Diastereoselective addition of amines to vinyl sulfone modified carbohydrates: A highly flexible methodology for the synthesis of new classes of deoxyaminosugars

Article abstract of DOI:10.1021/jo991380d

Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfony-α-D- erythro-hex-2-enopyranoside (5α) and methyl 2,3-dideoxy-4,6-O- (phenylmethylene)-3-C-phenylsulfonyl-β-D-erythro-hex-2-enopyranoside (5β) have been subjected to Michael addition reaction with various amines to develop a new methodology for the synthesis of new classes of aminosugars. Compound 5α reacted with primary amines to generate gluco- derivatives, but secondary amines produced both gluco- (major) and manno- (minor) isomers. Compound 5β, on the other hand, produced only gluco- isomers with both primary and secondary amines. The stereochemical course of addition of some of the amines to 5α and 5β are significantly different from that of the addition of amines to 3-nitroenopyranoses. The present route to the syntheses of various aminosugars with gluco- configurations from 5α and 5β constitutes a novel method for the introduction of N-monoalkylated and N,N- dialkylated amines to the C-2 carbon of pyranoses in equatorial configurations.

Full text of DOI:10.1021/jo991380d

J . Org. Chem. 2000, 65, 2637-2641
2637
Dia ster eoselective Ad d ition of Am in es to Vin yl Su lfon e Mod ified
Ca r boh yd r a tes: A High ly F lexible Meth od ology for th e Syn th esis
of New Cla sses of Deoxya m in osu ga r s
Bindu Ravindran,† Kandasamy Sakthivel,§ Cheravakkattu. G. Suresh,‡ and
Tanmaya Pathak*.†
aOrganic Chemistry Division (Synthesis) and bDivision of Biochemical Sciences,
National Chemical Laboratory, Pune 411 008, India
Received August 31, 1999
Methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl-R-D-erythro-hex-2-enopyranoside
(5r) and methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-3-C-phenylsulfonyl-â-D-erythro-hex-2-eno-
pyranoside (5â) have been subjected to Michael addition reaction with various amines to develop
a new methodology for the synthesis of new classes of aminosugars. Compound 5r reacted with
primary amines to generate gluco- derivatives, but secondary amines produced both gluco- (major)
and manno- (minor) isomers. Compound 5â, on the other hand, produced only gluco- isomers with
both primary and secondary amines. The stereochemical course of addition of some of the amines
to 5r and 5â are significantly different from that of the addition of amines to 3-nitroenopyranoses.
The present route to the syntheses of various aminosugars with gluco- configurations from 5r and
5â constitutes a novel method for the introduction of N-monoalkylated and N,N-dialkylated amines
to the C-2 carbon of pyranoses in equatorial configurations.
In tr od u ction
outcome of the reduction of the carbonyl group (C-4) is
dependent on the orientation of the C-2 substituent.2
Such limitations made this route less attractive for
synthetic work. The studies on the addition of nitrogen
nucleophiles to 3-nitro-hex-2-enopyranosides, however,
have remained limited mostly to gluco- and galactopy-
ranoses,3 and except for the preparation of a few diamino-
and triaminosugars,4 these nitrosugar derivatives have
not been utilized as intermediates for further synthetic
manipulations.
Aminosugars are one of the most important classes
of modified carbohydrates.1 The most common methods
for the synthesis of aminosugars involve the reactions
of amines with sugar-derived epoxides, tosylates, and
ketones, although several other minor methods are
also reported.1 Nucleophilic addition (Michael) to double
bonds activated by electron-withdrawing groups as
part of carbohydrates could, in theory, serve as a useful
methodology for the functionalization of monosaccha-
rides. Several examples of Michael addition of nitrogen
nucleophiles including amines to hex-2-enose2 and 3-ni-
tro-hex-2-enopyranosides3,4 have been reported. 2,3-
Dideoxy-hex-2-en-4-ulopyranosides, for example, have
been reacted with azide,2a partially protected amino acids
and benzylamine2b to generate several new classes of
aminosugars. The major drawbacks of using 4-uloses as
starting materials are that (a) the products will always
be 2,3-dideoxy derivatives and (b) the stereochemical
Resu lts a n d Discu ssion
During the course of our studies on the synthesis of
carbohydrate modified monovinyl sulfone5a and bisvinyl
sulfone substituted nucleosides,5b we envisaged that as
a result of the high reactivities of vinyl sulfones toward
a wide variety of nucleophiles, vinyl sulfone modified
carbohydrates could be utilized to generate a wide variety
of modified monosaccharides. Vinyl sulfone modified
carbohydrates are expected to offer the following advan-
tages: (a) Almost all carbohydrates, either in pyranose
or furanose forms, could be converted to their vinyl
sulfone derivatives very easily, the first step being the
simple nucleophilic displacements of sulfonylates1b or
regioselective opening of epoxides1b by alkyl or aryl
mercaptans at various positions. (b) Since sulfone chem-
istry has been exploited extensively over decades and its
compatibility with a wide variety of simple and complex
molecules and reaction conditions are well established,6
vinyl sulfone modified carbohydrates could be used
† Organic Chemistry Division (Synthesis).
‡ Division of Biochemical Sciences.
§ Present address: The Skaggs Institute for Chemical Biology and
the Department of Molecular Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, CA 92037.
(1) Ferrier, R. J . (Senior Reporter). Carbohydrate Chemistry; The
Royal Society of Chemistry, Cambridge: 1968-1996; Vols. 1-28. (b)
Collins, P. M.; Ferrier, R. J . Monosaccharides: Their Chemistry and
Their Roles in Natural Products; J ohn Wiley & Sons: Chichester, 1996.
(2) J egou, E.; Cleophax, J .; Leboul, J .; Gero, S. D. Carbohydr. Res.
1975, 45, 323. (b) Apostolopoulos, C. D.; Couladouros, E. A.; Georgiadis,
M, P. Liebigs Ann. Chem. 1994, 781. (c) Couladouros, E. A.; Constan-
tinou-Kokotou, V.; Georgiadis, M. P Kokotos, G. Carbohydr. Res. 1994,
254, 317.
(3) Nakagawa, T.; Sakakibara, T.; Kumazawa, S. Tetrahedron Lett.
1970, 11, 1645. (b) Rajabalee, F. J -M. Carbohydr. Res. 1973, 26, 219.
(c) Sakakibara, T.; Sudoh, R. Carbohydr. Res. 1976, 50, 191. (d)
Sakakibara, T.; Sudoh, R. J . Org. Chem. 1977, 42, 1746. (e) Sudoh, R.
Tetrahedron 1984, 40, 1533. (f) Sakakibara, T.; Ohkita, N.; Nakagawa,
T. Bull. Chem. Soc. J pn. 1992, 65, 446.
(4) Baer, H. H.; Neilson, T. J . Org. Chem. 1967, 32, 1068. (b)
Lichtenthaler, F. W.; Vors, P.; Mayer, N. Angew. Chem., Int. Ed. 1969,
8, 211.
(5) Bera, S.; Sakthivel, K.; Langley, G. J .; Pathak, T. Tetrahedron
1995, 51, 7857. (b) Bera, S.; Langley, G. J .; Pathak, T. J . Org. Chem.
1998, 63, 1754.
(6) Schank, K. In The Chemistry of Sulphones & Sulphoxides; Patai,
S., Rappoport, Z., Stirling, C., Eds.; J ohn Wiley & Sons: New York,
1988. (b) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993.
10.1021/jo991380d CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

2638 J . Org. Chem., Vol. 65, No. 9, 2000
Ravindran et al.
Sch em e 1
Sch em e 2
Sch em e 3
extensively as versatile synthons. (c) After using the
vinyl sulfone moiety as a tool for functionalization,
whenever necessary, the sulfone group could be removed
oxidatively6b,7 or reductively6b,8 with ease to regenerate
a hydroxyl group or methylene group, respectively, on
the carbon carrying the sulfone group. (d) Sulfur dioxide
extrusion reactions6 could be applied to cyclic and acyclic
derivatives to access further modified monosaccharides.
Thus, a more thorough study of the synthetic application
of the Michael addition to vinyl sulfones derived from
carbohydrates is highly desirable. To initiate a systematic
study on the reaction patterns of endocyclic monovinyl
sulfones derived from carbohydrates,9 the easily acces-
sible anomers methyl 2,3-dideoxy-4,6-O-(phenylmethyl-
ene)-3-C-phenylsulfonyl-R-D-erythro-hex-2-enopyrano-
side (5r) and methyl 2,3-dideoxy-4,6-O-(phenylmethylene)-
3-C-phenylsulfonyl-â-D-erythro-hex-2-enopyranoside (5â)
were selected as the first set of candidates.
Compounds 5r and 5â were, therefore, synthesized in
high yields from the known epoxides 1r and 1â, respec-
tively (Scheme 1). Epoxide 1r10 was reacted with thiophe-
nol in the presence of 1,1,3,3-tetramethylguanidine (TMG)
to afford 2r. The corresponding sulfone derivative 3r was
generated in quantitative yield by oxidizing 1r with
magnesium monoperoxypthalate (MMPP). Compound 3r
was mesylated at 0 °C using methanesulfonyl chloride
(MsCl) in pyridine. The crude mesylated product 4r was
subjected to an elimination reaction with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in dichloromethane to produce
5r in 88% overall yield (four steps from 1r). Similarly,
thiophenol in the presence of TMG opened epoxide 1â11
at the 3-position to generate 2â. Oxidation of 2â, followed
by mesylation and DBU treatment, generated the desired
compound 5â in 75% overall yield (four steps from 1â).
The R-vinyl sulfone derivative 5r was reacted with
various primary and secondary amines. Reaction condi-
tions and yields are summarized in Scheme 2. Primary
amines, such as isobutylamine and cyclohexylamine,
were found to add diastereoselectively to produce single
isomers 6a and 6b, respectively. The secondary amines,
pyrrolidine, piperdine, morpholine, and ethyl isonipeco-
tate, on the other hand, generated a mixture of C-2
isomers having 6c, 6d , 6e, and 6f as the major isomers,
respectively. The ratios of the isomers were determined
on the crude mixture (1H NMR) to avoid loss of any of
the isomers during column purification. The major gluco-
isomers, 6c-f, were separated by crystallization. The
minor manno- isomer 7c was isolated to unambiguously
establish its structure.
Similarly, the anomeric â-vinyl derivative 5â was
treated with isobutylamine, pyrrolidine, and morpholine.
These primary and secondary amines were found to add
diastereoselectively to produce single isomers 8a , 8c, and
8e, respectively (Scheme 3).
(7) Little, R. D.; Myong, S. O. Tetraheron Lett. 1980, 21, 3339. (b)
Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J . A. J . Org.
Chem. 1998, 63, 9728.
1
(8) Brow, A. C.; Carpino, A. L. J . Org. Chem. 1985, 50, 1749.
(9) Cassidy, J . F.; Williams, J . M. Tetrahedron Lett. 1986, 27, 4355.
(b) Sakakibara, T.; Takaki, I.; Tachimori, Y.; Yamamoto, A.; Ishido,
Y.; Sudoh, R. Carbohydr. Res. 1987, 160, C3. (c) Wu, J .-C.; Pathak, T.;
Tong, W.; Vial, J . M.; Remaud, G.; Chattopadhyaya, J . Tetrehedron
1988, 44, 6705. (d) Takai, I.; Yamamoto, A.; Ishido, Y.; Sakakibara,
T.; Yagi, E. Carbohydr. Res. 1991, 220, 195. (e) Marot, C.; Rollin, P.
Phosphorus, Sulfur Silicon Relat. Elem. 1994, 95-96, 503.
(10) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
The H NMR data of the Michael adducts are consis-
tent with the assigned structures. The J 1,2 values (3.1-
3.6 Hz) of compounds 6a -f are comparable to those of
methyl 2-N-alkylamino-2,3-dideoxy-3-nitro-4,6-O-(phen-
(11) Kim, K. S.; Vyas, D. M.; Szarek, W. A. Carbohydr. Res. 1979,
72, 25.

Synthesis of New Classes of Deoxyaminosugars
J . Org. Chem., Vol. 65, No. 9, 2000 2639
static repulsion by C1-O1 and C1-O5 bonds3d and (b)
thermodynamically more stable diequatorial products
should predominate.3d Nevertheless to explain the forma-
tion of manno- isomers (such as 7c), it is necessary to
assume the existence of a stereoelectronic factor respon-
sible for repelling the incoming secondary amines from
equatorial direction, although the exact nature of the
hindrance cannot be rationalized at this point.
F igu r e 1.
Compound 5â, on the other hand, on reaction with both
primary and bulky secondary amines produced thermo-
dynamically more stable diequatorial products. In this
case, it is difficult to establish conclusively whether the
electrostatic repulsion between attacking amines, C1-
O1 and C1-O5 bonds directed the nucleophiles to attack
the C-2 position of 5â from the equatorial direction,
resulting in the formation of single isomers 8. This
observation, nevertheless, falls more in line with the
generalized rule that in the case of an â-anomeric
substrate, a nucleophile should approach the C-2 site
preferably from the equatorial direction.3d
ylmethylene)-R-D-glucopyranosides (2.9-3.7 Hz).3b For
the minor isomer 7c, H-1 appeared as a singlet, which is
consistent with the very small J 1,2 values (equatorial
H-1-equatorial H-2 arrangement) reported for methyl
2-azido-2,3-dideoxy-3-nitro-4,6-O-(phenylmethylene)-R-D-
mannopyranoside (1 Hz) and the corresponding 2-cyano-
R-mannopyranoside (1.3 Hz).3c In case of 8a , 8c, and 8e,
H-1 signals appeared as doublets with large coupling
constant (J 1,2) values of 4.6-6.8 Hz, which are in line with
the large values reported for methyl 2-N-alkylamino-2,3-
dideoxy-3-nitro-4,6-O-(phenylmethylene)-â-D-glucopyran-
osides (7.7-8.5 Hz).3b
It has been reported that the addition of p-toluenethiol
to 1-p-tolylsulfonylcyclohexene produced cis-2-p-tolyl-
mercapto-1-p-tolylsulfonylcyclohexane and not the ther-
modynamically more stable trans product. It was estab-
lished that, because an arylsulfonyl group had a much
larger steric requirement than an arylmercapto group,
the former should tend to occupy an equatorial position.12
The stereochemistry of nucleophilic addition reactions to
more complicated systems such as 3-nitro-hex-2-enopy-
ranosides 10r and 10â (Figure 1),3 however, has been
discussed in terms of electrostatic interactions,3d stereo-
electronic control,3d steric hindrance,3d A(1,3) strain,3e and
also hydrogen bonding.3e A generalization that the axial
attack predominates over equatorial attack for 10r and
the converse is true for 10â has been arrived at on the
basis of reactions of 10r and 10â with several nucleo-
philes.3d Interestingly, one of the earliest works in this
area contradicted this generalization by reporting that,
irrespective of the anomeric configuration of the Michael
acceptor and steric bulk/nucleophilicity of the incoming
nucleophiles, addition of amines to 10r and 10â produced
thermodynamically more stable C-2 equatorial products.3b
Sterically demanding purine bases, however, added to
10r and 10â from the â3c and R3a sides, respectively. 2,3-
Dideoxy-hex-2-en-4-ulopyranosides, on the other hand,
always produced epimeric mixture at C-2.2
In light of the above observations, it can be stated that
the stereochemical course of addition of amines to 5 does
not fully obey any of the precedence. Structural analysis
by 1H NMR spectroscopy showed that in a partially rigid
bicyclic system of 5 the sterically bulky phenylsulfonyl
group will always occupy the equatorial position. In case
of 5R, primary amines always attacked the C-2 center
from the equatorial direction to produce thermodynami-
cally more stable diequatorial products. Interestingly,
however, sterically bulky secondary amines on reaction
with 5r produced a mixture of products, epimeric at C-2,
in comparison with the work of Rajabalee and co-
workers3b that produced only C-2 equatorial products
with both 10r and 10â. To explain the formation of a
mixture of products 6c-f and 7c-f, one has to bear in
mind the established rules that (a) secondary amines
carrying nonbonded electron pairs would face electro-
Con clu sion
We have established that vinyl sulfone modified
carbohydrates are very useful intermediates for the
synthesis of several new deoxyaminosugars. The
present study acquires greater importance in view of the
significant role of C-N equatorial bonds in carbohy-
drates. Thus, naturally occurring aminosugars, such as
D-glucosamine,1b D-galactosamine,1b D-lividosamine,1b,13
etc, which are vital components of biologically important
macromolecules, have their C-N bonds at C-2 in equa-
torial configurations. N-Alkyl- and N,N-dialkyl-D-glucos-
amine derivatives, for example, have been synthesized
in the past by N-alkylation or N,N-dialkylation of glu-
cosamine in a linear fashion.14 The other most commonly
used methods for the synthesis of aminosugars involved
the opening of epoxides 1r or 1â by amines which always
produced the C-3 deoxy C-3 aminosugars and not the C-2
deoxy C-2 aminosugars.15 Reactions of primary and
secondary amines with methyl 2,3-anhydro-4,6-O-(phen-
ylmethylene)-D-allopyranoside, on the other hand, pro-
duced exclusively the C-2 deoxy C-2 amino products with
the C-N bond in an axial configuration.16 Syntheses of
compounds 6 and 8 from 5r and 5â respectively, there-
fore, constitute one of the few examples of the introduc-
tion of N-monoalkylated and N,N-dialkylated amines to
the C-2 carbon of pyranoses in equatorial configurations.
Carbon nucleophiles also add to 5r and 5â with equal
ease but with a different pattern of diastereoselectivity,
leading to the synthesis of novel branched sugars; this
subject will be dealt with separately in a forthcoming
publication.17 Application of this methodology to various
other pyranose and furanose sugars is also currently in
progress.18
(13) Mori, T.; Ichyanasi, T.; Kondo, H.; Tokkunasa, T.; Oda, T.;
Munakata, T. J . Antibiot. Ser. A 1971, 24, 339.
(14) Takeda, R.; Ryu, S. Y.; Park, J . H.; Nakanishi, K. Tetrahedron,
1990, 46, 5533. (b) Vega-Perez, J . M.; Espartero, J . L.; Alkudia, F. J .
Carbohydr. Chem. 1993, 12, 477.
(15) Willams, N. R. Adv. Carbohydr. Chem. Biochem. 1970, 25, 109.
(16) Vega-Perez, J . M.; Candela, J . I.; Vega, M.; Iglesias-Guerra, F.
Carbohydr., Res. 1995, 279, C5.
(17) Sanki, A.; Pathak, T., unpublished results.
(18) Compounds 6 and 8 undergo desulfonation reactions to generate
derivatives and analogues of D-lividosamine (2-amino-2,3-dideoxy-D-
glucose). This topic will be discussed separately in a forthcoming
publication.
(12) Truce, W. E.; Levy, A. J . J . Am. Chem. Soc. 1961, 83, 4641.

2640 J . Org. Chem., Vol. 65, No. 9, 2000
Ravindran et al.
127.4, 128.1, 128.4, 132.8, 136.3, 140.5. Anal. Calcd for
C20H22O7S: C, 59.09; H, 5.45. Found: C, 58.96; H, 5.35.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined in
open-end capillary tubes and are uncorrected. All chemicals
were obtained from commercial suppliers and are used without
purification. TLC was carried out on precoated plates (Merck
silica gel 60, f254), and the spots were visualized with UV light.
Column chromatography was performed on silica gel (silica
gel 60, 230-400 mesh). 1H NMR spectra were recorded at 200
and 300 MHz in CDCl3 using the residual CHCl3 as standard,
and 13C NMR were recorded at 50.3 and 75 MHz in CDCl3
using the triplet centered at δ 77.0 as the standard. Optical
rotation was recorded at 589 nm.
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-â-D-er yth r o-h ex-2-en op yr a n osid e (5â). Com-
pound 3â (3.42 g, 8.44 mmol) in anhydrous pyridine (15 mL)
was reacted with methanesulfonyl chloride (2.09 mL, 27.02
mmol) at 4 °C overnight. After the usual workup, crude
mesylated product 4â in dichloromethane (70 mL) was treated
with DBU (2.52 mL, 16.88 mmol) for 5 min. Solvent was
evaporated under reduced pressure, and the resulting residue
was purified over silica gel (eluent 50% EtOAc-petroleum
ether) to yield a white fluffy solid 5â (7.55 g, 75%; four steps
from 1â). Mp: highly hygroscopic. [R]25D -8.9° (c 0.333, CHCl3).
1H NMR: δ 3.53 (s, 3H), 3.73 (m, 1H), 3.89 (t, J ) 11.3 Hz,
1H), 4.28 (dd, J ) 4.3, 10.2 Hz, 1H), 4.61 (m, 1H), 5.44 (m,
1H), 5.55 (s, 1H), 6.94 (m, 1H), 7.19-7.60 (m, 8H), 7.82 (m,
2H). 13C NMR: δ 55.1, 68.0 (CH2), 69.3, 73.2, 98.3, 101.5, 125.8,
127.5, 128.2, 128.6, 132.9, 136.2, 136.8, 139.8, 142.5.
Gen er a l P r oced u r e for th e Syn th esis of 6a -f, 8a , 8c,
a n d 8e. Solutions of 5r or 5â in neat amines (2-3 mL/mmol)
were heated separately for 1-24 h at various temperatures.
Amines were evaporated under reduced pressure. The result-
ing residues were dissolved in EtOAc and washed with water.
EtOAc solutions were dried over anhydrous Na2SO4 and
filtered, and the filtrates were evaporated under reduced
pressure. The residue was purified over silica gel. For second-
ary amines, major isomers were crystallized out from mixtures
of isomers. Analytical samples were prepared from methanol.
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-r-D-er yth r o-h ex-2-en op yr a n osid e (5r). To a
solution of 1r (3.20 g, 12.12 mmol) in DMF (15 mL) were added
thiophenol (6.24 mL, 60.6 mmol) and TMG (4.56 g, 36.36
mmol). The reaction mixture was heated for 3 h at 80-90 °C,
poured into saturated aqueous NaCl (80 mL), and extracted
with EtOAc (3 × 30 mL). The EtOAc layer was washed with
saturated aqueous NaHCO3 (2 × 15 mL), dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The resulting
syrup was purified over silica gel to yield 2r (4.26 g, 94%). To
a solution of 2r (4.26 g, 11.4 mmol) in methanol (25-30 mL)
was added MMPP (16.88 g, 34.17 mmol). The reaction mixture
was stirred for 2.5 h at ambient temperature and filtered, and
the filtrate was evaporated under reduced pressure. The
resulting residue was neutralized with saturated aqueous
NaHCO3 (70 mL), extracted with EtOAc (3 × 30 mL), washed
with water (3 × 15 mL), dried over anhydrous Na2SO4, and
concentrated to dryness under reduced pressure to yield 3r
quantitatively. To a solution of 3r in anhydrous pyridine (25
mL) was added methanesulfonyl chloride (2.82 mL, 36.45
mmol) in anhydrous pyridine (15 mL) at O°C, and the solution
was left overnight at 4 °C. The reaction mixture was poured
into saturated aqueous NaHCO3 (70 mL) and filtered. The
residue was dissolved in dichloromethane (60 mL), and the
solution was dried over anhydrous Na2SO4. DBU (3.41 mL,
22.78 mmol) was added to the dichloromethane solution of the
mesylated product 4r. After 5 min the solvent was evaporated
under reduced pressure, and the resulting residue was purified
over silica gel (eluent 40% EtOAc-petroleum ether) to yield a
white crystalline solid 5r (4.12 g, 88%; four steps from epoxide
Meth yl 2,3-Did eoxy-2-N-isobu tyla m in o-4,6-O-(p h en yl-
m eth ylen e)-3-C-ph en ylsu lfon yl-r-D-glu copyr an oside (6a).
A solution of 5r (0.79 g, 2.04 mmol) was heated in neat
isobutylamine (3 mL) for 1 h at 50-55 °C and converted
(eluent 60% EtOAc-petroleum ether) to a white solid 6a (0.84
1
g, 90%). Mp: 149-150 °C. [R]24 +38.3° (c 0.405, CHCl3). H
D
NMR: δ 0.94 (m, 6H), 1.74 (m, 1H), 2.48 (m, 2H), 3.42 (s, 3H),
3.48 (dd, J ) 3.5, 10.3 Hz, 1H), 3.67-4.00 (m, 4H), 4.21 (dd, J
) 3.4, 9.3 Hz, 1H), 4.83 (d, J ) 3.5 Hz, 1H), 5.33 (s, 1H), 7.05
(m, 2H), 7.16-7.39 (m, 6H), 7.79 (m, 2H). 13C NMR: δ 20.7,
20.8, 28.6, 55.5, 55.6 (CH2), 57.3, 62.4, 65.0, 69.4 (CH2), 76.5,
98.2, 101.8, 126.3, 128.0, 128.2, 128.6, 129.1, 133.1, 136.6,
142.0. MS EI m/z (%) 461 (M+, 4), 430 (M+ - OCH3, 5), 418
(M+ - CH(CH3)2, 100), 320 (M+ - SO2Ph, 35). Anal. Calcd for
1r). Mp: 196-198 °C. [R]28.5 -54.7° (c 1.154, CHCl3). 1H
C
24H31NO6S: C, 62.45; H, 6.77; N, 3.03. Found: C, 62.43; H,
D
7.17; N, 3.15.
NMR: δ 3.50 (s, 3H), 3.86 (m, 2H), 4.25 (m, 1H), 4.54 (m, 1H),
5.13 (dd, J ) 1.2, 2.8 Hz, 1H), 5.55 (s, 1H), 6.99 (m, 1H), 7.11-
7.57 (m, 8H), 7.80 (m, 2H). 13C NMR: δ 56.7, 64.1, 69.0 (CH2),
74.2, 95.8, 102.3, 126.5, 128.2, 128.7, 128.8, 129.3, 133.4, 135.5,
136.7, 140.4, 142.5. Anal. Calcd for C20H20O6S: C, 61.84; H,
5.19; S, 8.25. Found: C, 61.73; H, 5.17; S, 8.21.
Meth yl 2-N-Cycloh exyla m in o-2,3-d id eoxy-4,6-O-(p h en -
ylm et h ylen e)-3-C-p h en ylsu lfon yl-r-D-glu cop yr a n osid e
(6b). A solution of 5r (0.44 g, 1.13 mmol) in neat cylcohexy-
lamine (3 mL) was heated for 3.5 h at 80-90 °C and converted
(eluent 65% EtOAc-petroleum ether) to a white solid 6b (0.47
g, 85%). Mp: 152-153 °C. [R]28.5 +30.4° (c 0.412, CHCl3). 1H
D
Meth yl 3-Deoxy-4,6-O-(p h en ylm eth ylen e)-3-C-p h en yl-
su lfid e-â-D-a ltr op yr a n osid e (2â). Compound 2â was syn-
thesized by treating a DMF (10 mL) solution of 1â (2.64 g,
10.07 mmol) with thiophenol (5.18 mL, 50.07 mmol) in the
presence of TMG (3.79 mL, 30.22 mmol) for 2.5 h at 80-90
°C. After the usual workup (vide compound 2r), the syrup was
purified over silica gel (eluent 50% EtOAc-petroleum ether)
NMR: δ 1.10-2.05 (m, 10H), 2.56 (m, 1H), 3.43 (s, 3H), 3.47-
3.98 (m, 5H), 4.21 (dd, J ) 3.3, 9.2 Hz, 1H), 4.47 (d, J ) 3.3
Hz, 1H), 5.29 (s, 1H), 7.04 (m, 2H), 7.15-7.36 (m, 6H), 7.78
(m, 2H). 13C NMR: δ 24.8 (CH2), 24.9 (CH2), 25.9 (CH2), 32.6
(CH2), 34.9 (CH2), 54.7, 55.2, 62.2, 65.0, 69.1 (CH2), 76.2, 98.8,
101.5, 126.1, 127.7, 127.8, 128.3, 128.8, 132.8, 136.4, 142.1.
MS EI m/z (%) 487 (M+, 2), 346 (M+ - OCH3, 40). Anal. Calcd
for C26H33NO6S: C, 64.04; H, 6.82; N, 2.87; S, 6.58. Found: C,
64.20; H, 7.16; N, 2.95; S, 6.97.
1
to yield a white solid 2â (3.16 g, 84%). Mp: 142-143 °C. H
NMR: δ 3.54 (s, 3H), 3.82 (t, J ) 11.2 Hz, 1H), 4.00 (m, 3H),
4.34 (m, 2H), 4.29 (s, 1H), 5.59 (s, 1H), 7.19-7.52 (m, 10H).
13C NMR: δ 50.9, 56.9, 65.3, 69.0 (CH2), 71.5, 75.2, 98.9, 101.8,
126.3, 127.1, 128.1, 128.9, 129.0, 131.4, 134.7, 137.4. Anal.
Calcd for C20H22O5S: C, 64.15; H, 5.92; S, 8.56. Found: C,
64.14; H, 5.92; S, 8.77.
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-2-N-p yr r olid in o-r-D-glu cop yr a n osid e (6c). A
solution of 5r (1.01 g, 2.6 mmol) in neat pyrrolidine (4 mL)
was stirred for 3 h at ambient temperature and converted to
an isomeric mixture of 6c and 7c (1.42 g, 96%) in a ratio 1.6:1
(1H NMR). Com p ou n d 6c (yellow solid, 0.5 g, 42%). Mp: 132-
Meth yl 3-Deoxy-4,6-O-(p h en ylm eth ylen e)-3-C-p h en yl-
su lfon yl-â-D-a lt r op yr a n osid e (3â). Compound 2â (3.16 g,
8.44 mmol) was oxidized with MMPP (12.15 g, 25.33 mmol)
in methanol (20-25 mL) for 2.5 h at ambient temperature.
After the usual workup, the residue was purified over silica
gel (eluent 55% EtOAc-petroleum ether) to yield a white solid
133 °C. [R]28.5 +91.1° (c 1.318, CHCl3). 1H NMR: δ 1.40-
D
1.62 (m, 4H), 2.64 (m, 2H), 2.90 (m, 2H), 3.37 (s, 3H), 3.57-
4.12 (m, 5H), 4.24 (dd, J ) 3.4, 9.4 Hz, 1H), 4.84 (d, J ) 3.2
Hz, 1H), 5.36 (s, 1H), 7.25-7.48 (m, 8H), 7.84 (m, 2H). 13C
NMR: δ 24.0 (CH2), 47.7 (CH2), 54.5, 57.8, 62.5, 69.4 (CH2),
76.3, 98.7, 101.3, 126.1, 127.8, 128.2, 128.7, 132.5, 136.7, 142.2.
MS EI m/z (%) 459 (M+, 100), 428 (M+ - OCH3, 30), 318 (M+
- SO2Ph, 85). Anal. Calcd for C24H29NO6S: C, 62.72; H, 6.36;
N, 3.05. Found: C, 62.45; H, 6.52; N, 3.16.
1
3â quantitatively. Mp: 156-157 °C. H NMR: δ 3.60 (s, 3H),
3.67 (t, J ) 10.2 Hz, 1H), 4.02 (dd, J ) 2.6, 5.8 Hz, 1H), 4.23-
4.43 (m, 2H), 4.63 (m, 1H), 4.84 (m, 1H), 5.10 (d, J ) 1.4 Hz,
1H), 5.31 (s, 1H), 7.03-7.49 (m, 8H,), 7.83 (m, 2H). 13C NMR:
δ 56.5, 63.3, 64.8, 66.4, 69.1(CH2), 74.3, 99.2, 101.7, 125.8,

Synthesis of New Classes of Deoxyaminosugars
J . Org. Chem., Vol. 65, No. 9, 2000 2641
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-2-N-p yr r olid in o-r-D-m a n n op yr a n osid e (7c)
MS EI m/z (%) 545 (M+, 3), 404 (M+ - SO2Ph, 60). Anal. Calcd
for C28H35NO8S: C, 61.63; H, 6.46; N, 2.57. Found: C, 61.10;
H, 6.80; N, 2.59.
(yellow solid, 0.5 g, 42%). Mp: 160-161 °C. [R]28.5 +38.1° (c
D
1
0.126, CH2Cl2). H NMR: δ 1.75-1.88 (m, 4H), 2.73 (m, 4H),
Meth yl 2,3-Did eoxy-2-N-isobu tyla m in o-4,6-O-(p h en yl-
m eth ylen e)-3-C-p h en ylsu lfon yl â-D-glu cop yr a n osid e (8a ).
A solution of 5â (0.35 g, 0.902 mmol) in neat isobutylamine (3
mL) was heated at 60-65 °C for 3 h and converted (eluent
60% EtOAc-petroleum ether) to a white solid 8a (0.76 g, 84%).
3.43 (m, 3H), 3.66 (t, J ) 11.0 Hz, 1H), 3.84 (m, 2H), 4.30 (m,
2H), 4.75 (m, 1H), 4.85 (s, 1H), 5.40 (s, 1H), 7.18-7.47 (m, 8H),
7.79 (m, 2H). 13C NMR: δ 23.6 (CH2), 51.5 (CH2), 54.5, 58.2,
61.1, 62.0, 69.7 (CH2), 75.7, 98.9, 102.5, 126.6, 128.1, 128.3,
129.1, 129.2, 132.7, 137.1, 142.9. Anal. Calcd for C24H29NO6S:
C, 62.72; H, 6.36; N, 3.05; S, 6.63. Found: C, 62.27; H, 6.63;
N, 3.06.
Mp: 156-157 °C. [R]26.5 -70.7° (c 0.512, CHCl3). 1H NMR:
D
δ 0.97 (m, 6H), 1.73 (m, 1H), 2.61 (m, 1H), 2.74 (m, 1H), 3.55
(s, 3H), 3.29-3.77 (m, 4H), 3.97 (t, J ) 9.7 Hz, 1H), 4.27 (dd,
J ) 4.8, 10.6 Hz, 1H), 4.44 (d, J ) 6.6 Hz, 1H), 5.29 (s, 1H),
7.02 (m, 2H), 7.20-7.45 (m, 6H), 7.81 (m, 2H). 13C NMR: δ
20.6, 20.8, 28.9, 56.1 (CH2), 56.8, 57.5, 66.6, 66.9, 69.0 (CH2),
75.7, 101.3, 105.7, 126.0, 127.8, 128.3, 128.7, 129.0, 133.3,
136.3, 140.6. MS EI m/z (%) 461 (M+, 4), 418 (M+ - CH(CH3)2,
100). Anal. Calcd for C24H31NO6S: C, 62.45; H, 6.77; N, 3.03.
Found: C, 62.68; H, 7.26; N, 3.07.
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-2-N-p ip er id in o-r-D-glu cop yr a n osid e (6d ). A
solution of 5r (0.776 g, 2.0 mmol) in neat piperdine (3 mL)
was heated for 9 h at 90-100 °C and converted to an isomeric
mixture of 6d and 7d (0.90 g, 96%) in a ratio of 3.2:1 (1H NMR).
Com p ou n d 6d (pale yellow solid, 0.52 g, 55%). Mp: 120-
1
121 °C (decomp). [R]28.5 +80.5° (c 0.546, CHCl3). H NMR: δ
D
1.20-1.55 (m, 6H), 2.67 (m, 4H), 3.30 (dd, J ) 3.1,11.5 Hz,
1H), 3.35 (s, 3H), 3.45-4.07 (m, 4H), 4.17 (dd, J ) 3.1, 9.8 Hz,
1H), 4.80 (d, J ) 3.1 Hz, 1H), 5.17 (s, 1H), 7.10-7.43 (m, 8H),
7.85 (m, 2H). 13C NMR: δ 24.8 (CH2), 26.2 (CH2), 51.0 (CH2),
54.6, 61.9, 62.8, 63.9, 69.5 (CH2), 76.7, 98.2, 101.6, 126.3, 127.9,
128.2, 128.5, 128.9, 132.8, 136.7, 142.2. MS EI m/z (%) 473
(M+, 40), 442 (M+ - OCH3, 15), 332 (M+ - SO2Ph, 80). Anal.
Calcd for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96. Found: C,
63.28; H, 6.71; N, 2.99.
Meth yl 2,3-Dideoxy-4,6-O-(ph en ylm eth ylen e)-3-C-ph en -
ylsu lfon yl-2-N-p yr r olid in o-â-D-glu cop yr a n osid e (8c). A
solution of 5â (0.63 g, 1.62 mmol) in neat pyrrolidine (3 mL)
was stirred for 1.5 h at ambient temperature and converted
(eluent 55% EtOAc-petroleum ether) to a yellow solid 8c (0.64
1
g, 86%). Mp: 136-138 °C. [R]24 -27.8 (c 0.739, CHCl3). H
D
NMR: δ 1.56 (m, 4H), 2.65 (m, 4H), 3.41 (s, 3H), 3.56-4.31
(m, 4H), 4.30 (m, 1H), 4.44 (m, 1H), 4.67 (d, J ) 4.6 Hz, 1H),
5.49 (s, 1H), 7.28-7.40 (m, 8H), 7.84 (m, 2H). 13C NMR: δ
23.1 (CH2), 48.8 (CH2), 55.3, 59.7, 65.1, 66.6, 69.3 (CH2), 74.9,
100.7, 100.8, 125.7, 127.7, 128.3, 128.5, 132.6, 136.6, 141.5.
MS EI m/z (%) 459 (M+, 20), 318 (M+ - SO2Ph, 80). Anal. Calcd
for C24H29NO6S: C, 62.72; H, 6.36; N, 3.05. Found: C, 62.17;
H, 6.39; N, 3.02.
Meth yl 2,3-Did eoxy-2-N-m or p h olin o-4,6-O-(p h en yl-
m eth ylen e)-3-C-ph en ylsu lfon yl-r-D-glu copyr an oside (6e).
A solution of 5r (0.39 g, 1.0 mmol) in neat morpholine (2 mL)
was heated for 24 h at 80-90 °C and converted to an isomeric
mixture of 6e and 7e (0.45 g, 95%) in a ratio of 3.8:1 (1H NMR).
Com p ou n d 6e (yellow solid, 0.19 g, 40%). Mp: 228 °C
Met h yl 2,3-Did eoxy-2-N-m or p h olin o-4,6-O-(p h en yl-
m eth ylen e)-3-C-ph en ylsu lfon yl- â-D-glu copyr an oside (8e).
A solution of 5â (0.40 g, 1.03 mmol) in neat morpholine (3 mL)
was heated for 2 h at 90-100 °C and converted (eluent 65%
EtOAc-petroleum ether) to a yellow solid 8e (0.49 g, 90%).
(decomp). [R]28.5 +66.8° (c 0.435, CHCl3). 1H NMR: δ 2.84
D
(m, 4H), 3.42 (s, 3H), 3.85 (m, 8H), 4.06 (m, 1H), 4.19 (dd, J )
3.2, 9.7 Hz, 1H), 4.89 (d, J ) 3.1 Hz, 1H), 5.12 (s, 1H), 7.05
(m, 2H), 7.20-7.32 (m, 6H), 7.85 (m, 2H). 13C NMR: δ 49.8
(CH2), 54.4, 61.4, 62.5, 63.0, 67.1 (CH2), 69.1 (CH2), 76.3, 97.7,
101.5, 126.0, 127.6, 127.9, 128.3, 128.7, 132.7, 136.3, 141.9.
Mp: 179 °C (decomp). [R]28.5 -8.4° (c 1.042, CHCl3). 1H
D
NMR: δ 2.69 (m, 2H), 2.84 (m, 2H), 3.51 (s, 3H), 3.30-3.85
(m, 8H), 4.15 (t, J ) 9.5 Hz, 1H), 4.34 (dd, J ) 4.8, 10.9 Hz,
1H), 4.61 (d, J ) 6.8 Hz, 1H), 5.38 (s, 1H), 7.27-7.45 (m, 8H),
7.89 (m, 2H). 13C NMR: δ 49.7 (CH2), 56.1, 63.8, 65.2, 66.9
(CH2), 67.8, 69.2 (CH2), 75.2, 101.3, 102.0, 126.1, 128.1, 128.2,
MS EI m/z (%) 475 (M+, 32), 444 (M+ - OCH3, 15), 334 (M+
-
SO2Ph, 100). Anal. Calcd for C24H29NO7S: C, 60.61; H, 6.15;
N, 2.94. Found: C, 60.19; H, 5.94; N, 2.90.
Meth yl 2,3-Dideoxy-2-N-eth ylison ipecotate-4,6-O-(ph en -
ylm eth ylen e)-3-C-ph en ylsu lfon yl-r-D-glu copyr an oside (6f).
A solution of 5r (0.67 g, 1.72 mmol) in neat ethylisonipecotate
(3 mL) was heated at 90-100 °C for 10 h and converted (eluent
65% EtOAc-petroleum ether) to an isomeric mixture of 6f and
7f (0.73 g, 78%) in a ratio of 2.3:1 (1H NMR). Com p ou n d 6f
(white solid, 0.45 g, 48%). Mp: 195 °C (decomp). [R]28.5D +64.4°
128.8, 129.0, 133.2, 136.8, 142.1. MS EI m/z (%) 444 (M+
-
-
OCH3, 4), 334 (M+ - SO2Ph, 100). Anal. Calcd for C24H29
NO7S: C, 60.61; H, 6.15; N, 2.94. Found: C, 60.51; H, 6.97;
N, 2.98.
1
Ack n ow led gm en t. B.R and K.S thank the Council
for Scientific and Industrial Research, New Delhi for
fellowships. Financial support from the Department of
Science and Technology, New Delhi is gratefully
acknowledged.
(c 0.445, CHCl3). H NMR: δ 1.25 (m, 3H), 1.75 (m, 4H), 2.21
(m, 1H), 2.75 (m, 2H), 2.94 (m, 2H), 3.38 (s, 3H), 3.43-3.46
(m, 1H), 3.70-3.94 (m, 3H), 4.13 (m, 4H), 4.81 (d, J ) 3.1 Hz,
1H), 5.20 (s, 1H), 7.11-7.34 (m, 8H), 7.84 (m, 2H). 13C NMR:
δ 14.3, 28.4 (CH2), 28.5 (CH2), 41.4, 48.1 (CH2), 50.2 (CH2),
54.6, 60.1 (CH2), 61.8, 62.6, 63.3, 69.3 (CH2), 76.5, 98.3, 101.5,
126.2, 127.8, 128.1, 128.5, 128.9, 132.8, 136.6, 142.0, 175.1.
J O991380D