Synthesis of glycosides of 3-deoxy-4-thiopentopyranosid-2-uloses and their reduction products: 3-Deoxy-4-thiopentopyranosides

Article abstract of DOI:10.1016/S0008-6215(02)00292-6

Michael addition of common thiols to the enone system of (2S)-2-benzyloxy-2H-pyran-3(6H)-one (1) afforded the corresponding 3-deoxy-4-thiopentopyranosid-2-ulose derivatives (2-4). The reaction was highly diastereoselective, and the addition was governed by the quasiaxially disposed 2-benzyloxy substituent of the starting pyranone. As expected from the enantiomeric excess of 1 (ee >86%) the corresponding thiouloses 2-4 exhibited the same optical purity. However, the enantiomerically pure thioulose 5 was obtained by reaction of 1 with the chiral thiol, N-(tert-butoxycarbonyl)-L-cysteine methyl ester. The thio derivative 7 was also synthesized by reaction of 6 (enantiomer of 1) with the same chiral thiol. Alternatively, 4-thiopent-2-uloses 9-12 were prepared in high optical purity by 1,4-addition of thiols to (2S)-[(S)-2′-octyloxy]dihydropyranone 8. Similarly, reaction of 13 (enantiomer of 8) with benzenemethanethiol afforded 14 (enantiomer of 10). This way, the stereocontrol exerted by the anomeric center on the starting dihydropyranone led to 4-thiopentuloses of the D and L series. Sodium borohydride reduction of the carbonyl function of uloses 10 and 12 gave the corresponding 3-deoxy-4-thiopentopyranosid-2-uloses (16-19). The diastereomers having the β-D-threo configuration (16, 18) slightly predominated over the β-D-erythro (17, 19) analogues. However, the reduction of the enantiomeric pyranones 10 and 14 with K-Selectride was highly diastereofacial selective in favor of the β-D- and β-L-threo isomers 16 and 20, respectively.

Full text of DOI:10.1016/S0008-6215(02)00292-6

Carbohydrate Research 337 (2002) 2069–2076
www.elsevier.com/locate/carres
Synthesis of glycosides of 3-deoxy-4-thiopentopyranosid-2-uloses
and their reduction products: 3-deoxy-4-thiopentopyranosides
Mar´ıa Laura Uhrig, Oscar Varela*
CIHIDECAR-CONICET, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Exactas y Naturales,
Uni6ersidad de Buenos Aires. Pabello´n II, Ciudad Uni6ersitaria, 1428, Buenos Aires, Argentina
Received 1 April 2002; accepted 22 May 2002
Dedicated to Professor Derek Horton on the occasion of his 70th birthday
Abstract
Michael addition of common thiols to the enone system of (2S)-2-benzyloxy-2H-pyran-3(6H)-one (1) afforded the correspond-
ing 3-deoxy-4-thiopentopyranosid-2-ulose derivatives (2–4). The reaction was highly diastereoselective, and the addition was
governed by the quasiaxially disposed 2-benzyloxy substituent of the starting pyranone. As expected from the enantiomeric excess
of 1 (ee \86%) the corresponding thiouloses 2–4 exhibited the same optical purity. However, the enantiomerically pure thioulose
5 was obtained by reaction of 1 with the chiral thiol, N-(tert-butoxycarbonyl)-L-cysteine methyl ester. The thio derivative 7 was
also synthesized by reaction of 6 (enantiomer of 1) with the same chiral thiol. Alternatively, 4-thiopent-2-uloses 9–12 were
prepared in high optical purity by 1,4-addition of thiols to (2S)-[(S)-2%-octyloxy]dihydropyranone 8. Similarly, reaction of 13
(enantiomer of 8) with benzenemethanethiol afforded 14 (enantiomer of 10). This way, the stereocontrol exerted by the anomeric
center on the starting dihydropyranone led to 4-thiopentuloses of the
D and L series. Sodium borohydride reduction of the
carbonyl function of uloses 10 and 12 gave the corresponding 3-deoxy-4-thiopentopyranosid-2-uloses (16–19). The diastereomers
having the b-
D
-threo configuration (16, 18) slightly predominated over the b-D-erythro (17, 19) analogues. However, the reduction
of the enantiomeric pyranones 10 and 14 with K-Selectride® was highly diastereofacial selective in favor of the b-
D
- and b-L-threo
isomers 16 and 20, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Michael addition; Thio sugars; 3-Deoxy-4-thiopentopyranosid-2-uloses; 3-Deoxy-4-thiopentopyranosides
1. Introduction
matically non-cleavable analogues of the naturally oc-
curring disaccharides, which act as competitive
inhibitors.8,9 Similarly, (1“2)-2-S-thiodisaccarides
have been prepared.10 On the other hand, the products
of the coupling of thiols to enuloses showed to be
suitable precursors of annelated pyranosides.5,11 The
synthetic usefulness of these Michael additions are lim-
ited by the accessibility to the starting sugar enone. For
preparative-scale reactions, such versatile building
blocks should be prepared in a few, high-yielding steps.
In this regard, we have described a convenient one-pot
procedure for the synthesis of sugar enones from 2-ace-
toxyglycal derivatives, readily obtained from common
hexoses12 or pentoses.13 The resulting enulose deriva-
tives have been employed as chiral templates for the
synthesis of modified glycosides,14 ketonucleosides,15
and diamino tetradeoxy sugars component of antibi-
Thio sugars are gaining attention as potential thera-
peutics. The new developments, specially in the syn-
thetic and medicinal chemistry of thio sugars, are
important for carbohydrate drug design.1 The older
synthetic routes to target thio sugars are complex and
low-yielding approaches with questionable stereoselec-
tivity. More recently the conjugated addition of thiols
to sugar enones has been employed as a direct and
diastereoselective approach to prepare sulfur-containing
carbohydrates.2–8 This reaction has been used for the
synthesis of (1“4)-linked 4-thiodisaccharides, as enzy-
* Corresponding author. Tel.: +5411-4576-3346; fax: +
5411-4576-3352
E-mail address: varela@qo.fcen.uba.ar (O. Varela).
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00292-6

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M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
otics.16,17 More recently, we have studied Diels–Alder
cycloadditions13 and conjugated Michael additions18 to
enuloses. As continuation of such studies, we report
here the 1,4-addition of thiols to a number of glycosides
of 3,4-dideoxypent-3-enopyranosid-2-uloses having op-
posite configurations at the anomeric center, to deter-
mine the level of stereocontrol exerted by this
stereocenter on that generated at C-4. This procedure
would constitute a direct and stereoselective route of
access to 4-thiopentopyranosy-2-uloses, and hence to
which was prepared in one step by the tin(IV) chloride-
promoted glycosylation and rearrangement of 2-ace-
toxy-3,4-di-O-acetyl-D
-xylal.13 In the presence of
catalytic amounts of triethylamine, the a,b-unsaturated
carbonyl system of 1 acts as reactive Michael acceptor
for the addition of such thiols as ethanethiol, 2-
propanethiol, and benzenemethanethiol, to afford the
corresponding 4-thiopentopyranosid-2-ulose derivatives
2–4 (Scheme 1). As the starting compound 1 exhibited
an enantiomeric excess higher than 86% (ee \86%),
the conjugated addition products 2–4 had the same
optical purity, as verified in further experiments (see
below).
4-thiopentopyranosides, of both the
D and L series.
2. Results and discussion
The configuration of the new stereocenter at C-4 in
compounds 2–4 was determined as S, on the basis of
their H NMR spectra. Indeed, the small values for the
1
Michael additions were studied using the readily
accessible (2S)-2-benzyloxy-2H-pyran-3-(6H)-one (1),
proton–proton coupling constants (J) between H-4
Scheme 1.

M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
2071
An alternative route developed for the synthesis of
optically pure glycosides of 3-deoxy-4-thiopentopyran-
osid-2-uloses was based on the Michael addition of
thiols to (2S)-[(S)-2%-octyloxy]pyranone (8), readily pre-
pared by the Lewis acid-promoted reaction of (S)-2-oc-
with H-3,3% and with H-5,5% indicated an equatorial
disposition for H-4. Furthermore, the long-range cou-
pling constant J3%,5% (1.8 Hz) confirmed a quasi-equato-
rial relationship for H-3% and H-5% and an axial
orientation for the new substituent at C-4. A similar
coupling has been observed in related systems having
the same relative configuration as 2–4.8,18 Examination
tanol with 2-acetoxy-3,4-di-O-acetyl-D
-xylal.13 The use
of a chiral alcohol for the glycosylation of this glycal
derivative led to 8 in a high diastereomeric excess (de
\86%), which can be even increased by careful chro-
matographic purification of 8. The addition of
ethanethiol, benzenemethanethiol, and N-(tert-butoxy-
1
of the H NMR spectra of the crude reaction mixtures
of preparation of 2–4 revealed a negligible formation
of the diastereomer having an opposite configuration at
C-4. In one instance, such an isomer could be isolated
in a very low yield, as described later. The high
diastereofacial selectivity in the addition of thiols to
enone 1 is governed by the steric bulk of the axially
carbonyl)- -cysteine methyl ester to 8 (de \86%) af-
L
forded the respective enantiomerically pure adducts 9,
10 and 12 highly enriched in the major diastereomer (de
94–97%) after isolation by column chromatography.
Similar to the addition of thiols to 1, the reaction with
the analogous pyranone 8 was also highly diastereofa-
cial selective. However, the selectivity was strongly
influenced by the temperature; at higher temperatures
the reaction was faster but in turn, the selectivity was
somewhat lower. For example, only traces of the
diastereomer 11 were detected by NMR spectroscopy
when the addition of benzenemethanethiol to pure 8 (de
\96%) was conducted at 0–5 °C. The same reaction
performed at a higher temperature (40–45 °C) showed
by NMR spectroscopy a higher proportion of 11 (ꢀ
8%). This diastereomer arises from the attack of the
thiol from the sterically hindered b-face of the enone
(syn-addition). In general the syn-addition products
were slightly less polar than the major anti-addition
products; in particular, 10 and 11 showed a good
chromatographic separation that facilitated the isola-
tion of 11. Its structure was confirmed on the basis of
0
oriented anomeric substituent, in the preferred E con-
formation. Such a conformation in 1, as well as in
structurally related enones18 and enolones,19 is stabi-
lized by the anomeric effect, probably intensified by the
vicinal carbonyl group.13,19
The exclusive anti-addition mode of the thiols, in
respect to the anomeric substituent of 1, led us to
consider the synthesis of 3-deoxy-4-thioulose deriva-
tives in enantiomerically pure form. For this purpose,
we conducted the addition of the chiral thiol N-(tert-
1
butoxycarbonyl)-
L
-cysteine methyl ester to 1. The H
NMR spectrum of the resulting product revealed, as
expected, the formation of a diastereomeric mixture (5,
7), as the signals of H-3 and H-5 of 5 showed small
shoulders. Also, the 13C NMR spectrum exhibited small
satellites accompanying the resonances of C-3, C-5 and
the OMe group of 5 (ratio\13:1). The signals of lower
intensity were attributed to the diastereomer 7, the
product of addition of the chiral thiol to the enan-
tiomeric enone that contaminates 1. To confirm its
structure, compound 7 was synthesized by addition of
the chiral thiol employed previously, to the dihydropy-
ranone 6, the enantiomer of 1. Compound 6 was pre-
pared by the tin(IV) chloride-promoted glycosylation of
1
its H NMR spectrum, which showed large values for
the coupling constants of H-4 with H-3 and H-5, in
accordance with their trans-diaxial disposition. Again,
the long-range coupling between H-3% and H-5% indi-
cated a quasiequatorial relationship for those coupled
protons. These data were consistent with an equatorial
orientation of the sulfur substituent al C-4.
2-acetoxy-3,4-di-O-acetyl-L-arabinal with benzyl alco-
hol (Iriarte Capaccio, C.; Varela, O. unpublished re-
sults). The more intense peaks in the NMR spectra of
the addition product 7 exactly overlapped with the
minor ones present in the crude mixture of preparation
of 5. This way the identity of both diastereomers (5 and
7) was conclusively demonstrated. Their ratio in the
respective crude mixtures of reaction was in agreement
with the optical purity measured for the starting enones
(1 and 6) using chiral lanthanide shift reagents.13 Fur-
thermore, compounds 5 and 7 could be isolated as
enantiomerically pure adducts (de \95%) by column
chromatography. Therefore, the Michael addition was
useful for the synthesis of optically pure thio sugar
derivatives, having opposite configuration for the ring
stereocenters, even when the starting enones 1 and 6
were not absolutely enantiomerically pure.
To obtain a 4-thio-2-ulose derivative of the
the addition of benzenemethanethiol was applied to the
dihidropyranone 13 (enantiomer of 8) to give the b-
glycero product 14 (major) and the isomer 15. The
NMR spectra of 14 and 15 were respectively identical
to those of 10 and 11, as expected for enantiomeric
products.
Reduction of the carbonyl group of the 3-deoxy-4-
thiopentopyranosid-2-uloses will lead to the corre-
sponding 3-deoxy-4-thioglycoside derivatives. Thus,
sodium borohydride reduction of 10 gave two products,
which exhibited quite different mobilities by TLC. The
1H NMR spectrum of the mixture showed, in the
anomeric region, two signals at l 4.63 (J1,2 2.4 Hz) and
4.24 (J1,2 7.0 Hz), which corresponded, respectively, to
L series,
L-
the b-
D
-threo (16) and b- -erythro (17) epimers (1.6:1
D

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M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
Scheme 2.
ratio). The mixture could be readily separated by
column chromatography to afford the optically pure
3-deoxy-4-thioglycosides 16 and 17 (Scheme 2). The
column chromatography. Compound 18 exhibited in its
1H NMR spectrum J values indicative of an even
stronger preference for the 1C4 conformation, compared
with that of 16. Furthermore, the long-range coupling
between H-3% and H-5% was consistent with the diequa-
torial disposition of such protons found in the 1C4
conformer. This conformation is stabilized by the
anomeric effect as well as by the lack of 1,3-diaxial
interations between the substituents of the ring.
The selectivity observed for the reduction of pyra-
nones 10 and 12 was rather poor, in contrast with the
high anomeric stereocontrol reported for the hydride-
addition to a carbonyl group vicinal to the anomeric
center in enones14 and enolones.22 However, com-
pounds 10 and 12 possess in addition a quasiaxially
oriented thiobenzyl or thioalkyl group at C-4; hence
both faces of the ketone are hindered, resulting in a
lower selectivity. The reduction of the carbonyl func-
tion of a 4-thiohexopyranone, analogous to 10 and 12,
with a reducing agent having bulky substituents (L-Se-
lectride®) showed to be highly diastereoselective.8
Therefore, the reduction of the carbonyl group of 10
was conducted with K-Selectride® at low temperature.
The reaction proceeded highly stereoselectively with
1
coupling constants data from the H NMR spectrum of
16 showed time-averaged values indicative of a substan-
1
tial contribution of the C4 form in the conformational
equilibrium. For example, the values of J3%,4 (7.6 Hz)
and J4,5% (6.5 Hz) were smaller than those expected for
the trans-diaxial disposition of such coupled protons in
4
the C1 conformer. Derivatives of b-
D
-arabino and b-
D-
lyxo-pentopyranoses, which bear the same configura-
tion for the C-1, C-2 and C-4 stereocenters as 16,
1
showed also an appreciable proportion of the C4 form
in the conformational equilibrium.20,21 In contrast, as
observed for analogous pentopyranosides,20,21 com-
4
pound 17 adopts preferentially the C1 conformation,
according to the coupling constant values.
As found for 10, sodium borohydride reduction of
the carbonyl function of 12 led to an epimeric mixture
of the 3-deoxy-4-thioglycosides having the b-
D-threo
and b- -erythro configuration (1.5:1 ratio, established
D
by NMR). Due to the difficulty of the chromatographic
separation of the components of this mixture, they were
directly acetylated under standard conditions. The ace-
tyl derivatives 18 and 19 were readily isolated by
formation of the
D-threo isomer 16, which was isolated

M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
2073
in 79% yield. Only traces of the epimer 17 were detected
by H NMR spectroscopy of the crude mixture. The
General procedure for the synthesis of the 3-deoxy-4-
thiopentopyranosid-2-ulose glycosides 2–5, 7, 9–12, 14,
and 15.—To a solution of the 2H-pyran-3-(6H)-one
derivative13 (1, 6, 8, or 13, 1.0 mmol) in dry CH2Cl2
(2.0 mL) were added the thiol (1.5 mmol) and a cata-
lytic amount of Et3N (4 mL). After purging with nitro-
gen the vial was sealed, and the solution was stirred at
0–5 °C. When TLC monitoring of the reaction mixture
revealed complete consumption of the starting material
(5–10 h), the solution was concentrated. The residue
was purified by column chromatography using the sol-
vent indicated in each individual case. Representative
chromatographic fractions obtained in the purification
of Michael adducts prepared from 8 or 13 (having de
\86%) were monitored by NMR to establish the
diastereomeric composition. The purer fractions were
collected.
1
reduction of 10 seems to be governed by the steric
hindrance of the vicinal anomeric substituent rather
than by the thiobenzyl group at C-4. Reduction of the
pyranone 14 (the enantiomer of 10) with K-Selectride
led, as expected, to the 3-deoxy-4-thiopentopyranoside
20 (enantiomer of 16) having the b-L-threo configura-
tion. For comparative purposes, compound 20 was
conventionally acetylated to afford the 2-O-acetyl
derivative 21. Diagnostic coupling constants (J2,3, J3%,4
,
1
J4,5% and J3%,5%) from its H NMR spectrum indicated a
strong preference of 21 (similar to 18) for the con-
former having the substituents at C-1 and C-4 in an
axial disposition.
The configurational assignments for the 3-deoxy-4-
thiopentopyranosides 16–19 were confirmed on the ba-
sis of their 13C NMR spectra. Thus, compounds 17 and
Benzyl
3-deoxy-4-S-ethyl-4-thio-i-D-glycero-
19 having the b-
signals of C-1 and C-2 shifted downfield with respect to
the same signals of the b- -threo isomers 16 and 18.
These results showed an excellent correlation with the
respective analogous methyl 3-deoxypentopyran-
osides,23,24 except fot the shifting of the C-4 signal
which was shielded because of the replacement of an
oxygen by a sulfur-containing substituent.
D
-erythro configuration showed the
pentopyranosid-2-ulose (2).—Addition of ethanethiol to
1 (Rf 0.32, 5:1 hexane–EtOAc) afforded, after chro-
matography with 12:1 hexane–EtOAc, compound 2
(60% yield, ee \86%): Rf 0.36, 5:1 hexane–EtOAc;
D
1
[h]D −130.7° (c 1.0); H NMR: l 7.36 (bs, 5 H, Ph),
4.82, 4.64 (2 d, 2 H, J 11.7 Hz, PhCH2), 4.79 (bs, 1 H,
H-1), 4.44 (dd, 1 H, J4,5 2.9, J5,5% 12.0 Hz, H-5), 3.76
(ddd, 1 H, J3%,5% 1.8, J4,5% 3.3 Hz, H-5%), 3.48 (m, 1 H,
H-4), 3.15 (dd, 1 H, J3,4 5.1, J3,3% 15.4 Hz, H-3), 2.58 (m,
3 H, H-3%, CH3CH2S), 1.27 (t, 3 H, CH3CH2S); 13C
NMR: l 199.7 (C-2), 136.6, 128.6, 128.2, 128.1 (Ph),
98.5 (C-1), 70.0 (PhCH2), 63.0 (C-5), 42.5 (C-4), 41.9
(C-3), 25.0 (CH3CH2S), 14.6 (CH3CH2S). Anal. Calcd
for C14H18O3S: C, 63.13; H, 6.81; S, 12.04. Found: C,
63.19; H, 7.04; S, 11.74.
3. Experimental
General methods.—Melting points were determined
with a Fisher–Johns apparatus and are uncorrected.
Analytical thin-layer chromatography (TLC) was per-
formed on Silica Gel 60 F254 (E. Merck) aluminum-sup-
ported plates (layer thickness 0.2 mm). Visualization of
the spots was effected by exposure to UV light or by
charring with a solution of 5% (v/v) sulfuric acid in
EtOH, containing 0.5% p-anisaldehyde. Column chro-
matography was carried out with Silica Gel 60 (230–
400 mesh, E. Merck). Optical rotations were measured
with a Perkin–Elmer 343 digital polarimeter at 25 °C,
for solutions in CHCl3. Nuclear magnetic resonance
(NMR) spectra were recorded with a Bruker AC 200
or, when indicated, with a Bruker AMX 500 instru-
ment, in CDCl3 solutions using tetramethylsilane as an
internal standard. The signals from the 13C NMR spec-
tra were assigned by DEPT experiments. Elemental
analyses were performed at UMYMFOR-CONICET-
University of Buenos Aires. Fast-atom bombardment
mass spectra (FABMS) were conducted by LANAIS–
EMAR (Buenos Aires, Argentina) using a ZAB-VSEQ
mass spectrometer, Cs+ gun accelerated at 35 eV. Glyc-
erol was employed as matrix and as the standard for
calibration.
Benzyl
3-deoxy-4-S-(2-propyl)-4-thio-i-D-glycero-
pentopyranosid-2-ulose (3).—Addition of 2-propan-
ethiol to 1 gave, after chromatographic purification
with 12:1 hexane–EtOAc, compound 3 (50% yield, ee
\86%); Rf 0.39, 5:1 hexane–EtOAc; [h]D −118.3° (c
1
1.0); H NMR: l 7.37 (bs, 5 H, Ph), 4.83, 4.64 (2 d, 2
H, J 11.7 Hz, PhCH2), 4.77 (bs, 1 H, H-1), 4.43 (dd, 1
H, J4,5 2.9, J5,5% 12.0 Hz, H-5), 3.74 (ddd, 1 H, J3%,5% 1.8,
J4,5% 3.6 Hz, H-5%), 3.50 (m, 1 H, H-4), 3.14 (dd, 1 H, J3,4
5.1, J3,3% 15.3 Hz, H-3), 3.00 (m, 1 H, J 6.6 Hz,
Me2CHS), 2.56 (ddd, J3%,4 4.0 Hz, H-3%), 1.30 (d, 6 H,
(CH3)2CHS); 13C NMR: l 199.6 (C-2), 136.6, 128.5,
128.1 (Ph), 98.5 (C-1), 70.0 (PhCH2), 63.5 (C-5), 42.3
(C-3), 41.4 (C-4), 34.3 (Me2CHS), 23.5, 23.4 ((CH3)2C).
Anal. Calcd for C15H20O3S: C, 64.26; H 7.19; S, 11.43.
Found: C, 64.40; H 7.22; S, 11.76.
Benzyl
4-S-benzyl-3-deoxy-4-thio-i-D-glycero-
pentopyranosid-2-ulose (4).—Addition of benzen-
emethanethiol to 1, followed by chromatographic
purification with 15:1 hexane–EtOAc, afforded 4 (86%
yield, ee \86%): Rf 0.39, 5:1 hexane–EtOAc; [h]D
−96.4° (c 1.0); H NMR: l 7.35, 7.32 (2 bs, 10 H, 2
Ph), 4.81, 4.62 (2 d, 2 H, J 11.7 Hz, PhCH2O), 4.78 (bs,
1

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M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
1 H, H-1), 4.36 (dd, 1 H, J4,5 2.9, J5,5% 12.0 Hz, H-5),
3.82, 3.74 (2 d, 2 H, J 13.6 Hz, PhCH2S), 3.70 (ddd, 1
H, J3%,5% 1.8, J4,5% 3.1 Hz, H-5%), 3.29 (m, 1 H, H-4), 3.08
(dd 1 H, J3,4 5.1, J3,3% 15.0 Hz, H-3), 2.56 (ddd, 1 H, J3%,4
2.9 Hz, H-3%); 13C NMR: l 199.6 (C-2), 137.5, 136.6,
128.8, 128.7, 128.6, 128.2, 127.3 (2 Ph), 98.5 (C-1), 70.0
(PhCH2O), 62.9 (C-5), 42.1, 41.6 (C-3,4), 35.3
(PhCH2S). Anal. Calcd for C19H20O3S: C, 66.49; H,
6.14; S, 9.76. Found: C, 69.50; H, 6.12; S, 9.44.
(S)-2-Octyl
3-deoxy-4-S-ethyl-4-thio-i-D-glycero-
pentopyranosid-2-ulose (9).—Chromatographic purifi-
cation (40:1 hexane–EtOAc) of the reaction mixture of
addition of ethanethiol to 8 (de \86%; Rf 0.46, 6:1
hexane–EtOAc) afforded 9 (59% yield; de \95%): Rf
0.49 (6:1 hexane–EtOAc), [h]D −110.4° (c 1.0); 1H
NMR: l 4.73 (bs, 1 H, H-1), 4.44 (dd, 1 H, J4,5 2.9, J5,5%
12.1 Hz, H-5), 3.77 (m, 1 H, J 6.2 Hz, HCO octyl), 3.70
(ddd, 1 H, J3%,5% 2.2, J4,5% 3.3 Hz, H-5%), 3.45 (m, 1 H,
H-4), 3.10 (dd, 1 H, J3,4 5.1, J3,3% 15.0 Hz, H-3), 2.57 (q,
2 H, J 7.3 Hz, MeCH2S), 2.50 (ddd, 1 H, J3%,4 4.2 Hz,
H-3%), 1.63–1.22 (m, 16 H, CH3CH2S, 5 CH2 octyl,
CH3-1 octyl), 0.87 (t, 3 H, J 6.4 Hz, CH3-8 octyl); 13C
NMR: l 199.8 (C-2), 99.1 (C-1), 76.4 (HCO octyl), 62.7
(C-5), 42.6 (C-4), 41.7 (C-3), 36.4, 31.8, 29.3, 25.2, 24.9,
22.6 (MeCH2S, 5 CH2 octyl), 21.3 (CH3-1 octyl), 14.6,
14.1 (CH3-8 octyl, CH3CH2S). Anal. Calcd for
C15H28NO3S: C, 62.46; H, 9.78; S, 11.12. Found: C,
62.88; H, 9.90; S, 11.44.
Benzyl 3-deoxy-4-S-(methyl N-(tert-butoxycarbonyl)-
L
-cysteinat-3-yl)-4-thio-i-
ulose (5).—The crude mixture of reaction of 1 with
N-(tert-butoxycarbonyl)- -cysteine methyl ester (0.35 g,
D-glycero-pentopyranosid-2-
L
1.5 mmol) was examined by NMR spectroscopy, indi-
cating a 15:1 ratio of 5 and its diastereomer 7, which
was synthesized independently (see below). Chromato-
graphic purification of the mixture (5:1 hexane–EtOAc)
afforded 5 (76% yield): Rf 0.27 (2.5:1 hexane–EtOAc).
Crystallized from hexane compound 5 (de \95%) gave
1
mp 95 °C; [h]D −82.2° (c 0.9); H NMR (500 MHz): l
(S)-2-Octyl 4-S-benzyl-3-deoxy-4-thio-i-
pentopyranosid-2-ulose (10) and its h- -glycero analogue
D-glycero-
7.33 (m, 5 H, Ph), 5.33 (bs, 1 H, NH), 4.79, 4.61 (2 d,
2 H, J 11.7 Hz, PhCH2O), 4.73 (bs, 1 H, H-1), 4.53 (m,
1 H, NCHCO2), 4.40 (dd, 1 H, J4,5 2.6, J5,5% 12.2 Hz,
H-5), 3.76 (s, 3 H, OCH3), 3.72 (m, 1 H, J3,5%ꢀJ4,5% 2.5
Hz, H-5%), 3.50 (bs, 1 H, H-4), 3.13 (dd, 1 H, J3,4 5.2,
L
(11).—The reaction of 8 (de \96%) with benzen-
emethanethiol was conducted at ꢀ40 °C for 6 h. Mon-
itoring by TLC showed a faint spot (Rf 0.58, 6:1
hexane–EtOAc) and another more intense (Rf 0.49).
These two products were separated by column chro-
matography (40:1 hexane–EtOAc). The less polar com-
pound was identified as 11 (4% yield, de \96%): [h]D
3
2
J3,3% 15.3 Hz, H-3), 3.03 (dd, 1 H, J 5.0, J 13.4 Hz,
3
CCHaHbS), 2.95 (dd, 1 H, J 5.0 Hz, CCHaHbS), 2.54
(bd, 1 H, J3%,4 1.1 Hz, H-3%), 1.45 (s, 9 H, (CH3)3C); 13C
NMR: l 199.1 (C-2), 171.1 (CO2Me), 155.1 (NCO2),
136.4, 128.5, 128.1 (Ph), 98.3 (C-1), 80.3 (Me3CO), 69.9
(PhCH2O), 62.1 (C-5), 53.2 (NCHCO2), 52.6
(CO2CH3), 43.4 (C-4), 41.6 (C-3), 33.2 (CH2S), 28.2
((CH3)3C). Anal. Calcd for C21H29NO7S: C, 57.39; H,
6.65; S, 7.29. Found: C, 57.51; H, 6.92; S, 7.56.
1
−115.6° (c 0.7); H NMR: l 7.31 (bs, 5 H, Ph), 4.63
(bs, 1 H, H-1), 3.96 (apparent t, 1 H, J4,5:J5,5% 11.5
Hz, H-5), 3.77 (bs, 2 H, PhCH2), 3.75 (m, 1 H, HCO
octyl), 3.61 (ddd, 1 H, J3%,5% 1.9, J4,5% 4.8 Hz, H-5%), 3.08
(dddd, 1 H, J3,4 13.4, J3%,4 5.5 Hz, H-4), 2.70 (dd, 1 H,
J3,3% 14.2 Hz, H-3), 2.58 (ddd, 1 H, H-3%), 1.63–1.20 (m,
10 H, 5 CH2 octyl), 1.23 (d, 3 H, J 6.3 Hz, CH3-1
octyl), 0.87 (t, 3 H, J 6.3 Hz, CH3-8 octyl); 13C NMR:
l 199.8 (C-2), 137.8, 128.8, 128.7, 127.5 (Ph), 98.4
(C-1), 76.4 (HCO octyl), 62.8 (C-5), 42.6 (C-4), 41.7
(C-3), 36.4, 35.5, 31.7, 29.3, 25.1, 22.6 (PhCH2S, 5 CH2
octyl), 21.3, 14.1 (2 CH3 octyl).
Benzyl 3-deoxy-4-S-(methyl N-(tert-butoxycarbonyl)-
L
-cysteinat-3-yl) -4 -thio-i-L-glycero-pentopyranosid-2-
ulose (7).—Addition of N-(tert-butoxycarbonyl)-
L-cys-
teine methyl ester (1.5 mmol) to 6 afforded 7, which
was purified as described for 5. Compound 7 (86%
yield, de \95%): Rf 0.28 (2.5:1 hexane–EtOAc); mp
86 °C; [h]D +98.6° (c 0.9); 1H NMR (500 MHz): l 7.33
(m, 5 H, Ph), 5.33 (bs, 1 H, NH), 4.79, 4.61 (2 d, 2 H,
J 11.7 Hz, PhCH2O), 4.73 (s, 1 H, H-1), 4.53 (bs, 1 H,
NCHCO2), 4.42 (dd, 1 H, J4,5 2.6, J5,5% 12.2 Hz, H-5),
3.76 (s, 3 H, OCH3), 3.72 (ddd, 1 H, J3,5%ꢀJ4,5% 2.5 Hz,
H-5%), 3.50 (bs, 1 H, H-4), 3.12 (dd, 1 H, J3,4 5.0, J3,3%
15.3 Hz, H-3), 3.03 (dd, 1 H, 3J 4.0, 2J 13.9 Hz,
Following fractions from the column afforded 10
(82% yield, de \95%): [h]D −50.1° (c 1.0); H NMR:
1
l 7.30 (bs, 5 H, Ph), 4.73 (bs, 1 H, H-1), 4.35 (dd, 1 H,
J4,5 2.6, J5,5% 12.1 Hz, H-5), 3.75 (m, 3 H, PhCH2S,
HCO octyl), 3.64 (ddd, 1 H, J3%,5% 2.2, J4,5% 2.9 Hz, H-5%),
3.25 (m, 1 H, H-4), 3.04 (dd, 1 H, J3,4 5.1, J3,3% 15.0 Hz,
H-3), 2.49 (ddd, 1 H, J3%,4 4.0 Hz, H-3%), 1.65–1.25 (m,
10 H, 5 CH2 octyl), 1.22 (d, 3 H, J 6.6 Hz, CH3-1
octyl), 0.87 (t, J 6.3 Hz, CH3-8 octyl); 13C NMR: l
199.7 (C-2), 137.6, 128.8, 128.7, 127.3 (Ph), 99.1 (C-1),
76.3 (HCO octyl), 62.6 (C-5), 42.1 (C-4), 41.3 (C-3),
36.4, 35.3, 31.8, 29.3, 25.2, 22.6 (PhCH2, 5 CH2 octyl),
21.3, 14.1 (2 CH3 octyl). Anal. Calcd for C20H30O3S: C,
68.53; H, 8.63; S, 9.15. Found: C, 68.46; H, 8.85; S,
9.43.
3
CCHaHbS), 2.93 (dd, 1 H, J 5.6 Hz, CCHaHbS), 2.56
(bd, 1 H, J3%4 1.1 Hz, H-3%), 1.45 (s, 9 H, (CH3)3C); 13C
NMR: l 199.1 (C-2), 171.1 (CO2Me), 155.1 (NCO2),
136.4, 128.5, 128.1 (Ph), 98.3 (C-1), 80.3 (Me3CO), 69.9
(PhCH2O), 62.4 (C-5), 53.1 (NCHCO2), 52.7
(CO2CH3), 43.4 (C-4), 41.4 (C-3), 33.2 (CH2S), 28.2
((CH3)3C). Anal. Calcd for C21H29NO7S.0.5 H2O: C,
56.23; H, 6.74; S, 7.15. Found: C, 56.12; H, 6.74; S,
7.09.

M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
2075
(S)-2-Octyl 3-deoxy-4-S-(methyl N-(tert-butoxycar-
bonyl)- -cysteinat-3-yl)-4-thio-i- -glycero-pentopyran-
osid-2-ulose (12).—Reaction of N-(tert-butoxycar-
bonyl)- -cysteine methyl ester with 8 (de \86%) af-
11.7 Hz, H-5%), 3.02 (dddd, 1 H, J3,4 4.3, J3%,4 7.6 Hz,
H-4), 2.10 (ddd, 1 H, J2,3 7.4, J3,3% 13.1 Hz, H-3), 1.77
(ddd, 1 H, J2,3% 4.0, H-3%), 1.62–1.26 (m, 10 H, 5 CH2
octyl), 1.20 (d, 3 H, J 6.2 Hz, CH3-1 octyl), 0.88 (t, 3 H,
J 6.3 Hz, CH3-8 octyl); 13C NMR: l 138.1, 128.7, 128.5
127.1 (Ph), 98.6 (C-1), 75.2 (HCO octyl), 65.9 (C-2),
65.7 (C-5), 38.0 (C-4), 36.4, 35.6, 33.9, 31.8, 29.3, 25.3,
22.5 (C-3, PhCH2S, 5 CH2 octyl), 21.3, 14.0 (2 CH3
octyl). Anal. Calcd for C20H32O3S: C, 68.14; H, 9.15; S,
9.09. Found: C, 67.85; H, 9.10; S, 9.05.
From the next fraction of the column was isolated 17
(30 mg, 30% yield, de \96%): mp 53 °C; [h]D −70.0°
(c 0.5); 1H NMR: l 7.30 (bs, 5 H, Ph), 4.24 (d, 1 H, J1,2
7.0 Hz, H-1), 3.94 (ddd, 1 H, J3,5 2.2, J4,5 4.4, J5,5% 11.3
Hz, H-5), 3.75 (s, 2 H, PhCH2), 3.73 (m, 1 H, J 6.2 Hz,
HCO octyl), 3.40 (ddd, 1 H, J2,3 4.6, J2,3% 10.2 Hz, H-2),
3.28 (dd, 1 H, J4,5% 9.9, H-5%), 2.77 (dddd, 1 H, J3,4 4.4,
J3%,4 11.3 Hz, H-4), 2.27 (dddd, 1 H, J3,3% 12.8 Hz, H-3),
1.65–1.27 (m, 10 H, 5 CH2 octyl), 1.53 (ddd, 1 H,
H-3%), 1.21 (d, 3 H, J 6.3 Hz, CH3-1 octyl), 0.88 (t, 3 H,
J 6.2 Hz, CH3-8 octyl); 13C NMR: l 138.0, 128.7, 128.6,
127.2 (Ph), 104.0 (C-1), 76.2 (HCO octyl), 69.3 (C-2),
68.6 (C-5), 38.2 (C-4), 36.5, 35.3, 35.0, 31.7, 29.3, 25.4,
22.6 (C-3, PhCH2S, 5 CH2 octyl), 21.5, 14.0 (2 CH3
octyl). Anal. Calcd for C20H32O3S: C, 68.14; H, 9.15; S,
9.09. Found: C, 68.38; H, 9.31; S, 9.08.
(b) K-Selectride reduction of 10.—To a solution of 10
(0.10 g, 0.29 mmol) in anhydrous THF (2 mL), cooled
to −78 °C (CO2–acetone bath), was added under ni-
trogen a 1 M solution of K-Selectride in THF (0.35
mL, 0.35 mmol). The mixture was stirred at −78 °C
for 3 h, and then the temperature was rised to −20 °C,
and the stirring was continued for 1 h. The solution was
diluted with MeOH (5 mL) and neutralized with
Dowex 50W (H+) resin, filtered and concentrated. The
residue was treated and purified as described in (a).
Column chromatography afforded the pentopyranoside
16 (80 mg, 79% yield) which showed the same proper-
ties as those reported in (a).
L
D
L
forded, after column chromatography with 7.5:1
hexane–EtOAc, the 4-thio derivative 12 (90% yield, de
\94%): Rf 0.56 (2.5:1 hexane–EtOAc); [h]D −39.3° (c
1
0.9); H NMR: l 5.36 (bd, 1 H, J 7.0 Hz, NH), 4.72
(bs, 1 H, H-1), 4.53 (m, 1 H, NCHCO2), 4.44 (dd, 1 H,
J4,5 2.6, J5,5% 12.1 Hz, H-5), 3.79 (m, 1 H, HCO octyl),
3.77 (s, 3 H, CO2CH3), 3.69 (dt, 1 H, J3%,5%:J4,5% 2.5 Hz,
H-5%), 3.49 (s, 1 H, H-4), 3.12 (dd, 1 H, J3,4 5.1, J3,3%
15.4 Hz, H-3), 2.99 (t, 2 H, J 5.5 Hz, CH2S), 2.51 (bd,
1 H, H-3%), 1.63–1.25 (m, 10 H, 5 CH2 octyl), 1.45 (s, 9
H, (CH3)3C), 1.22 (d, 3 H, J 6.2 Hz, CH3-1 octyl), 0.87
(t, 3 H, J 6.6 Hz, CH3-8 octyl); 13C NMR: l 199.3
(C-2), 171.2 (CO2Me), 155.0 (NCO2), 99.0 (C-1), 80.3
(Me3CO), 61.9 (C-5), 53.2 (NCHCO2), 52.6 (CO2CH3),
43.6 (C-4), 41.4 (C-3), 36.3, 33.1, 31.7, 29.2, 25.1, 22.5
(CH2S, 5 CH2 octyl), 28.2 ((CH3)3C), 19.2, 14.0 (2 CH3
octyl). Anal. Calcd for C22H39NO7S·H2O: C, 55.09; H,
8.61; S, 6.68. Found: C, 55.18; H, 8.78; S, 6.49.
(R)-2-Octyl 4-S-benzyl-3-deoxy-4-thio-i-
L-glycero-
pentopyranosid-2-ulose (14) and its h- -glycero ana-
D
logue (15).—The conditions described for the synthesis
of 10 and 11 from 8 were applied for the preparation of
14 and 15, starting from 13 (enantiomer of 8). Column
chromatography of the reaction mixture gave com-
pound 15 (3% yield, de \95%): [h]D +111.4° (c 0.9);
1H and 13C NMR spectra were identical to those of its
enantiomer 11.
From further fractions from the column was isolated
the more polar diastereomer 14 (90% yield, de \94%):
[h]D +49.3 (c 1.2); 1H and 13C NMR spectra were
identical to the enantiomer 10.
(S)-2-Octyl
4-S-benzyl-3-deoxy-4-thio-i-D-threo-
(16) and i- -erythro-pentopyranoside (17)
D
(a) Sodium borohydride reduction of 10. To a solution
of thioulose 10 (0.10 g, 0.29 mmol) in MeOH (3 mL)
was added NaBH4 (11 mg, 0.29 mmol). The mixture
was stirred at room temperature for 20 min. The solu-
tion was neutralized with Dowex 50W (H+) resin,
filtered and concentrated. The residue was dissolved in
MeOH, and the solvent was evaporated in order to
remove boric acid. The procedure was repeated three
times to afford a syrup that showed two spots by TLC
(S)-2-Octyl 2-O-acetyl-3-deoxy-4-S-(methyl N-(tert-
butoxycarbonyl)-
L-cysteinat-3-yl)-4-thio-i-D-threo- (18)
and i- -erythro-pentopyranoside (19).—The sodium
D
borohydride reduction of 12 (0.16 g, 0.35 mmol) was
conducted as described for the reduction of 10 to give
the mixture of 18 and 19 in a 1.5:1 ratio, according to
the 1H NMR spectrum of the crude product. The
mixture was acetylated with 1:1 Ac2O–pyridine for 16
h. After the usual workup, the resulting syrup was
purified by column chromatography (9:1 hexane–
EtOAc). The less polar isomer (Rf 0.58, 2.5:1 hexane–
EtOAc) was identified as 18 (87 mg, 50% yield, de
\95%); [h]D −41.9° (c 0.8); 1H NMR: l 5.38 (bs, 1 H,
NH), 5.09 (ddd, 1 H, J1,2 2.6, J2,3 9.5, J2,3% 4.0 Hz, H-2),
4.84 (d, 1 H, H-1), 4.52 (m, 1 H, NCHCO2), 4.12 (dd,
1 H, J4,5 2.5, J5,5% 12.1 Hz, H-5), 3.76 (s, 3 H, OCH3),
3.68 (m, 1 H, J 6.2 Hz, HCO octyl), 3.45 (ddd,
1
(5:1 hexane–EtOAc) having Rf 0.53 and 0.47. The H
NMR spectrum of the crude mixture was recorded in
order to establish the ratio of products. Purification by
column chromatography (15:1 hexane–EtOAc) af-
forded first the less polar isomer, which was identified
as 16 (50 mg, 50% yield, de \98%): mp 52 °C; [h]D
1
−86.2° (c 0.9); HNMR (500 MHz): l 7.30 (bs, 5 H,
Ph), 4.63 (d, 1 H, J1,2 2.4 Hz, H-1), 3.95 (dd, 1 H, J4,5
3.3, J5,5% 11.7 Hz, H-5), 3.87 (m, 1 H, H-2), 3.74 (m, 3
H, PhCH2, HCO octyl), 3.34 (dd, 1 H, J4,5% 6.5, J5,5%

2076
M.L. Uhrig, O. Varela / Carbohydrate Research 337 (2002) 2069–2076
1 H, J3%,5% 1.1, J4,5% 4.3 Hz, H-5%), 3.12 (m, 1 H, H-4),
2.99 (d, 2 H, J 5.2 Hz, SCH2), 2.26 (ddd, 1 H, J3,4 4.3,
J3,3% 13.5 Hz, H-3), 2.08 (s, 3 H, CH3CO), 1.85 (ddd, 1
H, J3%,4 4.8 Hz, H-3%), 1.75–1.26 (m, 10 H, 5 CH2 octyl),
1.21 (d, 3 H, J 6.2 Hz, CH3-1 octyl), 0.88 (t, 3 H, J 6.4
Hz, CH3-8 octyl); 13C NMR: l 171.3, 170.2 (2 CO),
96.6 (C-1), 80.5 (Me3CO), 75.6 (HCO octyl), 67.5 (C-
2), 63.9 (C-5), 53.3 (NCHCO2), 52.6 (CO2CH3), 40.7
(C-4), 36.5, 33.7, 31.8, 30.2, 29.3, 25.2, 22.6 (C-3, CH2S,
5 CH2 octyl), 28.2 ((CH3)3C), 21.3, 21.0 (CH3CO,
CH3-1 octyl), 14.0 (CH3-8 octyl). Anal. Calcd for
C24H43NO8S: C, 57.01; H, 8.57; S, 6.33. Found: C,
56.81; H, 8.70; S, 5.85.
67.9 (C-2), 64.4 (C-5), 38.7 (C-4), 36.4, 35.5, 31.8, 30.2,
29.3, 25.1, 22.5 (C-3, CH2S, 5 CH2 octyl), 21.3, 21.0
(CH3CO, CH3-1 octyl), 14.0 (CH3-8 octyl). FABMS:
395 (M++1).
Acknowledgements
Financial support from the University of Buenos
Aires (Project X108) and from The National Research
Council of Repu´blica Argentina (CONICET) is grate-
fully acknowledged. O. V. is a Research Member of
CONICET.
The product having Rf 0.54 was isolated from further
fractions from the column, and it was characterized as
19 (56 mg, 32% yield); [h]D −19.2° (c 0.5); H NMR:
1
References
l 5.34 (bs, 1 H, NH), 4.64 (ddd, 1 H, J1,2 6.9, J2,3 4.8,
J2,3% 9.8 Hz, H-2), 4.53 (m, 1 H, NCHCO2), 4.42 (d, 1
H, H-1), 4.03 (ddd, 1 H, J3,5 2.2, J4,5 4.0, J5,5% 11.7 Hz,
H-5), 3.77 (s, 3 H, OCH3), 3.70 (m, 1 H, J 6.2 Hz,
HCO octyl), 3.29 (dd, 1 H, J4,5% 9.9 Hz, H-5%), 2.99 (t, 2
H, J 4.8 Hz, SCH2), 2.90 (dddd, 1 H, J3,4 4.0, J3%,4 9.9
Hz, H-4), 2.42 (dddd, 1 H, J3,3% 12.8 Hz, H-3), 2.05 (s,
3 H, CH3CO), 1.64–1.24 (m, 11 H, H-3%, 5 CH2 octyl),
1.20 (d, 3 H, J 6.2 Hz, CH3-1 octyl), 0.88 (d, 3 H, J 6.3
Hz, CH3-8 octyl); 13C NMR: l 171.1, 169.7 (2 CO),
101.6 (C-1), 80.6 (Me3CO), 76.8 (HCO octyl), 70.0
(C-2), 68.3 (C-5), 53.4 (NCHCO2), 52.7 (CO2CH3),
39.4 (C-4), 36.7, 34.2, 33.6, 31.9, 29.3, 25.1, 22.6 (C-3,
CH2S, 5 CH2 octyl), 28.3 ((CH3)3C), 21.7, 21.0
(CH3CO, CH3-1 octyl), 14.1 (CH3-8 octyl). Anal. Calcd
for C24H43NO8S: C, 57.01; H, 8.57; S, 6.33. Found: C,
56.69; H, 8.61; S, 5.91.
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1
[h]D +85.8° (c 1.0); H and 13C NMR spectra were
identical to those of the enantiomer 16.
Conventional acetylation of 20 afforded the 2-O-ace-
tyl derivative 21 in almost quantitative yield. Com-
1
pound 21 gave [h]D +58.8° (c 0.9); H NMR: l 7.31
(bs, 5 H, Ph), 5.10 (ddd, 1 H, J1,2 2.7, J2,3 9.0, J2,3% 3.8
Hz, H-2), 4.81 (d, 1 H, H-1), 4.04 (dd, 1 H, J4,5 3.3, J5,5%
11.9 Hz, H-5), 3.75 (s, 3 H, OCH3), 3.68 (m, 1 H, J 6.4
Hz, HCO octyl), 3.40 (ddd, 1 H, J3%,5% 0.9, J4,5% 4.9 Hz,
H-5), 2.95 (m, 1 H, H-4), 2.20 (ddd, 1 H, J3,4 4.2, J3,3%
13.4 Hz, H-3), 2.06 (s, 3 H, CH3CO), 1.81 (dddd, 1 H,
J3%,4 5.6 Hz, H-3%), 1.65–1.26 (m, 10 H, 5 CH2 octyl),
1.19 (d, 3 H, J 6.4 Hz, CH3-1 octyl), 0.87 (t, 3 H, J 6.3
Hz, CH3-8 octyl); 13C NMR: l 170.4 (CO), 137.9,
128.8, 128.7, 127.0 (Ph), 96.8 (C-1), 75.5 (HCO octyl),
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