Stereocontrolled formation of β-glucosides and related linkages in the absence of neighboring group participation: Influence of a trans-fused 2,3-O-carbonate group

Article abstract of DOI:10.1021/jo0508999

Phenyl 4,6-di-O-benzyl-2,3-O-carbonyl-β-D-glucothiopyranoside and the regiosiomeric phenyl 2,6-di-O-benzyl-3,4-O-carbonyl-β-D-glucothiopyranoside were prepared and studied as glucosyl donors at -60 °C in dichloromethane with preactivation by 1-benzenesulf

Full text of DOI:10.1021/jo0508999

Stereocontrolled Formation of â-Glucosides and Related Linkages
in the Absence of Neighboring Group Participation: Influence of a
trans-Fused 2,3-O-Carbonate Group
David Crich* and Prasanna Jayalath
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received May 5, 2005
Phenyl 4,6-di-O-benzyl-2,3-O-carbonyl-â-D-glucothiopyranoside and the regiosiomeric phenyl 2,6-
di-O-benzyl-3,4-O-carbonyl-â-D-glucothiopyranoside were prepared and studied as glucosyl donors
at -60 °C in dichloromethane with preactivation by 1-benzenesulfinyl piperidine before addition
of the acceptor alcohol. The 2,3-O-carbonate protected donor showed moderate to excellent
â-selectivity under these conditions depending on the acceptor employed, thereby providing a means
for 1,2-trans-equatorial glycosidic bonds without recourse to neighboring group participation and
its associated problem of ortho ester formation. In contrast, the 3,4-O-carbonate protected donor
showed moderate to no â-selectivity under the conditions employed. The results obtained in this
study with carbonate protected glucopyranosyl donors are contrasted with those obtained previously
in the manno- and rhamnopyranosyl series when the 2,3-O-carbonate protected is R-selective and
the 3,4-O-carbonate is â-selective.
Introduction
one-pot oligosaccharide synthesis and other iterative one-
pot glycosylation protocols,8 when less than perfect yields
lead to deletion sequences and complicate final product
isolation and purification. Our laboratory is interested
The synthesis of 1,2-trans-equatorial pyranosidic bonds
(e.g., the â-glucopyranosides) is dominated by neighbor-
ing group participation, as embodied in the use of dis-
armed, ester-protected glycosyl donors.1 This extremely
widespread methodology suffers from the competing
formation of glycosyl ortho esters, particularly when the
glycosylation sequence is conducted under basic condi-
tions, and of migration of the 2-O-acyl group to both the
anomeric center and the glycosyl acceptor.2 These del-
eterious side reactions, from which no carboxylate esters,
neither the highly hindered pivalates nor the highly
electron-deficient perfluoroalkylcarboxylates, are ex-
empt,3 are consequences of the mechanism and are
always potentially problematic.4 The need for increas-
ingly sophisticated oligosaccharide synthesis, driven by
potential biological applications,5 presents the need for
ever-more efficient and selective glycosylation reactions,
devoid of such potential yield-reducing side reactions.6
Nowhere is this more apparent than in the cutting edge
fields of polymer-supported automated,7 and programmed
(2) (a) Paulsen, H.; Herold, C.-P. Chem. Ber. 1970, 103, 2450. (b)
Bochkov, A. F.; Zaikov, G. E. Chemistry of the O-Glycosidic Bond;
Pergamon: Oxford, 1979. (c) Garegg, P. J.; Konradsson, P.; Kvarn-
strom, I.; Norberg, T.; Svensson, S. C. T.; Wigiliu, B. Acta Chem. Scand.
1985, B39, 569. (d) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield,
D. M. J. Am. Chem. Soc. 1998, 120, 13291. (e) Thompson, C.; Ge, M.;
Kahne, D. J. Am. Chem. Soc. 1999, 121, 1237. (f) Yang, Z.; Lin, W.;
Yu, B. Carbohydr. Res. 2000, 329, 879. (g) Banoub, J.; Bundle, D. R.
Can. J. Chem. 1979, 57, 2091. (h) Banoub, J. H.; Michon, F.; Rice, J.;
Rateb, L. Carbohydr. Res. 1983, 123, 109. (i) Be´rces, A.; Enright, G.;
Nukada, T.; Whitfield, D. M. J. Am. Chem. Soc. 2001, 123, 5460. (j)
Crich, D.; Dai, Z.; Gastaldi, S. J. Org. Chem. 1999, 64, 5224. (k) Crich,
D.; Dai, Z. Tetrahedron 1999, 55, 1569. (l) Yu, H.; Ensley, H. E.
Tetrahedron Lett. 2003, 44, 9363. (m) Be´rces, A.; Whitfield, D. M.;
Nukada, T.; do Santos, Z. I.; Obuchowska, A.; Krepinsky, J. J. Can. J.
Chem. 2004, 82, 1157.
(3) (a) Harreus, A.; Kunz, H. Liebigs 1986, 717. (b) Lemieux, R. U.;
Morgan, A. R. Can. J. Chem. 1965, 43, 2199. (c) Code´e, J. D. C.; van
den Bos, J.; Litjens, R. E. J. N.; Overkleeft, H. S.; van Boom, J. H.;
van der Marel, G. A. Org. Lett. 2003, 5, 1947. (d) Takatani, M.; Matsuo,
I.; Ito, Y. Carbohydr. Res. 2003, 338, 1073.
(4) A novel solution to this problem, neighboring group participation
by groups other than standard O-2 carboxylates has recently been
described. Kim, J.-H.; Yang, H.; Boons, G.-J. Angew. Chem., Int. Ed.
2005, 44, 947.
(1) Barresi, F.; Hindsgaul, O. J. Carbohydr. Chem. 1995, 14, 1043.
10.1021/jo0508999 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/28/2005
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J. Org. Chem. 2005, 70, 7252-7259

Stereocontrolled Formation of â-Glucosides
in the development of improved glycosylation methods,
such as the low-temperature activation of thioglycosides,9
and nontraditional methods for the stereocontrolled
glycosidic bond formation, as exemplified by â-mannoside
synthesis by means of torsionally disarming benzylidene
groups.10 We have shown how the 2,3-O-carbonate group
in manno- (1)11 and rhamnopyranosyl donors (2)12 is
highly R-directing in homogeneous coupling reactions, a
phenomenon we attribute to the half-chair conformation
imposed by this cis-fused, five-membered ring, which
lowers the activation barrier to oxacarbenium ion forma-
tion.11,12 In contrast, 3,4-O-carbonate protected rhamnosyl
donors (3) are moderately â-selective, which we ascribe
to the electron-withdrawing but nonparticipating effect
of this group.12 If the R-selective nature of the 2,3-O-
carbonate group in mannosyl and rhamnosyl donors is
indeed a function of the conformation imposed on the
pyranose ring by the cis-fused five-membered ring, it
seemed reasonable to expect that in the corresponding
glucopyranose systems, with the trans-fused ring junc-
tions, the electron-withdrawing, nonparticipating car-
bonate group might be induced to function as a â-di-
recting group even when spanning the 2,3-diol group.
Our intended work in this area was given additional
impetus by reports from Boons and Zhu,13 that donor 4
was R-selective under conditions closely related to our
own but in the unusual solvent combination of toluene/
1,4-dioxane (1/3). Even more intriguing are the reports
of Kerns and co-workers on the R-selectivity of the
oxazolidinone 5, thought to undergo initial in situ sulfe-
nylation to 6, and of the â-selectivity of the N-acetyl
derivative 7, under conditions even more closely related
to our own.14
moderately reactive glycosyl acceptors on activation with
1-benzenesulfinyl piperidine (BSP) and triflic anhy-
dride,9,15 in the presence of the hindered base 2,4,6-tri-
tert-butylpyrimidine (TTBP),16 in dichloromethane at -60
°C. On the other hand, in a limited range of experiments,
donor 9 showed a disappointing lack of stereoselectivity,
which, when taking into consideration the modestly
â-selective rhamnosyl donor 3, serves to highlight the
influence of the configuration of C2 on glycopyranosyla-
tion reactions.17
We report here that in line with our initial expectations
the glycosyl donor 8 is indeed â-selective with a range of
(5) (a) Dwek, R. A.; Butters, T. D. Chem. Rev. 2002, 102, 283. (b)
Dwek, R. A. Chem. Rev. 1996, 96, 683. (c) Bertozzi, C. R.; Kiessling,
L. L. Science 2001, 291, 2357. (d) Varki, A. Glycobiology 1993, 3, 97.
(6) Nukada, T.; Berces, A.; Whitfield, D. M. J. Org. Chem. 1999,
64, 9030.
(7) (a) Haase, W.-C.; Seeberger, P. H. Curr. Org. Chem. 2000, 4,
481. (b) Palmacci, E. R.; Hewitt, M. C.; Seeberger, P. H. Angew. Chem.,
Int. Ed. 2001, 40, 4433. (c) Plante, O. J.; Palmacci, E. R.; Seeberger,
P. H. Science 2001, 291, 1523. (d) Routenberg Love, K.; Seeberger, P.
H. Angew. Chem., Int. Ed. 2004, 43, 602. (e) Ratner, D. M.; Swanson,
E. R.; Seeberger, P. H. Org. Lett. 2003, 5, 4717.
Results and Discussion
Following the method of Ley,18 treatment of phenylthio
â-D-glucopyranoside19 with 2,2,3,3-tetramethoxybutane
under acid catalysis gave a separable mixture of the
bisacetals 10 and 11. These were individually benzylated
giving the fully protected thioglycosides 12 and 13.
Hydrolysis of the bisacetal functionality afforded the
diols 14 and 15, whose phosgenation provided donors 8
and 9.
(8) (a) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J.
Chem. Soc., Perkin Trans. 1 1998, 51. (b) Zhang, Z.; Ollmann, I. R.;
Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc.
1999, 121, 734. (c) Lee, H.-K.; Scanlan, C. N.; Huang, C.-Y.; Chang, A.
Y.; Calarese, D. A.; Dwek, R. A.; Rudd, P. M.; Burton, D. R.; Wilson,
I. A.; Wong, C.-H. Angew. Chem., Int. Ed. 2004, 43, 1000. (d) Mong, T.
K.-K.; Lee, H.-K.; Duron, S. G.; Wong, C.-H. Proc. Natl. Acad. Sci.
U.S.A. 2003, 100, 797. (e) Ye, X. S.; Wong, C. H. J. Org. Chem. 2000,
65, 2410. (f) Yamago, S.; Yamada, H.; Maruyama, T.; Yoshida, J.-i.
Angew. Chem., Int. Ed. 2004, 43, 2145. (g) Huang, X.; Huang, L.;
Wang, H.; Ye, X.-S. Angew. Chem., Int. Ed. 2004, 43, 5221. (h)
Yamago, S.; Kokubo, K.; Hara, O.; Masuda, S.; Yoshida, J.-I. J. Org.
Chem. 2002, 67, 8584. (i) France, R. R.; Compton, R. G.; Davis, B. G.;
Fairbanks, A. J.; Rees, N. V.; Wadhawan, J. D. Org. Biomol. Chem.
2004, 2, 2195.
(14) (a) Benakli, K.; Zha, C.; Kerns, R. J. J. Am. Chem. Soc. 2001,
123, 9461. (b) Kerns, R. J.; Zha, C.; Benakli, K.; Liang, Y.-Z.
Tetrahedron Lett. 2003, 44, 8069. (c) Wei, P.; Kerns, R. J. J. Org. Chem.
2005, 70, 4195. (d) Also see: Boysen, M.; Gemma, E.; Lahmann, M.;
Oscarson, S. Chem. Commun. 2005, 3044.
(15) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(16) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(17) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926.
(9) Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115.
(10) (a) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004,
126, 14930. (b) Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126,
15081. (c) Crich, D.; Yao, Q. J. Am. Chem. Soc. 2004, 126, 8232. (d)
Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1996,
61, 5280. (e) Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem.
Soc. 2004, 126, 9205. (f) Nukada, T.; Berces, A.; Whitfield, D. M.
Carbohydr. Res. 2002, 337, 765. (g) Nukuda, T.; Be´rces, A.; Wang, L.;
Zgierski, M. Z.; Whitfield, D. M. Carbohydr. Res. 2005, 340, 841.
(11) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291.
(12) Crich, D.; Vinod, A. U.; Picione, J. J. Org. Chem. 2003, 68, 8453.
(13) Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201.
(18) (a) Hense, A.; Ley, S. V.; Osborn, H.; Owen, D. R.; Poisson, J.-
F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997,
2023. (b) Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org.
Chem. 1996, 61, 3897. (c) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.;
Foster, A. C.; Ince, S. J.; Priepke, H. W. M.; Reynolds, D. J. Chem.
Rev. 2001, 101, 53.
(19) Motawia, M. S.; Olsen, C. E.; Enevoldsen, K.; Marcussen, J.;
Møller, B. L. Carbohydr. Res. 1995, 277, 109.
J. Org. Chem, Vol. 70, No. 18, 2005 7253

Crich and Jayalath
resolution was available; otherwise the assignments were
based on the 1JCH coupling constants.24 To guard against
1
the possibility that the JCH anomeric couplings were
influenced by the cyclic carbonate, as is the case with
both the R- and the â-glycosides with their half-chair
conformations arising from coupling to 1 and 2,11,12
selected examples were saponified and the spectral
data of the products examined. As is clear from Table 3,
in all systems there is a reduction in the 1JC1H1 coupling
constant on removal of the carbonate in the â-series,
suggesting a minor change in conformation, either of the
pyranose ring or of the exocyclic glycosidic C-O bond.25
Nevertheless, all hydrolyses confirmed the original ster-
eochemical assignments. Self-evidently these hydrolyses,
which were conducted with lithium hydroxide in aqueous
THF, also serve to confirm the ease with which the cyclic
carbonates can be removed.
In an attempt to shed more light on the influence of
the 2,3-O- and 3,4-O-carbonates in both the gluco- and
the rhamno-(manno-) manifolds, a series of low-temper-
ature experiments were conducted in which selected
donors were converted to the corresponding anomeric
triflates in CD2Cl2 at -60 °C whose decomposition
temperatures were then determined by variable-temper-
ature NMR spectroscopy (Table 4). The four triflate
decomposition temperatures recorded exhibited a range
of 45 °C, with the most stable being the 3,4-O-carbonate
protected rhamnose derivative 51 (Table 4, entry 4) and
the lowest the 2,3-O-carbonate protected rhamnosyl
triflate 50 (Table 4, entry 3). Interestingly, the two
glucosyl triflates 47 and 48 had the same decomposition
temperature (Table 4, entries 1 and 2), which was mid-
way between that of the mannosyl and rhamnosyl donors.
The wide spread in decomposition temperatures between
triflates 50 and 51 shadows the selectivity profile with
the 3,4-O-carbonates in the rhamnosyl series, giving good
â-selectivity consistent with the notion of a relatively
stable anomeric triflate (51) and a correspondingly short
lifetime for the transient contact ion pair with which it
is in equilibrium.26 The 2,3-O-carbonate protected rham-
nosyl triflate 50, on the other hand, has the lowest
decomposition temperature recorded in this study in
accordance with the high R-selectivity observed with this
series of compounds. The correlation between triflate
decomposition temperatures and â-selectivity observed
in the rhamnose series, which mirrors that seen previ-
ously with mannosyl triflates,27 obviously does not extend
to the glucose series. Presumably, this is because triflate
decomposition is a two-step process and is not governed
Examination of the 1H NMR spectra of 8 and 9,
1
especially their anomeric JCH coupling constants,20
revealed that both retained the standard 4C1 chair
conformations typical of the D-hexopyranosides. We
therefore proceeded to examine the coupling reactions of
both donors to a pair of simple, reactive substrates under
our standard conditions, with preactivation of the thiogly-
coside by means of BSP and Tf2O in the presence of
TTBP at -60 °C before addition of the acceptor alcohol.
The results of these coupling reactions, set out in Table
1, reveal that the 2,3-O-carbonyl protected donor is
indeed â-selective with the model alcohols (entries 1 and
4). The 3,4-O-carbonate, on the other hand, showed poor
selectivity with the simple model alcohol 3â-cholestanol
(Table 1, entry 2) and only modest â-selectivity with
1-adamantanol (Table 1, entry 5), whose reactions are
usually characterized by a high degree of selectivity in
favor of the â-anomer.21 Also included in Table 1 for ease
of comparison are the previous couplings (entries 3 and
6)12 of the 3,4-O-carbonate protected rhamnosyl donor 3
to the same model alcohols.
As expected, the 2,3-O-carbonate 8 is highly â-selective
with these simple model alcohols. On the other hand, the
3,4-O-carbonate 9 performed disappointingly with both
3â-cholestanol and 1-adamantanol. The results with the
3,4-O-carbonate 9 are to be contrasted with those ob-
tained with the 3,4-O-carbonate protected rhamnosyl
donor 3, which showed significantly better â-selectivity.
The contrast in selectivity between 3 and 9, which, unlike
1 and 2, and 8, are predicted to have the same pyranose
ring conformation, serves to highlight the fundamental
difference in selectivity between glucosyl and mannosyl/
rhamnosyl donors in the absence of neighboring group
participation on which we have previously commented.11
On the basis of these results, our study with the 2,3-
O-carbonyl protected donor 8 was expanded to include a
series of carbohydrate and amino acid based acceptor
alcohols (Table 2). These couplings each proceeded with
â-selectivity ranging from good to excellent depending on
the acceptor alcohol. The better selectivities were gener-
ally obtained with the less hindered primary alcohols.
However, this was not exclusively the case, and excellent
selectivity was obtained with two secondary alcohols,
raising the possibility of diastereomeric matching and
mismatching situations22 as are widely appreciated in the
broader context of asymmetric synthesis.23 A final coup-
ling with donor 9 served to confirm the relatively poor
selectivity obtained in the 3,4-O-carbonate series.
The anomeric stereochemistry in each of the above
(20) Key NMR data for 8: JH1,H2 9.5 Hz, JH2,H3 11.2 Hz, JH3,H4 9.5
1
Hz, JC1,H1 152.6 Hz. Key NMR data for 9: JH1,H2 8.8 Hz, JH2,H3 9.5
1
Hz, JH3,H4 11.3 Hz, JC1,H1 157.8 Hz.
(21) Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68,
8142.
(22) (a) Fraser-Reid, B.; Lo´pez, J. C.; Go´mez, A. M.; Uriel, C. Eur.
J. Org. Chem. 2004, 1387. (b) Paulsen, H. In Selectivity a Goal for
Synthetic Efficiency; Bartmann, W., Trost, B. M., Eds.; Verlag Che-
mie: Basel, 1984. (c) Spijker, N. M.; van Boeckel, C. A. A. Angew.
Chem., Int. Ed. Engl. 1991, 30, 180.
(23) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(24) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974,
293.
(25) Tvaroska, I.; Taravel, F. R. Adv. Carbohydr. Chem. Biochem.
1995, 51, 15.
(26) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004,
43, 5386.
3
couplings was assigned on the basis of the JH1,H2 coup-
ling constants in the usual manner when sufficient
(27) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
7254 J. Org. Chem., Vol. 70, No. 18, 2005

Stereocontrolled Formation of â-Glucosides
TABLE 1. Comparative Glycosylation Reactions with Donors 8 and 9
a Yields refer to isolated compounds unless otherwise stated. b Anomeric ratio determined by integration of the 1H NMR spectrum of
the crude reaction mixture.
exclusively by the position of the covalent anomeric
triflate/contact ion pair equilibrium. Thus, in the absence
of nucleophiles to capture the transient contact ion pair,
the ease of decomposition is also governed, among other
factors, by the overlap of the C2-H2 bond with the C-1
π-orbital of the oxacarbenium ion, which is dependent
on both configuration (gluco vs rhamno/manno) and
subtle conformational factors arising from the protecting
group array. Interestingly, the VT NMR study also
revealed the influence of protecting groups on the initial
thioglycoside activation. Thus, while thioglycosides 3, 7,
and 9 were activated by the BSP/Tf2O couple in minutes
at -60 °C, the 2,3-O-carbonate protected rhamnosyl
thioglycoside 49 was converted in approximately 15 min
at -60 °C to a complex mixture containing at least four
anomeric signals, which was only converted completely
to a clean anomeric triflate on warming to between -15
and -10 °C, by which time slow decomposition had set
in. This scenario, in which a series of moderately stable
intermediates is observed prior to the triflate formation,
is somewhat analogous to the observations of Lowary on
the activation of thioglycosides and glycosyl sulfoxides
in the 2,3-anhydrofuranose series.28 The seeming dispar-
ity between the relatively slow activation for 49 and the
facile decomposition of the corresponding triflate 50
reflects the different requirements of the two processes
with thioglycoside activation being dependent on the
nucleophilicity of the sulfur atom toward the thiophilic
species, which is reduced in the presence of strongly
electron-deficient protecting groups. A final thioglycoside
studied in this context was the 4,6-O-benzylidene-2,3-O-
carbonate protected thioglucoside 52, which was not
activated by the BSP/Tf2O combination below room
temperature.
Finally, having demonstrated that 2,3-O-carbonate
protected glucopyranosyl donors are moderately â-selec-
tive under our standard conditions with preactivation by
BSP and triflic anhydride in CH2Cl2 at low temperature,
we return to apparent contrast with the work of Boons
with the closely related donor 4 and of Kerns with the
glucosamine analogues 5-7. The discrepancy with the
work of Boons can most probably be explained by either
the different activation conditions29 or, especially, the use
(28) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J.
Am. Chem. Soc. 2003, 125, 13112.
J. Org. Chem, Vol. 70, No. 18, 2005 7255

Crich and Jayalath
TABLE 2. Further Glycosylation Reactions with Donors 8 and 9
a Yields refer to isolated compounds unless otherwise stated. b Anomeric ratio determined by integration of the 1H NMR spectrum of
the crude reaction mixture.
of the considerably more polar solvent combination of
toluene/dioxane (1/3). Kerns reported that the N-acetyl
oxazolidinone-protected glycosyl donor 7 was â-selective
with less hindered, more reactive alcohols but R-selective
with less reactive alcohols, a trend which at least
qualitatively parallels the results obtained here with
donor 8.14c,30 On the other hand, the donor derived from
5/6 was shown to be highly R-selective, pointing to a
significant influence of the N-substituent on glycosylation
stereoselectivity for which we have no explanation at
(29) Unfortunately, donor 8 was not activated by the BSP/Tf2O
system when it was premixed with acceptor alcohols. Rather, the
promoter system reacted preferentially with the alcohol, because of
the disarmed nature of 8.
7256 J. Org. Chem., Vol. 70, No. 18, 2005

Stereocontrolled Formation of â-Glucosides
TABLE 3. Selected Deprotections and Key NMR Data
1
3
a For disaccharides, only the JCH and JH1,H2 coupling constants for the newly formed glucosidic bond are given: assignments were
made by 1H,13C correlated spectroscopy.
present, other than perhaps the bulk of the S-phenyl
substituent on the oxazolidinone nitrogen, which may
lead to a considerably more hindered anomeric center and
retard â-face attack.31
(30) Neighboring group participation by the N-acetyl group in 7 was
excluded as the reason for â-selectivity on the basis of the inspection
of molecular models.14
(31) Recent work from our laboratory has highlighted the influence
of protecting group bulk on anomeric selectivity. Crich, D.; Jayalath,
P. Org. Lett. 2005, 7, 2277.
J. Org. Chem, Vol. 70, No. 18, 2005 7257

Crich and Jayalath
TABLE 4. Anomeric Triflates Chemical Shifts and Decomposition Temperatures
a No activation was observed between -78 and 25 °C.
85.2, 99.6, 100.1, 127.4, 128.9, 131.4, 133.3. ESIHRMS calcd
Conclusion
for C18H26O7S [M + Na]+: 409.1297. Found: 409.1291. 11:
[R]25 +100.4 (c, 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) δ:
We have demonstrated that 2,3-O-carbonate protected
glucopyranosyl donors show moderate to excellent â-se-
lectivity in glycosylations conducted at low temperature
in dichloromethane by our two-stage protocol with pre-
activation before addition of the nucleophile. These
reactions, which proceed through the intermediacy of
covalent glucosyl triflates, are â-selective in the complete
absence of neighboring group or solvent participation and
serve additionally to underline the importance of confor-
mational factors apparent from a comparison with simi-
larly protected mannosyl and rhamnosyl donors.
D
1.26 and 1.3 (2s, 6H), 3.20 and 3.27 (2s, 6H), 3.48 (t, J ) 9.0
Hz, 1H), 3.56 (m, 1H), 3.59 (t, J ) 9.5 Hz, 1H), 3.7 (m, 2H),
3.86 (dd, J ) 3.0, 12.0 Hz, 1H), 4.56 (d, J ) 9.5 Hz, 1H), 7.28
(m, 3H), 7.5 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 17.6, 17.7,
47.9, 61.3, 65.4, 69.3, 73.3, 78.0, 88.3, 99.5, 99.8, 128.32, 129.0,
131.4, 133.0. Anal. Calcd for C18H26O7S: C, 55.94; H, 6.78.
Found: C, 55.58; H, 6.62.
Phenyl 4,6-Di-O-benzyl-2,3-di-O-(2,3-dimethoxybutane-
2,3-diyl)-1-thio-â-D-glucopyranoside (12). Sodium hydride
(60%, 1.62 g, 40 mmol) was added to a cooled solution of 10
(4.87 g, 12.5 mmol) in DMF (20 mL). After the mixture was
stirred for 10 min, benzyl bromide (4 mL, 34 mmol) was added
and stirring was continued for 6 h at room temperature. The
solvents were removed under reduced pressure, and the
resulting mixture was diluted with dichloromethane (40 mL)
and washed with sat. NaHCO3. The organic layer was sepa-
rated and dried (anhydrous Na2SO4) and concentrated in
vacuo. Purification was done by flash column chromatography
on silica gel (hexane:ethyl acetate; 4:1) to yield 12 as a white
solid (6.97 g, 98%). Mp 117 °C; [R]25D -108 (c, 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3) δ: 1.34 and 1.36 (s, 6H), 3.2 and 3.3
(2s, 6H), 3.55 (ddd, J ) 2.0, 5.0, 9.5 Hz, 1H), 3.69-3.75 (m,
3H), 3.77 (dd, J ) 2.0, 11.0 Hz, 1H), 3.9 (t, J ) 9.5 Hz, 1H),
4.51 (d, J ) 12.0 Hz, 1H), 4.57 (d, J ) 8.5 Hz, 1H), 4.59 (d, J
) 9.0 Hz, 1H), 4.75 (d, J ) 10.0 Hz, 1H), 4.93 (d, J ) 11.0 Hz,
1H), 7.2-7.5 (m, 13H), 7.56-7.57 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ: 17.6, 17.8, 47.9, 48.1, 68.0, 69.0, 73.4, 74.6, 75.0,
75.5, 79.5, 84.8, 99.5, 100.1, 127.2, 127.5, 127.6, 127.8, 128.0,
128.3, 128.4, 128.8, 131.6, 133.5, 138.3. Anal. Calcd for
C32H38O7S: C, 67.82; H, 6.76. Found: C, 67.90; H, 6.67.
Experimental Section
Phenyl 2,3-Di-O-(2,3-dimethoxybutane-2,3-diyl)-1-thio-
â-D-glucopyranoside (10) and Phenyl 3,4-Di-O-(2,3-
dimethoxybutane-2,3-diyl)-1-thio-â-D-glucopyranoside
(11). A suspension of phenyl 1-thio-â-D-glucopyranoside19 (8.0
g, 29.4 mmol) in a solution of 2,2,3,3-tetramethoxybutane (1.2
equiv), trimethyl orthoformate (4 equiv), and methanol (120
mL) was treated with camphorsulfonic acid (0.05 equiv), and
then refluxed under Ar for 18 h. The cooled reaction mixture
was treated with powdered NaHCO3 and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography on silica gel (hexane:ethyl acetate,
3:2) to afford 10 and 11 in a 1:1 ratio (28.0 mmol, 94%
combined yield). 10: [R]25 -156.9 (c, 1.0, CHCl3). 1H NMR
D
(500 MHz, CDCl3) δ: 1.32 and 1.33 (2s, 6H), 3.20 and 3.27
(2s, 6H), 3.42 (m, 1H), 3.59 (t, J ) 9.6 Hz, 1H), 3.7-3.8 (m,
3H), 3.88 (dd, J ) 3.0, 12.0 Hz, 1H), 4.82 (d, J ) 9.9 Hz, 1H),
7.23-7.27 (m, 3H), 7.46-7.48 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ: 17.6, 17.7, 48.0, 48.2, 62.3, 67.5, 68.0, 74.3, 80.0,
Phenyl 4,6-Di-O-benzyl-1-thio-â-D-glucopyranoside (14).
A solution of compound 12 (5.98 g, 10.5 mmol) in dichlo-
7258 J. Org. Chem., Vol. 70, No. 18, 2005

Stereocontrolled Formation of â-Glucosides
romethane (20 mL) was added to a mixture of TFA and water
(10 mL, 19:1). The mixture was stirred for 2 h at room
temperature until all of the starting material was consumed
as confirmed by TLC. The mixture was neutralized with sat.
NaHCO3, and the organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The product was
purified by flash column chromatography on silica gel (hexane:
ethyl acetate; 3:2) to give 14 as a white solid (4.42 g, 93%).
NaHCO3, and the organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The product was
purified by flash column chromatography on silica gel (hexane:
ethyl acetate; 3:2) to give 15 as a white solid (3.59, 91%). Mp
105 °C. [R]25D -27.5 (c, 1.0, CHCl3). 1H NMR (500 MHz, CDCl3)
δ: 2.7 (bs, 2H), 3.35 (t, J ) 9.6 Hz, 1H), 3.47-3.51 (m, 1H),
3.56-3.63 (m, 2H), 3.75-3.81 (m, 2H), 4.57 (d, J ) 11.9 Hz,
1H), 4.60 (d, J ) 11.9 Hz, 1H), 4.66 (d, J ) 9.7 Hz, 1H), 4.7 (d,
J ) 10.0 Hz, 1H), 4.97 (d, J ) 10.9 Hz, 1H), 7.26-7.39 (m,
13H), 7.55-7.6 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 70.3,
71.5, 73.6, 75.1, 77.7, 78.2, 80.0, 87.3, 127.5, 127.7, 127.8, 128.1,
128.2, 128.4, 128.6, 128.9, 131.7, 133.7, 137.8, 137.9. Anal.
Calcd for C26H28O5S: C, 69.00; H, 6.24. Found: C, 68.88; H,
6.28.
Mp 78 °C. [R]25 +5.2 (c, 1.0, CHCl3). 1H NMR (500 MHz,
D
CDCl3) δ: 3.0 (bs, 2H), 3.38 (t, J ) 9.0 Hz, 1H), 3.51-3.53 (m,
2H), 3.68-3.82 (m, 3H), 4.52 (d, J ) 9.6 Hz, 1H), 4.57 (d, J )
12.0 Hz, 1H), 4.63 (d, J ) 11.2 Hz, 1H), 4.64 (d, J ) 12.0 Hz,
1H), 4.8 (d, J ) 11.2 Hz, 1H), 7.26-7.37 (m, 13H), 7.5-7.6
(m, 2H). 13C NMR (125 MHz, CDCl3) δ: 69.0, 72.2, 73.5, 74.7,
76.8, 78.2, 79.0, 87.7, 127.7, 127.8, 127.9, 128.0, 128.4,
128.5, 129.0, 132.0, 132.7, 138.17, 138.21. Anal. Calcd for
C26H28O5S: C, 69.00; H, 6.24. Found: C, 69.16; H, 6.25.
Phenyl 4,6-Di-O-benzyl-2,3-carbonyl-1-thio-â-D-glu-
copyranoside (8). To a stirred solution of 14 (2.33 g, 5.15
mmol) and triethylamine (2.15 mL, 15.4 mmol) in dichlo-
romethane (20 mL) at 0 °C was added a 20% solution of
phosgene in toluene (5 mL, 10.3 mmol) dropwise, and stirring
was continued for 2 h at room temperature. The mixture was
diluted with dichloromethane (20 mL) and washed with sat.
NaHCO3. The organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The crude was
purified by flash column chromatography on silica gel (hexane:
ethyl acetate; 3:1) to give 8 as a white solid (2.39 g, 97%). Mp
96 °C. [R]25D +10.2 (c, 1.0, CHCl3). 1H NMR (500 MHz, CDCl3)
δ: 3.6 (m, 1H), 3.75-3.80 (m, 2H), 3.82 (dd, J ) 9.5, 11.2 Hz,
1H), 3.9 (t, J ) 9.0 Hz, 1H), 4.35 (dd, J ) 9.6, 11.2 Hz, 1H),
4.52 (d, J ) 11.2 Hz, 1H), 4.53 (d, J ) 12.5 Hz, 1H), 4.6 (d, J
) 12.0, Hz, 1H), 4.78 (d, J ) 11.4 Hz, 1H), 4.85 (d, J ) 9.5 Hz,
1H), 7.26-7.35 (m, 13H), 7.6 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ: 68.2, 72.9, 73.5, 73.6, 76.2, 80.2, 82.4, 85.4, 127.6,
127.7, 128.0, 128.2, 128.4, 128.5, 129.1, 129.2, 134.7, 136.8,
137.9, 153.0. Anal. Calcd for C27H26O6S: C, 67.76; H, 5.48.
Found: C, 67.55; H, 5.62.
Phenyl 2,6-Di-O-benzyl-2,3-di-O-(2,3-dimethoxybutane-
2,3-diyl)-1-thio-â-D-glucopyranoside (13). Sodium hydride
(60%, 1.54 g, 38 mmol) was added to a cooled solution of 11
(4.29 g, 11.1 mmol) in DMF (20 mL). After the mixture was
stirred for 10 min, benzyl bromide (3.43 mL, 28 mmol) was
added, and stirring was continued for 6 h at room temperature.
The solvents were evaporated off under reduced pressure, and
the resulting mixture was diluted with dichloromethane (40
mL) and then washed with sat. NaHCO3. The organic layer
was separated and dried (anhydrous Na2SO4) and concentrated
in vacuo. Purification was done by flash column chromatog-
raphy on silica gel (hexane:ethyl acetate; 4:1) to yield 13 as a
white solid (6.2 g, 99%). Mp 92 °C. [R]26D +70.5 (c, 1.0, CHCl3).
1H NMR (500 MHz, CDCl3) δ: 1.29 and 1.35 (2s, 6H), 3.2 and
3.3 (2s, 6H), 3.5 (t, J ) 9.3 Hz, 1H), 3.64-3.67 (m, 1H), 3.73-
3.78 (m, 2H), 3.82 (dd, J ) 2.0, 11.5 Hz, 1H), 3.89 (t, J ) 9.6
Hz, 1H), 4.57 (d, J ) 11.8 Hz, 1H), 4.62 (d, J ) 11.9 Hz, 1H),
4.64 (d, J ) 9.4 Hz, 1H), 4.73 (d, J ) 10.6 Hz, 1H), 4.82 (d, J
) 10.6 Hz, 1H), 7.2-7.3 (m, 11H), 7.34-7.44 (m, 2H), 7.57-
7.59 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 17.6, 17.8, 47.9,
48.0, 65.7, 68.4, 74.8, 75.4, 76.7, 77.2, 77.7, 87.0, 99.5, 99.6,
127.3, 127.4, 127.7, 127.75, 128.2, 128.25, 128.3, 128.8, 132.8,
132.83, 138.4, 138.5. Anal. Calcd for C32H38O7S: C, 67.82; H,
6.76. Found: C, 67.94; H, 6.71.
Phenyl 2,6-Di-O-benzyl-3,4-carbonyl-1-thio-â-D-glu-
copyranoside (9). To a stirred solution of 15 (1.98 g, 4.3
mmol) and triethylamine (1.45 mL, 10.4 mmol) in dichlo-
romethane (20 mL) at 0 °C was added a 20% solution of
phosgene in toluene (4.3, 8.8 mmol) dropwise, and stirring was
continued for 2 h at room temperature. The mixture was
diluted with dichloromethane (20 mL) and washed with sat.
NaHCO3. The organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The crude was
purified by flash column chromatography on silica gel (hexane:
ethyl acetate; 3:1) to give 9 as a white solid (1.95 g, 94%). Mp
1
74 °C. [R]24 -35 (c, 1.0, CHCl3). H NMR (500 MHz, CDCl3)
D
δ: 3.68 (t, J ) 9.0 Hz, 1H), 3.70 (dd, J ) 4.8, 11.2 Hz, 1H), 3.8
(dd, J ) 2.5, 11.2 Hz, 1H), 3.91-3.94 (m, 1H), 4.13 (dd, J )
9.6, 11.3 Hz, 1H), 4.32 (dd, J ) 9.5, 11.3 Hz, 1H), 4.59 (s, 2H),
4.7 (d, J ) 8.8 Hz, 1H), 4.81 (d, J ) 11.2 Hz, 1H), 7.24-7.40
(m, 13H), 7.5-7.6 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 68.6,
73.4, 73.7, 75.2, 76.3, 77.0, 84.9, 87.3, 127.7, 127.9, 128.3, 128.4,
128.5, 128.6, 129.0, 131.9, 133.2, 136.7, 137.6, 153.5. Anal.
Calcd for C27H26O6S: C, 67.76; H, 5.48. Found: C, 67.77; H,
5.50.
General Procedure for Glycosylation with 8 and 9
Using the BSP/TTBP/Tf2O System. To a stirred solution of
donor (1 equiv), BSP (1.1 equiv), TTBP (1.5 equiv), and 4 Å
molecular sieves in CH2Cl2 (0.05 M in substrate), at -60 °C
under an Ar atmosphere, was added Tf2O (1.2 equiv). After
30 min of stirring at -60 °C, a solution of the glycosyl acceptor
(1.5 equiv) in CH2Cl2 (0.02 M in acceptor) was slowly added.
The reaction mixture was stirred for further 2 h at -60 °C
and was allowed to reach room temperature. The reaction
mixture was diluted with dichloromethane (10 mL), and
molecular sieves were filtered off and washed with saturated
NaHCO3. The organic layer was separated, dried, and con-
centrated. Purification by flash column chromatography on
silica gel, eluting with hexane/ethyl acetate mixtures, afforded
the corresponding R- and â-glucopyranosides.
General Procedure for Deprotection of 2,3- and 3,4-
O-Carbonates. To a solution of substrate (20 mg) in THF (2
mL) was added five drops of 1 M LiOH in water solution. The
reaction mixture was stirred until all of the starting material
was consumed as confirmed by TLC (∼2 h). The solvent was
removed under reduced pressure, and residue was dissolved
in CH2Cl2 (5 mL) and washed thoroughly with water. The
organic layer was separated, dried (Na2SO4), and concentrated
to give corresponding diols in quantitative yield.
Acknowledgment. We thank the NIH (GM62160)
for support of our work in this area.
Phenyl 2,6-Di-O-benzyl-1-thio-â-D-glucopyranoside (15).
A solution of compound 13 (4.95 g, 8.7 mmol) in dichlo-
romethane (20 mL) was added to a mixture of TFA and water
(10 mL, 19:1). The mixture was stirred for 2 h at room
temperature until all of the starting material was consumed
as confirmed by TLC. The mixture was neutralized with sat.
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0508999
J. Org. Chem, Vol. 70, No. 18, 2005 7259