A glycosylation driven strategy for the synthesis of anomerically pure vinyl sulfone-modified pent-2-enofuranoses and hex-2-enopyranoses

Article abstract of DOI:10.1055/s-2002-32960

Both α- and β-anomers of vinyl sulfone-modified pent-2-enofuranosides have been synthesized for the first time by taking advantage of the formation of α- and β-methyl glycosides in almost equal ratio only from derivatives of D-xylose. The strategy was equally applicable in the synthesis of α- and β-anomers of vinyl sulfone-modified hex-2-enopyranosides where a D-glucose derivative was selected over a D-allose derivative as the starting material because the former almost exclusively produced the required methyl pyranosides.

Full text of DOI:10.1055/s-2002-32960

LETTER
1241
A Glycosylation Driven Strategy for the Synthesis of Anomerically Pure Vinyl
Sulfone-modified Pent-2-enofuranoses and Hex-2-enopyranoses
Synthesis of
A
nom
d
erically
P
ur
i
e
V
inyl
t
Sulfon
y
e-modified
P
a
ent-2-enofuranos
K
es umar Sanki,a Tanmaya Pathak*a,b
a
Organic Chemistry Division (Synthesis), National Chemical Laboratory, Pune 411 008, India
b
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Fax +91(3222)82252; E-mail: tpathak@chem.iitkgp.ernet.in
Received 1 May 2002
ponent of aminoglycoside antibiotics) and its analogues
by us.16,17
Abstract: Both - and -anomers of vinyl sulfone-modified pent-
2-enofuranosides have been synthesized for the first time by taking
advantage of the formation of - and -methyl glycosides in almost
equal ratio only from derivatives of D-xylose. The strategy was
equally applicable in the synthesis of - and -anomers of vinyl sul-
fone-modified hex-2-enopyranosides where a D-glucose derivative
was selected over a D-allose derivative as the starting material be-
cause the former almost exclusively produced the required methyl
pyranosides.
In order to broaden the scope of this study and also to
gather information on the reaction patterns of endocyclic
mono-vinyl sulfones derived from pentofuranoses, we
needed to develop a practical methodology for the synthe-
sis of anomerically pure methyl 5-O-benzyl-2,3-dideoxy-
3-C-(p)-tolylsulfonyl- -D-erythro-pent-2-enofuranoside
6 and methyl 5-O-benzyl-2,3-dideoxy-3-C-(p)-tolylsulf-
onyl- -D-erythro-pent-2-enofuranoside 6 . Anomerically
pure vinyl sulfone-modified pent-2-enofuranoses were
needed because we wanted to use the anomeric configura-
tion as a tool to direct the diastereoselectivity of addition
of nucleophiles to the 2-position of these enofuranoses.
However, this particular requirement imposed greater re-
strictions on the choice of methodologies for the synthesis
of compounds 6 and 6 starting from a single and easily
accessible starting material.
Key words: modified carbohydrates, Michael acceptors, vinyl sulf-
one, pent-2-enofuranoside, hex-2-enopyranoside
The most common methods for the modification of
monosaccharides involve the reactions of various re-
agents with sugar derived epoxides, tosylates and ketones
although several other minor methods are also reported.1
Nucleophilic addition (Michael) to double bonds activat-
ed by electron withdrawing groups as part of carbohy-
drates should serve as a useful methodology for the
functionalization of monosaccharides. For example, stud-
ies on the Michael addition of nucleophiles to hex-2-
enose2–4 and 3-nitro-hex-2-enopyranosides5–12 have been
reported.
A retrosynthetic analysis of the route to 6 and 6 neces-
sitated the nucleophilic displacement of the p-tolylsulfo-
nyl group of the easily accessible18 starting material 5-
O-benzyl-1,2-O-isopropylidene-3-O-tosyl- -D-xylofura-
nose 1. Thus, the synthesis was initiated by reacting 1 with
p-thiocresol at 120 °C to produce the ribo-analogue 3 in
59% yield. The moderate yield of the ribo-product 3 can
be partly explained on the basis of the repulsion caused by
the 1,2-O-isopropylidene group to the incoming nucleo-
phile.1 Compound 3 on methanolysis produced the ano-
meric mixture of 4 and 4 in 78% yield. The anomers
were separated at this stage over a silica gel (230–400
mesh) column using a mixture of acetone: chloroform:pe-
troleum ether (1:1:8). Compounds 4 and 4 were oxi-
dized separately to the corresponding sulfone derivatives
5 and 5 in high yields. The sulfones 5 and 5 on treat-
ment with mesyl chloride and pyridine afforded smoothly
the desired vinyl sulfone-modified carbohydrates 6 and
6 in excellent yields (Scheme 1).
During the course of our studies on the synthesis and
properties of carbohydrate modified monovinyl sulfone13
and bisvinyl sulfone14 substituted nucleosides, we envis-
aged that due to the high reactivities of vinyl sulfones to-
wards various nucleophiles, vinyl sulfone-modified
carbohydrates could be utilized to generate a wide variety
of modified monosaccharides.
Vinyl sulfone-modified carbohydrates are expected to of-
fer several additional advantages for synthetic chemistry,
which have been detailed in earlier publications.15,16a Vi-
nyl sulfone-modified pyranoses, such as, methyl 2,3
dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl-
-D-erythro-hex-2-enopyranoside 22 and methyl 2,3
dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl-
-D-erythro-hex-2-enopyranoside 22 have been subject-
ed to reactions with various amines and the study has later
been utilized for the synthesis of D-lividosamine (a com-
Although at this stage the less efficient conversion of 1 to
3 was acceptable, the major drawback of this methodolo-
gy was the unacceptable ratio of 4 and 4 (1:10) in the
mixture. Lower ratio of -anomer 4 in the mixture of 4
and 4 contributed to the poor overall yield of the vinyl
sulfone derivative 6 (Scheme 1).
An examination of the percentage compositions of methyl
furanosides of D-ribose, D-arabinose, D-xylose and D-
lyxose at equilibrium revealed that the ratios of - and -
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1241,1244,ftx,en;G11902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1242
A. K. Sanki, T. Pathak
LETTER
It was, however possible to circumvent all these short-
comings by first converting the xylo-derivative 1 to an
anomeric mixture of 11 and 11 in a ratio 1:1.3 in high
yields (85–94% from several batches). In the absence of
any steric hindrance, the nucleophilic displacement of the
tosyl group of the mixture of 11 and 11 by p-thiocresol
proceeded smoothly to afford a mixture of 3-deoxy-3-C-
(p)-tolylsulfide-D-ribofuranosides 4 and 4 in 94% yield
(Scheme 3). The anomers 4 and 4 were separated at this
stage and were converted separately to 6 and 6 as de-
scribed in Scheme 1.
OR
BnO
BnO
O
a
b
O
O
O
O
S
O
(p)Tol
3
1 R = Ts
2 R = H
BnO
BnO
O
d
O
Y
OH
Y
OTs
O
BnO
X
4α
4β
b
a
(p)TolO2S
(p)Tol(O)nS
1
4α n = 0, X = H, Y = OMe
4β n = 0, X = OMe, Y = H
5α n = 2, X = H, Y = OMe
5β n = 2, X = OMe, Y = H
6α X = H, Y = OMe
6β X = OMe, Y = H
Y
c
c
OH
11α X = H, Y = OMe
11β X = OMe, Y = H
Scheme 1 Reagents and conditions: (a) p-thiocresol, NaOMe,
DMF, 115–120 °C, 3.5–4.0 h, 59%; (b) MeOH, concd H2SO4, 65–
70 °C, 3 h, 78% (4 :4 = 1:10); (c) MMPP, MeOH, r.t., 3 h,
Scheme 3 Reagents and conditions: (a) MeOH, concd H2SO4, 65–
70 °C, 3 h, 85–94% (11 :11 = 1:1.3); (b) p-thiocresol, NaOMe,
DMF, 115–120 °C, 3.5–4.0 h, 94%.
5
6
= 94%, 5 = 93%; (d) MsCl, pyridine, 0 °C to r.t., 18–24 h,
= 74%, 6 = 92%.
After devising a route for the synthesis of hitherto un-
known 6 and 6 using this novel approach, we turned our
attention to the synthesis of known 22 and 22 . The ex-
isting routes for the synthesis of hex-2-enopyranose deriv-
atives 22 and 22 are lengthy and each anomer requires
separate starting material for its synthesis.11,16a However,
for the continuation of research in this area we require rel-
atively large amount of anomerically pure 22 and 22
through a shorter route. In order to achieve this target we
applied the glycosylation driven strategy for the selection
of starting sugar for the synthesis of 22 and 22 . It has
been reported that the equilibrium mixture of methyl-D-al-
losides in methanol, contained more than 30% of
furanosides20,21 whereas D-glucose produced19 methyl-D-
pyranosides almost exclusively. Although the reported ra-
tio of - and -anomers were not close to the ideal value
of 1:1, in this case it was more important to get the methyl
pyranosides without any contamination of the corre-
sponding furanosides. This observation prompted us to
study the feasibility of using the known tosylate 12 as a
starting material,22 which could be converted to an ano-
meric mixture of 17 and 17 23 in a ratio 1:1.5. The -ano-
mer 17 , on treatment with thiophenol did not produce the
desired thiosugar 18 due to the in situ formation of 2,3-
O-anhydro-allo-derivative 19 .24
furanosides present at equilibrium were 1:3.4, 3.1:1, 1:1.5
and only , respectively.19 Thus, the pattern of glycosyl-
ation of various pentose sugars dictated us to select a D-
xylo-derivative based strategy for the synthesis of an ano-
meric mixture close to the ideal ratio of 1:1. Accordingly,
it was possible to synthesize a xylo-derivative 9 from 5-O-
benzyl-1,2-O-isopropylidene-3-O-mesyl- -D-ribofura-
nose 8 in 79% yield. Compound 9 on methanolysis pro-
duced the mixture of anomers 10 and 10 in a ratio 1.5:1
(Scheme 2). Although this ratio was acceptable for the
synthesis of both the anomers 6 and 6 , the overall yield
again dropped due to the addition of two synthetic steps
for converting 1 to the ribo-derivative 7 via a two-step
oxidation-reduction process.
STol(p)
O
BnO
BnO
b
O
O
O
O
ORO
9
7 R = H
a
8 R = Ms
STol(p)
BnO
X
However, it was possible to incorporate thiophenyl group
at the 3-position of the hexose sugar prior to pyranoside
formation to get two possible starting materials 14 and 15
by displacing the leaving groups of 12 and 13 respectively
by sodium thiophenolate. Here also, for reasons discussed
above, the gluco-derivative 15 was the starting material of
choice over the allo-derivative 14. Oxidation of 15 pro-
duced 16 in excellent yield. Treatment of 16 with acetyl
chloride in methanol afforded an anomeric mixture, which
was isolated as the benzylidene derivatives 21 and 21 in
c
O
Y
OH
10α X = H, Y = OMe
10β X = OMe, Y = H
Scheme 2 Reagents and conditions: (a) MsCl, pyridine, 0 °C, 24 h,
98%; (b) p-thiocresol, NaOMe, DMF, 145 °C, 3 h, 79%; (c) MeOH,
concd H2SO4, 65–70 °C, 3 h, 89% (10 :10 = 1.5:1).
Synlett 2002, No. 8, 1241–1244 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Anomerically Pure Vinyl Sulfone-modified Pent-2-enofuranoses
1243
N
O
a ratio 1:1.8. The anomers 21 and 21 were separated
and converted to the desired vinyl sulfone-modified hex-
2-enopyranoses 22 and 22 respectively. It was also pos-
sible to access 22 and 22 by first converting 15 to 20
and 20 in a ratio 2.2:1 (Scheme 4).26
N
BnO
OMe
N
BnO
O
X
Y
OMe
N
SO2Tol(p)
N
23
N
O
O
24 X = H; Y = SO2Tol(p)
25 X = SO2Tol(p); Y = H
Ph
O
O
c
O
O
OMe
Figure
O
O
OH
Y
Y
17α, 17β X = OTs; Y = H
18α, 18β X = H; Y = SPh
20α, 20β X = SPh; Y = H
21α, 21β X = SO2Ph; Y = H
12 X = OTs; Y = H
13 X = H; Y = OMs
14 X = H; Y = SPh
15 X = SPh; Y = H
References
a
(1) Collins, P. M.; Ferrier, R. J. Monosaccharides: Their
b
Chemistry and Their Roles in Natural Products; John Wiley
and Sons: Chichester, 1996, 189.
16 X = SO2Ph; Y = H
(2) Jegou, E.; Cleophax, J.; Leboul, J.; Gero, S. D. Carbohydr.
Res. 1975, 45, 323.
Ph
O
d
O
Ph
O
O
O
O
(3) Apostolopoulos, C. D.; Couladouros, E. A.; Georgiadis, M.
P. Liebigs Ann. Chem. 1994, 781.
O
PhO2S
OMe
Y
(4) Couladouros, E. A.; Constantinou-Kokotou, V.; Georgiadis,
M. P.; Kokotos, G. Carbohydr. Res. 1994, 254, 317.
(5) Baer, H. H.; Neilson, T. J. Org. Chem. 1967, 32, 1068.
(6) Lichtenthaler, F. W.; Vors, P.; Mayer, N. Angew. Chem., Int.
Ed. Engl. 1969, 8, 211.
(7) Nakagawa, T.; Sakakibara, T.; Kumazawa, S. Tetrahedron
Lett. 1970, 1645.
(8) Rajabalee, F. J.-M. Carbohydr. Res. 1973, 26, 219.
(9) Paulsen, H.; Greve, W. Chem. Ber. 1974, 107, 3013.
(10) Sakakibara, T.; Tachimori, Y.; Sudoh, R. Tetrahedron 1984,
40, 1533.
22α X = H; Y = OMe
22β X = OMe; Y = H
19α
Scheme 4 Reagents and conditions: (a) PhSH, NaOMe, DMF,
125 °C, 2 h, 80%;(b) MMPP, MeOH, r.t., 3 h, 94%; (c) i. CH3COCl,
MeOH, 1 h, reflux, 24 h; ii. 1,1-dimethoxytoluene, p-TSA, DMF,
100 °C, 71% (in two steps; 21 :21 = 1:1.8); (d) i. MsCl, pyridine,
0 °C 12 h; ii. DBU, CH2Cl2, r.t., 15 min, 96% (in two steps for 22 ),
96% (in two steps for 22 ).
In order to establish the influence of anomeric configura-
tion on the diastereoselectivity of addition of various nu-
cleophiles to these highly reactive Michael acceptors, 6
and 6 were reacted separately with 1,2,4-triazole in the
presence of 1,1,3,3-tetramethylguanidine in DMF at am-
bient temperature. Compound 6 25 produced a single iso-
mer 23 [82%;1H NMR: = 5.12 (1 H, d, J = 2.0 Hz, H-1);
Calcd for C22H25N3O5S: C, 59.58; H, 5.67; N, 9.47.
Found: C, 59.77; H, 5.96; N, 9.33] where the nucleophile
approached the C-2 position from the -face. Compound
6 , on the other hand produced a separable mixture (total
yield 75% in a ratio of 1:1) of ribo-derivative 24 [1H
NMR: = 5.08 (1 H, s, H-1); Calcd for C22H25N3O5S: C,
59.58; H, 5.67; N, 9.47. Found: C, 59.48; H, 5.64; N, 9.66]
and xylo-derivative 25 (1H NMR: = 5.05 (1 H, d, J = 3.9
Hz, H-1); Calcd for C22H25N3O5S: C, 59.58; H, 5.67; N,
9.47. Found: C, 59.92; H, 5.29; N, 9.36]. For the forma-
tion of both 24 and 25, the nucleophile attacked the C-2
position of 6 exclusively from the -face (Figure).27 All
new compounds were characterized by NMR spectrosco-
py and elemental analysis.
(11) Sakakibara, T.; Takai, I.; Yamamoto, A.; Tachimori, Y.;
Sudoh, R.; Ishido, Y. Carbohydr. Res. 1987, 169, 189.
(12) Seta, A.; Tokuda, K.; Kaiwa, M.; Sakakibara, T. Carbohydr.
Res. 1996, 281, 129.
(13) Bera, S.; Sakthivel, K.; Langley, G. J.; Pathak, T.
Tetrahedron 1995, 51, 7857.
(14) Bera, S.; Langley, G. J.; Pathak, T. J. Org. Chem. 1998, 63,
1754.
(15) Simpkins, N. S. Sulphones in Organic Synthesis, 1st Ed.;
Pergamon Press: Oxford, 1993, 183.
(16) (a) Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T. J.
Org. Chem. 2000, 65, 2637. (b) Suresh, C. G.; Ravindran,
B.; Rao, K. N.; Pathak, T. Acta Cryst., Sect. C 2000, C56,
1030.
(17) (a) Ravindran, B.; Deshpande, S. G.; Pathak, T. Tetrahedron
2001, 57, 1093. (b) Ravindran, B.; Pathak, T. Ind. J. Chem.
B 2001, 40, 1114.
(18) Yamashita, A.; Rosowsky, A. J. Org. Chem. 1976, 41, 3422.
(19) Collins, P. M.; Ferrier, R. J. Monosaccharides: Their
Chemistry and Their Roles in Natural Products; John Wiley
and Sons: Chichester, 1996, 63.
(20) Evans, M. E.; Angyal, S. J. Carbohydr. Res. 1972, 25, 43.
(21) Methanolysis of 1,2:5,6-di-O-isopropylidene- -D-
allofuranose in the presence of acid produced more than six
products, see: Williams, J. M. Carbohydr. Res. 1970, 13,
281.
Acknowledgement
(22) Nayak, U. G.; Whistler, R. L. J. Org. Chem. 1969, 34, 3819.
(23) Peat, S.; Wiggins, L. F. J. Chem. Soc. 1938, 1088.
(24) Compound 19 on reaction with thiophenol produced 2-
substituted D-altro-derivative, see: Hanessian, S.; Plessas,
N. R. Chem. Commun. 1968, 706.
This work has been supported by a research grant from the DST,
New Delhi. AKS thanks CSIR, New Delhi for a fellowship.
Synlett 2002, No. 8, 1241–1244 ISSN 0936-5214 © Thieme Stuttgart · New York

1244
A. K. Sanki, T. Pathak
LETTER
(25) Analytical and spectroscopic data of selected compounds.
6 : Gummy material. Found: C, 64.48; H, 5.90; S, 8.67.
C20H22O5S requires C, 64.15; H, 5.91; S, 8.56%; 1H NMR:
= 6.59 (1 H, s), 5.88 (1 H, d, J = 4.4 Hz), 5.13 (1 H, m), 4.44
(2 H, s, PhCH2), 3.85 (1 H, dd, J = 10.7, 2.4 Hz), 3.60 (1 H,
dd, J = 10.7, 4.4 Hz), 3.39 (3 H, s, OMe), 2.42 (3 H, s,
ArMe). 6 : Gummy material. Found: C, 64.41; H, 6.36; S,
8.81. C20H22O5S requires C, 64.15; H, 5.91; S, 8.56%; 1H
NMR: = 6.60 (1 H, s), 5.72 (1 H, s), 4.95 (1 H, d, J = 6.3
Hz), 4.47 (2 H, s, PhCH2), 3.83 (1 H, dd, J = 10.7, 2.4 Hz),
3.50 (1 H, m), 3.42 (3 H, s, OMe), 2.43 (3 H, s, ArMe). 16:
White solid, mp 158–159 °C. Found: C, 56.19; H, 6.90; S,
8.62. C18H24O7S requires C, 56.23; H, 6.28; S, 8.34%; 1H
NMR: = 5.96 (1 H, d, J = 3.9 Hz), 4.96 (1 H, d, J = 3.5 Hz),
1.49 (3 H, s, Me), 1.35 (3 H, s, Me), 1.29 (3 H, s, Me), 1.21
(3 H, s, Me).
(26) Compounds 22 and 22 have been synthesized earlier11,16a
from D-glucose in 14 steps (7 steps for each anomer). The
present method makes use of common intermediates upto
compounds 21 and 21 , thereby drastically reducing the
overall purification steps. Although overall yields for both
the methods are comparable, methyl -D-glucopyranoside,
which has been used in the earlier synthesis,11,16a is far too
expensive a starting material to be used in a large-scale
multi-step synthesis.
(27) The configurations at the C-2 and C-3 positions of 23–25
have been established unambiguously. The data will be
published as part of a full paper.
Synlett 2002, No. 8, 1241–1244 ISSN 0936-5214 © Thieme Stuttgart · New York