The chemistry of isopropenyl glycopyranosides. Transglycosylations and other reactions

Article abstract of DOI:10.1021/jo960190p

Various anomerically pure isopropenyl α- and β-glycopyranosides have been synthesized and shown to undergo synthetically useful transglycosylation reactions with a variety of primary and secondary carbohydrate alcohols. Although stable when stored, isopro

Full text of DOI:10.1021/jo960190p

5024
J . Org. Chem. 1996, 61, 5024-5031
Th e Ch em istr y of Isop r op en yl Glycop yr a n osid es.
Tr a n sglycosyla tion s a n d Oth er Rea ction s
H. Keith Chenault,* Alfredo Castro, Laura F. Chafin, and J ie Yang
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received J anuary 30, 1996X
Various anomerically pure isopropenyl R- and â-glycopyranosides have been synthesized and shown
to undergo synthetically useful transglycosylation reactions with a variety of primary and secondary
carbohydrate alcohols. Although stable when stored, isopropenyl glycosides are readily activated
as glycosyl donors by a variety of electrophiles, including N-iodosuccinimide/triflic acid, trimethylsilyl
triflate, and triflic anhydride. Under conditions that retard formation of the glycosyl cation, the
reactivity of isopropenyl glycosides is diverted away from transglycosylation and toward electrophilic
addition across the vinyl ether double bond.
In tr od u ction
At the beginning of our work, we envisioned that
isopropenyl glycosides would be activated as glycosyl
donors by electrophiles in a manner similar to that
already observed by Fraser-Reid and co-workers with
n-pentenyl glycosides.11 In fact, the expectation was that
conjugation of the electrophilic double bond with the
glycosidic oxygen would make isopropenyl glycosides even
more reactive than n-pentenyl glycosides. The mecha-
nism of activation was expected to involve initial capture
of the electrophile (E+) by the vinyl ether double bond of
1 leading to the formation of cation 2 or 3 (Scheme 1).
Collapse of 2 or 3 to form glycosyl oxocarbenium cation
5 and acetone derivative 4 would be followed by nucleo-
philic attack on 5 to generate glycoside 7. If the isopro-
penyl glycoside contained an ester protecting group at
C-2, neighboring-group participation would lead to the
formation of a resonance-stabilized dioxocarbenium ion
6, which would then undergo nucleophilic attack to
generate exclusively the 1,2-trans-glycoside (e.g., â-glu-
coside) 7â. An alternative reaction would involve direct
nucleophilic attack on 2 or 3 to generate the addition
product 8.
We describe here the stereoselective synthesis of a
variety of isopropenyl R- and â-glycopyranosides and the
use of these compounds as glycosyl donors for oligosac-
charide synthesis. The effects of varying the promoter,
glycosyl donor, and glycosyl acceptor have been studied.
It turns out that isopropenyl glycosides are poised
delicately between two manifolds of reactivity. Solvent,
promoter, and protecting groups on the glycosyl donor
can direct the reactivity of isopropenyl glycosides toward
either transglycosylation or electrophilic addition.
Oligosaccharides and glycoconjugates play important
roles in cellular development, adhesion, communication,
migration, infection, and disease.1,2 Work aimed at the
preparation and study of these compounds has resulted
in the development of a variety of new glycosylating
agents.2,3 Among those more recently introduced are
thioglycosides,4-6 glycosyl trichloroacetimidates,7 glycosyl
fluorides,8-10 n-pentenyl glycosides,11 glycosyl sulfoxides12
and sulfones,13 selenoglycosides,14 and glycosyl phos-
phites.15 We and others have introduced the use of iso-
propenyl16,17 and other vinyl glycosides18 as glycosyl
donors.
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(1) (a) Glycobiology; Welply, J . K., J aworski, E., Eds.; Wiley-Liss:
New York, 1990; Vol. 3. (b) Neurobiology of Glycoconjugates; Margolis,
R. U., Margolis, R. K., Eds.; Plenum: New York, 1989. (c) Rademacher,
T. W.; Parekh, R. B.; Dwek, R. A. Ann. Rev. Biochem. 1988, 57, 785-
838. (d) Glycoconjugates; Horowitz, M. I., Ed.; Academic: New York,
1982; Vols. 3 and 4. (e) The Molecular Immunology of Complex
Carbohydrates; Wu, A. M., Ed.; Plenum: New York, 1988. (f) Thiem,
J . In Trends in Synthetic Carbohydrate Chemistry; Horton, D., Hawk-
ins, L. D., McGarvey, G. J ., Eds.; American Chemical Society: Wash-
ington, DC, 1989; pp 131-149. (g) Shen, T. Y. Ann. N.Y. Acad. Sci.
1987, 507, 272-280. (h) Guerra, F. I.; Neumann, J . M.; Huynh-Dinh,
T. Tetrahedron Lett. 1987, 28, 3581-3584. (i) Targeting of Drugs With
Synthetic Systems; Gregoriadis, G., Senior, J ., Poste, G., Eds.; Ple-
num: New York, 1986.
(2) Halcomb, R. L.; Wong, C.-H. Curr. Opin. Struct. Biol. 1993, 3,
694-700.
(3) (a) Meldal, M. Curr. Opin. Struct. Biol. 1994, 4, 710-718. (b)
Kanie, O.; Hindsgaul, O. Curr. Opin. Struct. Biol. 1992, 2, 674-681.
(4) (a) Mukaiyama, T.; Nakatsuka, T.; Shoda, S. Chem. Lett. 1979,
487-490. (b) Nicolaou, K. C.; Saitz, S. P.; Papahatjis, D. P. J . Am.
Chem. Soc. 1983, 105, 2430-2434.
(5) Anderson, F.; Fu¨gedi, P.; Garegg, P. J .; Nashed, M. Tetrahedron
Lett. 1986, 27, 3919-3922.
(6) Fu¨gedi, P.; Garegg, P. J . Carbohydr. Res. 1986, 149, C9-C12.
(7) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. 1994, 50, 21-
123.
Resu lts a n d Discu ssion
(8) Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981, 431-
432.
Syn th esis of Isop r op en yl Glycop yr a n osid es. Re-
action of bis(acetonyl)mercury19 with glycopyranosyl
halides 9a -f resulted in O-glycosylation20 and produced
the corresponding isopropenyl â-glycopyranosides 10a -f
(9) Nicolaou, K. C.; Dole, R. E.; Papahatjis, D. P.; Randall, J . L. J .
Am. Chem. Soc. 1984, 106, 4189-4192.
(10) (a) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G.
Tetrahedron Lett. 1988, 29, 3567-3570. (b) Suzuki, K.; Maeta, H.;
Matsumoto, T. Tetrahedron Lett. 1989, 30, 4853-4856.
(11) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt,
J . R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942.
(12) (a) Khane, D.; Walker, S.; Chen, Y.; Van Engen, D. J . Am.
Chem. Soc. 1989, 111, 6881-6882. (b) Raghavan, S.; Khane, D. J . Am.
Chem. Soc. 1993, 115, 1580-1581.
(16) Chenault, H. K.; Castro, A. Tetrahedron Lett. 1994, 35, 9145-
9148.
(17) Marra, A.; Esnault, J .; Veyrie`res, A.; Sinay¨, P. J . Am. Chem.
Soc. 1992, 114, 6354-6360.
(13) Brown, D. S.; Ley, S. V.; Vile, S. Tetrahedron Lett. 1988, 29,
4873-4876.
(14) Mehta, S.; Pinto, B. M. J . Org. Chem. 1993, 58, 3269-3276.
(15) (a) Martin, T. J .; Brescello, R.; Toepfer, A.; Schmidt, R. R.
Glycoconjugate J . 1993, 10, 16-25. (b) Kondo, H.; Aoki, S.; Ichikawa,
Y.; Halcomb, R. L.; Ritzen, H.; Wong, C.-H. J . Org. Chem. 1994, 59,
864-877.
(18) (a) Boons, G.-J .; Isles, S. Tetrahedron Lett. 1994, 35, 3593-
3596. (b) Vankar, Y. D.; Vankar, P. S.; Behrendt, M.; Schmidt, R. R.
Tetrahedron 1991, 47, 9985-9992.
(19) Lutsenko, I. F.; Khomutov, R. M. Doklady Akad. Nauk. S.S.S.R.
1955, 102, 97-99.
(20) de Raadt, A.; Ferrier, R. J . Carbohydr. Res. 1991, 216, 93-
107.
S0022-3263(96)00190-9 CCC: $12.00 © 1996 American Chemical Society

Chemistry of Isopropenyl Glycopyranosides
J . Org. Chem., Vol. 61, No. 15, 1996 5025
Sch em e 1
Ta ble 1. Syn th esis of Isop r op en yl â-D-Glycop yr a n osid es
Sch em e 2
in generally good yield (Table 1). The reaction was
successful with ester or ether protecting groups, a gly-
cosyl chloride or bromide, and derivatives of both a
disaccharide and an amino sugar. In all cases, the
â-glycoside was produced as a single diastereomer.21
Attempts to prepare isopropenyl sialoside 12 by a similar
reaction of either sialosyl bromide 11a 22 or sialosyl
chloride 11b23 with bis(acetonyl)mercury failed. Instead,
elimination led to the formation of glycal 1324 (Scheme
2). Such elimination is a common problem in the
synthesis of sialosides.
Sch em e 3
Isopropenyl 2,3,4,6-tetra-O-pivaloyl-R-D-glucopyrano-
side (16) was prepared stereoselectively as outlined in
Scheme 3.25 Acid-catalyzed exchange of the anomeric
pivaloyloxy group of penta-O-pivaloyl-â-D-glucopyranose
(14)26 led to the formation of 15 as the only anomer.
Regioselective methylidenation of 15 by dimethylti-
tanocene27 generated 16 as the only product. It appears
that the regioselectivity exhibited by dimethyltitanocene
results from both a steric preference for acetate rather
than pivaloate esters as well as an electronic preference
for an anomeric acyloxy group rather than other, less
electrophilic acyloxy groups. The reaction of penta-O-
acetyl-R-D-glucopyranose with dimethyltitanocene exhib-
its some regioselectivity, generating the isopropenyl
glucoside and a mixture of the other, regioisomeric
monoisopropenyl ethers in a 1.3:1.0 ratio, as determined
(21) It is unclear whether the stereoselective formation of 10a -f is
due to neighboring-group participation or a concerted mechanism with
a cyclic transition state in which mercury coordinates the departing
halide and delivers the enolate nucleophile from the opposite face of
the pyranose ring. The reaction of 9c with inversion suggests a
concerted mechanism, but reaction of 9f (R:â ) 1:1) to give exclusively
â glycoside might suggest neighboring-group participation. The unusu-
ally low yield of 10f, however, leaves open the possibility that only
the R anomer of 9f reacted successfully to give 10f and that it did so
by a concerted mechanism.
1
by H NMR.
Isopropenyl glycosides are stable and are readily
purified by column chromatography on silica gel. Iso-
propenyl â-glycosides bearing ester protecting groups
have shown no decomposition, as determined by change
1
in melting point or H NMR spectrum, even after being
stored for over two years at room temperature.
(22) Paulsen, H.; Tietz, H. Carbohydr. Res. 1984, 125, 47-64.
(23) (a) Marra, A.; Sinay¨, P. Carbohydr. Res. 1989, 190, 317-322.
(b) Sabesan, S.; Neira, S.; Davidson, F.; Duus, J . Ø.; Bock, K. J . Am.
Chem. Soc. 1994, 116, 1616-1634.
Tr a n sglycosyla tion s: Th e Effect of P r om oter . To
investigate the ability of various electrophiles to promote
transglycosylation by isopropenyl glycosides, the coupling
(24) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. J pn. 1987,
60, 631-636.
(25) Chenault, H. K.; Chafin, L. F. J . Org. Chem. 1994, 6167-6169.
(26) Becker, D.; Galili, N. Tetrahedron Lett. 1992, 33, 4775-4778.
(27) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392-
6394.

5026 J . Org. Chem., Vol. 61, No. 15, 1996
Chenault et al.
Sch em e 4
Sch em e 5
Ta ble 2. Ability of Va r iou s Electr op h iles To P r om ote
Tr a n sglycosyla tion of 17 by 10b (Sch em e 4)
promoter
NIS/triflic acid
trimethylsilyl triflate
triflic anhydride
silver triflate
solvent
yielda
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
70%
69%
65%
24% (24h)
48%
DMTST
triflic acid
no reaction
no reaction
no reaction
no reaction
no reaction
no reaction
trimethylsilyl iodide
NIS or NBS
N-(phenylselenyl)phthalimide
Cp2Zr(OTf)2(THF)
Hg(CN)2/HgBr2
CuBr2/nBu4NBr
glycosides. Neither NIS nor NBS promoted the coupling
of 10b and 17. Despite precedent for their activities as
promoters of transglycosylation, N-(phenylselenyl)phthal-
imide,33 Zr(Cp2)(OTf)2THF,10 mercuric cyanide/mercuric
bromide,34 and cupric bromide/tetra-n-butylammonium
bromide (TBAB),35 also failed to promote the transgly-
cosylation of 17 by 10b. Each left only unreacted starting
materials after 19-48 h.
1:5 DMF-CH2Cl2 no reaction
a
Reaction of 0.077 mmol of 17 and 0.155 mmol of 10b in 2 mL
of solvent at 0 °C.
of 10b with glycosyl acceptor 17 was used as a represen-
tative reaction (Scheme 4). Trimethylsilyl triflate (TM-
SOTf),17,28 N-iodosuccinimide/triflic acid (NIS/TfOH),29
and triflic anhydride (Tf2O)30 all led to the formation of
disaccharide 18 in good yield (Table 2). Reactions were
carried out at 0 °C, in acetonitrile, and were complete
within 2-5 min. Silver triflate (AgOTf)31 promoted the
reaction 10b and 17 to form 18 in low yield, but only after
prolonged reaction time. When triflic acid (TfOH) alone
was tested as promoter, 10b failed to react with 17 or
the trimethylsilyl ether of 17,32 and 10b was recovered
unchanged. Thus, TMSOTf does not promote reaction
of 10b and 17 by silylating the glycosyl acceptor and
generating TfOH.17 Furthermore, neither NIS/TfOH,
TMSOTf, Tf2O, nor AgOTf activate isopropenyl glycosides
toward transglycosylation simply by acting as a source
of TfOH. Silylating agents, such as trimethylsilyl iodide
(TMSI), that are less electrophilic than TMSOTf also
failed to promote reaction of 10b. Dimethyl(methylthio)-
sulfonium triflate (DMTST)6 promoted rapid coupling of
17 and 10b, but the yield of 17 was lower than that
obtained with NIS/TfOH, TMSOTf, or Tf2O. Interest-
ingly, DMTST is the only promoter that led exclusively
to the formation of disaccharide from 10b when dichlo-
romethane was used as the solvent (see Addition Reac-
tions: The Effect of Solvent).
When iodonium dicollidine perchlorate (IDCP)36 was
examined as promoter,11 10b and 17 reacted but failed
to produce 18. Instead, electrophilic addition formed 19
as a 1:1 mixture of diastereomers (Scheme 5).37 Mixed
iodoacetonide 19 was produced whether the reaction was
run in dichloromethane or acetonitrile (see Addition Re-
actions: The Effect of Solvent). Similarly, reaction of 16
and 17 with IDCP produced 20 as the only dimeric
species (Scheme 5).
Ad d ition Rea ction s: Th e Effect of Solven t. All of
the preceding, successful transglycosylation reactions,
except the one with DMTST as promoter, used acetoni-
trile as solvent. However, when the same reactions were
performed in a less polar solvent, electrophilic addition
across the isopropenyl ether occurred, as when IDCP was
the promoter (Scheme 5). Reaction of 10b and 17 with
NIS/TfOH in dichloromethane led to the formation of 19
in 41% yield (Table 3). No disaccharide product 17 was
observed. Likewise, reaction of 16 and 17 in dichlo-
romethane, with NIS/TfOH as promoter, gave 20 as the
sole product (Scheme 5). When 10b and 17 were reacted
with TMSOTf in dichloromethane, a mixture of disac-
charide 18 and the mixed acetonide 21 was obtained
(Scheme 6).
It was not obvious, initially, whether the favorable
influence of acetonitrile on disaccharide formation was
We and others20 have observed transglycosylation
when isopropenyl glycosides were reacted with NIS or
N-bromosuccinimide (NBS) in protic solvents, such as
methanol or water. In 99:1 acetonitrile-water, isopro-
penyl glycosides hydrolyze readily in the presence of NIS
or NBS. In the absence of acidic protons or excess
nucleophile, however, NIS and NBS are not electrophilic
enough to promote transglycosylation by isopropenyl
(33) (a) Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron
1985, 41, 4835-4841. (b) Nicolaou, K. C.; Claremon, D. A.; Barnette,
W. E.; Seitz, S. P. J . Am. Chem. Soc. 1979, 101, 3704-3706. (c) Ito,
Y.; Ogawa, T. Tetrahedron Lett. 1988, 29, 1061-1064.
(34) (a) Helferich, B.; Weis, K. Chem. Ber. 1956, 89, 314-321. (b)
Arnap, J .; Lonngren, J . Acta Chem. Scand. B 1978, 32, 696-670.
(35) Sato, S.; Mori, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1986, 155,
C6-C10.
(36) Lemieux, R. U.; Morgan, A. R. Can. J . Chem. 1965, 43, 2190-
2198.
(28) Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981,
93, C6-C9.
(37) For examples of electrophilic addition to glycosyl enol ethers
or formation of glycosyl acetals, see: (a) Reference 20. (b) Koto, S.;
Inada, S.; Narita, T.; Morishima, N.; Zen, S. Bull. Chem. Soc. J pn.
1982, 55, 3665-3666. (c) Tietze, L. F.; Seele, R.; Leiting, B.; Krach, T.
Carbohydr. Res. 1988, 180, 253-262. (d) Lehmann, J .; Ziser, L.
Carbohydr. Res. 1988, 183, 301-309. (e) Barrett, A. G. M.; Bezuiden-
houdt, B. C. B.; Gasiecki, A. F.; Howell, A. R.; Russell, M. A. J . Am.
Chem. Soc. 1989, 111, 1392-1396. (f) Tietze, L. F.; Beller, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 868-869.
(29) Konradsson, P.; Mootoo, D. R.; McDevitt, R. E.; Fraser-Reid,
B. J . Chem. Soc., Chem. Commun. 1990, 270-272.
(30) Dobarro-Rodriguez, A.; Trumtel, M.; Wessel, H. P. J . Carbohydr.
Chem. 1992, 11, 255-263.
(31) Hanessian, S.; Banoub, J . Carbohydr. Res. 1977, 53, C13-C16.
(32) (a) Mukaiyama, T.; Matsubara, K. Chem. Lett 1992, 1755-1758.
(b) Kreuzer, M.; Thiem, J . Carbohydr. Res. 1986, 149, 347-361.

Chemistry of Isopropenyl Glycopyranosides
J . Org. Chem., Vol. 61, No. 15, 1996 5027
Ta ble 3. Effect of Solven t on th e Distr ibu tion of
P r od u cts F or m ed by th e Rea ction of 10b a n d 17a
double bond to become kinetically dominant. It appears
that trace protic species, such as water or tert-butyl
alcohol, favor glycosyl cation formation by specific sol-
vation,39 not by covalent complex formation.40 Ironically,
hydrolysis of unprotected isopropenyl glycopyranosides
in completely aqueous solution proceeds by electrophilic
addition of water across the vinyl ether double bond, not
by formation of the glycosyl oxocarbenium intermediate.25
promoter
IDCP
solvent
18
19
CH3CNb
-
-
70%
-
36%
31%
75%
53%
53%
-
41%
-
25%
-
b
CH2Cl2
NIS/TfOH
CH3CNc
b
CH2Cl2
c
4:1 ether:CH2Cl2
4:1 dry ether:CH2Cl2
50 mM tBuOH in CH2Cl2
c
c
To investigate the possibility that mixed glycosyl ketals
19-21 were mechanistic intermediates in the formation
of disaccharide 18,41 iodoacetonide 19 was subjected to
reaction conditions in which 10b and 17 form disaccha-
ride. Exposure of 19 to NIS/TfOH in acetonitrile caused
immediate conversion of 19 to 2,3,4,6-tetra-O-pivaloyl-
D-glucopyranose and 17, which were recovered quanti-
tatively. By comparison, disaccharide 18 was stable
when subjected to the same reaction conditions and was
recovered quantitatively.
a
Reaction of 0.077 mmol of 17 and 0.077-0.155 mmol of 10b
in 2 mL of solvent at 0 °C. The quantity of glycosyl donor 10b
affected the yields but not the identities of products formed. b 0.077
mmol of 10b. c 0.155 mmol of 10b.
Sch em e 6
Effect of th e Glycosyl Accep tor . To determine the
effect of the glycosyl acceptor on the outcome of trans-
glycosylation reactions, 10b was reacted with various
glycosyl acceptors, using TMSOTf or NIS/TfOH as pro-
moter (Table 4). Yields of â-glycosides were good, except
for that from the reaction of the sterically hindered
glycosyl acceptor 28.
the result of a bulk solvent (dielectric constant) effect or
the result of specific complexation (and thereby stabiliza-
tion) of the glycosyl oxocarbenium ion 5 or 6 (Scheme 1)
by acetonitrile. Specific complexation of glycosyl cations,
leading to the formation of N-glycosylnitrilium ions, is
known to be responsible for the stereochemical outcome
of some glycosylation reactions performed in nitrile
solvents.17,38 Insight into the present system came from
the observation that trace quantities of water in nonpolar
solvents, like dichloromethane or diethyl ether, led to
improved selectivity for the formation of disaccharide. For
example, in a 4:1 mixture of incompletely dried diethyl
ether and dichloromethane, reaction of 10b and 17 with
NIS/TfOH as promoter gave 18 as the sole dimeric
product. However, when the same reaction was run
using scrupulously dried diethyl ether, a 6:5 mixture of
18 and 19 was produced (Table 3).
The glycosylations of pent-4-enyl 2,3,6-tri-O-benzyl-â-
D-glucopyranoside (24) and phenyl 2,3,4-tri-O-benzyl-1-
thio-â-D-glucopyranoside (30)42 are significant since no
self-coupling of either 24 or 30 was detected by TLC or
1H NMR. Both 24 and 30 are less reactive toward the
promoters used than 10b, despite the fact that 10b bears
electronically “disarming”43 ester protecting groups and
compounds 24 and 30 bear electronically “arming” ethe-
real protecting groups.44 We have recently used the
selective activation of 10b in the presence of 24 or 30 to
prepare trisaccharides via two successive glycosylations
performed in one reaction vessel.16,45
Effects of Va r iou s Glycosyl Don or s. To determine
the effects of the glycosyl donor on transglycosylation
reactions, various glycosyl donors were reacted with 17
as a representative glycosyl acceptor. When 10b (Scheme
4) was replaced by its R anomer, 16, reaction with 17
gave â-disaccharide 18 as a single diastereomer, in yields
similar to those obtained from 10b. Thus, it appears that
The effect of trace water could be mimicked by deliber-
ate introduction of another protic solvent, tert-butyl
alcohol, into the reaction mixture. When 10b and 17
were reacted with NIS/TfOH in dichloromethane con-
taining one mole equivalent (∼50 mM) of tert-butyl
alcohol, 18 was produced in 75% yield (Table 3). Further
experiments demonstrated that the yield of 18 was not
particularly sensitive to the concentration (25-100 mM)
or absolute quantity (0.5-2.0 equivalents) of tert-butyl
alcohol present. To our knowledge, this is the first
example of improving the yield of a transglycosylation
reaction by adding a protic solvent.
(39) The effect of trace quantities of protic solvents is too dramatic
to be due simply to the change in bulk dielectric constant.
(40) Specific (covalent) complexation of the glycosyl cation interme-
diate would have led to the enhanced formation of hydrolysis product
or tert-butyl glycoside, not the observed disaccharide.
The results obtained with various solvents and pro-
moters suggest that subtle energetic effects steer the
reactivity of isopropenyl glycopyranosides toward trans-
glycosylation or electrophilic addition. Factors that favor
cation formation (strong electrophile, polar solvent) lead
to outright addition of the electrophile to the isopropenyl
glycoside, followed by formation of the glycosyl cation and
then disaccharide. Factors that retard cation formation
(weak electrophile, nonpolar solvent) cause nucleophile-
assisted electrophilic addition across the vinyl ether
(41) For intramolecular glycosyl delivery via acetal rearrangement,
see: (a) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33,
1765-1767. For intramolecular glycosyl delivery via orthoester rear-
rangement, see: (b) Reference 28. (c) Gass, J .; Strobl, M.; Loibner, A.;
Kosma, P.; Za¨hringer, U. Carbohydr. Res. 1993, 244, 69-84. (d)
Sznaidman, M. L.; J ohnson, S. C.; Crasto, C.; Hecht, S. M. J . Org.
Chem. 1995, 60, 3942-3943.
(42) (a) Anderson, L.; Pfaffli, P. J .; Hixson, S. Carbohydr. Res. 1972,
23, 195-206. (b) Kova˜c, P.; Lerner, L. Carbohydr. Res. 1988, 184, 87-
112.
(43) For discussions of electronically armed and disarmed glycosyl
donors, see (a) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J . Am. Chem. Soc. 1988, 110, 5583-5584. (b) Friesen, R. W.;
Danishefsky, S. J . J . Am. Chem. Soc. 1989, 111, 6656-6660. (c)
Halcomb, R. L.; Danishefsky, S. J . J . Am. Chem. Soc. 1989, 111, 6661-
6666. (d) Veeneman, G. H.; van Boom, J . H. Tetrahedron Lett. 1990,
31, 275-278.
(38) (a) Pougny, J .-R.; Sinay¨, P. Tetrahedron Lett. 1976, 4073-4076.
(b) Lemieux, R. U.; Ratcliffe, R. M. Can. J . Chem. 1979, 57, 1244-
1251. (c) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694-
696. (d) Pavia, A. A.; Ung-Chhun, S. N.; Durand, J . L. J . Org. Chem.
1981, 46, 3158-3160. (e) Ratcliffe, A.; Fraser-Reid, B. J . Chem. Soc.,
Perkin Trans. 1 1990, 747-750.
(44) A similar result based on the differential reactivity of seleno-
and thioglycosides has been reported: Mehta, S.; Pinto, B. M.
Tetrahedron Lett. 1991, 32, 4435-4438.
(45) Castro, A. Ph.D. Dissertation, University of Delaware, 1995.

5028 J . Org. Chem., Vol. 61, No. 15, 1996
Chenault et al.
Ta ble 4. â-Glycosyla tion of Va r iou s Glycosyl Accep tor s
Sch em e 8
by 10ba
Ta ble 5. Effects of Tem p er a tu r e a n d Solven t on th e
Ster eoselective Cou p lin g of 10d a n d 17 (Sch em e 8)a
solvent
temperature, °C
yield, %
R:â
dichloromethaneb
rt
rt
35
rt
64
70
96
84
95
90
50
85
1.2:1.0
1.0:1.7
5:1
7:1
6:1
2.5:1.0
1:3
3.5:1.0
acetonitrilec
diethyl ether
0
-30
-78
rt
diisopropyl ether
a
Unless specified otherwise, reactions were conducted with 0.10
mmol of 10d , 0.11 mmol of 17, and 0.10 mmol of TMSOTf as
b
promoter. Reaction of 0.059 mmol of 10d , 0.053 mmol of 17, and
0.064 mmol of IDCP. c Reaction of 0.16 mmol of 10d , 0.077 mmol
of 17, and 0.093 mmol of TMSOTf .
ethereal protecting groups. When 10d and 17 were
reacted with IDCP in dichloromethane, a 1.2:1.0 mixture
of disaccharide 3548 and its â anomer was obtained in
64% overall yield (Scheme 8). Despite the relatively weak
electrophile and nonpolar solvent, disaccharide formation
occurred instead of addition across the isopropenyl ether
(see Addition Reactions: The Effect of Solvent). Appar-
ently, the relatively electron-releasing ethereal protecting
groups lower the energy barrier to glycosyl cation forma-
tion from 10d relative to that from the ester-protected
glycosides, 10a -c and 16.
When 10d and 17 were reacted with TMSOTf at room
temperature in diethyl ether,49 a 7:1 mixture of 35 and
its â anomer was produced in 84% yield. Interestingly,
the stereoselectivity for formation of R product decreased
upon both increasing and reducing the temperature of
the reaction (Table 5). When 10d and 17 were reacted
in the presence of excess DMTST and TBAB,50,51 10d
could be seen by TLC to react almost instantaneously
and generate the corresponding glycosyl bromide in situ.
Slower reaction (69 h) of the equilibrating mixture of R
and â glycosyl bromides led to the formation of 35 in 53%
yield as a 9.3:1.0 mixture of R and â anomers.
a
Reaction of 1 equiv of glycosyl acceptor and 1.5-3.0 equiv of
10b in 2 mL of solvent at 0 °C.
Sch em e 7
Finally, the use of an isopropenyl glycoside as an
aminoglycosyl donor was investigated. Reaction of 10f
and 17 with TMSOTf as promoter, either in acetonitrile
at 0 °C or in dichloromethane at -25 °C, generated the
corresponding â disaccharide, 36,52 in 40% yield as the
only dimeric product.
both 10b and 16 generate the same glycosyl cation
intermediate. Because 10b is more conveniently pre-
pared and exhibits greater shelf life than 16, we chose
early on to use 10b as a glycosyl donor over 16.
Isopropenyl galactopyranoside 10c behaved similar to
10b. It and 17 reacted with TMSOTf in acetonitrile to
give disaccharide 34 in 77% yield (Scheme 7). Acetylated
glucopyranoside 10a also behaved similar to 10b, except
that the transglycosylation reactions of 10a proceeded
with yields lower than those of 10b, presumably because
of complications due to orthoester formation.46
(48) Thiem, J .; Kreuzer, M. Carbohydr. Res. 1986, 149, 347-361.
(49) The use of ether as solvent is known to promote the formation
of 1,2-cis-disaccharides: (a) Igarashi, K.; Irisawa, J .; Honma, T.
Carbohydr. Res. 1975, 39, 213-225. (b) Reference 8. (c) Hashimoto,
S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984, 25, 1379-1382.
(d) Mukaiyama, T.; Katsurada, M.; Takashima, T. Chem. Lett. 1991,
985-988.
(50) Tetraalkylammonium bromide salts promote the equilibration
of R-glycosyl bromides to the more reactive â-glycosyl bromides, leading
to stereoselective R-glycoside formation in dichloromethane: Lemieux,
R. U.; Hendriks, K. B.; Stick, R. V.; J ames, K. J . Am. Chem. Soc. 1975,
97, 4056-4062.
(51) DMTST and TBAB have been used to promote the stereoselec-
tive formation of 1,2-cis-disaccharides, using thioglycosides as glycosyl
donors. See reference 5.
Tetra-O-benzyl glucopyranoside 10d was investigated
as an isopropenyl glycoside bearing nonparticipating47
(46) Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48.
(47) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
(52) Ogawa, T.; Ito, Y. Carbohydr. Res. 1990, 202, 165-175.

Chemistry of Isopropenyl Glycopyranosides
J . Org. Chem., Vol. 61, No. 15, 1996 5029
tetra-O-pivaloyl-R-D-galactopyranosyl bromide (9c) (1.83 g) was
reacted with bis(acetonyl)mercury (1.99 g) for 48 h. Chroma-
tography (8:1 hexane-ethyl acetate) afforded 10c (1.12 g, 64%)
Con clu sion
In conclusion, isopropenyl glycopyranosides are stable
upon storage and yet are readily activated as glycosyl
donors by a variety of electrophiles. Transglycosylation
reactions proceed in good yield and seem to be fairly
general with respect to both the glycosyl residue being
transferred and the nature of the carbohydrate glycosyl
acceptor. A novel electronic effect of solvent, protecting
groups, and promoter was discovered and found to
influence the products formed. Factors which favor the
formation of the glycosyl oxocarbenium cation (strong
electrophile, polar solvent, electron-releasing protecting
groups on the glycosyl donor) lead to transglycosylation.
Factors which retard the formation of the glycosyl cation
(weak electrophile, nonpolar solvent, electron-withdraw-
ing protecting groups on the glycosyl donor) lead to
addition across the isopropenyl ether double bond.
1
as a white solid: mp 126-127 °C; H NMR δ 5.42 (d, J ) 3.1
Hz, 1H), 5.35 (dd, J ) 8.0, 10.4 Hz, 1H), 5.13 (dd, J ) 3.3,
10.5 Hz, 1H), 4.92 (d, J ) 8.0 Hz, 1H), 4.18-4.02 (m, 6H), 1.79
(s, 3H), 1.25, 1.16, 1.14 and 1.10 (4 s, 9H each); IR (KBr) 2980,-
1741, 1481, 1280, 1146, 1082 cm-1; LSIMS m/z 563.4 (M +
Li+), 499.5. Anal. Calcd for C29H48O10: C, 62.57; H, 8.69.
Found: C, 62.57; H, 8.69.
Isop r op en yl 2,3,4,6-Tetr a -O-ben zyl-â-D-glu cop yr a n o-
sid e (10d ). According to the procedure described for the
preparation of 10b, 2,3,4,6-tetra-O-benzyl-R-D-glucopyranosyl
chloride (9d )54 (2.48 g) was reacted with bis(acetonyl)mercury
(2.8 g). After 24 h, TLC (diethyl ether-hexane 1:1) showed
disappearance of starting material (Rf 0.68) and appearance
of product (Rf 0.72). Chromatography (9:1 hexane-ethyl
acetate, containing 1% Et3N) afforded 10d (2.19 g, 85%) as a
waxy solid: mp 61-64 °C; 1H NMR δ 7.32-7.12 (m, 20H), 4.91
(d, J ) 10.9 Hz, 2H), 4.84-4.70 (m, 4H), 4.61-4.49 (m, 3H),
4.23 (d, J ) 1.8 Hz, 1H), 4.08 (br s, 1H), 3.77-3.52 (m, 6H),
1.87 (s, 3H); IR (film) 2906, 2863, 1644, 1497, 1454 , 1385,
1265, 1072 cm-1; LSIMS m/z 603.3 (M + Na+).
Exp er im en ta l Section
Gen er a l P r oced u r es. Acetonitrile, chloroform, and dichlo-
romethane were purified by distillation from CaH2 under
argon. Diethyl ether and tetrahydrofuran were purified by
distillation from sodium/benzophenone under argon. TMSOTf,
Tf2O, TfOH, TESOTf, and tBuOH were distilled under argon
prior to use. DMTST53 and IDCP36 were prepared as previ-
ously described. Column chromatography was performed on
silica gel 60 (230-400 mesh).
Isopr open yl Hepta-O-acetyl-â-D-m altopyr an oside (10e).
As described for the synthesis of 10b, hepta-O-acetyl-R-D-
maltopyranosyl bromide (9e)55 (1.0 g) was reacted with bis-
(acetonyl)mercury (0.90 g) for 68 h. Chromatography (2:1
hexane-ethyl acetate) afforded 10e (0.58 g, 60%) as a white
1
solid: mp 181-182 °C; H NMR δ 5.39 (d, J ) 4.1 Hz, 1H),
5.34 (t, J ) 10.4 Hz, 1H), 5.27 (t, J ) 8.7 Hz, 1H), 5.02 (t, J )
9.8 Hz, 1H), 4.93 (m, 2H), 4.84 (dd, J ) 4.0, 10.5 Hz, 1H), 4.41
(dd, J ) 2.7, 11.9 Hz, 1H), 4.25-4.19 (m, 2H), 4.14 (d, J ) 2.0
Hz, 1H), 4.09-3.93 (m, 4H), 3.79 (m, 1H), 2.10, 2.08, 2.03, 2.01,
1.99 and 1.98 (6 s, 21H), 1.76 (s, 3H).
1H and 13C NMR spectra (250 and 62.9 MHz, respectively)
were recorded at ambient temperature with samples in CDCl3.
Liquid secondary ion mass spectroscopy (LSIMS) was per-
formed using Cs+(20 eV) as the ionizing beam and m-
nitrobenzyl alcohol or glycerol as the matrix. In some cases,
LiCl or NaI was added to the matrix to enhance the relative
intensity of the quasi-molecular ions. Of the alkali metal
cations examined, Na was found to enhance the relative
intensity of the quasi-molecular ion more than Li, K, or Cs.
The relative intensity of the quasi-molecular ion was found to
be insensitive to the counterion (F, Cl, Br, I) present in the
matrix additive.
Isop r op en yl 3,4,6-Tr i-O-a cetyl-2-d eoxy-2-p h th a lim id o-
â-D-glu cop yr a n osid e (10f). According to the procedure
described for the preparation of 10b, 3,4,6-tri-O-acetyl-2-deoxy-
2-phthalimido-D-glucopyranosyl bromide (9f)56 (0.69 g) was
reacted with bis(acetonyl)mercury (0.87 g). After 1 h, TLC
(chloroform-methanol 19:1) showed disappearance of starting
material (Rf 0.62) and appearance of product (Rf 0.54). Chro-
matography (3:1 hexane-ethyl acetate) afforded 10f (0.30 g,
1
45%) as a pale yellow solid: mp 182-184 °C; H NMR δ 7.85
Bis(a ceton yl)m er cu r y.19 2-Methoxypropene (11.5 mL)
was added dropwise from an addition funnel to a stirred
suspension of yellow mercuric oxide (10.82 g) and mercuric
acetate (0.40 g) in 6 mL of methanol and 3 mL of distilled
water, at 0 °C. After 30 min at room temperature, the initially
orange mixture had turned gray. The mixture was filtered
through a fine (4-5.5 µm) fritted funnel. On cooling to 0 °C,
the mercurial compound precipitated as a gray solid (16.2 g,
(dd, J ) 3.0, 5.5 Hz, 2H), 7.73 (dd, J ) 3.0, 5.5 Hz, 2H), 5.83
(dd, J ) 9.0, 10.6 Hz, 1H), 5.78 (d, J ) 8.5 Hz, 1H), 5.17 (dd,
J ) 9.1, 10.1 Hz, 1H), 4.45 (dd, J ) 8.6, 10.7 Hz, 1H), 4.31 (dd,
J ) 5.5, 12.3 Hz, 1H), 4.17-4.09 (m, 2H), 4.05 (br s, 1H), 3.94
(ddd, J ) 2.3, 5.4, 10.2 Hz, 1H), 2.08, 2.02 and 1.86 (3 s, 3H
each), 1.64 (s, 3H); IR (KBr) 3488, 1754, 1714, 1390, 1047 cm-1
;
LSIMS m/z 498.2 (M + Na+).
1-O-Ace t yl-2,3,4,6-Te t r a -O-p iva loyl-r-D -glu cop yr a -
n ose (15). To a stirred solution of 10.14 g of 1426 in 120 mL
of acetic anhydride was added dropwise 7 mL of concentrated
sulfuric acid. After 1 h, the mixture was poured onto ice and
extracted with chloroform. The organic layer was washed
with saturated NaHCO3 and water, dried over anhydrous
MgSO4, and evaporated under reduced pressure. Recrystal-
lization of the crude product from ethanol yielded 5.64 g (60%)
1
86%): mp 66-67 °C; H NMR δ 2.46 (s, 2H), 2.15 (s, 3H).
Isop r op en yl 2,3,4,6-Tetr a -O-p iva loyl-â-D-glu cop yr a n o-
sid e (10b). 2,3,4,6-Tetra-O-pivaloyl-R-D-glucopyranosyl bro-
mide (9b)46 (1.0 g) in chloroform (10 mL) was added to
bis(acetonyl)mercury (1.1 g) in chloroform (20 mL). The
mixture was heated at reflux for 27 h, cooled and then washed
with 10% potassium thiocyanate, 1 M sodium bicarbonate, and
water. The organic layer was dried (MgSO4) and evaporated
under reduced pressure. Chromatography (12:1 hexane-ethyl
acetate) afforded 10b (0.69 g, 72%) as a white solid: mp 120-
1
of 15: mp 144-145 °C; H NMR δ 6.34 (d, J ) 3.9 Hz, 1H),
5.53 (t, J ) 9.8 Hz, 1H), 5.17 (t, J ) 9.8 Hz, 1H), 5.05 (dd, J
) 3.9, 10.0 Hz, 1H), 4.16-4.04 (m, 3H), 2.15 (s, 3H), 1.22-
1.10 (m, 36H); IR (film) 2974, 1745, 1550, 1279, 1138, 1009
cm-1; LSIMS m/ z 581 (M + Na+) 499, 397, 295, 211, 126, 109.
Anal. Calcd for C28H46O11: C, 60.20; H, 8.30. Found: C, 60.33;
H, 8.30 .
1
123 °C; H NMR δ 5.35 (t, J ) 9.5 Hz, 1H), 5.14 (dd, J ) 8.0,
9.6 Hz, 1H), 5.08 (t, J ) 9.6 Hz, 1H), 4.91 (d, J ) 8.0 Hz, 1H),
4.19 (dd, J ) 1.8, 12.2 Hz, 1H), 4.13 (d, J ) 2.0 Hz, 1H), 4.06
(br s, 1H), 4.02 (dd, J ) 6.8, 12.2 Hz, 1H), 3.80 (ddd, J ) 1.8,
6.8, 10.0 Hz, 1H), 1.76 (s, 3H), 1.18, 1.14, 1.13 and 1.10 (4 s,
9H each); 13C NMR δ 178.0, 177.2, 176.6, 176.4, 158.1, 97.6,
86.9, 72.8, 72.3, 70.9, 68.3, 62.4, 38.9, 38.8, 27.2, 27.1, 20.3;
IR (KBr) 2973, 1745, 1481, 1280, 1143, 1085 cm-1; LSIMS m/z
563.4 (M + Li+), 499.3. Anal. Calcd for C29H48O10: C, 62.57;
H, 8.69. Found: C, 62.53; H, 8.75.
Isop r op en yl 2,3,4,6-Tetr a -O-p iva loyl-r-D-glu cop yr a n o-
sid e (16). To 2.03 g of 15 was added 22 mL of a 0.5 M solution
of dimethyltitanocene27 in toluene. The reaction was protected
(54) (a) Iversen, T.; Bundle, D. R. Carbohydr. Res. 1982, 103, 29-
40. (b) Austin, P. W.; Hardy, F. E.; Buchanan, J . G.; Baddiley, J . J .
Chem. Soc. 1964, 2128-2137.
(55) Brauns, D. H. J . Am. Chem. Soc. 1929, 51, 1820-1831.
(56) Lemieux, R. U.; Takeda, T.; Chung, B. In Synthetic Methods
for Carbohydrates; El Khadem, H. S., Ed.; American Chemical
Society: Washington, DC, 1976; pp 91-115.
Isop r op en yl 2,3,4,6-Tetr a -O-p iva loyl-â-D-ga la ctop yr a -
n osid e (10c). As described for the synthesis of 10b, 2,3,4,6-
(53) Ravenscroft, M.; Roberts, R. M. G.; Tillet, J . G. J . Chem. Soc.,
Perkin Trans. 2 1982, 1569-1572.

5030 J . Org. Chem., Vol. 61, No. 15, 1996
Chenault et al.
from light and heated at 65 °C for 15 h. The orange solution
was diluted with petroleum ether, filtered, and evaporated
under reduced pressure. Chromatography of the orange
residue (acetone-petroleum ether 2:98) afforded 1.30 g (64%)
Reaction of 10b and 17 as above, except using NIS (17.3
mg) and TfOH (18 µL) as promoter, yielded 19 (41%). Reaction
of 10b and 17 as above, except using CH3CN as solvent, gave
19 (53%). Reaction of 0.155 mmol of each of 10b and 17 as
above, except using NIS (35 mg) and TfOH (15 µL) as promoter
and 2.5 mL of 4:1 diethyl ether-dichloromethane as solvent,
generated 19 (25%) and 18 (31%).
1
of 16: mp 104-105 °C; H NMR δ 5.61 (t, J ) 9.8 Hz, 1H),
5.50 (d, J ) 3.8 Hz, 1H), 5.10 (t, J ) 9.8 Hz, 1H), 4.85 (dd, J
) 3.8, 10.0 Hz, 1H), 4.30 (d, J ) 2.0, 1H), 4.14-3.97 (m, 4H),
1.82 (s, 3H), 1.18-1.10 (m, 36H); IR (film) 2973, 1743, 1643,
1550, 1460, 1140, 1051, 760 cm-1; LSIMS m/ z 579 (M + Na+),
499, 397, 295, 211, 127, 109. Anal. Calcd for C29H48O10: C,
62.57; H, 8.69. Found: C, 62.66; H, 8.96.
6-O-[2-Iodo-1-m eth yl-1-(2,3,4,6-tetr a-O-pivaloyl-r-D-glu -
cop yr a n osyloxy)et h yl]-1,2:3,4-d i-O-isop r op ylid en e-r-D-
ga la ctop yr a n ose (20). According to the general glycosylation
procedure, 16 (43 mg) and 17 (20 mg) were reacted in
dichloromethane with NIS (17.3 mg) and TfOH (18 µL). TLC
(hexane-ethyl acetate 2:1) showed disappearance of 10b (Rf
0.87) and 17 (Rf 0.26) and appearance of product (Rf 0.85).
Chromatography (10% ethyl acetate in hexane) afforded 19
(50%) as a waxy solid that was an approximately 1:1 mixture
of epimers at the newly formed acetal center: mp 54-58 °C;
1H NMR δ 5.57-5.49 (m, 2H), 5.45 (d, J ) 5.0 Hz, 1H), 5.11
(dd, J ) 9.6, 10.0 Hz, 1H), 4.91 and 4.87 (2 d, J ) 3.9 Hz, 1H),
4.56 (dd, J ) 2.1, 8.0 Hz, 1H), 4.31-4.12 (m, 3H), 4.07-3.99
(m, 2H), 3.90 (m, 1H), 3.66-3.25 (m, 4H), 1.63, 1.52, 1.40, 1.31,
1.30 (5 s, 3H each), 1.20, 1.15, 1.13 and 1.10 (4 s, 9H each);
13C NMR δ 178.2, 177.6, 177.1, 176.4, 109.2, 108.6, 101.1, 96.3,
90.1, 70.9, 70.7, 70.0, 68.3, 66.8, 62.4, 62.1, 38.8, 30.8, 29.7,
27.4, 27.3, 27.2, 27.1, 26.2, 26.0, 25.0, 24.4, 23.1, 11.0; IR (film)
2973, 1743, 1480, 1398, 1280, 1139, 1072 cm-1; LSIMS
m/z 949.5 (M + Li+), 499.4 (C26H43O9)+. Anal. Calcd for
C41H67O16I: C, 52.23; H, 7.16; I, 13.46. Found: C, 52.29; H,
7.40; I, 13.13.
1,2:3,4-Di-O-isop r op ylid en e-6-O-[1-m et h yl-1-(2,3,4,6-
tetr a -O-p iva loyl-â-D-glu cop yr a n osyloxy)eth yl]-r-D-ga la c-
top yr a n ose (21). According to the general glycosylation
procedure, 10b (86 mg) and 17 (20 mg) were reacted in
dichloromethane with TMSOTf (18 µL) as promoter. TLC
(hexane-ethyl acetate 2:1) showed disappearance of starting
materials and appearance of two products (Rf 0.84 and Rf 0.81).
Chromatography (0.8% methanol in 1,2-dichloroethane) af-
forded 21 (32%) as a white waxy solid: mp 73-75 °C: 1H NMR
δ 5.49 (d, J ) 5.0 Hz, 1H), 5.28 (ddd, J ) 1.8, 7.5, 9.1 Hz, 1H),
5.08-4.96 (m, 3H), 4.62 (dd, J ) 2.3, 8.0 Hz, 1H), 4.30 (dd, J
) 2.3, 5.0 Hz, 1H), 4.29 (dd, J ) 1.7, 7.8 Hz, 1H), 4.20 (dd, J
) 1.7, 12.1 Hz, 1H), 3.91 (dd, J ) 6.7, 12.1 Hz, 1H), 3.87 (m,
1H), 3.68 (ddd, J ) 1.7, 6.8, 10.1 Hz, 1H), 3.60-3.56 (m, 2H),
1.53 and 1.52 (2 s, 6 H), 1.43 and 1.32 (2 s, 6H each), 1.18,
1.13, 1.12 and 1.08 (4 s, 9H each); 13C NMR δ 178, 177, 176,
109.5, 108.6, 102.2, 96.4, 93.8, 73.1, 72.5, 71.2, 70.9, 70.8, 69.0,
66.6, 62.6, 60.3, 38.8, 38.7, 28.3, 27.3, 27.23, 27.20, 27.1, 26.2,
25.1, 24.9, 24.7; IR (film) 2975, 2875, 1744, 1481, 1461, 1398,
1383, 1371, 1280, 1141, 1073 cm-1; LSIMS m/z 839.5 (M +
Na+), 801.5, 499.3. Anal. Calcd for C41H68O16: C, 60.28; H,
8.39. Found: C, 60.24; H, 8.05.
Meth yl 2,3,6-Tr i-O-ben zyl-4-O-(2,3,4,6-tetr a -O-p iva loyl-
â-D-glu cop yr a n osyl)-r-D-glu cop yr a n osid e (23). According
to the general glycosylation procedure, 10b (129 mg) and 2257
(36 mg) were reacted in acetonitrile with TMSOTf (21 µL). TLC
(hexane-ethyl acetate 2:1) showed disappearance of 10b and
22 (Rf 0.59) and appearance of product (Rf 0.76). Chromatog-
raphy (9% ethyl acetate in hexanes) afforded 51.6 mg (69%)
of 23 as a syrup: 1H NMR δ 7.45, 7.36 and 7.22 (3 m, 15H),
4.96 (d, J ) 11.3 Hz, 1H), 4.85-4.78 (m, 4H), 4.72-4.53 (m,
5H), 4.28 (d, J ) 12.1 Hz, 1H), 4.05 (dd, J ) 1.7, 12.0 Hz, 1H),
3.99 (m, 1H), 3.89-3.69 (m, 4H), 3.57-3.47 (m, 2H), 3.34 (s,
3H), 3.24 (m, 1H), 1.18, 1.15, 1.12 and 1.07 (4 s, 9H each); IR
(film) 2970, 2873, 1745, 1480, 1455, 1398, 1367, 1281, 1139,
1046 cm-1; LSIMS m/z 969.2 (M + Li+), 499.2. Anal. Calcd
for C54H74O15: C, 67.34; H, 7.74. Found: C, 67.27; H, 8.09.
P en t-4-en yl 2,3,6-Tr i-O-ben zyl-â-D-glu copyr an oside (24).
Pent-4-enyl 2,3-di-O-benzyl-4,6-O-benzylidene-â-D-glucopyra-
noside58 (0.74 g) was reacted with sodium cyanoborohydride
and HCl in THF.57 TLC (hexane-ethyl acetate 2:1) showed
disappearance of starting material (Rf 0.88) and formation of
Gen er a l P r oced u r e for Glycosyla tion Rea ction s. Gly-
cosyl acceptor, glycosyl donor (1-2 equiv), and activated,
powdered 4-Å molecular sieves were combined in 2 mL of dry
solvent and stirred for 30 min at room temperature. The
mixture was cooled to 0 °C, and promoter was added. Within
5 min, reaction was complete as judged by TLC. The reaction
mixture was neutralized with Et3N (∼0.2 mL per 0.077 mmol
of glycosyl acceptor), diluted with ethyl acetate (10 mL),
filtered, and transferred to a separatory funnel. The organic
layer was washed with 10% sodium thiosulfate (if NIS was
used in the promoter mixture), 1 M sodium bicarbonate,
distilled water, and brine. It was then dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure.
Chromatography gave the desired disaccharide as a pure
compound. Excess glycosyl donor could be recovered as 2,3,4,6-
tetra-O-pivaloylglucose.
1,2:3,4-Di-O-isopr opyliden e-6-O-(2,3,4,6-tetr a-O-pivaloyl-
â-D-glu cop yr a n osyl)-r-D-ga la ctop yr a n ose (18). According
to the general glycosylation procedure, 10b (86 mg) and 17
(20 mg) were reacted in acetonitrile with NIS (17.3 mg) and
TfOH (18 µL). Chromatography (0.8% methanol in 1,2-
dichloroethane) afforded 18 (70%) as a syrup: 1H NMR δ 5.45
(d, J ) 4.9 Hz, 1H), 5.28 (t, J ) 9.5 Hz, 1H), 5.09 (t, J ) 9.5
Hz, 1H), 5.02 (dd, J ) 7.9, 9.5 Hz, 1H), 4.56 (d, J ) 7.9 Hz,
1H), 4.55 (dd, J ) 2.4, 7.9 Hz, 1H), 4.25 (dd, J ) 2.3, 5.0 Hz,
1H), 4.18 (dd, J ) 1.8, 8.0 Hz, 1H), 4.17 (dd, J ) 1.8, 12 Hz,
1H), 4.05 (dd, J ) 5.4, 12.2 Hz, 1H), 3.99 (dd, J ) 4.6, 10.2
Hz, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.59 (dd, J ) 6.4, 10.3
Hz, 1H), 1.47 (s, 3H), 1.40 (s, 3H), 1.29 (s, 6H), 1.20, 1.14, 1.12
and 1.08 (4 s, 9H each); 13C NMR δ 178.1, 177.2, 176.6, 176.4,
109.2, 108.5, 101.2, 96.2, 72.3, 71.2, 71.1, 70.6, 70.5, 68.7, 68.2,
67.1, 62.0, 38.9, 38.7, 27.12, 27.05, 26.1, 25.9, 25.0, 24.3; IR
(film) 2974, 2874, 1744, 1481, 1461, 1398, 1370, 1280, 1139,
1070 cm-1; LSIMS m/z 765 (M + Li+), 499. Anal. Calcd for
C38H62O15: C, 60.14; H, 8.23. Found: C, 59.90; H, 8.33.
Reaction of 10b and 17 as above, except using TMSOTf (18
µL) or Tf2O (15 µL) as promoter, yielded 18 (69 or 65%,
respectively). Reaction of 10b and 17 as above, except using
1 mol equiv of tBuOH (∼50 mM) in dichloromethane as
solvent, gave 18 (75%). The use of DMTST (40 mg) as
promoter and dichloromethane as solvent generated 18 (48%).
Reaction of 10b and 17 in acetonitrile, using AgOTf (19.8 mg)
as promoter, required stirring for 24 h at room temperature
to go to completion and yielded 18 (24%).
6-O-[2-Iod o-1-m eth yl-1-(2,3,4,6-tetr a -O-p iva loyl-â-D-glu -
cop yr a n osyloxy)et h yl]-1,2:3,4-d i-O-isop r op ylid en e-r-D-
ga la ctop yr a n ose (19). According to the general glycosylation
procedure, 10b (43 mg) and 17 (20 mg) were reacted in
dichloromethane with IDCP (0.077 mmol) as promoter. Col-
umn chromatography (12% ethyl acetate in hexane) afforded
19 (53%) as a waxy solid that was an approximately 1:1
mixture of epimers at the newly formed acetal center: mp 65-
1
68 °C; H NMR δ 5.50 (m, 1H), 5.29 (m, 1H), 5.16-4.95 (m,
3H), 4.64 (m, 1H), 4.36-4.20 (m, 3H), 3.97-3.21 (m, 7H), 1.61,
1.58, 1.56, 1.54, 1.53, 1.48, 1.41 and 1.33 (8 s, 15H), 1.21, 1.19,
1.131, 1.127 and 1.08 (5 s, 36H); 13C NMR δ 179.3, 178.1, 178.0,
177.1, 176.6, 176.5, 109.7, 109.5, 108.8, 108.7, 101.3, 101.0,
96.4, 96.3, 94.2, 93.3, 73.0, 72.8, 72.7, 72.5, 71.6, 70.9, 70.8,
70.6, 70.3, 68.7, 68.1, 66.8, 66.2, 65.9, 62.6, 62.5, 62.4, 61.8,
60.5, 38.9, 38.7, 27.3, 27.2, 27.12, 27.05, 26.1, 26.03, 25.98, 25.3,
24.9, 24.72, 24.65, 24.3, 23.2, 13.6, 9.8; IR (film) 2976, 2874,
1744 , 1481, 1461, 1398, 1383, 1370, 1280, 1141, 1073 cm-1
;
(57) Garegg, P. J .; Hultberg, H. Carbohydr. Res. 1981, 93, C10-
C11.
(58) Mootoo, D. R.; Date, V.; Fraser-Reid, B. J . Am. Chem. Soc. 1988,
110, 2662-2663.
LSIMS m/z 965.4 (M + Na+), 499.3. Anal. Calcd for
C41H67O16I: C, 52.23; H, 7.16; I, 13.46. Found: C, 52.13; H,
7.20; I, 13.46.

Chemistry of Isopropenyl Glycopyranosides
J . Org. Chem., Vol. 61, No. 15, 1996 5031
product (Rf 0.63). After aqueous workup, chromatography
afforded 24 as a yellow syrup (76%): 1H NMR δ 7.36-7.26
(m, 15H), 5.81(ddt, J ) 6.7, 10.2, 17.0 Hz, 1H), 5.05-4.90 (m,
4H), 4.71 (d, J ) 11.5 Hz, 2H), 4.58-4.55 (m, 2H), 4.40 (d, J
) 7.3 Hz, 1H), 3.94 (dt, J ) 6.4, 9.5 Hz, 1H), 3.78-3.41 (m,
7H), 2.51 (d, J ) 1.9 Hz, 1H), 2.15 (m, 2H), 1.74 (m, 2H); IR
(film) 3445, 2913, 2871, 1496, 1454, 1364, 1063 cm-1; LSIMS
m/z 541.2 (M + Na+), 433.1. Anal. Calcd for C32H38O6: C,
74.11; H, 7.38. Found: C, 73.88; H, 7.35.
dure, 10b (103 mg) and 32 (20 mg) were reacted in 2.5 mL of
acetonitrile with NIS (42 mg) and TfOH (16 µL). TLC
(hexane-ethyl acetate 6:2) showed disappearance of 10b (Rf
0.83) and 32 (Rf 0.34) and appearance of product (Rf 0.76).
Chromatography (5% ethyl acetate in hexane) afforded 42 mg
(64%) of 33 as a clear oil: 1H NMR δ 5.28 (t, J ) 9.4 Hz, 1H),
5.06 (dd, J ) 9.5, 9.9 Hz, 1H), 4.98 (dd, J ) 8.0, 9.6 Hz, 1H),
4.46 (d, J ) 8.0 Hz, 1H), 4.19 (dd, J ) 1.9, 12.1 Hz, 1H), 4.02
(dd, J ) 5.8, 12.1 Hz, 1H), 4.02 (t, J ) 6.7 Hz, 2H), 3.79 (dt, J
) 6.5, 9.4 Hz, 1H), 3.69 (ddd, J ) 1.9, 5.8, 10.0 Hz, 1H), 3.40
(dt, J ) 6.8, 9.4 Hz, 1H), 2.02 (s, 3H), 1.58-1.49 (m, 4H), 1.22
(br s, 12H), 1.19 (s, 9H), 1.123 and 1.121 (2s, 18H), 1.08 (s,
9H); IR (film) 2969, 2857, 1741, 1480, 1461, 1397, 1356, 1280,
1143, 1038 cm-1; LSIMS m/z 737.3 (M + Na+), 499.3. Anal.
Calcd for C38H66O12: C, 63.84; H, 9.30. Found: C, 64.06; H,
9.22.
P en t-4-en yl 2,3,6-Tr i-O-ben zyl-4-O-(2,3,4,6-tetr a -O-p iv-
a loyl-â-glu cop yr a n osyl)-â-D-glu cop yr a n osid e (25). Ac-
cording to the general glycosylation procedure, 10b (86 mg)
and 24 (40 mg) were reacted in acetonitrile with TMSOTf (16
µL). TLC (hexane-ethyl acetate 7:2) showed disappearance
of 10b (Rf 0.74) and 23 (Rf 0.40) and appearance of product
(Rf 0.67). Chromatography (15% ethyl acetate in hexane)
afforded 54.9 mg (70%) of 25 as a syrup: 1H NMR δ 7.46-
7.23 (m, 15H), 5.81 (ddt, J ) 6.7, 10.2, 17.0 Hz, 1H), 5.05-
4.79 (m, 10H), 4.69-4.63 (m, 4H), 4.38 (d, J ) 12.1 Hz, 1H),
4.29 (dd, J ) 7.9, 10.0 Hz, 1H), 4.07-3.92 (m, 2H), 3.82-3.67
(m, 2H), 3.48 (t, J ) 9.0 Hz, 1H), 3.31-3.21 (m, 3H), 2.15 (m,
2H), 1.74 (m, 2H), 1.18, 1.16, 1.14 and 1.10 (4 s, 9H each); IR
(film) 2972, 2873, 1745, 1480, 1454 , 1397, 1367, 1280, 1138,
1050 cm-1; LSIMS m/z 1023.1 (M + Li+), 499.3. Anal. Calcd
for C58H80O15: C, 68.48; H, 7.93. Found: C, 68.50; H, 7.72.
Meth yl 2,4,6-Tr i-O-ben zyl-3-O-(2,3,4,6-tetr a -O-p iva loyl-
â-D-glu cop yr a n osyl)-r-D-glu cop yr a n osid e (27). According
to the general glycosylation procedure, 10b (129 mg) and 2659
(36 mg) were reacted in acetonitrile with TMSOTf (21 µL). TLC
(hexane-ethyl acetate 2:1) showed disappearance of 10b and
26 (Rf 0.57) and appearance of product (Rf 0.80). Chromatog-
raphy (0.8% methanol in 1,2-dichloroethane) afforded 54.9 mg
(74%) of 27 as a syrup: 1H NMR δ 7.42, 7.30 and 7.25 (3 m,
15H), 5.34-5.26 (m, 2H), 5.14-5.05 (m, 2H), 4.99 (d, J ) 11.2
Hz, 1H), 4.70-4.33 (m, 8H), 4.09 (m, 2H), 3.67-3.50 (m, 5H),
3.27 (s, 3H), 1.21, 1.15, 1.14 and 1.13 (4 s, 9H each); IR (film)
2972, 2873, 1745, 1480, 1455, 1398, 1368, 1280, 1140, 1052
cm-1; LSIMS m/z 985.7 (M + Na+), 499.3. Anal. Calcd for
C54H74O15: C, 67.34; H, 7.74. Found: C, 67.02; H, 7.44.
1,2:5,6-Di-O-isopr opyliden e-3-O-(2,3,4,6-tetr a-O-pivaloyl-
â-D-glu cop yr a n osyl)-R-D-glu cofu r a n osid e (29). According
to the general glycosylation procedure, 10b (86 mg) and 28
(20 mg) were reacted in acetonitrile with TMSOTf (18 µL). TLC
(hexane-ethyl acetate 2:1) showed disappearance of 10b and
28 (Rf 0.30) and appearance of product (Rf 0.82). Chromatog-
raphy (0.8% methanol in 1,2-dichloroethane) afforded 13.5 mg
(23%) of 29 as a white solid: mp 156-158 °C; 1H NMR δ 5.94
(d, J ) 3.7 Hz, 1H), 5.27 (t, J ) 9.4 Hz, 1H), 5.09 (t, J ) 9.7
Hz, 1H), 5.01 (dd, J ) 8.1, 9.4 Hz, 1H), 4.57 (d, J ) 7.9 Hz,
1H), 4.53 (d, J ) 3.7 Hz, 1H), 4.20-3.93 (m, 5H), 3.75-3.62
(m, 3H), 1.44 (s, 3H), 1.30 (s, 6H), 1.29 (s, 3H), 1.20, 1.125,
1.120 and 1.08 (4 s, 9H each); IR (KBr) 2970, 2933, 1743, 1481,
1458, 1383, 1282, 1140, 1035 cm-1; LSIMS m/z 781.6 (M +
Na+), 499.3. Anal. Calcd for C38H62O15: C, 60.14; H, 8.23.
Found: C, 59.80; H, 8.08.
1,2:3,4-Di-O-isopr opyliden e-6-O-(2,3,4,6-tetr a-O-pivaloyl-
â-D-ga la ctop yr a n osyl)-r-D-ga la ctop yr a n ose (34). Accord-
ing to the general glycosylation procedure, 10c (86 mg) and
17 (20 mg) were reacted in acetonitrile with TMSOTf (18 µL).
TLC (hexane-ethyl acetate 2:1) showed disappearance of 10c
(Rf 0.86) and 17 (Rf 0.26) and appearance of product (Rf 0.80).
Chromatography (0.8% methanol in 1,2-dichloroethane) af-
forded 34 (77%) as a syrup: 1H NMR δ 5.45 (d, J ) 4.9 Hz,
1H), 5.38 (d, J ) 3.1 Hz, 1H), 5.21 (dd, J ) 8.1, 10.2 Hz, 1H),
5.07 (dd, J ) 2.5, 10.4 Hz, 1H), 4.56 (d, J ) 7.7 Hz, 1H), 4.55
(dd, J ) 3.3, 7.8 Hz, 1H), 4.26-4.10 (m, 3H'), 4.02-3.92 (m,
4H), 3.62 (dd, J ) 6.4, 10.0 Hz, 1H), 1.47 (s, 3H), 1.40 (s, 3H),
1.30 (s, 3H), 1.29 (s, 3H), 1.24, 1.15, 1.14 and 1.08 (4 s, 9H
each); IR (film) 2977, 2874, 1790, 1481, 1461, 1398, 1382, 1370,
1280, 1140, 1072 cm-1
.
1,2:3,4-Di-O-isop r op ylid en e-6-O-(2,3,4,6-tetr a -O-ben zyl-
D-glu cop yr a n osyl)-r-D-ga la ctop yr a n ose (35).48 According
to the general glycosylation procedure, 10d (34 mg) and 17
(13.8 mg) were reacted in dichloromethane with IDCP (0.064
mmol). TLC (diethyl ether-hexane 1:1) showed disappearance
of 10d (Rf 0.94) and 17 (Rf 0.30) and formation of product (Rf
0.62). Chromatography (15% ethyl acetate in hexane) afforded
29.3 mg (64%) of a 1.2:1.0 mixture of 35 and its â anomer.
The ratio of anomers was determined by integration of the
NMR signals for the anomeric protons of the R (δ 5.50, d, J )
5.0 Hz) and â (δ 5.55, d, J ) 5.0 Hz) anomers.
Reaction of 10d (89 mg) and 17 (20 mg) as above, except
with acetonitrile as solvent and TMSOTf (18 µL) as promoter,
yielded 42 mg (70%) of a 1.0:1.7 mixture of 35 and its â anomer.
Reaction of 10d (58 mg) and 17 (28 mg) at various tempera-
tures in diethyl or diisopropyl ether with TMSOTf (20 µL) as
promoter gave 35 and its â anomer in various yields and
anomeric ratios (Table 5). Reaction of 10d (89 mg), 17 (20
mg), and TBAB (124 mg) in acetonitrile with DMTST (40 mg)
for 69 h at rt gave 31.6 mg (53%) of a 9.3:1.0 mixture of 35
and its â anomer.
1,2:3,4-Di-O-isop r op ylid en e-6-O-(3,4,6-t r i-O-a cet yl-2-
d eoxy-2-p h th a lim id o-â-D-glu cop yr a n osyl)-r-D-ga la ctop y-
r a n ose (36).52 According to the general glycosylation proce-
dure, 10f (38 mg) and 17 (10.5 mg) were reacted in 1 mL of
acetonitrile at 0 °C with TMSOTf (15 µL). Within 5 min, TLC
(hexane-ethyl acetate 1:1) showed disappearance of 10f (Rf
0.63) and 17 (Rf 0.46) and appearance of product (Rf 0.48).
Chromatography (33% ethyl acetate in hexane) afforded 36
(40%) as a yellow solid: mp 205-207 °C.
P h en yl 2,3,4-Tr i-O-ben zyl-6-O-(2,3,4,6-tetr a -O-p iva loyl-
â-D-glu cop yr a n osyl)-1-th io-â-D-glu cop yr a n osid e (31). Ac-
cording to the general glycosylation procedure, 10b (31 mg)
and 3042 (13 mg) were reacted in 1 mL of acetonitrile with
TMSOTf (11 µL). TLC (hexane-ethyl acetate 4:1) showed
disappearance of 10b (Rf 0.75) and 30 (Rf 0.31) and appearance
of product (Rf 0.56). Chromatography (12.5% ethyl acetate in
hexane) afforded 25 mg (65%) of 31 as a syrup: 1H NMR δ
7.54-7.21 (m, 20H), 5.13 (t, J ) 9.3 Hz, 1H), 5.02 (dd, J )
9.4, 9.7 Hz, 1H), 4.93 (dd, J ) 8, 9.4 Hz, 1H), 4.90-4.69 (m,
6H), 4.55 (d, J ) 10.9 Hz, 1H), 4.44 (d, J ) 8.0 Hz, 1H), 4.21
(dd, J ) 1.4, 12.2 Hz, 1H), 3.98-3.90 (m, 2H), 3.79-3.64 (m,
2H), 3.47-3.27 (m, 4H), 1.20, 1.16, 1.10 and 1.08 (4 s, 9H each);
Reaction of 10f and 17 as above, except performing the
reaction at -25 °C and using 1 mL of CH2Cl2 as solvent, gave
10.8 mg (40%) of purified 36.
Ack n ow led gm en t. This work has been supported,
in part, by the National Science Foundation (CHE 90-
19078), the Petroleum Research Fund (ACS-PRF 25395-
G1), and the University of Delaware Research Founda-
tion. We thank Dr. Gordon Nicol and Adam Bratis for
LSIMS data, Dr. Fred Askham for providing Zr-
(Cp2)(OTf)2THF, Dr. Subramanium Sabesan for provid-
ing 11b, Robert Meagley for providing 32, and J aneen
Argyros for preparing 30.
IR (film) 2904 , 2874, 1747, 1499, 1439, 1359, 1151, 1078 cm-1
;
LSIMS m/z 1062.6 (M + Na+). Anal. Calcd for C59H76O14S:
C, 68.05; H, 7.36; S, 3.08. Found: C, 68.01; H, 8.01; S, 2.94.
10-Acetoxyd ecyl 2,3,4,6-Tetr a -O-p iva loyl-â-D-glu cop y-
r a n osid e (33). According to the general glycosylation proce-
(59) Koto, S.; Takebe, Y.; Zen, S. Bull. Chem. Soc. J pn. 1972, 45,
291-293.
J O960190P