Diastereoselective C-C bond formation at C-5 of vinyl sulfone-modified hex-5-enofuranosyl carbohydrates: Diversity-oriented synthesis of branched-chain sugars and beyond

Article abstract of DOI:10.1021/jo062373+

(Chemical Equation Presented) This is the first report on the diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified hex-5-enofuranosides. The stereoelectronic properties of the substituents at the C-3 position and their interactions

Full text of DOI:10.1021/jo062373+

Diastereoselective C-C Bond Formation at C-5 of Vinyl
Sulfone-Modified Hex-5-enofuranosyl Carbohydrates:
Diversity-Oriented Synthesis of Branched-Chain Sugars and Beyond
Indrajit Das,† Tarun K. Pal,† Cheravakkattu G. Suresh,‡ and Tanmaya Pathak*,†
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India, and DiVision of
Biochemical Sciences, National Chemical Laboratory, Pune 411 008, India
tpathak@chem.iitkgp.ernet.in
ReceiVed NoVember 17, 2006
This is the first report on the diastereoselective addition of carbon nucleophiles to vinyl sulfone-modified
hex-5-enofuranosides. The stereoelectronic properties of the substituents at the C-3 position and their
interactions with the incoming carbon nucleophiles control the diastereoselectivity of addition at the C-5
position, favoring the formation of L-ido derivatives as major products in most of the cases studied. This
new concept of stereocontrolled carbon-carbon bond formation in vinyl sulfone-modified carbohydrates
is general in nature. The novel chirons generated by this diversity-oriented synthetic method have been
implemented in the preparation of a wide range of hexofuranosyl C-5 branched-chain sugars, bicyclic
derivatives, chirally pure enals, and densely functionalized carbocycles.
Introduction
chirons, useful for further transformations.2-4 Although C-C
bond formation at the C-2 or C-3 carbons of carbohydrates has
been studied extensively,1-4 C-5 branched-chain sugars derived
from hexofuranosyl carbohydrates have also generated consider-
able interest as starting materials for the synthesis of natural
and non-natural products. The most common methods for the
synthesis of C-5 branched-chain sugars from carbohydrate
precursors in general involve either a direct attack of carbon
nucleophiles at the C-5 of a C-5 ulose derivative 1-3 or the
Branched-chain sugars, having carbon substituents at the
nonterminal carbon atoms of the chains, are components of
many natural products, especially antibiotics.1,2 Branched-chain
sugars also constitute an important class of functionalized
† Indian Institute of Technology.
‡ National Chemical Laboratory.
(1) Yoshimura, J. AdV. Carbohydr. Chem. Biochem. 1984, 42, 69.
(2) (a) Collins, P. M.; Ferrier, R. J. Monosaccharides: Their Chemistry
and Their Roles in Natural Products; John Wiley & Sons: Chichester, UK,
1996. (b) Ferrier, R. J. Carbohydrate Chemistry: Monosaccharides,
Disaccharides and Specific Oligosaccharides; The Royal Society of
Chemistry: Cambridge, 1968-2001; Vols. 1-32.
(3) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Press: Oxford, 1983.
(4) Witczak, J. Z., Nieforth, K. A., Eds. Carbohydrates in Drug Design;
Marcel Dekker Inc.: New York, 1997.
10.1021/jo062373+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/20/2007
J. Org. Chem. 2007, 72, 5523-5533
5523

Das et al.
reduction of C-5 alkylidene glycosides 4 generated from sugar
aldehydes or ketones (Figure 1).2b On the other hand, Michael-
type addition of carbon nucleophiles to electron-deficient hex-
5-enofuranosyl carbohydrates 5-8 has been used to a limited
extent for the functionalization of the C-5 of carbohydrates, with
compound 8 being the more widely used Michael acceptor.2b
alization of the C-5 position of hexoses.7f,11 We observed that,
in the case of vinyl sulfone-modified hex-2-enopyranosides and
pent-2-enofuranosides 10pyr and 10fur (Figure 2), carbon
FIGURE 2. Vinyl sulfone-modified hex-2-enopyranosides and pent-
2-enofuranosides.
nucleophiles added in a diastereoselective fashion to C-2 of the
planar olefinic systems from a direction opposite to that of the
disposition of the anomeric methoxy group.7f This anomeric
configuration-directed stereocontrolled carbon-carbon bond
formation in vinyl sulfone-modified carbohydrates has been
implemented in the synthesis of new hexopyranosyl and
pentofuranosyl branched-chain sugars.7f We therefore envisaged
that the reactions of vinyl sulfone-modified hex-5-enofurano-
sides 14a-c and 14f (Scheme 1) with carbon nucleophiles
FIGURE 1. Sugar-derived ketones, alkylidenes, and Michael acceptors.
Interestingly, the strategy for the functionalization of a carbon
center away from the pyranose or furanose ring using a vinyl
sulfone-modified carbohydrate has not been explored in spite
of the efficient use of a vinyl sulfone-modified pyranose
derivative as a Michael acceptor for the synthesis of maytansi-
nol.5 Michael-type addition reaction of carbon nucleophiles to
vinyl sulfone-modified carbohydrates in general should be
considered as an efficient route for the synthesis of branched-
chain sugars mainly because almost all carbohydrates could be
converted to their vinyl sulfone derivatives very easily.6,7
Moreover, the products of such reactions carrying sulfone
functionalities have the potential to undergo a wide variety of
transformations during desulfonylation.8 We have established
that vinyl sulfone-modified carbohydrates are useful intermedi-
ates for the synthesis of various amino and branched-chain
sugars.7 In the area of furanosides, except for the only report
on the use of a vinyl sulfone-modified hex-5-enofuranoside (9:
R′ ) Bn; E isomer) as a substrate for cycloaddition reaction,9
no such system was studied at all to establish its potential as
synthetic intermediates for the synthesis of branched-chain
sugars.10
SCHEME 1. Synthesis of Vinyl Sulfone-Modified
Hex-5-enofuranosidesa
Our interest in the area of branched-chain sugars prompted
us to look for a vinyl sulfone-based strategy for the function-
(5) Isobe, M.; Kitamura, M.; Goto, T. J. Am. Chem. Soc. 1982, 104,
4997.
(6) (a) Patai, S., Rappoport, Z., Stirling, C., Eds. The Chemistry of
Sulfones & Sulphoxides; John Wiley & Sons: New York, 1988. (b)
Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press: Oxford,
1993. (c) Sakakibara, T.; Takai, I.; Yamamoto, A.; Tachimori, Y.; Sudoh,
R.; Ishido, Y. Carbohydr. Res. 1987, 169, 189. (d) Sakakibara, T.; Shindo,
T.; Hirai, H. Carbohydr. Res. 2002, 337, 2061.
a Reagents and conditions: (i) pTolSNa, DMF, 100 °C, 4 h, 89%; (ii)
MMPP, MeOH, rt, 6 h, 93%; (iii) MsCl, py, 0-4 °C, 24 h; (iv) py, reflux,
2 h, 86% (E:Z ) 2:1); (v) DDQ, DCM-H2O (20:1), rt, 18 h, 88%; (vi)
Ac2O, py, DMAP, rt, 20 h, 92%.
(7) (a) Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T. J. Org.
Chem. 2000, 65, 2637. (b) Ravindran, B.; Deshpande, S. G.; Pathak, T.
Tetrahedron 2001, 57, 1093. (c) Suresh, C. G.; Ravindran, B.; Pathak, T.;
Narasimha Rao, K.; Sasidhar Prasad, J. S.; Lokanath, N. K. Carbohydr.
Res. 2002, 337, 1507. (d) Sanki, A. K.; Pathak, T. Synlett 2002, 1241. (e)
Sanki, A. K.; Pathak, T. Tetrahedron 2003, 59, 7203. (f) Sanki, A. K.;
Suresh, C. G.; Falgune, U. D.; Pathak, T. Org. Lett. 2003, 5, 1285. (g)
Pathak, T. Eur. J. Org. Chem. 2004, 3361. (h) Das, I.; Suresh, C. G.; Pathak,
T. J. Org. Chem. 2005, 70, 8047. (i) Das, I.; Pathak, T. Org. Lett. 2006, 8,
1303.
(8) For a review on desulfonylation, see: Najera, C.; Yus, M. Tetrahedron
1999, 40, 10547.
(9) Trost, B. M.; Seoane, P.; Mignani, S.; Acemoglu, M. J. Am. Chem.
Soc. 1989, 111, 7287.
should be studied in a systematic manner to establish the
usefulness of these compounds. Moreover, efficient and dia-
stereocontrolled alkylation at C-5 followed by desulfonylation
of the addition product using a variety of reaction conditions8
would lead to a range of C-6 functionalized C-5 branched sugars.
Although, unlike in the case of 10pyr and 10fur (Figure 2), no
directive group was available at C-4, adjacent to the electrophilic
reactive site C-5 of 14a-c and 14f, like the amination of 14a-
c,7h we argued that the stereoelectronic properties of the
substituents at the C-3 position would influence the stereose-
lectivity of addition of carbon nucleophiles at C-5 of these
(10) (a) Barton, D. H. R.; Gero, S. D.; Quiclet-Sire, B.; Samadi, M. J.
Chem. Soc., Chem. Commun. 1988, 1372. (b) Musicki, B.; Widlanski, T.
S. Tetrahedron Lett. 1991, 32, 1267.
(11) Ravindran, B.; Pathak, T. J. Org. Chem. 1999, 64, 9715.
5524 J. Org. Chem., Vol. 72, No. 15, 2007

DiVersity-Oriented Synthesis of Branched-Chain Sugars
SCHEME 2. Diastereoselective Addition of Carbon
Nucleophiles to Vinyl Sulfone-Modified
Hex-5-enofuranosidesa
compounds, thereby opening up a new route for the diastereo-
selective C-C bond formation at C-5.12
Results and Discussion
Synthesis of Vinyl Sulfone-Modified Hex-5-enofurano-
sides. Vinyl sulfones 14a-c were synthesized from a reported
epoxide derived from bisisopropylidene D-glucose.7h To broaden
the scope of the present study, in addition to 14a-c, we also
prepared the 3-O-acetyl derivative 14f as follows. The easily
accessible 3-O-p-methoxybenzyl-protected epoxide 1113 was
reacted with sodium tolylthiolate to get 12 in high yield.
Oxidation of 12 with magnesium monoperoxyphthalate hexahy-
drate (MMPP) produced 13. Mesylation of sulfone 13 followed
by the base treatment of the mesylated product afforded the
vinyl sulfone 14d (E/Z ) 2:1) in 86% yield. Compound 14d
was deprotected with DDQ in DCM in 88% yield, and the free
hydroxy derivative 14e was acetylated to afford 14f in good
overall yield (Scheme 1).
Reactions of Vinyl Sulfone-Modified Hex-5-enofuranosides
with Carbon Nucleophiles. We initiated the study with the most
widely used carbon nucleophiles generated from nitromethane
and dimethylmalonate. Thus, vinyl sulfones 14a-c and 14f were
reacted with a sodium salt generated from nitromethane in 1,4-
dioxane to produce mixtures of addition products 15a/16a (5.5:
1), 15b/16b (>9:<1), 15c/16c (1.5:1), and 15f/16f (4.5:1),
respectively, in high yields. The sodium salt of dimethylma-
lonate reacted at a much faster rate with 14a-c in 1,4-dioxane
to generate mixtures of addition products 17a/18a (5:1), 17b/
18b (9:1), and 17c/18c (1.5:1), respectively, in very good yields
(Scheme 2). It is noteworthy that the free hydroxy compound
14e under the same reaction conditions produced an inseparable
mixture of at least four compounds.
Selection of solvent for achieving satisfactory diastereomeric
ratios of products in the mixture of 15/16 and 17/18 was crucial.
A brief study with 14a and both the nucleophiles using different
solvents indicated the profound influence of solvents on the
reactions. It is evident from Tables 1 and 2 that DMF is the
least efficient solvent in terms of the selectivity of formation
of diastereomers and also rates of reaction. 1,4-Dioxane on the
other hand was the best among the solvents used.
a Reagents and conditions: (i) CH3NO2, NaH, 1,4-dioxane, rt, 2-3 days;
(ii) CH2(CO2Me)2, NaH, 1,4-dioxane, rt, 30-35 min.
TABLE 1. Reactions of 14a with NaCH2NO2 in Different
Solventsa,b
To explain the diastereoselectivity of addition of amines to
14a-c, we postulated the formation of a H-bonded precursor
having the geometry of a six-membered ring.7h However, the
same concept is not applicable here because the negatively
charged carbon nucleophiles are not capable of forming H-bonds
with OMe or OBn groups present at C-3 positions of 14a and
14b. An alternative explanation based on the model suggested14
for the addition of primary amines to E (or Z)-6-bromo-5,6-
dideoxy-1,2-O-isopropylidene-3-O-methyl-R-D-xylohept-5-eno-
l,4-furanurononitriles was invoked to explain the product
distribution in our case. Thus, a carbon nucleophile would be
repelled by the OMe group of 14b and would be forced to attack
the double bond from the other side, resulting in the formation
of the L-ido product preferentially (Figure 3A). In the case of
14c, however, the carbon nucleophile would be repelled by the
reaction
time
Sl no.
solvent
DMF
acetonitrile
1,4-dioxane
15a:16a
15a + 16a
1
2
3
36 h
>5 days
3 days
3:1
4:1
5.5:1
84%
62%
86%
a No reaction in 2,2-dimethoxypropane, benzene, and toluene; starting
material recovered. b All reactions were carried out at rt.
TABLE 2. Reactions of 14a with NaCH(CO2Me)2 in Different
Solventsa,b
reaction
time
Sl no.
solvent
17a:18a
17a + 18a
1
2
3
4
DMF
acetonitrile
12 h
3:1
4:1
4:1
5:1
89%
91%
89%
94%
1.25 h
1 h
0.5 h
2,2-dimethoxy propane
1,4-dioxane
a No reaction in benzene and toluene; starting material recovered. b All
reactions were carried out at rt.
(12) The stereoselectivity of hydroboration of a C-methylene derivative
at C-5 is also dependent on the substitution patterns at C-3. See: Liang,
D.; Schuda, A. D.; Fraser-Reid, B. Carbohydr. Res. 1987, 164, 229.
(13) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
ring oxygen and would attack the double bond from both sides,
resulting in a loss of diastereoselectivity of addition (Figure 3A).
(14) Tronchet, J. M. J.; Martin, O. R. Carbohydr. Res. 1981, 96, 167.
J. Org. Chem, Vol. 72, No. 15, 2007 5525

Das et al.
SCHEME 3. Synthesis of C-5-Deoxy-C-5-methyl L-Idosides
and D-Glucosidesa
A critical situation would arise in the case of 14a. In theory,
compound 14a should have resulted in the same diastereose-
lective product formation as was the case for 14b. However,
we presumed that an additional factor such as the equilibrium
between two rotamers 14a-A and 14a-B would block both sides
of C-5 resulting in a lower diastereoselectivity but still favoring
the formation of the L-ido isomer (Figure 3B). The acetyl-
protected 14f behaved more like 14a (Figure 3B) and produced
mixtures of products with poorer diastereoselectivity. It should
be noted that in the above discussion we excluded the contribu-
tion of ring conformations to the diastereoselectivity of additions
of nucleophiles to vinyl sulfones 14a-c because we presumed
that the isopropylidene group would impose partial rigidity to
furanose rings.
t
a Reagents and conditions: (i) KtBuO, BuOH, KMnO4, H2O, 40 min;
(ii) NaBH4, EtOH, rt, 16 h; (iii) TBDMSCl, DCM, DMAP, Et3N, 24 h;
(iv) Mg, MeOH, rt, 14 h; (v) H2, Pd-C (10%), HCOOH, EtOH, 6 h.
derivative 25a (47%) and L-talo derivative 25c (36%) as major
compounds (Scheme 3).
The identities of compounds 25a and 25c were established
as follows. Compound 25a was hydrogenated with 10% Pd-C
to afford 27, a reported compound in 89% yields.12 Synthesis
of 27 from 25a established unambiguously the configuration at
C-5 (L-ido) of the latter product, which in turn also established
the identity of 15a. Consequently, 26a (and 16a) was identified
as the D-gluco derivative. We intended to reverse the config-
uration of the hydroxyl group at C-3 to access 25c through an
alternative route. Thus, 27 was oxidized with PDC, and the ulose
thus obtained was reduced with NaBH4 to the corresponding
D-allo derivative. The product was benzylated with BnBr/NaH
FIGURE 3. (A) Proposed mode of addition of carbon nucleophiles to
14b and 14c. (B) Effects of the “up” 3-O-benzyl group on the proposed
mode of addition of carbon nucleophiles to 14a.
Structural Elucidation. Out of six pairs of products only
one pair, 17c and 18c, could be separated at this stage (Scheme
2). The major product (52%) was identified unambiguously as
the L-talo derivative 17c with the help of the X-ray of its single
crystal. Compound 18c was therefore identified as the D-allo
derivative. Other compounds were taken forward for separation
and structural identification.
1
to obtain a compound which was identical to 25c (mixed H
After several experimentations, we realized that compounds
15a/16a, 15b/16b, and 15c/16c were better separated once the
nitromethylene group was converted to a hydroxymethylene
group. This conversion also enabled us to diversify our
methodology for the synthesis of important synthetic intermedi-
ates. Thus, 15a/16a, 15b/16b, and 15c/16c were subjected
separately to a modified Nef carbonyl synthesis15 to generate
the corresponding aldehydes 19-21 (Scheme 3).
The crude aldehydes were reduced with NaBH4 to the
corresponding alcohols 22-24 in good overall yields in two
steps. Compounds 22-24 were protected with a tert-butyldi-
methylsilyl group, and the protected compounds were desulfo-
nylated with Mg in MeOH to generate compounds 25a/26a,
25b/26b, and 25c/26c in good overall yields. Compounds 25a/
26a and 25c/26c were separated at this stage to obtain the L-ido
NMR). Since compound 25c originated from the nitromethane
adduct 15c, it was concluded that the major product of
nitromethane addition to 14c (Scheme 2) was an L-talo derivative
15c, and the minor product 16c was a D-allo derivative.
Compounds 17a/18a and 17b/18b were separated and identi-
fied using a decarboxylation strategy. Thus, 17a/18a was treated
with NaCl in a DMSO-H2O mixture at 130 °C16 to obtain
monoester 28 (Scheme 4). Although 28 was still a mixture of
two diastereomers, its reductive desulfonylation by Mg in MeOH
furnished a single compound 29. In this case, the minor isomer
could not be isolated. Alternatively, 28 was desulfonylated,
debenzylated, and simultaneously converted into an alcohol 31
using LAH. The product was however isolated as the single
diacetyl derivative 32 (Scheme 4).
(15) Kornblum, N.; Erickson, A. S.; Kelly, W. J.; Henggeler, B. J. Org.
Chem. 1982, 47, 4534.
(16) Tadano, K.; Maeda, H.; Hoshino, M.; Iimura, Y.; Suami, T. J. Org.
Chem. 1987, 52, 1946.
5526 J. Org. Chem., Vol. 72, No. 15, 2007

DiVersity-Oriented Synthesis of Branched-Chain Sugars
SCHEME 4. Synthesis of Deoxyheptose Sugarsa
SCHEME 5. Synthesis of a Bicyclic Lactonea
a Reagents and conditions: (i) KOH, MeOH, H2O, 3 h; (ii) H2, Pd-C
(10%), MeOH, HCOOH, 6 h.
Thus, 17c and 18c were taken through the same sequence of
reactions described in Scheme 3 to obtain the monoesters 35
and 36 in good yields. The aryl sulfonyl moieties of both of
these compounds were reductively removed, and ester moieties
were reduced in a one-pot reaction using LAH. The products
thus obtained were collected as their diacetyl derivatives 37 and
38, respectively, in good overall yields (Scheme 6). Compounds
37, 38 as well as 32, 33 (Scheme 4) represent new classes of
protected deoxyheptose sugars2b of unknown properties. Since
the O-benzyl group is not expected18a to undergo LAH-promoted
debenzylation, the formation of 31, 37, and 38 from 28, 35,
and 36, respectively, may be considered as unusual reactions.
However, there is at least one report on the debenzylation of a
protected alcohol with LAH under “vigorous” conditions,18b and
studies on the use of alkylalanes for regioselective debenzylation
of pentoses18c have been reported. Since the latter reactions
reportedly involve complexation of an aluminium atom with
sugar oxygens,18c we presume that complexation of an alu-
minium atom with sugar ring oxygen(s) is also triggering
debenzylation in our case; however, a detailed study is necessary
for delineating the exact mechanism of debenzylation of 28,
35, and 36.
a Reagents and conditions: (i) NaCl, DMSO-H2O (10:1), 130 °C, 20
h; (ii) Mg, MeOH, rt, 12h; (iii) LiAlH4, THF, rt, 18-20 h; (iv) Ac2O, py,
rt, 16 h.
The R configuration at C-5 of compounds 28, 29, 31, and 32
was established by converting 29 into a known17 synthetic
intermediate 34 [C-Me R; [R]24D -7.1 (c 0.1, CHCl3); reported17
[R]24 -7.2 (c 0.83, CHCl3)] in two steps (Scheme 5). Since
D
compound 28 originated from the dimethylmalonate adducts
17a/18a, it was concluded that the major product of this mixture
(Scheme 2) was 17a (L-ido type), and the minor product was
certainly 18a (D-gluco type). Similarly, the mixture of 17b/18b
was converted to a monoacetyl derivative 33 via monoester 30
(Scheme 4). In this case, 30 was isolated as a single compound.
The identity of 30 was established unambiguously with the help
of the X-ray of its single crystal. Therefore, the major product
of the dimethylmalonate reaction of 14a was 17b (L-ido type),
and the minor product must be 18b (D-gluco type).
SCHEME 6. Synthesis of Deoxyheptose Sugarsa
Compounds 25b and 26b were the only pair which could
not be separated at any stage (Scheme 3). Since all of the
reactions of nitromethane and dimethylmalonate produced L-ido
compounds as the major components, we assigned 25b (and
15b) as the L-ido derivative, and 26b (and 16b) as the D-gluco
analogue.
Synthetic Applications of Branched-Chain Sugars. In order
to highlight the usefulness of the branched-chain sugars gener-
ated so far with the help of our methods, we converted these
chirons into important intermediates for further applications in
organic synthesis. Compounds 15a-c/17a-c on the one hand
and 16a-c/18a-c on the other offered an easy access to a wide
range of chirally pure C-5 modified carbohydrates. These
compounds or any of their derivatives were expected to find
wide applications in organic synthesis. For example, compound
27 (Scheme 3) was identified in the literature as an intermediate
for the synthesis of 1,3,9-trideoxy-3,5-di-C-methyl-L-talitol,
which was a potential chiron for the C-33-C-37 segment of
amphotericin B.12 Compound 34 (Scheme 5) on the other hand
was an important intermediate used earlier for the synthesis of
(4R)-4-[(E)-2-butenyl]-4,N-dimethyl-L-threonine (MeBmt), a
â-hydroxy-R-amino acid (Scheme 5).17
a Reagents and conditions: (i) NaCl, DMSO-H2O (10:1), 24 h, 130
°C; (ii) LiAlH4, THF, rt, 18-20 h; (iii) Ac2O, py, rt, 16 h.
Compounds 19-21 were easily converted to vinyl aldehydes
39-41, respectively, by eliminating the aryl sulfonyl group
(17) (a) Rama Rao, A. V.; Yadav, J. S.; Chandrasekhar, S.; Srinivas Rao,
C. Tetrahedron Lett. 1989, 30, 6769. (b) Rama Rao, A. V.; Yadav, J. S.;
Srinivas Rao, C.; Chandrasekhar, S. J. Chem. Soc., Perkin Trans. 1 1990,
1211.
(18) (a) For a recent review on debenzylation, see: Weissman, S. A.;
Zewge, D. Tetrahedron 2005, 61, 7833. (b) Kutney, J. P.; Abdurahman,
N.; Gietsos, C.; Le Quesne, P.; Piers, E.; Vlattas, I. J. Am. Chem. Soc.
1970, 92, 1727. (c) Jia, C.; Zhang, Y.; Zhang, L.-H.; Sinay, P.; Sollogoub,
M. Carbohydr. Res. 2006, 341, 2135.
J. Org. Chem, Vol. 72, No. 15, 2007 5527

Das et al.
SCHEME 9. Synthesis of a Bicyclic Nitro Derivativea
under basic conditions (Scheme 7). Although R,â-unsaturated
aldehydes, such as 2-isopropylacrolein,19 were extensively used
in synthetic organic chemistry, to the best of our knowledge,
there was only one report on a carbohydrate derivative (39: X
) OH; Y ) H)20 related to 39-41. Until now, the potential of
compounds such as 39-41 as synthetic intermediates remained
unexplored.
SCHEME 7. Synthesis of Vinyl Aldehydes
a Reagents and conditions: (i) MeONa, MeOH, rt, 2.5 h, 83%; (ii) Ag2O,
MeI, rt, 6 h, 62%, or Ag2O, I2, THF, rt, 18 h, 59%.
Some of our newly synthesized chirons were also utilized
for the synthesis of cyclic compounds not reported so far.
Compound 31, for example, was easily converted to a bicyclic
derivative 42 in two reaction sequences, such as selective
tosylation of the primary alcohol followed by base treatment
(Scheme 8).
Since one of the most important applications of branched-
chain sugars as chirons is in the synthesis of carbocycles,2b,22
we subjected mixtures of 17a/18a and 17b/18b separately to
deisopropylidenation followed by concomitant cyclization under
acidic conditions. The major products thus obtained were
acetylated to furnish bicyclic lactones 45 and 46 (Scheme 10).
Elucidation of crystal structures of 45 and 46 unambiguously
established the configurations at newly built chiral centers of
these compounds.
SCHEME 8. Synthesis of a Bicyclic Ether Derivativea
SCHEME 10. Synthesis of Carbocycles
a Reagents and conditions: (i) TsCl, py-toluene, 72 h; (ii) NaOH, THF-
H2O (9:1), 3 h.
Interestingly, when the free hydroxylated compound 43
obtained from 15f/16f was subjected to methylation using Ag2O/
MeI, a non-methylated compound was obtained. Treatment of
43 with Ag2O and I2 in THF also afforded the same compound
(Scheme 9). However, treatment of 43 with Ag2O in THF in
the absence of MeI or I2 did not produce the same compound.
The X-ray of the single crystal of the product confirmed
structure 44. There are only a few reports on 1-deoxy-1-nitro
sugars.21 To the best of our knowledge, this is the only report
on the cyclization of a nitroalcohol. It may be argued that the
“aci-nitro” group formed in the presence of Ag2O was iodinated
at the R-position. The iodo intermediate thus formed underwent
cyclization to produce 44.
In conclusion, we have established an efficient and new
methodology for the functionalization of the C-5 position of
hexofuranosides through the Michael addition of carbon nu-
cleophiles to vinyl sulfone-modified hex-5-enofuranosides. The
C-C bond formation was diastereoselective in nature and led
to the generation of a plethora of branched-chain sugars. The
diversity-oriented synthesis and the compatibility of these
branched-chain sugars with a range of reaction conditions
resulted into the synthesis of new sugar-derived sulfone, nitro,
diester, aldehyde, alcohol, monoester, lactone, and vinyl alde-
hyde. Yet another group of synthetic manipulations furnished
new deoxyheptoses, bicyclic ethers, and densely functionalized
carbocycles. Some of these compounds are known for their
applications in organic synthesis. The potentials of most of the
products are yet to be explored as chirally pure intermediates.
(19) For selected references, see: (a) Huang, Y.; Iwama, T.; Rawal, V.
H. J. Am. Chem. Soc. 2000, 122, 7843. (b) Jung, M.; Groth, U. Synlett
2002, 2015. (c) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem.
2003, 68, 1030. (d) Breit, B.; Heckmann, G.; Zahn, S. K. Chem.sEur. J.
2003, 9, 425. (e) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5,
4931. (f) Groth, U.; Jung, M.; Vogel, T. Synlett 2004, 1054. (g) Reynolds,
N. T.; Rovis, T. Tetrahedron 2005, 61, 6368. (h) Dirnberger, T.; Werner,
H. Organometallics 2005, 24, 5127. (i) Groth, U.; Jung, M.; Vogel, T.
Chem.sEur. J. 2005, 11, 3127.
(20) Rauter, A. P.; Weidmann, H. Ann. 1982, 2231.
(21) (a) Mahmood, K.; Vasella, A.; Bernet, B. HelV. Chim. Acta 1991,
74, 1555. (b) Baumberger, F.; Beer, D.; Christen, M.; Prewo, R.; Vasella,
A. HelV. Chim. Acta 1986, 69, 1191. (c) Beer, D.; Bieri, J. H.; Macher, I.;
Prewo, R.; Vasella, A. HelV. Chim. Acta 1986, 69, 1172. (d) Meuwly, R.;
Vasella, A. HelV. Chim. Acta 1986, 69, 751. (e) Julina, R.; Vasella, A.
HelV. Chim. Acta 1985, 68, 819.
(22) For a review on carbocycles from carbohydrates, see: Ferrier, R.
J.; Middleton, S. Chem. ReV. 1993, 93, 2779.
5528 J. Org. Chem., Vol. 72, No. 15, 2007

DiVersity-Oriented Synthesis of Branched-Chain Sugars
mixture was poured into ice-cold water, and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over anhyd Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure to obtain a residue. The residue
was purified over a silica gel column to afford 14d (1.8 g, 86%):
eluent, EtOAc/petroleum ether (1:3); yellow gum; 1H NMR of the
mixture (CDCl3) δ 1.31 (s, 6H), 1.46 (s, 6H), 2.41/2.44 (each s,
6H), 3.81/3.82 (each s, 6H), 3.99-4.01 (m, 2H), 4.36-4.62 (m,
6H), 4.82-4.83 (m, 2H), 5.91-5.94 (m, 2H), 6.39-6.72 (m, 2H),
6.84-6.98 (m, 4H), 7.17-7.28 (m, 10H), 7.71-7.75 (m, 4H).
Compound 14e. To a well-stirred solution of 14d (1.5 g, 3.26
mmol) in DCM-H2O (20:1) was added DDQ (1.2 equiv/mmol),
and the mixture was stirred at ambient temperature for 18 h. After
completion of the reaction (TLC), the reaction mixture was poured
into a saturated solution of NaHCO3, and the mixture was extracted
with DCM (3 × 10 mL). The combined organic layers were dried
over anhyd Na2SO4 and filtered, and the filtrate was concentrated
under reduced pressure to obtain a residue. The resulting residue
was purified over a silica gel column to afford 14e (0.98 g, 88%):
eluent, EtOAc/petroleum ether (1:1); yellow gum; 1H NMR of the
mixture (CDCl3) δ 1.33 (s, 6H), 1.39 (s, 6H), 2.42/2.44 (each s,
6H), 4.30 (m, 1H), 4.54-4.60 (m, 2H), 4.88 (m, 1H), 5.60-5.64
(m, 1H), 5.92-6.00 (m, 2H), 6.28-6.47 (m, 3H), 6.70-7.01 (m,
2H), 7.26-7.37 (m, 4H), 7.73-7.80 (m, 4H).
Compound 14f. To a well-stirred solution of 14e (0.88 g, 2.58
mmol) in py (10 mL) were added acetic anhydride (2 equiv/mmol)
and DMAP (catalytic), and the mixture was stirred at ambient
temperature for 20 h. After completion of the reaction (TLC), the
reaction mixture was poured into saturated ice-cold solution of
NaHCO3, and the mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried over anhyd Na2SO4 and
filtered, and the filtrate was concentrated under reduced pressure
to obtain a residue. The resulting residue was purified over a silica
gel column to afford 14f (0.91 g, 92%): eluent, EtOAc/petroleum
ether (1:3); yellow gum; 1H NMR of the mixture (CDCl3) δ 1.29/
1.31 (each s, 6H), 1.47 (s, 6H), 1.90/2.00 (each s, 6H), 2.41/2.42
(each s, 6H), 4.54-4.56 (m, 2H), 4.92-4.94 (m, 2H), 5.25-5.27
(m, 1H), 5.45-5.46 (m, 1H), 5.90-5.94 (m, 2H), 6.13-6.37 (m,
2H), 6.71-6.74 (m, 2H), 7.28-7.34 (m, 4H), 7.70-7.78 (m, 4H).
General Procedure for the Synthesis of 15a/16a, 15b/16b, 15c/
16c, 15f/16f, 17a/18a, 17b/18b, and 17c/18c. Compound 14a, 14b,
14c, or 14f (1 mmol) was stirred at room temperature separately
with the sodium salt of nitromethane or dimethylmalonate (2.5
equiv/mmol) in dry 1,4-dioxane (8 mL) for 30 min to 72 h. After
completion of the reaction (TLC), the reaction mixture was poured
into a saturated solution of NH4Cl, and the product was extracted
with EtOAc (3 × 10 mL). The combined organic layers were dried
over anhyd Na2SO4 and filtered, and the filtrate was concentrated
under reduced pressure to obtain a residue. The resulting residue
was purified over a silica gel column [eluent, EtOAc/petroleum
ether (1:3)] to afford inseparable mixtures of 15a/16a, 15b/16b,
15c/16c, 15f/16f, 17a/18a, or 17b/18b. Compounds 17c/18c could
be separated at this stage.
Experimental Section
General Methods. Melting points were determined in open-end
capillary tubes and are uncorrected. Carbohydrates and other fine
chemicals were obtained from commercial suppliers and are used
without purification. Solvents were dried and distilled following
the standard procedures. TLC was carried out on precoated plates
(Merck silica gel 60, f254), and the spots were visualized with a
UV light or by charring the plates dipped in 5% H2SO4-MeOH
solution or 5% H2SO4/vanillin/EtOH solution. Column chromatog-
raphy was performed on silica gel (60-120 or 230-400 mesh).
1H and 13C NMR spectra for most of the compounds were recorded
at 200 and 50.3 MHz, respectively, in CDCl3 unless stated
otherwise. Optical rotations were recorded at 589 nm. Compounds
25a,12 26a,12 27,12 and 3417 are reported in the literature. The spectral
data of these compounds reported by us below are compared directly
to the corresponding literature.
Compound 12. To a well-stirred solution of 11 (3.0 g, 9.31
mmol) in DMF (4 mL/mmol) were added p-thiocresol (5 equiv/
mmol) and NaOMe (2.5 equiv/mmol). The mixture was heated at
100 °C with stirring for 4 h under N2. After completion of the
reaction (TLC), the reaction mixture was poured into a saturated
solution of NaHCO3 and the product was extracted with EtOAc (3
× 10 mL). The combined organic layers were dried over anhyd
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure to obtain a residue. The residue was purified over a silica
gel column to afford sulfide 12 (3.7 g, 89%): eluent, EtOAc/
petroleum ether (1:5); yellow gum; [R]24D -6.2 (c 4.0, CHCl3); 1H
NMR (CDCl3) δ 1.30 (s, 3H), 1.45 (s, 3H), 2.30 (s, 3H), 2.73 (d,
J ) 4.6 Hz, 1H), 2.95 (m, 1H), 3.29 (dd, J ) 3.3, 14.0 Hz, 1H),
3.80 (s, 3H), 4.04 (m, 2H), 4.45 (m, 1H), 4.56 (m, 2H), 5.91 (d, J
) 3.7 Hz, 1H), 6.86 (d, J ) 8.5 Hz, 2H), 7.08 (d, J ) 7.9 Hz, 2H),
7.25 (m, 4H); 13C NMR (CDCl3) δ 20.8 (CH3), 26.1 (CH3), 26.6
(CH3), 39.6 (CH2), 55.0 (CH3), 67.2 (CH), 71.7 (CH2), 81.3 (CH),
81.5 (CH), 82.2 (CH), 105.0 (CH), 111.5 (C), 113.8 (2 × CH),
129.1 (C), 129.4 (2 × CH), 129.6 (2 × CH), 130.1 (2 × CH),
131.5 (C), 136.2 (C), 159.4 (C). Anal. Calcd for C24H30O6S: C,
64.55; H, 6.77. Found: C, 64.48; H, 6.73.
Compound 13. To a well-stirred solution of sulfide 12 (2.4 g,
5.37 mmol) in dry MeOH (10 mL/mmol) was added magnesium
monoperoxyphthalate hexahydrate (2.5 equiv/mmol), and the
mixture was stirred for 6 h under N2. After completion of the
reaction (TLC), MeOH was evaporated to dryness under reduced
pressure and the residue was dissolved in saturated NaHCO3. The
mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhyd Na2SO4 and filtered, and the
filtrate was concentrated under reduced pressure to obtain a residue.
The residue was purified over a silica gel column to obtain sulfone
13 (2.4 g, 93%): eluent, EtOAc/petroleum ether (1:3); yellow gum;
[R]24 +17.0 (c 4.8, CHCl3); H NMR (CDCl3) δ 1.28 (s, 3H),
1
D
1.44 (s, 3H), 2.44 (s, 3H), 3.26 (m, 1H), 3.42 (d, J ) 2.9 Hz, 1H),
3.56 (dd, J ) 1.8, 14.5 Hz, 1H), 3.82 (s, 3H), 4.03 (m, 1H), 4.53
(m, 4H), 5.80 (d, J ) 3.7 Hz, 1H), 6.89 (d, J ) 8.6 Hz, 2H), 7.28
(m, 4H), 7.76 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3) δ 21.6 (CH3),
26.2 (CH3), 26.8 (CH3), 55.3 (CH3), 59.9 (CH2), 64.2 (CH), 72.2
(CH2), 80.8 (CH), 81.5 (CH), 82.5 (CH), 105.0 (CH), 111.9 (C),
114.0 (2 × CH), 127.9 (2 × CH), 129.3 (C), 129.6 (2 × CH),
130.0 (2 × CH), 136.5 (C), 144.9 (C), 159.6 (C). Anal. Calcd for
C24H30O8S: C, 60.24; H, 6.32. Found: C, 60.44; H, 6.44.
Compound 15a/16a. Compound 14a (0.8 g, 1.86 mmol) was
converted to an inseparable mixture of two diastereomers 15a/16a
1
following the general procedure (0.78 g, 86%): yellow gum; H
NMR of the mixture (CDCl3) δ 1.29/1.30 (each s, 6H), 1.44/1.46
(each s, 6H), 2.43 (s, 6H), 3.21-3.23 (m, 6H), 3.98 (m, 2H), 4.43-
4.45 (m, 4H), 4.60-4.67 (m, 4H), 4.84-4.85 (m, 4H), 5.86 (each
d, 2H), 7.26-7.36 (m, 14H), 7.66-7.68 (m, 4H).
Compound 14d. To a well-stirred solution of compound 13 (2.2
g, 4.60 mmol) in pyridine (5 mL/mmol) was added methanesulfonyl
chloride (4 equiv/mmol) in pyridine (1 mL/mmol of MsCl) dropwise
at 0 °C under N2. After completion of the addition, the reaction
mixture was kept at 4 °C. After 16 h (TLC), the reaction mixture
was poured into ice-cold water, and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried over
anhyd Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure to obtain a residue. The residue was heated under
reflux with pyridine (4 mL/mmol). After 2 h (TLC), the reaction
Compound 15b/16b. Compound 14b (0.52 g, 1.47 mmol) was
converted to an inseparable mixture of two diastereomers 15b/16b
1
following the general procedure (0.54 g, 89%): yellow gum; H
NMR of the mixture (CDCl3) δ 1.25/1.30 (each s, 6H), 1.44/1.46
(each s, 6H), 2.47 (s, 6H), 3.16 (m, 2H), 3.23-3.27 (m, 2H), 3.28/
3.32 (each s, 6H), 3.33-3.37 (m, 4H), 4.36-4.38 (m, 2H), 4.53-
4.54 (m, 2H), 4.84-4.86 (m, 4H), 5.81 (each d, 2H), 7.37-7.40
(m, 4H), 7.79-7.82 (m, 4H).
J. Org. Chem, Vol. 72, No. 15, 2007 5529

Das et al.
Compound 15c/16c. Compound 14c (0.44 g, 1.02 mmol) was
converted to an inseparable mixture of two diastereomers 15c/16c
following the general procedure (0.42 g, 83%): yellow gum; H
layers were dried over anhyd Na2SO4 and filtered, and the filtrate
was concentrated under reduced pressure to obtain a residue 19,
20, or 21. The crude residue was dissolved in ethanol (10 mL),
cooled in an ice bath, sodium borohydride (2.5 equiv/mmol) was
added, and the solution was stirred for 16 h. Then the reaction
mixture was poured into ice-cold water, and the mixture was
extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over anhyd Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure to obtain a residue. The
resulting residue was purified over a silica gel column [eluent,
EtOAc/petroleum ether (1:1)] to afford an inseparable mixture of
two diastereomers 22, 23, or 24.
Compound 22. Compound 15a/16a (0.55 g, 1.12 mmol) was
converted to an inseparable mixture of two diastereomers 22
following the general procedure (0.42 g, 80%): 1H NMR of the
mixture (CDCl3) δ 1.29 (s, 6H), 1.44/1.46 (each s, 6H), 2.40/2.43
(each s, 6H), 2.61-2.63 (m, 2H), 3.14-3.33 (m, 6H), 3.87-3.98
(m, 4H), 4.25-4.30 (m, 2H), 4.40-4.48 (m, 2H), 4.58-4.67 (m,
4H), 5.81/5.86 (each d, 2H), 7.23-7.38 (m, 14H), 7.65-7.76 (m,
4H).
Compound 23. Compound 15b/16b (0.6 g, 1.44 mmol) was
converted to an inseparable mixture of two diastereomers 23
following the general procedure (0.45 g, 81%): 1H NMR of the
mixture (CDCl3) δ 1.29 (s, 6H), 1.45/1.46 (each s, 6H), 2.44 (s,
6H), 2.48-2.56 (m, 2H), 3.07-3.16 (m, 2H), 3.27/3.38 (each s,
6H), 3.28-3.46 (m, 2H), 3.61-3.62 (m, 2H), 3.73-3.75 (m, 2H),
3.88-3.92 (m, 2H), 4.20-4.26 (m, 2H), 4.51-4.56 (m, 2H), 5.79/
5.82 (each d, 2H), 7.32-7.38 (m, 4H), 7.77-7.81 (m, 4H).
Compound 24. Compound 15c/16c (0.42 g, 0.85 mmol) was
converted to an inseparable mixture of two diastereomers 24
following the general procedure (0.29 g, 74%): 1H NMR of the
mixture (CDCl3) δ 1.34 (s, 6H), 1.54 (s, 6H), 2.43 (s, 6H), 3.25-
3.35 (m, 4H), 3.59-3.81 (m, 8H), 4.02-4.07 (m, 2H), 4.48-4.62
(m, 4H), 4.74-4.80 (m, 2H), 5.66/5.70 (each d, 2H), 7.31-7.37
(m, 14H), 7.70-7.80 (m, 4H).
General Procedure for the Synthesis of 25a/26a, 25b/26b, and
25c/26c. Compound 22, 23, or 24 (1 mmol) was reacted with tert-
butyldimethylchlorosilane (1 mmol) in the presence of a catalytic
amount of DMAP and Et3N (1.5 mmol) in dichloromethane (10
mL) at room temperature under Ar. After 24 h, the mixture was
poured into ice-water, and the aqueous solution was extracted with
dichloromethane (3 × 10 mL). The combined organic layers were
dried over anhyd Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure to obtain a residue. The residue
in dry MeOH (10 mL) was treated with Mg turnings (15 mmol) at
ambient temp. After 7 h, another portion of Mg turnings (15 mmol)
and dry MeOH (6 mL) were added. The mixture was stirred for an
additional 7 h. The reaction mixture was filtered through Celite.
The residue was washed thoroughly with MeOH. The filtrates were
pooled together, and the liquid was concentrated under reduced
pressure. The resulting residue was dissolved in EtOAc (20 mL)
and filtered. The filtrate was washed with water, dried over anhyd
Na2SO4, and filtered, and the filtrate was concentrated under reduced
pressure to obtain a residue. The residue was purified over a silica
gel column to afford 25a/26a, 25b/26b, or 25c/26c.
1
NMR of the mixture (CDCl3) δ 1.33/1.35 (each s, 6H), 1.61 (s,
6H), 2.46 (s, 6H), 3.25-3.63 (m, 8H), 4.13 (m, 4H), 4.46-4.80
(m, 8H), 5.68 (2d, 2H), 7.19-7.47 (m, 14H), 7.69-7.81 (m, 4H).
Compound 15f/16f. Compound 14f (0.4 g, 1.05 mmol) was
converted to an inseparable mixture of two diastereomers 15f/16f
1
following the general procedure (0.37 g, 79%): yellow gum; H
NMR of the mixture (CDCl3) δ 1.29 (s, 6H), 1.46 (s, 6H), 2.12/
2.15 (each s, 6H), 2.45 (s, 6H), 2.99-3.15 (m, 4H), 3.28-3.39
(m, 2H), 4.38-4.52 (m, 4H), 4.73-5.04 (m, 4H), 5.21-5.34 (m,
2H), 5.82/5.89 (each d, 2H), 7.36-7.40 (m, 4H), 7.75-7.83 (m,
4H).
Compound 17a/18a. Compound 14a (0.78 g, 1.81 mmol) was
converted to an inseparable mixture of two diastereomers 17a/18a
1
following the general procedure (0.96 g, 94%): yellow gum; H
NMR of the mixture (CDCl3) δ 1.26/1.29 (each s, 6H), 1.43/1.46
(each s, 6H), 2.38/2.42 (each s, 6H), 3.25-3.35 (m, 2H), 3.40-
3.44 (m, 4H), 3.64/3.69 (each s, 6H), 3.71/3.74 (each s, 6H), 3.98-
4.08 (m, 2H), 4.21-4.23 (m, 2H), 4.45-4.70 (m, 8H), 5.70/5.80
(each d, 2H), 7.16-7.36 (m, 14H), 7.45-7.70 (m, 4H).
Compound 17b/18b. Compound 14b (0.72 g, 2.03 mmol) was
converted to an inseparable mixture of two diastereomers 17b/18b
1
following the general procedure (0.94 g, 95%): yellow gum; H
NMR of the mixture (CDCl3) δ 1.26/1.30 (each s, 6H), 1.42/1.45
(each s, 6H), 2.44 (s, 6H), 3.20-3.31 (m, 2H), 3.35/3.37 (each s,
12H), 3.43-3.54 (m, 2H), 3.64/3.68 (each s, 6H), 3.73-3.76 (m,
2H), 3.82-3.84 (m, 2H), 4.18-4.22 (m, 2H), 4.41-4.56 (m, 4H),
5.76/5.78 (each d, 2H), 7.30-7.37 (m, 4H), 7.76-7.80 (m, 4H).
Compound 17c and 18c. Compound 14c (0.5 g, 1.16 mmol)
was converted to a separable mixture of two diastereomers 17c
and 18c following the general procedure (0.59 g, 90%). Compound
17c (0.34 g, 52%): eluent, EtOAc/petroleum ether (1:3); white
crystalline solid; solvent of crystallization ) EtOAc and petroleum
ether; mp 151 °C; [R]24D +23.4 (c 0.3, CHCl3); 1H NMR (CDCl3)
δ 1.34 (s, 3H), 1.53 (s, 3H), 2.39 (s, 3H), 2.93 (m, 1H), 3.48 (m,
1H), 3.66 (s, 3H), 3.72 (s, 3H), 3.79 (m, 2H), 3.90 (dd, J ) 4.4,
8.7 Hz, 1H), 4.29 (t, J ) 8.0 Hz, 1H), 4.64 (m, 2H), 4.80 (d, J )
11.1 Hz, 1H), 5.67 (d, J ) 3.6 Hz, 1H), 7.17 (d, J ) 8.1 Hz, 2H),
7.34 (m, 5H), 7.59 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl3) δ 21.5
(CH3), 26.7 (CH3), 26.8 (CH3), 36.0 (CH), 50.8 (CH), 52.2 (CH3),
52.8 (CH3), 53.1 (CH2), 71.6 (CH2), 77.2 (CH), 77.8 (CH), 80.9
(CH), 103.7 (CH), 113.3 (C), 127.7 (CH), 127.8 (2 × CH), 128.0
(2 × CH), 128.3 (2 × CH), 129.6 (2 × CH), 136.5 (C), 137.8 (C),
144.4 (C), 168.1 (C), 168.5 (C); IR (KBr) 1730, 1754 cm-1. Anal.
Calcd for C28H34O10S: C, 59.77; H, 6.09. Found: C, 59.75; H,
6.46. Compound 18c (0.23 g, 35%): eluent, EtOAc/petroleum ether
(1:3); yellow gum; [R]24D +7.2 (c 0.19, CHCl3); 1H NMR (CDCl3)
δ 1.30 (s, 3H), 1.51 (s, 3H), 2.39 (s, 3H), 3.24 (m, 1H), 3.32 (m,
1H), 3.59 (m, 2H), 3.66 (s, 3H), 3.70 (s, 3H), 3.79 (m, 1H), 4.27
(dd, J ) 3.2, 9.1 Hz, 1H), 4.43 (m, 1H), 4.54 (d, J ) 11.5 Hz,
1H), 4.70 (d, J ) 11.5 Hz, 1H), 5.56 (d, J ) 3.5 Hz, 1H), 7.33 (m,
7H), 7.76 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3) δ 21.5 (CH3),
26.6 (2 × CH3), 34.3 (CH), 52.1 (CH), 52.4 (CH3), 52.8 (CH3),
53.2 (CH2), 72.1 (CH2), 77.1 (CH), 77.6 (CH), 79.6 (CH), 103.8
(CH), 113.2 (C), 127.8 (CH), 128.0 (2 × CH), 128.1 (2 × CH),
128.3 (2 × CH), 129.8 (2 × CH), 136.7 (C), 137.5 (C), 144.6 (C),
168.0 (C), 168.2 (C); IR (KBr) 1731 cm-1. Anal. Calcd for
C28H34O10S: C, 59.77; H, 6.09. Found: C, 60.17; H, 6.18.
Compound 25a and 26a. Compound 22 (0.4 g, 0.86 mmol) was
converted to a separable mixture of two diastereomers 25a and 26a
following the general procedure. Compound 25a (0.17 g, 47%):
eluent, EtOAc/petroleum ether (1:6); yellow oil; [R]23 -31.5 (c
D
1
0.15, CHCl3) [[R]23 -32.0 (c 1.1, CHCl3)];12 selected H NMR
D
General Procedure for the Synthesis of 22, 23, and 24. A
mixture of 15a/16a, 15b/16b, or 15c/16c was dissolved separately
in tert-butyl alcohol (30 mL) at 60 °C. Warm solution was added
to potassium tertiary butoxide (2.5 mmol). The mixture was stirred
under N2 for 20 min while cooling to room temperature, and then
ethyl acetate (75 mL) was added. This was immediately followed
by an ice-cold solution of KMnO4 (1 mmol) in 30 mL of water.
The mixture was stirred vigorously for 20 min, and then the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic
(CDCl3) δ 0.83 (d, J ) 6.9 Hz, 3H) [0.82 (d, J ) 4.2 Hz, 3H)],12
3.81 (d, J ) 2.9 Hz, 1H) [3.81 (d, J ) 3.0 Hz, 1H)],12 4.59 (d, J
) 3.9 Hz, 1H) [4.59 (d, J ) 4.2 Hz, 1H)],12 5.89 (d, J ) 3.9 Hz,
1H) [5.88 (d, J ) 4.2 Hz, 1H)];12 13C NMR (CDCl3) δ -5.5, -5.4,
13.1, 18.2, 25.8, 26.2, 26.5, 34.4, 64.9, 71.6, 81.0, 81.4, 81.7, 104.7,
111.1, 127.8, 127.8, 128.3, 137.3. Anal. Calcd for C23H38O5Si: C,
65.36; H, 9.06. Found: C, 65.01; H, 8.84. Compound 26a (0.05
g, 15%): eluent, EtOAc/petroleum ether (1:6); yellow oil; [R]27.6
D
-48.6 (c 0.05, CHCl3); selected 1H NMR (CDCl3) δ 1.09 (d, J )
5530 J. Org. Chem., Vol. 72, No. 15, 2007

DiVersity-Oriented Synthesis of Branched-Chain Sugars
6.8 Hz, 3H) [1.09 (d, J ) 8.6 Hz, 3H)],12 3.84 (d, J ) 2.9 Hz, 1H)
[3.83 (d, J ) 3.0 Hz, 1H)],12 4.62 (d, J ) 3.9 Hz, 1H) [4.61 (d, J
) 4.2 Hz, 1H)],12 5.91 (d, J ) 4.0 Hz, 1H) [5.90 (d, J ) 4.2 Hz,
1H)];12 13C NMR (CDCl3) δ -5.5, -5.4, 14.6, 18.2, 25.8, 26.3,
34.1, 65.0, 71.5, 81.6, 81.8, 81.9, 104.3, 111.1, 127.9, 127.9, 128.4,
137.5. Anal. Calcd for C23H38O5Si: C, 65.36; H, 9.06. Found: C,
64.96; H, 9.34.
Compound 25b/26b. Compound 23 (0.18 g, 0.47 mmol) was
converted to an inseparable mixture of two diastereomers 25b/26b
(9:1) following the general procedure (0.12 g, 72%): eluent, EtOAc/
petroleum ether (1:6); yellow oil; 1H NMR of the mixture (CDCl3)
δ -0.01-0.04 (m, 12H), 0.88 (s, 18H), 0.93/1.09 (each d, 6H),
1.31/1.47 (each s, 12H), 1.97-2.04 (m, 2H), 3.39/3.40 (each s, 6H),
3.51-3.75 (m, 6H), 3.91-3.98 (m, 2H), 4.54-4.57 (m, 2H), 5.87
(d, 2H).
(TLC), the reaction mixture was poured into a saturated solution
of NH4Cl, and the product was extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried over anhyd Na2SO4 and
filtered, and the filtrate was concentrated under reduced pressure
to obtain a residue. The resulting residue was purified over a silica
gel column to afford compound 25c (0.06 g, 40%).
General Procedure for the Synthesis of 28, 30, 35, and 36. A
stirred solution of 17a/18a, 17b/18b, 17c, or 18c in a mixture of
DMSO (10 mL) and H2O (1 mL) containing NaCl (5 equiv/mmol)
was heated at 130 °C for 20-24 h. After completion of the reaction
(TLC), the reaction mixture was poured into a saturated solution
of NaCl, and the aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic layers were dried over anhyd Na2SO4
and filtered, and the filtrate was concentrated under reduced pressure
to obtain a residue. The residue was purified over silica gel column
to afford 28, 30, 35, or 36.
Compound 28. Compound 17a/18a (0.52 g, 0.92 mmol) was
converted to an inseparable mixture of two diastereomers 28 (3:1)
following the general procedure (0.35 g, 75%): eluent, EtOAc/
petroleum ether (1:2); yellow gum; 1H NMR of the mixture (CDCl3)
δ 1.34 (s, 6H), 1.45 (s, 6H), 2.41/2.45 (each s, 6H), 2.66-2.95 (m,
6H), 3.21-3.30 (m, 4H), 3.62/3.63 (each s, 6H), 3.88-3.90 (m,
2H), 4.36-4.46 (m, 4H), 4.52-4.66 (m, 4H), 5.81/5.84 (each d,
2H), 7.16-7.38 (m, 14H), 7.64-7.72 (m, 4H).
Compound 29. To a well-stirred solution of 28 (0.4 g, 0.79
mmol) in dry MeOH (10 mL) was added Mg turnings (15 mmol)
under Ar. The mixture was stirred at ambient temp. After 6 h,
another portion of Mg turnings (15 mmol) and dry MeOH (6 mL)
were added. The mixture was stirred for an additional 6 h. The
reaction mixture was filtered through Celite. The residue was
washed thoroughly with MeOH. The filtrates were pooled together,
and the liquid was concentrated under reduced pressure. The
resulting residue was dissolved in EtOAc (20 mL) and filtered. The
filtrate was washed with water, dried over anhyd Na2SO4, and
filtered, and the filtrate was concentrated under reduced pressure
to obtain a residue. The residue was purified over a silica gel column
Compound 25c and 26c. Compound 24 (0.15 g, 0.32 mmol)
was converted to a separable mixture of two diastereomers 25c
and 26c following the general procedure. Compound 25c (0.05 g,
36%): eluent, EtOAc/petroleum ether (1:6); yellow oil; [R]24
D
+76.9 (c 0.1, CHCl3); 1H NMR (CDCl3) δ 0.03 (s, 6H), 0.73 (d, J
) 7.1 Hz, 3H), 0.89 (s, 9H), 1.35 (s, 3H), 1.50 (s, 3H), 1.91 (m,
1H), 3.47 (m, 1H), 3.60 (m, 2H), 4.11 (dd, J ) 3.0, 9.2 Hz, 1H),
4.53 (m, 2H), 4.79 (d, J ) 12.1 Hz, 1H), 5.68 (d, J ) 3.6 Hz, 1H),
7.32 (m, 5H); 13C NMR (CDCl3) δ -5.4 (CH3), -5.3 (CH3), 10.5
(CH3), 18.3 (C), 25.9 (3 × CH3), 26.6 (CH3), 26.7 (CH3), 36.6
(CH), 65.5 (CH2), 71.9 (CH2), 77.2 (CH), 77.8 (CH), 78.4 (CH),
103.9 (CH), 112.6 (C), 128.0 (3 × CH), 128.4 (2 × CH), 137.7
(C). Anal. Calcd for C23H38O5Si: C, 65.36; H, 9.06. Found: C,
65.26; H, 9.14. Compound 26c (0.03 g, 24%): eluent, EtOAc/
petroleum ether (1:6); yellow oil; [R]23D +59.4 (c 0.2, CHCl3); 1H
NMR (CDCl3) δ 0.02 (s, 6H), 0.87 (s, 9H), 0.97 (d, J ) 6.9 Hz,
3H), 1.35 (s, 3H), 1.57 (s, 3H), 1.85 (m, 1H), 3.45 (m, 1H), 3.68
(m, 2H), 3.95 (m, 1H), 4.53 (m, 2H), 4.76 (d, J ) 11.7 Hz, 1H),
5.70 (d, J ) 3.9 Hz, 1H), 7.34 (m, 5H); 13C NMR (CDCl3) δ -5.4
(2 × CH3), 13.3 (CH3), 18.3 (C), 25.9 (3 × CH3), 26.7 (2 × CH3),
38.6 (CH), 64.9 (CH2), 71.9 (CH2), 77.4 (CH), 79.3 (CH), 80.2
(CH), 103.8 (CH), 112.6 (C), 127.9 (CH), 128.1 (2 × CH), 128.4
(2 × CH), 137.7 (C). Anal. Calcd for C23H38O5Si: C, 65.36; H,
9.06. Found: C, 65.49; H, 9.35.
to afford compound 29 (0.17 g, 61%): eluent, EtOAc/petroleum
1
ether (1:5); yellow oil; [R]24 -53.8 (c 0.17, CHCl3); H NMR
D
(CDCl3) δ 0.83 (d, J ) 6.7 Hz, 3H), 1.31 (s, 3H), 1.49 (s, 3H),
2.19 (dd, J ) 9.3, 15.0 Hz, 1H), 2.48 (m, 1H), 2.76 (dd, J ) 3.8,
15.0 Hz, 1H), 3.65 (s, 3H), 3.86 (m, 2H), 4.46 (d, J ) 11.7 Hz,
1H), 4.62 (d, J ) 3.9 Hz, 1H), 4.70 (d, J ) 11.7 Hz, 1H), 5.90 (d,
J ) 3.9 Hz, 1H), 7.34 (m, 5H); 13C NMR (CDCl3) δ 15.8 (CH3),
26.2 (CH3), 26.6 (CH3), 29.3 (CH), 38.4 (CH2), 51.3 (CH3), 71.7
(CH2), 81.2 (CH), 81.8 (CH), 83.7 (CH), 104.7 (CH), 111.3 (C),
127.9 (3 × CH), 128.4 (2 × CH), 137.2 (C), 173.3 (C); IR (KBr)
1734 cm-1. Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found:
C, 65.43; H, 7.31.
Compound 27. Compound 25a (0.05 g, 0.12 mmol), a catalytic
amount of 10% Pd-C, and a few drops of 88% aqueous formic
acid in ethanol (10 mL) were stirred at room temperature under a
H2 atmosphere. After 6 h, the residue was filtered, and the filtrate
was concentrated under reduced pressure to obtain a residue, and
the resulting residue was purified over a silica gel column to afford
27 (0.036 g, 89%): eluent, EtOAc/petroleum ether (1:1); yellow
oil; [R]23D -13.3 (c 0.1, CHCl3) [[R]23D -13.08 (c 1.3, CHCl3)];12
1
selected H NMR (CDCl3) δ 1.03 (d, J ) 7.1 Hz, 3H) [1.01 (d, J
) 7.0 Hz, 3H)],12 2.04 (m, 1H) [2.05 (m, 1H)],12 3.56 (dd, J )
4.6, 9.8 Hz, 1H) [3.52 (dd, J ) 4.8, 9.8 Hz, 1H)],12 3.78 (dd, J )
5.7, 9.8 Hz, 1H) [3.78 (dd, J ) 5.5, 9.8 Hz, 1H)],12 4.49 (d, J )
3.7 Hz, 1H) [4.48 (d, J ) 4.0 Hz, 1H)],12 5.89 (d, J ) 3.8 Hz, 1H)
[5.87 (d, J ) 4.0 Hz, 1H)];12 13C NMR (CDCl3) δ -5.6 (2 × CH3),
14.7 (CH3), 18.2 (C), 25.8 (3 × CH3), 26.1 (CH3), 26.6 (CH3),
34.9 (CH), 64.3 (CH2), 75.3 (CH), 82.0 (CH), 85.1 (CH), 104.3
(CH), 111.2 (C). Anal. Calcd for C16H32O5Si: C, 57.80; H, 9.70.
Found: C, 57.66; H, 9.45.
Compound 25c from Compound 27. Compound 27 (0.12 g,
0.36 mmol) was oxidized by CrO3 (0.14 g), py (0.06 mL), and
acetic anhydride (0.03 mL) in dry dichloromethane (10 mL). The
residue obtained was dissolved in ethanol (10 mL), cooled in an
ice bath, sodium borohydride (2.5 equiv/mmol) was added, and
the solution was stirred at ambient temperature for 16 h. Then the
reaction mixture was poured into ice-cold water, and the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic
layers were dried over anhyd Na2SO4 and filtered, and the filtrate
was concentrated under reduced pressure to obtain a residue. The
residue was benzylated with NaH (1.2 equiv/mmol), PhCH2Br (1.2
equiv/mmol), and DMF (5 mL). After completion of the reaction
Compound 30. Compound 17b/18b (0.32 g, 0.66 mmol) was
converted to 30 following the general procedure (0.22 g, 77%):
eluent, EtOAc/petroleum ether (1:2); white crystalline solid; solvent
of crystallization ) DCM/petroleum ether; mp 100 °C; [R]23D -56.3
1
(c 0.37, CHCl3); H NMR (CDCl3) δ 1.28 (s, 3H), 1.44 (s, 3H),
2.44 (s, 3H), 2.79 (m, 4H), 3.23 (s, 3H), 3.29 (m, 1H), 3.37 (m,
1H), 3.64 (s, 3H), 4.30 (m, 1H), 4.50 (d, J ) 3.9 Hz, 1H), 5.79 (d,
J ) 3.8 Hz, 1H), 7.35 (d, J ) 8.3 Hz, 2H), 7.78 (d, J ) 8.3 Hz,
2H); 13C NMR (CDCl3) δ 21.6 (CH3), 26.2 (CH3), 26.7 (CH3), 30.3
(CH), 33.3 (CH2), 51.5 (CH3), 55.5 (CH2), 57.2 (CH3), 79.5 (CH),
80.9 (CH), 83.7 (CH), 104.4 (CH), 111.6 (C), 128.0 (2 × CH),
129.8 (2 × CH), 136.4 (C), 144.6 (C), 172.3 (C); IR (KBr) 1731
cm-1. Anal. Calcd for C20H28O8S: C, 56.06; H, 6.59. Found: C,
56.46; H, 6.71.
General Procedure for the Synthesis of 32, 33, 37, and 38.
To a well-stirred solution of 28, 30, 35, or 36 in dry THF (10 mL)
was added LiAlH4 (5 equiv/mmol) at 0 °C under Ar, and the mixture
was stirred at ambient temp. After completion of the reaction (TLC),
saturated NH4Cl solution was added and the mixture was extracted
with EtOAc (3 × 10 mL). The combined organic layers were dried
over anhyd Na2SO4 and filtered, and the filtrate was concentrated
J. Org. Chem, Vol. 72, No. 15, 2007 5531

Das et al.
under reduced pressure to obtain a residue. The residue was
acetylated with pyridine and acetic anhydride and purified after
usual work up to afford compound 32, 33, 37, or 38.
(CH), 113.0 (C), 127.8 (2 × CH), 128.0 (2 × CH), 128.3 (2 ×
CH), 129.8 (3 × CH), 136.6 (C), 137.2 (C), 144.6 (C), 171.9 (C);
IR (KBr) 1734 cm-1. HRMS [ES+, (M + Na)+]: for C26H32O8-
SNa calcd 527.1716, obsd 527.1719.
Compound 32. Compound 28 (0.2 g, 0.4 mmol) was converted
to 32 via diol 31 following the general procedure (0.08 g, 65%):
Compound 37. Compound 35 (0.16 g, 0.32 mmol) was
converted to 37 following the general procedure (0.077 g, 77%):
eluent, EtOAc/petroleum ether (1:3); yellow oil; [R]22 -24.3 (c
D
0.23, CHCl3); 1H NMR (CDCl3) δ 0.84 (d, J ) 6.6 Hz, 3H), 1.30
(s, 3H), 1.51 (s, 3H), 1.97-2.17 (m, 3H), 2.04 (s, 3H), 2.10 (s,
3H), 3.90 (dd, J ) 2.5, 9.9 Hz, 1H), 4.16 (t, J ) 6.6 Hz, 2H), 4.46
(d, J ) 3.8 Hz, 1H), 5.16 (d, J ) 2.6 Hz, 1H), 5.87 (d, J ) 3.8 Hz,
1H); 13C NMR (CDCl3) δ 15.6 (CH3), 20.8 (CH3), 21.0 (CH3), 26.1
(CH3), 26.5 (CH3), 29.3 (CH), 32.8 (CH2), 62.6 (CH2), 76.0 (CH),
83.2 (CH), 83.3 (CH), 104.3 (CH), 111.7 (C), 169.9 (C), 171.1
(C); IR (KBr) 1737 cm-1. HRMS [ES+, (M + Na)+]: for C15H24O7-
Na calcd 339.1420, obsd 339.1406.
eluent, EtOAc/petroleum ether (1:3); yellow oil; [R]24 +32.8 (c
D
1
0.3, CHCl3); H NMR (CDCl3) δ 0.94 (d, J ) 6.7 Hz, 3H), 1.31
(s, 3H), 1.52 (s, 3H), 1.87 (m, 3H), 2.02 (s, 3H), 2.11 (s, 3H), 3.96
(dd, J ) 5.9, 8.9 Hz, 1H), 4.10 (m, 2H), 4.56 (dd, J ) 5.1, 9.1 Hz,
1H), 4.76 (t, J ) 4.6 Hz, 1H), 5.75 (d, J ) 3.9 Hz, 1H); 13C NMR
(CDCl3) δ 14.9 (CH3), 20.7 (CH3), 20.9 (CH3), 26.5 (CH3), 26.7
(CH3), 31.5 (CH2), 32.4 (CH), 62.5 (CH2), 73.9 (CH), 77.4 (CH),
80.7 (CH), 103.7 (CH), 112.6 (C), 170.2 (C), 171.1 (C); IR (KBr)
1741 cm-1. Anal. Calcd for C15H24O7: C, 56.95; H, 7.65. Found:
C, 56.56; H, 7.28.
Compound 33. Compound 30 (0.3 g, 0.7 mmol) was converted
to 33 following the general procedure (0.158 g, 79%): eluent,
Compound 38. Compound 36 (0.08 g, 0.16 mmol) was
converted to 38 following the general procedure (0.037 g, 74%):
EtOAc/petroleum ether (1:3); yellow oil; [R]24 -48.2 (c 0.3,
D
eluent, EtOAc/petroleum ether (1:3); yellow oil; [R]24 +19.8 (c
1
CHCl3); H NMR (CDCl3) δ 0.91 (d, J ) 6.6 Hz, 3H), 1.32 (s,
D
0.18, CHCl3); 1H NMR (CDCl3) δ 0.96 (d, J ) 6.7 Hz, 3H), 1.33
(s, 3H), 1.48 (s, 3H), 1.83 (m, 3H), 2.04 (s, 3H), 2.13 (s, 3H),
4.01-4.15 (m, 3H), 4.61 (dd, J ) 5.1, 9.2 Hz, 1H), 4.77 (m, 1H),
5.77 (d, J ) 3.9 Hz, 1H); 13C NMR (CDCl3) δ 13.9 (CH3), 20.7
(CH3), 20.9 (CH3), 26.5 (CH3), 26.7 (CH3), 31.0 (CH), 31.7 (CH2),
62.4 (CH2), 73.2 (CH), 77.4 (CH), 80.0 (CH), 103.8 (CH), 112.7
(C), 170.3 (C), 171.1 (C); IR (KBr) 1742 cm-1. Anal. Calcd for
C15H24O7: C, 56.95; H, 7.65. Found: C, 56.86; H, 7.58.
3H), 1.51 (s, 3H), 2.03 (s, 3H), 1.95-2.11 (m, 3H), 3.40 (s, 3H),
3.59 (d, J ) 3.0 Hz, 1H), 3.77 (dd, J ) 2.9, 10.0 Hz, 1H), 4.16 (t,
J ) 7.1 Hz, 2H), 4.56 (d, J ) 4.0 Hz, 1H), 5.88 (d, J ) 3.9 Hz,
1H); 13C NMR (CDCl3) δ 15.6 (CH3), 21.0 (CH3), 26.1 (CH3), 26.5
(CH3), 29.1 (CH), 32.7 (CH2), 57.5 (CH3), 62.7 (CH2), 80.9 (CH),
83.7 (CH), 84.5 (CH), 104.6 (CH), 111.0 (C), 171.2 (C); IR (KBr)
1738 cm-1. Anal. Calcd for C14H24O6: C, 58.32; H, 8.39. Found:
C, 57.94; H, 8.53.
General Procedure for the Synthesis of 39, 40, and 41.
Compound 19, 20, or 21 in dichloromethane (10 mL) was treated
with Et3N (2.5 equiv/mmol) for 2.5 h at ambient temperature. After
completion of the reaction (TLC), solvent was evaporated to dryness
under reduced pressure and the resulting residue was purified over
a silica gel column to afford 39, 40, or 41.
Compound 34. To a well-stirred solution of 29 (0.12 g, 0.34
mmol) in MeOH-H2O (4:1) was added KOH (2 equiv/mmol), and
the mixture was stirred at ambient temp. After completion of the
reaction (TLC), solvent was evaporated to dryness under reduced
pressure to obtain a residue, and the residue was dissolved in
saturated NH4Cl. The aqueous part was washed with EtOAc (3 ×
10 mL). The combined organic layers were dried over anhyd Na2-
SO4 and filtered, and the filtrate was concentrated under reduced
pressure to obtain a residue. The residue was hydrogenated with
10% Pd-C and MeOH under H2 atmosphere to afford 34 (0.057
Compound 39. Compound 19 (0.3 g, 0.65 mmol) was converted
to 39 following the general procedure (0.14 g, 70%): eluent, EtOAc/
petroleum ether (1:5); yellow oil; [R]24 -46.2 (c 0.44, CHCl3);
D
1H NMR (CDCl3) δ 1.33 (s, 3H), 1.50 (s, 3H), 4.27-4.63 (m, 4H),
5.02 (m, 1H), 5.98 (d, J ) 3.7 Hz, 1H), 6.25 (s, 1H), 6.69 (s, 1H),
7.16-7.31 (m, 5H), 9.55 (s, 1H); 13C NMR (CDCl3) δ 26.3 (CH3),
26.8 (CH3), 72.4 (CH2), 77.5 (CH), 81.9 (CH), 82.9 (CH), 104.2
(CH), 111.9 (C), 127.7 (2 × CH), 127.9 (CH), 128.3 (2 × CH),
135.7 (CH2), 137.3 (C), 145.0 (C), 192.9 (CH); IR (KBr) 1690
cm-1. HRMS [ES+, (M + Na)+]: for C17H20O5Na calcd 327.1208,
obsd 327.1172.
g, 73%): eluent, EtOAc/petroleum ether (1:3); yellow oil; [R]24
D
-7.1 (c 0.1, CHCl3) [[R]24 -7.2 (c 0.83, CHCl3)];17 selected H
1
D
NMR (CDCl3) δ 1.17 (d, J ) 6.5 Hz, 3H), 2.28 [2.24],17 2.42
[2.43],17 2.47 [2.46],17 4.33 [4.33],17 4.67 [4.67],17 4.70 [4.71],17
5.92 (d, J ) 3.7 Hz, 1H) [5.92 (d, J ) 4.0 Hz, 1H)];17 13C NMR
(CDCl3) δ 17.6 (CH3), 26.1 (CH3), 26.6 (CH3), 28.0 (CH), 32.0
(CH2), 75.2 (CH), 84.0 (2 × CH), 104.8 (CH), 112.3 (C), 168.9
(C); IR (KBr) 1740 cm-1. Anal. Calcd for C11H16O5: C, 57.89; H,
7.07. Found: C, 58.02; H, 7.37.
Compound 40. Compound 20 (0.25 g, 0.65 mmol) was
converted to 40 following the general procedure (0.118 g, 80%):
eluent, EtOAc/petroleum ether (1:6); yellow oil; [R]24D -101.6 (c
0.35, CHCl3); 1H NMR (CDCl3) δ 1.34 (s, 3H), 1.51 (s, 3H), 3.28
(s, 3H), 4.08 (d, J ) 3.4 Hz, 1H), 4.62 (d, J ) 3.8 Hz, 1H), 4.97
(m, 1H), 5.96 (d, J ) 3.8 Hz, 1H), 6.23 (s, 1H), 6.66 (s, 1H), 9.58
(s, 1H); 13C NMR (CDCl3) δ 26.2 (CH3), 26.8 (CH3), 58.0 (CH3),
77.5 (CH), 82.0 (CH), 83.8 (CH), 104.1 (CH), 111.9 (C), 135.4
(CH2), 145.0 (C), 192.9 (CH); IR (KBr) 1690 cm-1. Anal. Calcd
for C11H16O5: C, 57.89; H, 7.07. Found: C, 57.93; H, 7.06.
Compound 41. Compound 21 (0.22 g, 0.48 mmol) was
converted to 41 following the general procedure (0.06 g, 41%):
eluent, EtOAc/petroleum ether (1:4); yellow oil; [R]24D +125.5 (c
0.12, CHCl3); 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.62 (s, 3H), 3.97
(m, 1H), 4.49 (d, J ) 12.2 Hz, 1H), 4.64 (m, 2H), 4.82 (d, J ) 8.8
Hz, 1H), 5.80 (d, J ) 3.6 Hz, 1H), 6.12 (s, 1H), 6.40 (s, 1H), 7.31
(m, 5H), 9.54 (s, 1H); 13C NMR (CDCl3) δ 26.5 (CH3), 26.8 (CH3),
72.3 (CH2), 76.0 (CH), 77.8 (CH), 81.2 (CH), 104.2 (CH), 113.3
(C), 128.0 (3 × CH), 128.4 (2 × CH), 136.4 (CH2), 137.4 (C),
145.8 (C), 192.2 (CH); IR (KBr) 1695 cm-1. HRMS [ES+, (M +
Na)+]: for C17H20O5Na calcd 327.1208, obsd 327.1172.
Compound 35. Compound 17c (0.3 g, 0.53 mmol) was converted
to 35 following the general procedure (0.2 g, 74%): eluent, EtOAc/
petroleum ether (1:2); yellow oil; [R]24 +30.3 (c 0.36, CHCl3);
D
1H NMR (CDCl3) δ 1.32 (s, 3H), 1.53 (s, 3H), 2.43 (s, 3H), 2.60
(m, 3H), 3.22 (m, 1H), 3.50 (m, 1H), 3.61 (s, 3H), 3.70 (m, 1H),
4.11 (m, 1H), 4.47 (d, J ) 11.5 Hz, 1H), 4.55 (t, J ) 4.1 Hz, 1H),
4.74 (d, J ) 11.5 Hz, 1H), 5.63 (d, J ) 3.7 Hz, 1H), 7.28 (m, 7H),
7.70 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3) δ 21.6 (CH3), 26.7 (2
× CH3), 32.7 (CH), 33.8 (CH2), 51.6 (CH3), 55.5 (CH2), 71.8 (CH2),
77.4 (CH), 78.2 (CH), 80.1 (CH), 103.6 (CH), 113.1 (C), 128.0 (5
× CH), 128.5 (2 × CH), 129.8 (2 × CH), 136.4 (C), 137.2 (C),
144.6 (C), 172.0 (C); IR (KBr) 1733 cm-1. Anal. Calcd for
C26H32O8S: C, 61.89; H, 6.39. Found: C, 62.26; H, 6.18.
Compound 36. Compound 18c (0.2 g, 0.35 mmol) was converted
to 36 following the general procedure (0.125 g, 70%): eluent,
EtOAc/petroleum ether (1:2); yellow oil; [R]23 +34.9 (c 0.26,
D
1
CHCl3); H NMR (CDCl3) δ 1.29 (s, 3H), 1.51 (s, 3H), 2.41 (s,
3H), 2.68 (m, 3H), 3.28 (m, 2H), 3.53 (s, 3H), 3.59 (dd, J ) 4.4,
8.9 Hz, 1H), 4.01 (m, 1H), 4.42 (d, J ) 11.5 Hz, 1H), 4.51 (t, J )
4.1 Hz, 1H), 4.66 (d, J ) 11.5 Hz, 1H), 5.60 (d, J ) 3.8 Hz, 1H),
7.32 (m, 7H), 7.76 (d, J ) 8.3 Hz, 2H); 13C NMR (CDCl3) δ 21.5
(CH3), 26.5 (CH3), 26.6 (CH3), 32.8 (CH), 34.0 (CH2), 51.4 (CH3),
55.8 (CH2), 71.7 (CH2), 77.3 (CH), 78.6 (CH), 79.8 (CH), 103.6
Compound 42. To a well-stirred solution of 31 (0.15 g, 0.65
mmol) in a 1:1 toluene/pyridine mixture (1.5 mL) was added tosyl
chloride (1.2 equiv/mmol) in toluene (5 mL) at -10 °C. After 72
h at 6 °C, the mixture was filtered and the filtrate was concentrated
5532 J. Org. Chem., Vol. 72, No. 15, 2007

DiVersity-Oriented Synthesis of Branched-Chain Sugars
under reduced pressure to obtain a residue. The residue was purified
over a silica gel column. Then the purified compound was treated
with THF-H2O (9:1) and NaOH (2 equiv/mmol). After completion
of the reaction (TLC), saturated NH4Cl solution was added and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhyd Na2SO4 and filtered, and the
filtrate was concentrated under reduced pressure to obtain a residue.
The residue was purified over a silica gel column to afford 42 (0.12
General Procedure for the Synthesis of 45 and 46. A mixture
of compounds 17a/18a or 17b/18b was stirred at room temperature
with 90% trifluoroacetic acid (10 mL) for 3.5 h. After completion
of the reaction (TLC), solvent was evaporated to dryness under
reduced pressure to get a residue. The residue was acetylated with
acetic anhydride and pyridine and purified after usual work up to
afford compound 45 or 46.
Compound 45. A mixture of compounds 17a/18a (0.9 g, 1.60
mmol) was converted to 45 following the general procedure (0.57
g, 62%): eluent, EtOAc/petroleum ether (1:2); white crystalline
solid; solvent of crystallization ) EtOAc and petroleum ether; mp
212 °C; [R]24D +39.5 (c 0.4, CHCl3); 1H NMR (CDCl3) δ 1.97 (s,
3H), 2.06 (s, 3H), 2.42 (s, 3H), 2.88 (m, 1H), 3.24 (m, 2H), 3.70
(s, 3H), 3.94 (m, 1H), 4.74 (dd, J ) 11.3, 40.9 Hz, 2H), 5.25 (m,
1H), 5.54 (d, J ) 4.9 Hz, 1H), 5.63 (d, J ) 5.0 Hz, 1H), 7.16 (d,
J ) 8.0 Hz, 2H), 7.41 (m, 5H), 7.67 (d, J ) 8.3 Hz, 2H); 13C
NMR (CDCl3) δ 20.2 (CH3), 20.4 (CH3), 21.7 (CH3), 41.5 (CH),
53.0 (CH2), 53.1 (CH3), 56.3 (C), 67.3 (CH), 70.3 (CH), 73.0 (CH2),
74.0 (CH), 75.8 (CH), 128.1 (2 × CH), 128.3 (2 × CH), 128.5
(CH), 128.7 (2 × CH), 130.2 (2 × CH), 134.8 (C), 136.3 (C), 145.7
(C), 165.2 (C), 168.3 (C), 168.7 (C), 169.7 (C); IR (KBr) 1736,
1758, 1817 cm-1. Anal. Calcd for C28H30O11S: C, 58.53; H, 5.26.
Found: C, 58.32; H, 5.40.
g, 87%): eluent, EtOAc/petroleum ether (1:5); yellow oil; [R]24
D
1
-33.9 (c 0.1, CHCl3); H NMR (CDCl3) δ 1.11 (d, J ) 6.8 Hz,
3H), 1.31-1.41 (br s, 4H), 1.50 (s, 3H), 1.61 (m, 1H), 1.85 (m,
1H), 3.36 (m, 1H), 3.82 (m, 2H), 4.03 (m, 1H), 4.43 (d, J ) 3.8
Hz, 1H), 5.89 (d, J ) 3.8 Hz, 1H); 13C NMR (CDCl3) δ 18.3 (CH3),
26.1 (CH3), 26.6 (CH3), 28.1 (CH2), 30.6 (CH), 66.7 (CH2), 77.4
(CH), 79.3 (CH), 83.7 (CH), 105.0 (CH), 111.2 (C). Anal. Calcd
for C11H18O4: C, 61.66; H, 8.47. Found: C, 61.32; H, 8.45.
Compound 43. To a well-stirred solution of 15f/16f (0.33 g,
0.74 mmol) in MeOH (15 mL) was added NaOMe (1.5 equiv/
mmol), and the mixture was stirred at ambient temperature for 2.5
h. After completion of the reaction (TLC), MeOH was evaporated
to dryness under reduced pressure, and the residue was dissolved
in saturated NaHCO3. The mixture was extracted with EtOAc (3
× 10 mL). The combined organic layers were dried over anhyd
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure to obtain a residue. The residue was purified over a silica
gel column to obtain compound 43 (0.25 g, 83%): eluent, EtOAc/
petroleum ether (1:1); yellow gum; 1H NMR of the mixture (CDCl3)
δ 1.34 (s, 6H), 1.45 (s, 6H), 2.46 (s, 6H), 3.07-3.64 (m, 6H), 4.18-
4.36 (m, 6H), 4.47-4.82 (m, 4H), 5.85/5.89 (each d, 2H), 7.30-
7.42 (m, 4H), 7.76-7.82 (m, 4H).
Compound 46. A mixture of compounds 17b/18b (0.75 g, 1.54
mmol) was converted to 46 following the general procedure (0.41
g, 53%): eluent, EtOAc/petroleum ether (1:2); white crystalline
solid; solvent of crystallization ) EtOAc and petroleum ether; mp
1
166 °C; [R]24 +22.1 (c 0.23, CHCl3); H NMR (CDCl3) δ 1.96
D
(s, 3H), 2.06 (s, 3H), 2.49 (s, 3H), 2.91 (m, 1H), 3.25 (m, 2H),
3.56 (s, 3H), 3.71 (s, 3H), 3.74 (m, 1H), 5.20 (m, 1H), 5.48 (m,
1H), 5.61 (d, J ) 5.0 Hz, 1H), 7.40 (d, J ) 8.0 Hz, 2H), 7.76 (d,
J ) 8.3 Hz, 2H); 13C NMR (CDCl3) δ 20.1 (CH3), 20.3 (CH3),
21.6 (CH3), 41.2 (CH), 53.0 (CH3), 53.2 (CH2), 56.3 (C), 58.8
(CH3), 66.8 (CH), 70.2 (CH), 75.7 (CH), 76.5 (CH), 128.1 (2 ×
CH), 130.2 (2 × CH), 135.2 (C), 145.7 (C), 165.2 (C), 168.3 (C),
168.6 (C), 169.5 (C); IR (KBr) 1734, 1759, 1826 cm-1. Anal. Calcd
for C22H26O11S: C, 53.01; H, 5.26. Found: C, 53.08; H, 5.66.
Compound 44. To a well-stirred solution of 43 (0.18 g, 0.45
mmol) in MeI (5 mL) was added Ag2O (1.0 equiv/mmol), and the
mixture was stirred at ambient temperature for 6 h. After completion
of the reaction (TLC), saturated NH4Cl solution was added, and
the mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhyd Na2SO4 and filtered, and the
filtrate was concentrated under reduced pressure to obtain a residue.
The residue was purified over a silica gel column to afford
compound 44 (0.11 g, 62%): eluent, EtOAc/petroleum ether (1:
4); white crystalline solid; solvent of crystallization ) DCM and
1
petroleum ether; mp 155 °C; [R]26 +107.0 (c 0.1, CHCl3); H
Acknowledgment. This work has been supported by a
research grant from the Department of Science and Technology,
New Delhi, India. I.D. and T.K.P. thank the Council of Scientific
and Industrial Research, New Delhi, India, for a fellowship.
D
NMR (CDCl3) δ 1.31 (s, 3H), 1.43 (s, 3H), 2.46 (s, 3H), 3.19 (m,
1H), 3.46 (m, 1H), 3.70 (m, 1H), 4.73 (d, J ) 3.7 Hz, 1H), 4.85
(m, 1H), 4.99 (d, J ) 2.4 Hz, 1H), 5.60 (d, J ) 5.2 Hz, 1H), 5.85
(d, J ) 3.6 Hz, 1H), 7.38 (d, J ) 8.2 Hz, 2H), 7.81 (d, J ) 8.2 Hz,
2H); 13C NMR (CDCl3) δ 21.6 (CH3), 26.5 (CH3), 26.9 (CH3), 45.2
(CH), 53.0 (CH2), 81.7 (CH), 82.4 (CH), 89.8 (CH), 106.3 (CH),
110.1 (CH), 112.8 (C), 128.1 (2 × CH), 130.1 (2 × CH), 135.4
(C), 145.4 (C); IR (KBr) 1558, 1561 cm-1. Anal. Calcd for C17H21-
NO8S: C, 51.12; H, 5.30; N, 3.51. Found: C, 51.33; H, 4.99; N,
3.77.
Supporting Information Available: Crystallographic informa-
tion files for 17c, 30, 44, 45, and 46 and spectra for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO062373+
J. Org. Chem, Vol. 72, No. 15, 2007 5533