (c = 0.36, acetone).
=
–33.6 (c = 0.27, EtOH), Rf 0.39 (CHCl3–i-PrOH, 10:1;
KMnO4). IR spectrum, ν, cm–1: 3400, 2918, 1450
(–OH), 1192 (O–C–O), 110, 1016, 9473 (C–O), 758
6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcy-
clohexylsulfanyl]-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (IV). Thiol I, 1.3 mmol (0.224 g),
cesium carbonate, 1.3 mmol (0.424 g), and TBAI,
1.3 mmol (0.48 g), were dissolved in 3 ml of ethanol
under stirring in a stream of argon. After 5 min,
1 mmol (0.37 g) of compound II was added, and the
mixture was heated for 48 h under reflux. The solvent
was removed under reduced pressure, and the product
was isolated by column chromatography on silica gel
using petroleum ether–ethyl acetate (5:1) as eluent.
1
(C–S). H NMR spectrum (CDCl3), δ, ppm: 0.87–
0.95 m (1H, 4′-Hax), 0.91 d (3H, 7′-H, J = 6.2 Hz),
0.91 d (3H, 9′-H, J = 6.4 Hz), 0.96 d (3H, 10′-H, J =
6.7 Hz), 1.08–1.30 m (3H, 2′-H, 3′-Hax, 6′-Hax), 1.58–
1.83 m (3H, 8′-H, 3′-Heq, 4′-Heq), 1.88–2.07 m (2H,
6′-Heq, 5′-H), 2.77–2.85 m (2H, 6-H), 3.01 br.s (1H,
OH), 3.20–3.25 m (1H, 1′-H), 3.42 s (3H, OMe), 3.85–
3.91 m (1H, 5-H), 4.00 br.s (1H, 3-H), 4.08 br.s (1H,
4-H), 4.12 br.s (1H, 2-H), 4.34 br.s (1H, OH), 4.93 s
(1H, 1-H). 13C NMR spectrum (CDCl3), δC, ppm:
20.71 (C9′), 21.05 (C10′), 22.13 (C7′), 25.77 (C3′), 26.18
(C5′), 29.91 (C8′), 34.69 (C6), 35.31 (C4′), 39.72 (C6′),
45.38 (C1′), 48.56 (C2′), 54.92 (C7), 68.06 (C5), 78.51
(C3), 78.88 (C4), 88.20 (C2), 109.60 (C1). Found, %:
C 58.29; H 9.16; S 9.12. C17H32O5S. Calculated, %:
C 58.59; H 9.26; S 9.20.
Yield up to 94%, yellowish viscous liquid, [α]D20
=
–23.4 (c = 0.36, acetone), Rf 0.49 (petroleum ether–
EtOAc, 5:1; phosphomolybdic acid in ethanol as
developer). IR spectrum, ν, cm–1: 2916, 1454, 1377,
1210, 1169, 1140 (O–C–O), 1071, 999, 916, 862
1
(C–O), 735 (C–S). H NMR spectrum (CDCl3), δ,
Methyl 6-deoxy-6-[(1S,2S,5R)-2-isopropyl-5-
methylcyclohexylsulfanyl]-β-D-galactopyranoside
(Vb). Yield 9%, yellowish viscous liquid, [α]D20 = +82.3
(c = 0.04, EtOH), Rf 0.23 (CHCl3–i-PrOH, 10:1;
ppm: 0.82–0.90 m (1H, 4′-Hax), 0.88 d (3H, 7′-H, J =
6.3 Hz), 0.90 d (3H, 10′-H, J = 6.5 Hz), 0.97 d (3H,
9′-H, J = 6.5 Hz), 1.01–1.26 m (3H, 2′-H, 3′-Hax,
6′-Hax), 1.35 s (3H, 8-H), 1.36 s (3H, 11-H), 1.46 s
(3H, 9-H), 1.55 s (3H, 12-H), 1.64–1.77 m (3H, 4′-Heq,
3′-Heq, 8′-H), 1.91–2.02 m (2H, 6′-Heq, 5′-H), 2.76 d
(2H, 6-H, J = 7.2 Hz), 3.21–3.25 m (1H, 1′-H), 3.86 t.d
(1H, 5-H, J = 7.1, 1.2 Hz), 4.31 d.d (1H, 2-H, J = 5.0,
2.3 Hz), 4.38 d.d (1H, 3-H, J = 7.9, 1.6 Hz), 4.63 d.d
(1H, 4-H, J = 7.9, 2.3 Hz), 5.55 d (1H, 1-H, J =
5.0 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 20.88
(C10′), 21.10 (C9′), 22.24 (C7′), 24.46 (C12), 24.93 (C8),
25.85 (C3′), 25.99 (C11), 26.09 (C5′), 26.25 (C9), 29.96
1
KMnO4). H NMR spectrum (CDCl3), δ, ppm: 0.87–
0.95 m (1H, 4′-Hax), 0.91 d (3H, 7′-H, J = 6.2 Hz),
0.93 d (3H, 9′-H, J = 6.2 Hz), 0.98 d (3H, 10′-H, J =
6.2 Hz), 1.08–1.34 m (3H, 2′-H, 5′-Hax, 6′-Hax), 1.62–
1.80 m (3H, 8′-H, 3′-Heq, 4′-Heq), 1.92–2.03 m (2H,
6′-Heq, 5′-H), 2.70–2.80 m (2H, 6-H), 3.20–3.25 m
(1H, 1′-H), 3.52 s (3H, OMe), 3.72–3.79 m (1H, 5-H),
3.95 d.d (1H, 2-H, J = 6.9, 4.6 Hz), 4.10–4.16 m (1H,
4-H), 4.22 d (1H, 3-H, J = 6.9 Hz), 4.87 d (1H, 1-H,
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SYNTHESIS AND ASYMMETRIC OXIDATION OF THIOGLYCOSIDES
371
J = 4.6 Hz). Found, %: C 58.40; H 9.18; S 9.14.
C17H32O5S. Calculated, %: C 58.59; H 9.26; S 9.20.
α-1-H, J = 2.6 Hz). 13C NMR spectrum (CDCl3–
DMSO-d6), δC, ppm: 21.15 (C9′), 21.38 (C10′), 22.52
(C7′), 26.00 (C3′), 26.47 (C5′), 30.09 (C8′), 32.61 and
32.67 (C6), 35.34 (C4′), 41.04 (C6′), 47.30 and 47.39
(C1′), 48.74 (C2′); 68.95, 69.73, 69.96, 70.03, 70.17,
72.31, 73.95, 74.52 (C2, C3, C4, C5), 93.14 (α-C1),
98.00 β-C1). Found, %: C 57.39; H 8.96; S 9.48.
C16H30O5S. Calculated, %: C 57.46; H 9.04; S 9.59.
6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcy-
clohexylsulfanyl]-2-methoxy-D-galactopyranose
(VI) (a mixture of α- and β-anomers, 3:1). Yield 32%,
white powder, mp 140°C (decomp.), [α]D20 = +69.9 (c =
0.14, EtOH), Rf 0.16 (CHCl3–i-PrOH, 10:1; KMnO4).
IR spectrum, ν, cm–1: 3354, 2916, 2436, 1451 (–OH);
1192 (O–C–O), 1140 (C–OH), 1076, 1042, 936 (C–O);
Oxidation of 6-deoxy-6-[(1S,2S,5R)-2-isopropyl-
5-methylcyclohexylsulfanyl]-1,2:3,4-di-O-isopro-
pylidene-α-D-galactopyranose (IV). a. With
m-chloroperoxybenzoic acid. A solution of 1.2 mmol
(0.295 g) of 70% m-CPBA in 2 ml of chloroform was
slowly added dropwise under vigorous stirring to
a solution of 1 mmol (0.416 g) of sulfide IV in 3 ml of
chloroform, cooled to 0°C. The mixture was continu-
ously stirred for 5–7 days, the solvent was distilled off
under reduced pressure, and the residue was subjected
to column chromatography on silica gel using petro-
leum ether–ethyl acetate (1:1) as eluent.
1
748 (C–S). H NMR spectrum (CDCl3–MeOD), δ,
ppm: 0.74–0.84 m (2H, 4′-Hax), 0.77 d (6H, 7′-H, J =
6.8 Hz), 0.80 d (3H, 9′-H, J = 6.7 Hz), 0.85 d (3H,
10′-H, J = 6.7 Hz), 0.95–1.19 m (6H, 2′-H, 3′-Hax,
6′-Hax), 1.51–1.70 m (6H, 8′-H, 3′-Heq, 4′-Heq), 1.80–
1.93 m (4H, 5′-H, 6′-Heq), 2.61–2.79 m (4H, 6-H),
3.06–3.12 m (2H, 1′-H), 3.35 s (3H, α-OMe), 3.46 s
(3H, β-OMe), 3.39–3.93 m (8H, 2-H, 3-H, 4-H, 5-H),
4.03 d (1H, β-1-H, J = 7.4 Hz), 4.65 d (1H, α-1-H, J =
3.8 Hz). 13C NMR spectrum (CDCl3–MeOD), δC, ppm:
20.56 (C9′), 20.67 (C10′), 21.79 (C7′), 25.55 (C3′), 26.09
(C5′), 29.68 (C8′), 31.94 and 32.33 (C6), 35.10 (C4′),
40.74 (C6′), 47.60 and 48.13 (C1′), 48.83 (C2′), 55.16
and 56.68 (OMe); 68.72, 69.31, 70.01, 70.13, 70.36,
71.02, 73.53, 74.32 (C2, C3, C4, C5); 99.62 (α-C1),
103.97 (β-C1). Found, %: C 56.15; H 9.12; S 8.52.
C17H32O5S. Calculated, %: C 58.59; H 9.26; S 9.20.
b. With TBHP–VO(acac)2. A flask equipped with
a stirrer was charged with 1 mmol (0.416 g) of sulfide
IV in 5 ml of chloroform and 0.01 mmol (2.7 mg) of
VO(acac)2. The mixture was stirred for 5 min, a solu-
tion of 2.5 mmol of TBHP in chloroform was slowly
added, and the mixture was stirred for 3 h at room
temperature. The solvent was distilled off, and the
products were isolated by column chromatography on
silica gel using petroleum ether–ethyl acetate (1:1) as
eluent.
Deprotection of compound IV with trifluoro-
acetic acid in chloroform. Trifluoroacetic acid,
4 mmol (0.3 ml), was slowly added dropwise under
vigorous stirring to a solution of 1 mmol (0.416 g) of
sulfide IV in 5 ml of chloroform. The mixture was
stirred for 72 h, the solvent was distilled off under
reduced pressure, and the residue was subjected to
column chromatography on silica gel using CHCl3–
i-PrOH (3:1) as eluent.
c. With CHP–VO(acac)2. Sulfide IV, 1 mmol
(416 mg), was mixed with 0.01 mmol (2.6 mg) of
VO(acac)2 dissolved in 5 ml of chloroform, a solution
of 1.1 mmol of CHP in chloroform was added under
continuous stirring, the mixture was stirred for 2 h, and
the solvent was distilled off under reduced pressure.
The products were isolated by column chromatography
on silica gel using petroleum ether–ethyl acetate (1:1)
as eluent.
6-Deoxy-6-[(1S,2S,5R)-2-isopropyl-5-methylcy-
clohexylsulfanyl]-D-galactopyranose (VII) (a mix-
ture of α- and β-anomers, 1:1). Yield 98%, transparent
viscous liquid, [α]D20 = +31.7 (c = 0.11, EtOH), Rf 0.37
(CHCl3–i-PrOH, 3:1; KMnO4). IR spectrum, ν, cm–1:
3428, 2920, 2251, 1692, 1668 (–OH); 1202, 1028
(C–OH); 1171 (O–C–O); 1053, 1006, 824 (C–O); 762
(C–S). 1H NMR spectrum (CDCl3–DMSO-d6), δ, ppm:
0.79–0.90 m (2H, 4′-Hax), 0.86 d (6H, 7′-H, J =
5.6 Hz), 0.88 d (3H, 9′-H, J = 5.6 Hz), 0.93 d (3H,
10′-H, J = 6.7 Hz), 1.01–1.23 m (6H, 2′-H, 3′-Hax,
6′-Hax), 1.51–1.73 m (6H, 8′-H, 3′-Heq, 4′-Heq), 1.78–
1.93 m (4H, 6′-Heq, 5′-H), 2.54–2.69 m (4H, 6-H),
3.10–3.20 m (2H, 1′-H), 3.18–3.89 m (8H, 2-H, 3-H,
4-H, 5-H), 4.23 d (1H, β-1-H, J = 6.7 Hz), 4.91 d (1H,
Asymmetric oxidation of sulfide IV with the
Bolm system (general procedure). A solution of
0.01 mmol (2.6 mg) of VO(acac)2 and 0.05 mmol of
(S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)cyclo-
hexane-1,2-diamine (L1) or (1S,2R)-[(3,5-di-tert-butyl-
2-hydroxybenzylidene)amino]indan-2-ol (L2) in 2 ml
of methylene chloride was stirred for 5 min, 1 mmol
(0.416 g) of sulfide IV was added, and 1.1 mmol
(0.112 ml) of 30% hydrogen peroxide was then added
dropwise. The mixture was stirred for 96 h at room
temperature and filtered, the solvent was distilled off
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

PESTOVA et al.
372
under reduced pressure, and the residue was subjected
to column chromatography on silica gel using petro-
leum ether–ethyl acetate (1:1) as eluent.
50.62 (C2′), 53.02 (C6), 61.99 (C5), 62.23 (C1′), 70.44
(C2), 71.13 (C3), 73.55 (C4), 96.25 (C1), 109.33 (C7),
109.49 (C10). Found, %: C 61.27; H 8.88; S 7.41.
C22H38O6S. Calculated, %: C 61.37; H 8.90; S 7.45.
6-Deoxy-6-{(S)-[(1S,2S,5R)-2-isopropyl-5-methyl-
cyclohexyl]sulfinyl}-1,2:3,4-di-O-isopropylidene-
α-D-galactopyranose (VIII). Colorless powder,
mp 91°C, [α]D20 = –11.0 (c = 0.33, acetone), Rf 0.48
(petroleum ether–EtOAc, 1:1; KMnO4). IR spectrum,
ν, cm–1: 2924, 1454, 1254, 1213; 1169 (O–C–O); 1071
(C–O); 1036, 1001, 918, 860 (S=O); 731 (C–S).
1H NMR spectrum (CDCl3), δ, ppm: 0.87–0.97 m (1H,
4′-Hax), 0.89 d (3H, 7′-H, J = 6.4 Hz), 0.94 d (3H,
10′-H, J = 6.7 Hz), 0.97 d (3H, 9′-H, J = 6.7 Hz), 1.16–
1.40 m (2H, 2′-H, 6′-Hax), 1.35 s (3H, 8-H), 1.36 s (3H,
11-H), 1.46 s (3H, 9-H), 1.59 s (3H, 12-H), 1.62–
1.90 m (4H, 3′-Hax, 3′-Heq, 4′-Heq, 8′-H), 1.99–2.12 m
(1H, 5′-H), 2.41–2.50 m (1H, 6′-Heq), 3.01–3.15 m
(2H, 6-H), 3.25–3.30 m (1H, 1′-H), 4.34–4.44 m (3H,
2-H, 4-H, 5-H), 4.68 d.d (1H, 3-H, J = 7.8, 2.4 Hz),
5.53 d (1H, 1-H, J = 5.1 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 21.24 (C10′), 21.51 (C9′), 22.75 (C7′),
24.54 (C12), 24.99 (C8), 25.81 (C3′), 25.99 (C11), 26.02
(C9), 27.81 (C5′), 29.02 (C8′), 34.36 (C6′), 35.07 (C4′),
47.67 (C2′), 52.14 (C6), 57.01 (C1′), 62.58 (C5), 70.34
(C2), 70.88 (C3), 72.21 (C4), 96.48 (C1), 109.10 (C7),
109.43 (C10). Found, %: C 61.25; H 8.83; S 7.38.
C22H38O6S. Calculated, %: C 61.37; H 8.90; S 7.45.
Deprotection of sulfoxides VIII and IX (general
procedure). Trifluoroacetic acid, 4 mmol (0.3 ml), was
slowly added dropwise under vigorous stirring to
a solution of 1 mmol (0.43 g) of sulfoxide VIII or IX
in 5 ml of chloroform. The mixture was continuously
stirred for 72 h, the solvent was distilled off under
reduced pressure, and the residue was subjected to
column chromatography on silica gel using chloro-
form–propan-2-ol (3:1) as eluent.
6-Deoxy-6-{(S)-[(1S,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyl]sulfinyl}-D-galactopyranose (X)
(a mixture of α- and β-anomers, 1:1). Yield 91%,
white powder, Rf 0.37 (CHCl3–i-PrOH, 3:1; phospho-
molybdic acid in ethanol), mp 138°C (decomp.),
[α]D20 = +30.1 (c = 0.21, ethanol). IR spectrum, ν, cm–1:
3366, 2928, 1680, 1452 (OH), 1144 (O–C–O), 1065
1
(C–O), 1030, 1006, 802 (S=O), 721 (C–S). H NMR
spectrum (D2O), δ, ppm: 0.80 d (6H, 7′-H, J = 6.4 Hz),
0.83 d (6H, 9′-H), 0.87–1.00 m (2H, 4′-Hax), 0.90 d
(6H, 10′-H, J = 6.4 Hz), 1.24–1.84 m (6H, 2′-H, 3′-Hax,
6′-Hax), 1.56–1.69 m (2H, 8′-H), 1.69–1.89 m (6H,
3′-Heq, 4′-Heq, 5′-H), 2.23–2.33 (2H, 6′-Heq), 3.12–
3.28 m (6H, 1′-H, 6-H), 3.41 d (1H, α-2-H, J =
7.9 Hz), 3.44 d (1H, β-2-H, J = 7.7 Hz), 3.59 d (1H,
β-3-H, J = 3.3 Hz), 3.63 d (1H, α-3-H, J = 3.3 Hz),
3.71–3.69 m (3H, 4-H, β-5-H), 4.35 t (1H, α-5-H, J =
6.8 Hz) 4.53 d (1H, β-1-H, J = 7.9 Hz), 5.18 d (1H,
α-1-H, J = 3.9 Hz). 13C NMR spectrum (D2O), δC,
ppm: 20.51 (C9′), 20.59 (C10′), 21.94 (C7′), 25.96 (C3′),
27.87 (C5′), 29.09 (C8′), 33.50 (C6′), 34.29 (C4′), 46.66
(C2′), 50.93 and 51.37 (C6), 57.65 and 57.72 (C1′);
65.85, 68.01, 69.09, 69.59, 69.98, 70.16, 71.54, 72.72
(C2, C3, C4, C5); 92.56 (α-C1), 96.56 (β-C1). Found %,
C 54.75; H 8.59; S 9.10. C16H30O6S. Calculated, %:
C 54.83; H 8.63; S 9.15.
6-Deoxy-6-{(R)-[(1S,2S,5R)-2-isopropyl-5-methyl-
cyclohexyl]sulfinyl}-1,2:3,4-di-O-isopropylidene-
α-D-galactopyranose (IX). White powder, mp 104°C,
[α]D20 = +10.8 (c = 0.15, acetone), Rf 0.43 (petroleum
ether–EtOAc, 1:1: KMnO4). IR spectrum, ν, cm–1:
2922, 1456, 1379, 1213; 1169 (O–C–O); 1071 (C–O);
1
1042, 1001, 920, 862 (S=O); 731 (C–S). H NMR
spectrum (CDCl3), δ, ppm: 0.83 d (3H, 7′-H, J =
6.4 Hz), 0.89 d (3H, 10′-H, J = 6.7 Hz), 0.92–1.03 m
(1H, 4′-Hax), 1.03 d (3H, 9′-H, J = 6.4 Hz), 1.20–
1.40 m (2H, 2′-H, 6′-Hax), 1.32 s (3H, 8-H), 1.36 s (3H,
11-H), 1.47 s (3H, 9-H), 1.60 s (3H, 12-H), 1.54–
1.66 m (1H, 5′-H), 1.73 q.d (1H, 3′-Hax, J = 12.9,
3.2 Hz), 1.82–1.99 m (3H, 3′-Heq, 4′-Heq, 6′-Heq), 2.16–
2.28 m (1H, 8′-H), 2.77 d.d (1H, 6-HA, J = 12.8,
1.5 Hz), 3.00 d.d (1H, 6-HB, J = 12.8, 10.5 Hz), 3.27–
3.31 m (1H, 1′-H), 4.18 d.d (1H, 4-H, J = 7.9, 1.8 Hz),
4.32 d.d (1H, 2-H, J = 4.9, 2.5 Hz), 4.44 d.t (1H, 5-H,
J = 10.4, 1.5 Hz), 4.7 d.d (1H, 3-H, J = 7.9, 2.5 Hz),
5.52 d (1H, 1-H, J = 4.9 Hz). 13C NMR spectrum
(CDCl3), δC, ppm: 21.91 (C9′), 21.12 (C10′), 22.49 (C7′),
24.42 (C11), 25.08 (C8), 25.91 (C3′), 25.95 (C9), 26.27
(C12), 27.68 (C5′), 29.01 (C8′), 35.59 (C4′), 37.49 (C6′),
6-Deoxy-6-{(R)-[(1S,2S,5R)-2-isopropyl-5-meth-
ylcyclohexyl]sulfinyl}-D-galactopyranose (XI)
(a mixture of α- and β-anomers, 1:1). Yield 99%,
white powder, Rf 0.29 (CHCl3–i-PrOH, 3:1; phospho-
molybdic acid in ethanol), mp 140°C (decomp.),
[α]D20 = +39.9 (c = 0.21, ethanol). IR spectrum, ν, cm–1:
3362, 2955, 1680, 1456 (OH); 1141 (O–C–O); 1053
1
(C–O); 1034, 920, 802 (S=O); 721 (C–S). H NMR
spectrum (D2O), δ, ppm: 0.79 d (6H, 7′-H, J = 5.6 Hz),
0.88 d (6H, 9′-H, J = 6.7 Hz), 0.93 d (6H, 10′-H, J =
6.7 Hz), 0.91–1.00 m (2H, 4′-Hax), 1.30–1.51 m (8H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

SYNTHESIS AND ASYMMETRIC OXIDATION OF THIOGLYCOSIDES
2′-H, 3′-Hax, 5′-H, 6′-Hax), 1.73–1.99 m (8H, 3′-Heq, REFERENCES
373
4′-Heq, 6′-Heq, 8′-H), 2.96–3.20 m (4H, 6-H), 3.39–
3.50 m (3H, 1′-H, β-2-H), 3.62–3.91 m (5H, α-2-H,
3-H, 4-H), 3.97 d.d (1H, β-5-H, J = 11.3, 2.3 Hz),
4.41 d (1H, α-5-H, J = 11.8 Hz), 4.55 d (1H, β-1-H, J =
8.2 Hz), 5.21 d (1H, α-1-H, J = 3.6 Hz). 13C NMR
spectrum (D2O), δC, ppm: 20.99 (C9′), 21.07 (C10′),
21.59 (C7′), 25.69 (C3′), 27.58 (C5′), 29.24 (C8′), 34.74
(C4′), 36.51 (C6′), 49.15 (C2′), 49.96 and 50.10 (C6),
62.41 and 62.57 (C1′); 63.69, 68.05, 68.21, 69.13,
70.78, 71.29, 71.50, 72.79 (C2, C3, C4, C5); 92.46 (α-C1),
96.55 (β-C1). Found %, C 54.71; H 8.55; S 9.08.
C16H30O6S. Calculated, %: C 54.83; H 8.63; S 9.15.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013