Highly diastereoselective α-mannopyranosylation in the absence of participating protecting groups

Article abstract of DOI:10.1021/jo9910482

S-Phenyl 2,6-di-O-benzyl-3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)- 1- thia-α-D-mannopyranoside and its sulfoxide, following activation at -78 °C with benzenesulfenyl triflate or trifiic anhydride, respectively, provide the corresponding α-mannosyl triflate as demonstrated by NMR spectroscopy. On addition of an acceptor alcohol α-mannosides are then formed. Similarly, S- phenyl 2,3-O-carbonyl-4,6-O-benzylidene-1-thia-α-D-mannopyranoside and ethyl 3-O-benzoyl-4,6-O-benzylidene-2-O-(tert-butyldimethylsilyl)-1-thia-α-D- mannopyranoside both provide α-mannosides on activation with benzenesulfenyl triflate followed by addition of an alcohol. These results stand in direct contrast to the highly β-selective couplings of comparable glycosylations with 2,3-di-O-benzyl-4,6-O-benzylidene protected mannosyl donors and draw attention to the subtle interplay of reactivity and structure in carbohydrate chemistry.

Full text of DOI:10.1021/jo9910482

J . Org. Chem. 2000, 65, 1291-1297
1291
High ly Dia ster eoselective r-Ma n n op yr a n osyla tion in th e Absen ce
of P a r ticip a tin g P r otectin g Gr ou p s
David Crich,* Weiling Cai, and Zongmin Dai
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Received J une 30, 1999
S-Phenyl 2,6-di-O-benzyl-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-1-thia-R-D-mannopyranoside and
its sulfoxide, following activation at -78 °C with benzenesulfenyl triflate or triflic anhydride,
respectively, provide the corresponding R-mannosyl triflate as demonstrated by NMR spectroscopy.
On addition of an acceptor alcohol R-mannosides are then formed. Similarly, S-phenyl 2,3-O-
carbonyl-4,6-O-benzylidene-1-thia-R-D-mannopyranoside and ethyl 3-O-benzoyl-4,6-O-benzylidene-
2-O-(tert-butyldimethylsilyl)-1-thia-R-D-mannopyranoside both provide R-mannosides on activation
with benzenesulfenyl triflate followed by addition of an alcohol. These results stand in direct contrast
to the highly â-selective couplings of comparable glycosylations with 2,3-di-O-benzyl-4,6-O-
benzylidene protected mannosyl donors and draw attention to the subtle interplay of reactivity
and structure in carbohydrate chemistry.
In tr od u ction
and which leads with excellent selectivity to R-manno-
sides. Additionally, we report on the effect of a cyclic 2,3-
O-carbonate protected system and also of a 3-O-benzoyl
system, both of which overcome the â-directing influence
of the 4,6-O-benzylidene group resulting in the highly
selective formation of R-mannosides.
We have recently described methods for the direct
synthesis of â-mannopyranoside which proceed by means
of R-mannosyl triflates generated in situ from glycosyl
sulfoxides or thioglycosides with triflic anhydride or
benzenesulfenyl triflate, respectively.1-6 The stereose-
lectivity of these reactions is a function of the protecting
groups on the mannose ring with the 2,3-di-O-benzyl-
4,6-benzylidene system being highly â-selective as con-
trasted with the 2,3,4,6-tetra-O-benzyl one, which shows
little or no selectivity.1-5 We interpret this effect in terms
of the ability of the protecting group set to stabilize the
intermediate R-mannosyl triflate with respect to the
corresponding ion pair. In effect, in Fraser-Reid’s termi-
nology,7 the 4,6-benzylidene system torsionally disarms
the covalent triflate toward collapse to the ion pair. This
notion has been supported computationaly in a series of
related glucopyranosyl pentenyl glycosides.8 Thus, in the
4,6-benzylidene-protected system, the R-mannosyl triflate
reacts predominantly via an SN2-like9 displacement,
whereas in the tetrabenzyl system the ion pair is more
accessible, which leads to a competing SN1 process and
the associated loss of stereoselectivity. We report below
on the chemistry of an alternative bicyclo[4.4.0]decane-
like system, in which the mannose 3- and 4-OH groups
are spanned by Ley’s bisacetal type protecting group,10-13
Resu lts a n d Discu ssion
The 4,6-O-benzylidene protecting group is very versa-
tile; it may be readily converted to the 6-O-benzyl-4-OH
or the 4-O-benzyl-6-OH systems at will, or be cleaved to
the 4,6-diol under hydrogenolytic or acidic conditions, or
even transformed into the 6-bromo-6-deoxy-4-O-benzoyl
system.14,15 Nevertheless, the present requirement for
this protecting group constitutes a limitation of our
chemistry, especially insofar as it puts the â-L-rham-
nopyranosides beyond our reach, and we are therefore
driven to investigate alternative protecting systems.
We were attracted by the vicinal bisacetals, introduced
by the Ley group,10-13 as they permit the highly regiose-
lective protection of the trans vicinal diols, to boot the
3,4-OH’s in the mannopyranose series. Thus, the S-ethyl
and S-phenyl thiomannosides (1) and (2) were exposed
to butane-2,3-dione in the presence of trimethyl ortho-
formate and catalytic camphorsulfonic acid to give the
corresponding 3,4-bisacetals (3) and (4), respectively.
Exhaustive benzylation then provided 5 and 6, which,
on exposure to Oxone afforded the corresponding sulfox-
ides 7 and 8. In line with precedent from this laboratory,3
the oxidation of these axial thioglycosides was extremely
(1) Crich, D.; Sun, S. J . Org. Chem. 1996, 61, 4506.
(2) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198.
(3) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(4) Crich, D.; Sun, S. J . Am. Chem. Soc. 1998, 120, 435.
(5) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217.
(6) Some glycosyl sulfoxides react with Tf2O by alternative mech-
anisms: Gildersleeve, J .; Pascal, R. A.; Kahne, D. J . Am. Chem. Soc.
1998, 120, 5961.
(7) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J .
Am. Chem. Soc. 1988, 110, 5583.
(8) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J . Org. Chem.
1996, 61, 5280.
(11) Grice, P.; Ley, S. V.; Pietruszka, J .; Priepke, H. W. M.; Warriner,
S. L. J . Chem. Soc., Perkin Trans. 1 1997, 351.
(12) 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.
(13) Montchamp, J .-L.; Tian, F.; Hart, M. E.; Frost, J . W. J . Org.
Chem. 1996, 61, 3897.
(14) Grindley, T. B. In Modern Methods in Carbohydrate Chemistry;
Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic: Amsterdam,
1996; p 225.
(9) We expressly refer to the â-selective mannosylations as being
SN2-like, rather than SN2, so as not to exclude the possibility that the
reactions actually proceed via the kinetically indistinguishable contact
ion pair mechanism.
(10) Douglas, N. L.; Ley, S. V.; Osborn, H. M. J .; Owen, D. R.;
Priepke, H. W. M.; Warriner, S. L. Synlett 1996, 793.
(15) Calinaud, P.; Gelas, J . In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Dekker: New York, 1997; p 3.
10.1021/jo9910482 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

1292 J . Org. Chem., Vol. 65, No. 5, 2000
Crich et al.
Ta ble 1. Ma n n osyla tion s w ith th e 3,4-O-Bisa ceta ls
larly assign all the other coupling products. Consistent
with this assignment is the fact that the R-cholesteryl
mannoside has a more positive specific rotation than
it’s â-anomer.3,19-21 The obvious conclusion to be drawn
from this series of experiments is that the 3,4-bis-
acetal protecting system promotes highly R-selective
couplings.
product
recovered
donor
acceptor
(% yield)
R/â ratio
donor (%)
5
6
6
7
8
8
8
26
26
10
12
14
16
18
20
22
10
14
11 (52), 9 (15)
13 (57), 9 (12)
15 (60), 9 (17)
17 (65), 9 (27)
19 (88), 9 (8)
21 (62), 9 (30)
23 (55), 9 (29)
27 (56)
>95/5
>95/5
>95/5
5/1
>95/5
>95/5
>95/5
>95/5
>95/5
24
22
12
0
0
0
0
33
10
28 (82)
selective, giving only one discernible stereoisomer, which
we assign the SR configuration on the basis of analogy.16
A series of coupling reactions was conducted in which
either the thiomannoside 5 or 6 was activated with
benzenesulfenyl triflate or the sulfoxide 7 or 8 was
activated with triflic anhydride, before introduction of the
acceptor. All experiments were conducted at -78 °C in
dichloromethane in the presence of 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) as a hindered base. It is
immediately evident from the results presented in Table
1 that these couplings were not as high yielding as those
previously reported with the 4,6-O-benzylidene-protected
donors. Appreciable quantities of the hydrolysis product
9 were isolated from couplings using the sulfoxide donors
(Table 1). The moderate yields in the case of the thiogly-
coside donors were the result of incomplete conversion
of the donor (Table 1). The reactions were, however,
selective giving, with one exception, a single anomer
within the limits of our NMR detection. NOE experi-
ments were not conclusive, and therefore, we turned to
We considered the possibility that these R-selective
mannosylations arose through an SN2-like displacement
of a â-mannosyl triflate (24), rather than on the antici-
pated intermediate R-mannosyl triflate (25). Indeed, in
the glucopyranose series where R-selective coupling is
seen even in the presence of the 4,6-O-benzylidene
protecting group, we invoke such a displacement on a
minor â-glucopyranosyl triflate through a Curtin-Ham-
mett-type kinetic scheme.22 As the anomeric effect is
greater in mannopyranosides than in glucopyrano-
sides,23,24 such a pathway is not usually a problem with
the 4,6-O-benzylidene-protected mannopyranosyl tri-
flates. However, we reasoned that in the present instance
the axial methoxy group on the R-face of the bisacetal
protecting group might destabilize the R-triflate (25) with
respect to the â-anomer (24) through an unfavorable
electrostatic interaction. We therefore treated thioglyco-
side 6 with sodium cyanoborohydride and HCl in THF
leading to the formation of 26 in 92% isolated yield. The
stereochemistry of this reduction is explained in the usual
manner by invoking axial attack by the hydride on the
1
measurement of the J CH coupling between the anomeric
carbon and its associated proton. It is widely appreciated
that in standard chair conformers of O-glycopyranosides
a value of approximately 173 Hz is diagnostic for the axial
glycoside, whereas a coupling constant of around 163 Hz
signifies an equatorial glycoside.17 Indeed, this rule is
nicely followed in the 4,6-benzylidene-protected man-
nopyranosides.18 In the present series, we typically found
coupling constants around 170 Hz and so suggestive of
an R-linkage. In one instance, that of coupling to 3â-
cholesterol, we typically obtained a 5/1 mixture of ano-
1
mers and so were able to determine the anomeric J CH
coupling for both the equatorial and the axial glycoside.
1
The major cholesteryl glycoside had J CH of 165.9 Hz,
while the minor one showed 155.9 Hz. We therefore
assign the major isomer as the R-mannoside and simi-
(19) Hudson, C. S. J . Am. Chem. Soc. 1909, 31, 66.
(20) Hudson, C. S. J . Am. Chem. Soc. 1926, 48, 1424.
(21) Hudson, C. S. J . Am. Chem. Soc. 1930, 52, 1680.
(22) Crich, D.; Cai, W. J . Org. Chem. 1999, 64, 4926.
(23) Lemieux, R. U.; Morgan, A. R. Can. J . Chem. 1965, 43, 2214.
(24) Lemieux, R. U. In Molecular Rearrangements, Part 2; De Mayo,
P., Ed.; Wiley: New York, 1964; p 709.
(16) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. R.;
Wink, D. J . J . Chem. Soc., Chem. Commun. 1998, 2763.
(17) Bock, K.; Pedersen, C. J . Chem. Soc., Perkin Trans. 2 1974,
293.
(18) Crich, D.; Dai, Z. Tetrahedron 1999, 55, 1569.

R-Mannopyranosylation in the Absence of Protecting Groups
J . Org. Chem., Vol. 65, No. 5, 2000 1293
intermediate oxacarbenium ions. It was confirmed by
NOE experiments, which established the spatial proxim-
ity of the newly introduced protons in the protecting
group to either H3 or H4 of the mannose ring. Following
activation by PhSOTf in the usual way, 26 was coupled
to alcohols 10 and 14. Again, as seen from Table 1, the
yields were only moderate but the selectivity was high
in favor of the R-mannoside, which negates this line of
reasoning.
demonstrated in this and previous work,3,5,6 the question
arises as to how such apparently minor changes in
protecting groups wreck such major changes in stereo-
selectivity. Our current interpretation of the reaction3,5
centers around the formation of â-mannosides via an SN2-
like9 displacement of the R-mannosyl triflates, with the
R-mannosides resulting from a dissociative pathway. On
this basis, it seems likely that any change in selectivity
may be the result of a shift in the relative energies of
the covalent triflates, contact and solvent separated ion
pairs provoked by the change in protecting groups. Such
an interplay between both anomers of covalently bound
glycosyl donors and the several ion pairs possible is a
well-appreciated phenomenon in carbohydrate chemis-
try,25 and indeed, in nucleophilic substitution in gen-
eral.26,27
In support of this argument, we draw attention to the
work of Fraser-Reid and collaborators who studied the
bromonium ion promoted hydrolysis of a series of three
glucosyl pentenyl glycosides 34-36. The rates of hydroly-
sis were found to differ considerably, with 34 being the
slowest and 36 the fastest.8 Ab initio calculations, with
slightly simplified model systems, indicated that the
activation energies required to collapse the activated
pentenyl glycosides to the corresponding oxacarbenium
ions 37-39, respectively, were highest for 34 and lowest
for 36, in agreement with the order of rates of hydrolysis.8
This order of reactivity toward cation formation also
corresponds directly with the sequence of â-selectivities
observed with our series of similarly protected mannosyl
donors and hints at the importance of cations related to
39 in the present R-selective couplings.
We therefore turned to an NMR investigation of the
stability of the intermediate formed on activation of
sulfoxide 7 by triflic anhydride. Thus, a solution of 7 and
DTBMP in CD2Cl2 was cooled to -78 °C under Ar in the
1
probe of the NMR spectrometer and a H NMR spectrum
recorded. The tube was then removed from the probe, and
Tf2O, precooled to -78 °C, was quickly added before the
tube was returned to the cold probe and a new spectrum
registered. This spectrum showed the sulfoxide to have
been completely consumed in the time frame of this
experiment (<5 min) and that one new very major
carbohydrate-based species had been formed. The ano-
meric proton of this substance resonated at δH 6.03 in
the form of a slightly broadened singlet. A 13C NMR
spectrum, also recorded at -78 °C, put the anomeric
1
carbon at δC 105.0 and the value of the anomeric J CH
coupling at 184.2 Hz. These values are entirely consistent
with those recorded for a range of R-glycosyl triflates
previously observed in this laboratory5,22 and lead us to
assign the first intermediate as the R-mannosyl triflate
25. On gradual warming of the probe, this species was
seen to be stable until approximately 5 °C, with decom-
position being complete by 17 °C. The decomposition
reaction was relatively clean and led to the isolation of
one major product in 56% yield. The structure of this
decomposition product was assigned as 29 on the basis
of the spectroscopic data. Evidently, this species arises
from the cyclization of an anomeric oxacarbenium ion
onto the proximal 2-O-benzyl ether. We note that this
mode of decomposition is different from that observed
with the 4,6-O-benzylidene-protected R-mannosyl and
R-glucosyl triflates 30 and 31, which provided the glycals
32 and 33, respectively.5,22
We have also briefly investigated the use of disarming
protecting groups,7 in conjunction with the 4,6-O-ben-
zylidene group in the hope of improving the â-selectivity
of the coupling even further. We directed our attention
at the 2,3-O-carbonate 40 and the 3-O-benzoate 41.
Carbonate 40 in particular was thought promising in
view of the fact that the similarly protected mannosyl
bromide 42 has been used previously in â-selective
mannosylations by the insoluble silver salt method.28 The
3-O-benzoate 41 was targeted, as it was thought that an
ester at this position would be moderately disarming29,30
and unlikely to lead to neighboring group participation.
(25) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; J ames, K. J . Am.
Chem. Soc. 1975, 97, 4056.
(26) Winstein, S.; Clippinger, E.; Fainberg, A. H.; Heck, R.; Robinson,
G. C. J . Am. Chem. Soc. 1956, 78, 328.
(27) For one among many discussions of ion pairs in solvolyses,
see: Sneen, R. A. Acc. Chem. Res. 1973, 6, 46.
(28) Gorin, P. A. J .; Perlin, A. S. Can. J . Chem. 1961, 39, 2474.
(29) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J . Chem.
Soc., Perkin Trans. 1 1998, 51.
(30) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J . Am. Chem. Soc. 1999, 121, 734.
Given that R-mannosyl triflates are intermediates in
these glycosylation reactions, as has been adequately

1294 J . Org. Chem., Vol. 65, No. 5, 2000
Crich et al.
Both substances were readily prepared from the corre-
sponding diols 43 and 44, respectively; 40 by treatment
of 43 with phosgene and 41 by monobenzoylation of 44,
giving 45, followed by silylation. Coupling reactions were
carried out by activation of the thioglycosides in CH2Cl2,
at -78 °C in the presence of DTBMP, with PhSOTf,
followed by addition of 14 as acceptor. In both cases, the
isolated yield of coupled product was moderate (60% and
69%) but the selectivities were high, and only one anomer
was isolated. The products 46 and 47 from both reactions
were readily converted to a single diol 48, by either
saponification or saponifaction followed by desilylation,
4
respectively. As 48 is in the standard C1 chair conforma-
tion, it was readily assigned as the R-mannoside on the
1
basis of the anomeric J CH coupling of 170.4 Hz and the
absence of the unusually upfield H5 multiplet (δH 3.1-
3.3). This latter is diagnostic of the â-mannosides in the
4,6-O-benzylidene-protected series in the absence of
disarming protecting groups.3 Both coupling products 46
and 47 were therefore assigned as the R-mannosides,
contrary to our initial expectations. This verification of
stereochemistry, by conversion to 48, was especially
necessary in the case of the 2,3-O-carbonate 46 owing to
1
its unusual conformation. Thus, the J CH anomeric cou-
pling constant of the product 46 (171.2 Hz) is very close
to that of authentic â-mannosides, with the same protect-
ing group array 49 (170.9-172.0 Hz),31 which implies
that one or both of these compounds has a nonstandard
conformation. Likewise, in both the R- and â-mannosides
46 and 49, respectively, the mannose H5 signal resonates
in the range δH 3.6-3.9, whereas we typically find it to
be at δ 3.1-3.3 in 4,6-benzylidene-protected â-manno-
sides.3 Taken as a whole, these data indicate that neither
dissolved in dry methanol (10 mL) followed by the addition of
butane-2,3-dione (99.0 mg, 0.15 mL, 1.71 mmol), HC(OMe)3
(0.88 g, 0.91 mL, 8.3 mmol), and camphor-10-sulfonic acid (34.0
mg, 0.15 mmol). The reaction mixture was then heated to
reflux for 72 h before it was cooled to room temperature and
quenched by addition of Et3N (0.1 mL). The reaction mixture
then was concentrated under vacuum, and the residue ob-
tained was recrystalized from diethyl ether/hexane (1/3) to give
3 or 4, respectively.
S-Eth yl 3,4-O-(2′,3′-d im eth oxybu ta n e-2′,3′-d iyl)-1-th ia -
r-D-m a n n op yr a n osid e (3) was prepared as an oil in 80%
yield according to the general protocol: [R]D ) +217° (c 2.7,
4
the R- nor the â-mannosides adopt the standard C1 chair
conformation when protected by the 2,3-O-carbonate
group. On the basis of the NMR data for his â-manno-
sides, Kunz indicates that an 0H5 half-chair is the
preferred conformation and that this is enforced by the
requirements of the cyclic carbonate group.31 We see no
reason to disagree with this conclusion and suggest that
the mannose ring of 46 adopts a similar conformation.
The corollary to this argument is that any R-triflate (50)
1
CHCl3); H NMR (CDCl3) δ 5.34 (s, 1 H), 4.15 (m, 2 H), 4.04
(m, 1 H), 4.00 (m, 1 H), 3.83 (m, 2 H), 3.29 (s, 3 H), 3.28 (s, 3
H), 2.63 (m, 2 H), 1.29 (s, 3 H), 1,27 (s, 3 H), 1.23 (t, J ) 7.0
Hz, 3 H); 13C NMR (CDCl3) δ 100.5, 99.9, 84.6, 71.2, 71.0, 68.9,
63.2, 61.2, 48.1, 48.0, 25.2, 17.8, 17.7, 14.9. Anal. Calcd for
C
14H26O7S: C, 49.69; H, 7.74. Found: C, 49.86; H, 7.85.
S-P h en yl 3,4-O-(2′,3′-dim eth oxybu tan e-2′,3′-diyl)-1-th ia-
r-D-m a n n op yr a n osid e (4) was prepared as a white crystal-
0
derived from activation of 40 will also have the H5 half-
line solid in 66% yield according to the general protocol: mp
1
201 °C; [R]D ) +282° (c 2.8, CHCl3); H NMR (CDCl3) δ 7.34
chair conformation leading, again, to a perturbation of
any equilibrium with contact and solvent separated ion
pairs and, so, a change in mechanism of displacement of
the triflate.
(m, 5 H), 5.57 (s, 1 H), 4.28 (dt, J ) 2.2, 6.0 Hz, 1 H), 4.23 (m,
1 H), 4.19 (t, J ) 6.0 Hz, 1 H), 4.07 (dd, J ) 1.8, 6.0 Hz, 1 H),
3.81 (m, 2 H), 3.34 (s, 3 H), 3.28 (s, 3 H), 1.36 (s, 3 H), 1.34 (s,
3 H); 13C NMR (CDCl3) δ 131.9, 129.0, 127.6, 100.4, 99.8, 87.9,
71.4, 70.9, 68.6, 62.9, 60.9, 48.1, 47.9, 17.7, 17.6. Anal. Calcd
for C18H26O7S: C, 55.94; H, 6.78. Found: C, 55.94; H, 6.77.
Gen er a l Meth od for th e 2,6-Di-O-ben zyla tion of th e
3,4-O-Bisa ceta ls. 3 or 4 (3.1 mmol) was dissolved in THF (30
mL), stirred vigorously, and treated with benzyl bromide (2.0
mL, 16.8 mmol) followed by portionwise addition of NaH (0.71
g, 17.8 mmol) at 0 °C. The so-obtained suspension was then
heated to reflux with stirring for 3 h before it was cooled to
room temperature and the reaction quenched by addition of
ice-water (10 mL) and then EtOAc (50 mL). The organic phase
was decanted off and the aqueous layer extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed with
brine and dried (Na2SO4), and the solvent was removed under
vacuum to give an oil, which was purified by chromatography
on silica gel eluting with EtOAc/hexane (1/5).
With regard to the R-selectivity of the 3-O-benzoate,
we suggest that, contrary to our initial expectation,
neighboring group participation underlies the R-selectiv-
ity. Indeed, inspection of molecular models suggests that
1
the pyranose ring can readily adopt a S5 twist conforma-
tion, which permits the formation of the bridged cation
without imposing undue strain on the fused 4,6-O-
benzylidene ring.
Con clu sion
Three different sets of protecting groups have been
found to confer high R-selectivity on mannosylation
reactions conducted by the triflate method.
Exp er im en ta l Section 32
S-Eth yl 2,6-d i-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-
2′,3′-d iyl)-1-th ia -r-D-m a n n op yr a n osid e (5), a syrup, was
prepared in 83% yield according to the general protocol: [R]D
) +156 (c 2.6, CHCl3); 1H NMR (CDCl3) δ 7.31 (m, 10 H), 5.32
(d, J ) 1.1 Hz, 1 H), 4.90 (d, J ) 12.1 Hz, 1 H), 4.68 (d, J )
12.1 Hz, 1 H), 4.64 (d, J ) 12.0 Hz, 1 H), 4.54 (d, J ) 12.0 Hz,
Gen er a l Meth od for th e P r ep a r a tion of th e 3,4-O-
Bisa ceta ls. The thiomannopyranoside 1 or 2 (1.5 mmol) was
(31) Guenther, W.; Kunz, H. Carbohydr. Res. 1992, 228, 217.
(32) For general experimental details see footnote 3.

R-Mannopyranosylation in the Absence of Protecting Groups
J . Org. Chem., Vol. 65, No. 5, 2000 1295
1 H), 4.40 (m. 2 H), 4.02 (m, 1 H), 3.78 (m, 3 H), 3.27 (s, 3 H),
3.20 (s, 3 H), 2.61 (m, 2 H), 1.35 (s, 3 H), 1.28 (s, 3 H), 1.24 (t,
J ) 7.4 Hz, 3 H); 13C NMR (CDCl3) δ 138.7, 128.3, 127.9, 127.6,
100.1, 99.7, 83.7, 77.7, 73.4, 72.9, 71.1, 69.7, 68.9, 64.2, 48.0,
25.4, 17.9, 11.8. Anal. Calcd for C28H38O7S: C, 64.84; H, 7.38.
Found: C, 65.04; H, 7.43.
was diluted with EtOAc (20 mL), dried over Na2SO4, and
concentrated to give a residue that was purified by chroma-
tography on silica gel eluting with EtOAc/hexane (1/5) or by
preparative TLC.
2,6-Di-O-ben zyl-3,4-O-(2′,3′-dim eth oxybu tan e-2′,3′-diyl)-
r/â-D-m a n n op yr a n ose (9): [R]D ) +14.0 (c ) 5.4, CHCl3); 1H
NMR (CDCl3) δ 7.27 (m, 10 H), 5.21 (s, 1 H), 4.84 (d, J ) 12.3
Hz, 1 H), 4.57 (m, 3 H), 4.23 (t, J ) 10.2 Hz, 1 H), 3.95 (dd, J
) 2.7, 10.5 Hz, 1 H), 3.72 (m, 4 H), 3.22 (s, 3 H), 3.19 (s, 1 H),
1.33 (s, 3 H), 1.27 (s, 3 H); 13C NMR (CDCl3) δ 138.7, 128.3,
127.9, 127.6, 127.5, 100.0, 99.7, 94.5, 75.6, 73.6, 73.1, 71.8, 68.9,
68.6, 63.7, 48.1, 17.9. Anal. Calcd for C26H33O8‚0.33H2O: C,
64.71; H, 7.10. Found: C, 65.17; H, 6.98.
S-P h en yl 2,6-di-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-
2′,3′-d iyl)-1-th ia -r-D-m a n n op yr a n osid e (6), a white crystal-
line solid, was prepared in 80% yield according to the general
protocol: mp 210 °C; [R]D ) +164 (c 1.7, CHCl3); 1H NMR
(CDCl3) δ 7.30 (m, 15 H), 5.54 (s, 1 H), 4.89 (d, J ) 12.2 Hz, 1
H), 4.69 (d, J ) 12.1 Hz, 1 H), 4.61 (d, J ) 12.0 Hz, 1 H), 4.50
(d, J ) 12.0 Hz, 1 H), 4.44 (dt, J ) 3.7, 10.5 Hz, 1 H), 4.28 (t,
J ) 10.2 Hz, 1 H), 4.06 (dd, J ) 2.7 Hz, 10.5 Hz, 1 H), 3.97
(dd, J ) 1.5, 3 Hz, 1 H), 3.80 (d, J ) 3.6 Hz, 2 H), 3.37 (s, 3 H),
3.21 (s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H); 13C NMR (CDCl3) δ
138.7, 134.5, 131.9, 129.1, 128.3, 127.9, 127.6, 100.1, 99.8, 87.4,
77.7, 73.4, 72.8, 71.9, 69.6, 68.9, 64.1, 48.1, 17.9. Anal. Calcd
for C32H38O7S: C, 67.82; H, 6.76. Found: C, 67.90; H, 6.84.
Gen er a l P r otocol for th e Oxid a tion of Th ioglycosid es
to Glycosyl Su lfoxid es. An aqueous solution (20 mL) of
Oxone (0.62 g, 1 mmol) was added to 5 or 6 (2 mmol) in THF
(20 mL) at 0 °C, and the reaction mixture was stirred for 3 h
(TLC) and then worked up by addition of EtOAc (30 mL). The
aqueous layer was extracted by EtOAc (2 × 10 mL), and the
combined organic layers were concentrated to give a residue
that was purified by chromatography, eluting with EtOAc/
hexane (1:3) to give the sulfoxides (85%).
Meth yl
3-O-ben zyl-2-O-[2,6-d i-O-ben zyl-3,4-O-(2′,3′-
d im eth oxybu ta n e-2′,3′-d iyl)-r-D-m a n n op yr a n osyl]-4,6-O-
ben zylid en e-r-D-m a n n op yr a n osid e (11): [R] D ) +6.1 (c 1.4,
1
CHCl3); H NMR (CDCl3) δ 7.35 (m, 20 H), 5.60 (s, 1 H), 5.14
(s, 1 H), 4.74 (m, 3 H), 4.62 (m, 4 H), 4.24 (dd, J ) 3.6, 8.8 Hz,
1 H), 4.14 (dd, J ) 20, 9.6 Hz, 1 H), 4.08 (m, 4 H), 3.75 (m, 4
H), 3.75 (m, 4 H), 3.31 (s, 3 H), 3.20 (s, 3 H), 3.17 (s, 3 H), 1.33
(s, 3 H), 1.30 (s, 3 H); 13C NMR (CDCl3) δ 138.9, 138.8, 138.6,
138.4, 137.8, 137.6, 134.4, 129.7, 128.9, 128.8, 128.5, 128.3
128.1, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 127.3, 127.1,
126.0, 101.7 (1J CH ) 171 Hz), 101.4 (1J CH ) 159 Hz), 100.9 (1J CH
) 173 Hz), 99.7, 99.5, 79.0, 76.0, 75.8, 73.3, 72.9, 72.8, 71.4,
69.0, 68.7, 63.9, 63.5, 54.6, 47.9, 47.8, 17.8. Anal. Calcd for
C
47H56O13: C, 68.10; H, 6.81. Found: C, 67.84; H, 6.94.
3-O-[2,6-Di-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-2′,3′-
S-Eth yl 2,6-d i-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-
2′,3′-d iyl)-1-th ia -r-D-m a n n op yr a n osid e S-oxid e (7): [R]D )
d iyl)-r-D-m a n n op yr a n osyl]-1,2;5,6-d i-O-isop r op ylid en e-
r-D-glu cofu r a n ose (13): [R]D ) +11.0 (c 1.4, CHCl3); 1H NMR
(CDCl3) δ 7.31(m, 10 H), 5.82 (d, J ) 3.6 Hz, 1 H), 5.12 (d, J
) 1.1 Hz, 1 H), 4.89 (d, J ) 12.3 Hz, 1 H), 4.76 (d, J ) 3.6 Hz,
1 H), 4.69 (d, J ) 12.3 Hz, 1 H), 4.59 (d, J ) 4.5 Hz, 2 H), 4.25
(d, J ) 1.8 Hz, 1 H), 4.00 (m, 3 H), 3.96 (m, 3 H), 3.83 (dd, J
) 6.3, 10.2 Hz, 1 H), 3.75 (d, J ) 6.3 Hz, 1 H), 3.70 (m, 1 H),
3.27 (s, 3 H), 3.20 (s, 3 H), 1.50 (s, 3 H), 1.39 (s, 3 H), 1.35 (s,
3 H), 1.30 (s, 3 H), 1.29 (s, 3 H), 1.11 (s, 3 H); 13C NMR (CDCl3)
δ 138.8, 138.6, 129.1, 128.3, 127.9, 127.6, 127.5, 111.9, 109.3,
105.4, 100.7 (1J CH ) 171 Hz), 100.0, 99.8, 83.6, 81.4, 81.3, 75.6,
73.7, 73.1, 72.8, 71.9, 69.0, 67.8, 63.9, 52.4, 48.2, 48.0, 26.9,
26.1, 25.6, 17.9. Anal. Calcd for C38H52O13: C, 63.67; H, 7.31.
Found: C, 63.69; H, 7.49.
6-O-[2,6-Di-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-2′,3′-
d iyl)-r-D-m a n n op yr a n osyl]-1,2;3,4-d i-O-isop r op ylid en e-
r-D-ga la ctop yr a n ose (15): [R]D ) +7.3 (c 0.9, CHCl3); 1H
NMR (CDCl3) δ 7.30 (m, 10 H), 5.50 (d, J ) 4.8 Hz, 1 H), 4.94
(s, 1 H), 4.91 (d, J ) 12.3 Hz, 1 H), 4.62 (m, 4 H), 4.29 (dd, J
) 2.4, 4.9 Hz, 1 H), 4.22 (t, J ) 10.2 Hz, 1 H), 4.16 (dd, J )
1.8, 8.1 Hz, 1 H), 4.06 (dd, J ) 2.8, 10.3 Hz, 1 H), 3.99 (m, 2
H), 3.74 (m, 5 H), 3.31 (s, 3 H), 3.25 (s, 3 H), 1.53 (s, 3 H), 1.49
(s, 3 H), 1.37 (s, 6 H), 1.32 (s, 3 H); 13C NMR (CDCl3) δ 139.0,
138.8, 128.3, 127.9, 127.7, 127.4, 109.5, 108.7, 99.9, 99.7, 98.9
(1J CH ) 169 Hz), 96.4 (1J CH ) 178 Hz), 75.9, 73.5, 71.4, 71.0,
70.8, 69.2 68.8, 68.7, 65.4, 65.2, 63.8, 48.1, 48.0, 26.2, 26.1,
25.0, 24.7, 17.9. Anal. Calcd for C38H52O13: C, 63.67; H, 7.31.
Found: C, 62.49; H, 7.34.
3â-Ch olester yl 2,6-d i-O-ben zyl-3,4-O-(2′,3′-d im eth oxy-
bu ta n e-2′,3′-d iyl)-r-D-m a n n op yr a n osid e (17r): [R]D ) +7.1
(c 1.8, CHCl3); 1H NMR (CDCl3) δ 7.35 (m, 10 H), 5.24 (d, J )
4.7 Hz, 1 H), 4.96 (s, 1 H), 4.94 (d, J ) 12.3 Hz, 1 H), 4.67 (d,
J ) 12.4 Hz, 1 H), 4.63 (d, J ) 12 Hz, 1 H), 4.55 (d, J ) 12 Hz,
1 H), 4.20 (t, J ) 10 Hz, 1 H), 4.08 (dd, J ) 2.8, 14.4 Hz, 1 H),
3.76 (d, J ) 4.4 Hz, 2 H), 3.57 (d, J ) 1.2 Hz, 1 H), 3.48 (m, 1
H), 3.29 (s, 3 H), 3.19 (s, 3 H), 2.35 (dd, J ) 4.8 Hz, 13.2 Hz,
1 H), 2.27 (t, J ) 12.0 Hz, 1 H), 1.90 (m, 5 H), 1.16 (s, 3 H),
1.15 (s, 3 H), 1.12 (m, 39 H); 13C NMR (CDCl3) δ 140.8, 139.0,
138.8, 128.3, 128.0, 127.6, 127.4, 127.3, 121.9, 99.9, 99.7, 97.4
(1J CH ) 165.9 Hz), 73.5, 73.2, 71.5, 70.0, 69.3, 64.2, 56.9, 56.3,
50.2, 48.2, 47.9, 42.5, 40.1, 39.9, 39.7, 37.2, 36.8, 36.4, 35.9,
32.0, 28.4, 28.2, 27.8, 24.5, 23.9, 22.9 22.7 21.2, 19.5, 18.9, 18.0,
12.0. Anal. Calcd for C53H78O8: C, 75.50; H, 9.32. Found: C,
75.59; H, 9.22.
1
+153 (c 1.0, CHCl3); H NMR (CDCl3) δ 7.28 (m, 10 H), 4.99
(d, J ) 1.1 Hz, 1 H), 4.67 (d, J ) 1.1 Hz, 1 H), 4.63 (m, 1 H),
4.53 (d, J ) 2 Hz, 1 H), 4.49 (d, J ) 1.2 Hz, 1 H), 4.36 (m, 1
H), 4.23 (m, 2 H), 3.82 (dt, J ) 1.1, 6.3 Hz, 1 H), 3.62 (m, 1 H),
3.31 (s, 3 H), 3.20 (s, 3 H), 2.97 (m, 1 H), 2.70 (m, 1 H), 1.40 (s,
3 H), 1.29 (s, 3 H); 13C NMR (CDCl3) δ 138.6, 128.4, 128.3,
128.3, 127.7, 127.6, 127.5, 100.1, 99.9, 93.1, 77.0, 74.1, 73.6,
72.9, 69.2, 68.9, 63.1, 52.4, 48.4, 48.1, 43.8, 17.9, 5.9. Anal.
Calcd for C28H38O8S: C, 62.90; H, 7.16. Found: C, 63.42; H,
7.47.
S-P h en yl 2,6-di-O-ben zyl-3,4-O-(2′,3′-d im eth oxybu ta n e-
2′,3′-d iyl)-1-th ia -r-D-m a n n op yr a n osid e S-oxid e (8): [R]D )
+175 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.65-7.24 (m, 15 H),
4.92 (d, J ) 10.8 Hz, 1 H), 4.62 (d, J ) 10.8 Hz, 1 H), 4.46 (s,
2 H), 4.36 (m, 3 H), 4.23 (m, 2 H), 3.80 (d, J ) 13.8 Hz, 1 H),
3.62 (dd, J ) 6.0 Hz, 11.1 Hz, 1 H), 3.36 (s, 3 H), 3.21 (s, 3 H),
1.36 (s, 3 H), 1.32 (s, 3 H); 13C NMR (CDCl3) δ 142.1, 138.4,
138.0, 131.4, 129.1, 128.4, 128.3, 128.0, 127.6, 124.8, 100.1,
99.9, 97.5, 74.0, 73.6, 73.0, 69.2, 69.0, 63.3, 48.5, 48.2, 17.9.
Anal. Calcd for C32H38O8S: C, 65.96; H, 6.57. Found: C, 66.15;
H, 6.72.
Gen er a l P r oced u r e for th e Cou p lin g Rea ction of
Th ioglycosid es w ith Activa tion by P h SOTf. PhSCl (0.42
mg 0.3 mmol) in 1 mL of dry dichloromethane (2 mL) was
added slowly to AgOTf (91 mg, 0.4 mmol) in dichloromethane
(2 mL) containing pulverized 3Α molecular sieves (20 mg) at
-78 °C. After the mixture was stirred for 5 min, a solution of
donor (0.1 mmol) and DTBMP (41 mg. 0.2 mmol) in dichlo-
romethane (1 mL) was slowly added. After a further 15 min,
the acceptor (0.2 mmol) in dichloromethane (1 mL) was added.
The reaction was quenched after stirring for 2 h at -78 °C by
addition of NaHCO3 (satd, 1 mL). The reaction mixture then
was diluted with EtOAc (20 mL), filtered over Na2SO4, and
concentrated. The residue obtained was purified by chroma-
tography on silica gel, eluting with EtOAc/hexane (1/5) or by
preparative TLC.
Gen er a l P r oced u r e for th e Cou p lin g Rea ction of
Glycosyl Su lfoxid es w ith Activa tion by Tf2O. The sulfox-
ide (0.1 mmol) and DTBMP (41 mg, 0.2 mmol) were dissolved
in dichloromethane (3 mL) under Ar and the solution cooled
to -78 °C, followed by the rapid addition of Tf2O (1 8µL, 0.12
mmol). The acceptor (0.2 mmol) in dichloromethane (2 mL)
was added slowly after 10 min, after which time the reaction
mixture was stirred for 2 h before it was quenched at -78 °C
by addition of NaHCO3 (satd, 0.5 mL). The resulting mixture
3â-Ch olester yl 2,6-d i-O-ben zyl-3,4-O-(2′,3′-d im eth oxy-
bu ta n e-2′,3′-d iyl)-â-D-m a n n op yr a n osid e (17â): [R]D ) +1.9
(c 1.5, CHCl3); 1H NMR (CDCl3) δ 7.37 (m, 10 H), 5.32 (d, J )

1296 J . Org. Chem., Vol. 65, No. 5, 2000
Crich et al.
(s, 3 H), 1.17(d, J ) 6.8 Hz, 3 H), 1.15 (d, J ) 6.8 Hz, 3 H); 13
NMR (CDCl3) δ 139.0, 138.4, 128.9, 128.4, 128.0, 127.6, 127.5,
127.3, 125.9, 101.4 (1J CH ) 158 Hz), 100.9 (1J CH ) 172 Hz),
79.1, 77.7, 75.9, 75.7, 73.2, 73.0, 72.6, 71.3, 69.2, 68.9, 63.6,
54.9, 17.4, 17.3. Anal. Calcd for C45H52O11: C, 70.29; H, 6.82.
Found: C, 70.31; H, 7.06.
5.2 Hz, 1 H), 4.92 (s, 2 H), 4.62 (s, 2 H), 4.56 (s, 1 H), 4.03 (t,
J ) 10 Hz, 1 H), 3.87 (d, J ) 11.2 Hz, 1 H), 3.66 (m, 5 H), 3.23
(s, 3 H), 3.18 (s, 3 H), 1.33 (s, 3 H), 1.27 (s, 3 H), 0.68-2.26
(m, 60 H); 13C NMR (CDCl3) δ 141.8, 139.0, 137.9, 134.8, 129.0,
128.1, 128.0, 127.6, 127.5, 127.2, 126.2, 122.0, 99.6, 96.4 (1J CH
) 155.9 Hz), 78.7, 74.9, 73.9, 73.4, 72.0, 70.0, 69.4, 68.9, 64.4,
64.0, 57.1, 56.8, 50.5, 48.3, 48.0, 42.5, 40.0, 39.6, 39.0, 38.0,
36.7, 36.3, 35.9, 32.3, 30.0, 28.5, 28.1, 24.4, 24.0, 23.0, 22.6,
21.4, 19.2, 18.0, 12.0. Anal. Calcd for C53H78O8: C, 75.50; H,
9.32. Found: C, 75.59; H, 9.22.
C
6-O-[2,6-Di-O-ben zyl-3,4-O-(bu ta n e-2′,3′-d iyl)-r-D-m a n -
n op yr a n osyl]-1,2;3,4-d i-O-isop r op ylid en e-r-D-ga la ctop y-
1
r a n ose (28): [R]D ) +20.0 (c 1.3, CHCl3); H NMR (CDCl3) δ
7.32 (m, 10 H), 5.52 (d, J ) 5.0 Hz, 1 H), 4.91 (s, 1 H), 4.83 (d,
J ) 12.5 Hz, 1 H), 4.70 (d, J ) 12.5 Hz, 1 H), 4.69 (d, J ) 12.5
Hz, 1 H), 4.59 (dd, J ) 3.5, 8 Hz, 1 H), 4.52 (d, J ) 12.5 Hz, 1
H), 4.31 (dd, J ) 2.4, 5.0 Hz, 1 H), 4.18 (dd, J ) 1.8, 7.9 Hz,
1 H), 3.95 (m, 1 H), 3.71 (m, 5 H), 3.35 (m, 2 H), 1.50 (s, 3 H),
1.45 (s, 3 H), 1.32 (s, 6 H), 1.18 (d, J ) 5.6 Hz, 3 H), 1.08 (d,
J ) 5.6 Hz, 3 H); 13C NMR (CDCl3) δ 139.0, 128.1, 127.4, 127.2,
110.0, 109.0, 98.5 (1J CH ) 171 Hz), 96.2 (1J CH ) 174 Hz), 77.4,
76.4, 75.4, 75.0, 72.8, 72.6, 71.0, 70.9, 70.5, 68.6, 65.6, 25.9,
25.8, 24.8, 24.4, 17.3, 17.2. Anal. Calcd for C36H48O11: C, 65.84;
H, 7.37. Found: C, 65.19; H, 7.35.
1-Ad a m a n ta n yl 2,6-d i-O-ben zyl-3,4-O-(2′,3′-d im eth oxy-
bu ta n e-2′,3′-d iyl)-r-D-m a n n op yr a n osid e (19): [R]D ) +13.3
1
(c 0.9, CHCl3); H NMR (CDCl3) δ 7.39 (m, 10 H), 5.19 (s, 1
H), 4.94 (d, J ) 12 Hz, 1 H), 4.67 (s, 1 H), 4.62 (s, 1 H), 4.54
(d, J ) 12 Hz, 1 H), 4.13 (m, 3 H), 3.74 (d, J ) 2.4 Hz, 2 H),
3.52 (s, 1 H), 3.29 (s, 3 H), 3.12 (s, 3 H), 1.74 (m, 15 H), 1.33
(s, 3 H), 1.29 (s, 3 H); 13C NMR (CDCl3) δ 139.3, 139.0, 128.3,
128.0, 127.6, 127.4, 99.9, 99.7, 92.7 (1J CH ) 172 Hz), 74.6, 73.4,
73.0, 70.5, 69.3, 69.2, 64.3, 48.1, 47.9, 42.4, 36.4, 30.8, 18.1.
Anal. Calcd for C36H48O8: C, 71.03; H, 7.95. Found: C, 71.23;
H, 8.13.
Gen er a tion a n d Decom p osition of Tr ifla te 25. Isola -
tion of Decom p osition P r od u ct 29. Sulfoxide 7 (5.1 mg, 0.01
mmol) was mixed with DTBMP (4.5 mg, 0.02 mmol) and
dissolved in CH2Cl2-d2 (0.5 mL) in an NMR tube under an Ar
atmosphere and the 1H NMR spectrum recorded at -78 °C.
Cold Tf2O (5 µL, 0.012 mmol) was then injected at -78 °C.
The 1H NMR spectrum, taken immediately at the same
temperature, revealed 7 sulfoxide to have been completely-
consumed and a major new compound formed with an ano-
meric proton chemical shift of δ ) 6.03 (br s). The 13C NMR
spectrum revealed the anomeric carbon to resonate at δ )
Meth yl 2,3,4-tr i-O-a cetyl-6-O-[2,6-d i-O-ben zyl-3,4-(2′,3′-
d im et h oxyb u t a n e-2′,3′-d iyl)-r-D-m a n n op yr a n osyl]-r-D-
glu cop yr a n osid e (21): [R]D ) +10.5 (c 1.0, CHCl3); 1H NMR
(CDCl3) δ 7.30 (m, 10 H), 5.43 (t, J ) 0.3 Hz, 1 H), 4.84 (m, 5
H), 4.60 (m, 3 H), 4.18 (t, J ) 10.8 Hz, 1 H), 4.02 (dd, J ) 2.7,
10.2 Hz, 1 H), 3.86 (m, 2 H), 3.70 (m, 3 H), 3.54 (dd, J ) 2.8,
10.4 Hz, 1 H), 3.36 (s, 3 H), 3.26 (s, 3 H), 3.17 (s, 3 H), 2.06 (s,
3 H), 1.99 (s, 3 H), 1.94 (s, 3 H), 1.31 (s, 3 H), 1.25 (s, 3 H); 13
NMR (CDCl3) δ 170.3, 169.6, 138.9, 138.7, 128.3, 128.1, 127.6,
127.5, 99.9, 99.7, 99.4 (1J CH ) 170 Hz), 96.6 (1J CH ) 170 Hz),
75.6, 73.5, 73.2, 71.3, 71.1, 70.5, 69.5, 69.1, 68.9, 68.0, 65.5,
63.8 55.3, 48.0, 20.9, 20.8, 17.9. Anal. Calcd for C39H52O16
1H2O: C, 58.93; H, 6.85. Found: C, 58.28; H, 6.56.
C
1
105.0 with J CH ) 184.2 Hz. The temperature of the probe was
1
‚
then raised in 10 K steps, with observation by H NMR until
decomposition was complete around 290 K. On a slightly larger
N -Be n zyloxyca r b on yl-O-[2,6-d i-O-b e n zyl-3,4-(2′,3′-
d im e t h o x y b u t a n e -2′,3′-d iy l)-r-D -m a n n o p y r a n o s y l]-
ser in e m eth yl ester (23): [R]D ) +9.8 (c 3.4, CHCl3); 1H NMR
(CDCl3) δ 7.31 (m, 10 H), 5.80 (d, J ) 8.5 Hz, 1 H), 5.10 (s, 2
H), 4.93 (d, J ) 12 Hz, 1 H), 4.76 (s, 1 H), 4.58 (m, 4 H), 4.17
(m, 2 H), 3.90 (m, 2 H), 3.79 (m, 4 H), 3.72 (m, 3 H), 3.27 (s, 3
H), 3.18 (s, 3 H), 1.33 (s, 3 H), 1.27 (s, 3 H); 13C NMR (CDCl3)
δ 138.8, 138.6, 128.7, 128.4, 128.1, 127.9, 127.6, 127.5, 100.8
(1J CH ) 170 Hz), 99.9, 99.7, 75.7, 73.6, 73.4, 71.8, 69.2, 68.7,
preparative scale, the decomposition product 29 was isolated
in 56% yield: [R]D ) +9.0 (c 2.5, CHCl3); H NMR (CDCl3) δ
1
7.28 (m, 9 H), 5.04 (d, J ) 15.5 Hz, 1 H), 4.78 (d, J ) 15.2 Hz,
1 H), 4.57 (d, J ) 12.0 Hz, 1 H), 4.53 (d, J ) 12.9 Hz, 1 H),
4.34 (s, 1 H), 4.06 (t, J ) 12.0 Hz, 1 H), 3.99 (dd, J ) 3.3, 10.2
Hz, 1 H), 3.90 (dd, J ) 0.9, 3.1 Hz, 1 H), 3.82 (m, 2 H), 3.68
(dd, J ) 6.6, 11.2 Hz, 1 H), 3.32 (s, 3 H), 3.18 (s, 3 H), 1.42 (s,
3 H), 1.30 (s, 3 H); 13C NMR (CDCl3) δ 138.6, 135.5, 131.9,
130.8, 128.9, 128.3, 127.8, 127.5, 127.0, 124.2, 100.5, 99.8, 78.5,
74.2, 73.6, 72.2, 71.0, 69.4, 68.4, 63.9, 48.3, 48.0, 18.0. Anal.
Calcd for C26H32O7: C, 68.40; H, 7.07. Found: C, 68.04; H,
7.14.
67.2, 63.6, 54.5, 48.1, 48.0, 17.9. Anal. Calcd for C38H47NO12
:
C, 64.30; H, 6.67; N, 1.97. Found: C, 64.48; H, 6.90; N, 1.75.
S-P h en yl 2,6-Di-O-b en zyl-3,4-O-(b u t a n e-2′,3′-d iyl)-1-
th ia -r-D-m a n n op yr a n osid e (26). NaCNBH3 (0.31 g, 5 mmol)
was added to a THF solution (10 mL) of 6 (55.4 mg, 1 mmol)
containing 3Å pulverized molecular sieves. After the solution
was cooled to 0 °C, 1 N HCl in diethyl ether was added until
the pH was 3-4. The reaction mixture was stirred at 0 °C for
2 h and then quenched by the addition of saturated NaHCO3
(10 mL). The aqueous phase was separated and extracted by
EtOAc (2 × 5 mL). The combined organic layers were dried
over Na2SO4 and concentrated. The residue was purified by
the chromatography on silica gel eluting with EtOAc/hexane
(1/3) to give 26 (51.0 mg, 92%): [R]D ) +197 (c 1.0, CHCl3);
1H NMR (CDCl3) δ 7.35 (m, 15 H), 5.57 (d, J ) 0.7 Hz, 1 H),
4.83 (d, J ) 12.4 Hz, 1 H), 4.72 (d, J ) 12.4 Hz, 1 H), 4.64 (d,
J ) 12 Hz, 1 H), 4.50 (d, J ) 12 Hz, 1 H), 4.35 (m, 1 H), 4.14
(dd, J ) 1.2, 1.4 Hz, 1 H), 3.93 (dd, J ) 9.6 Hz, 1 H), 3.87 (m,
3 H), 3.42 (m, 2 H), 1.19 (d, J ) 6 Hz, 3 H), 1.12 (d, J ) 6 Hz,
3 H); 13C NMR (CDCl3) δ 138.6, 138.1, 134.1, 131.9, 128.9,
128.2, 128.1, 127.5, 127.4, 127.3, 127.2, 88.8, 77.9, 77.4, 77.0,
76.9, 76.6, 73.1, 72.4, 71.5, 71.4, 68.7, 17.4, 17.3. Anal. Calcd
for C30H34O5S: C, 71.12; H, 6.76. Found: C, 70.98; H, 6.75.
Meth yl 3-O-ben zyl-2-O-[2,6-d i-O-ben zyl-3,4-O-(bu ta n e-
2′,3′-d iyl)-r-D-m a n n op yr a n osyl]-4,6-O-b en zylid en e-r-D-
m a n n op yr a n osid e (27): [R]D ) +24.4 (c 1.6, CHCl3); 1H NMR
(CDCl3) δ 7.45 (m, 20 H), 5.61 (s, 1 H), 5.21 (s, 1 H), 4.80 (s, 1
H), 4.77 (d, J ) 12 Hz, 1 H), 4.64 (d, J ) 12 Hz, 2 H), 4.63 (s,
1 H), 4.55 (m, 3 H), 4.26 (dd, J ) 4.4, 10 Hz, 1 H), 4.10 (m, 1
H), 4.07 (dd, J ) 11.2 Hz, 1 H), 3.94 (dd, J ) 3.2, 6.8 Hz, 2 H),
3.85 (d, J ) 1 0 Hz, 2 H), 3.80 (m, 2 H), 3.77 (dd, J ) 4.4, 14.4
Hz, 1 H), 3.73 (dd, J ) 6.8, 10.4 Hz, 1 H), 3.37 (m, 2 H), 3.20
S-P h en yl 2,3-O-Ca r b on yl-4,6-O-ben zylid en e-1-t h ia -r-
D-m a n n op yr a n osid e (40). A solution of 43 (2.0 g, 5.55 mmol)
in pyridine (12 mL) was cooled to 0 °C before phosgene (7.0
mL, 6.66 mmol) in hexane was added dropwise in 10 min. After
completion, the reaction mixture was poured slowly into a
mixture of ice-water and saturated NaHSO3. The organic
layer was separated. After drying on Na2SO3, concentration
and trituration with Et2O afforded the carbonate 40 (1.8 g,
4.81 mmol, 87%): 1H NMR (CDCl3) δ 7.30-7.50 (m, 10 H), 5.90
(s, 1 H), 5.60 (s, 1 H), 4.86-5.00 (m, 2 H), 4.18-4.35 (m, 2 H),
3.89-4.00 (m, 1 H), 3.75 (t, J ) 10.0 Hz, 1 H); 13C NMR (CDCl3)
δ 153.2, 136.6, 136.6, 131.1, 129.7, 129.6, 129.1, 128.6, 126.3,
102.1, 82.9, 79.0, 77.4, 75.1, 68.4, 61.1; ν 1818 cm-1; MS
(electrospray) m/z 408.9 (M + Na). Anal. Calcd for C20H18O6S:
C, 62.16; H, 4.70. Found: C, 62.22; H, 4.73.
6-O-[2,3-O-Ca r bon yl-4,6-O-ben zylid en e-r-D-m a n n op y-
r a n osyl]-1,2:3,4-d i-O-isop r op ylid e n e -r-D-ga la ct op yr a -
n ose (46). A solution of AgOTf (250 mg, 0.90 mmol) in CH2Cl2
(6 mL) was cooled under Ar to -78 °C. PhSCl (130 mg, 0.90
mmol) in CH2Cl2 (2 mL) was added dropwise in 10 min. After
being stirred 10 min, a solution of 40 (104 mg, 0.30 mmol)
and DTBMP (185 mg, 0.90 mmol) in CH2Cl2 (3 mL) was added
dropwise. After another 10 min, a solution of acceptor 14 (156
mg, 0.60 mmol) in CH2Cl2 (3 mL) was added. The reaction was
stirred for a further 1 h and then allowed to warm to 0 °C,
before it was quenched with two drops of saturated NaHSO3.
The mixture was filtered on Celite and then washed with
aqueous NaHSO3 and brine. After drying on Na2SO4 and
concentration, chromatography on silica gel (eluent: hexane/

R-Mannopyranosylation in the Absence of Protecting Groups
J . Org. Chem., Vol. 65, No. 5, 2000 1297
EtOAc 8/1) gave 46 (96 mg, 60%): 1H NMR (CDCl3) δ 7.35-
7.51 (m, 5 H), 5.50 (d, J ) 5.0 Hz, 1 H), 5.16 (s, 1 H), 4.85 (t,
J ) 7.2 Hz, 1 H), 4.71 (d, J ) 7.0 Hz, 1 H), 4.60 (dd, J ) 2.3,
8.0 Hz, 1 H), 4.35 (m, 2 H), 4.20 (m, 1 H), 3.78-4.00 (m, 3 H),
3.68-3.78 (m, 2 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.35 (s, 6 H);
13C NMR (CDCl3) δ 153.4, 136.7, 129.5, 128.5, 126.3, 109.7,
108.9, 102.0, 96.5, 95.9 (1J CH ) 171.2 Hz), 78.7, 76.6, 75.3, 71.1,
70.8, 70.5, 68.7, 67.1, 66.1, 59.6, 52.4, 29.8, 26.3, 26.1, 25.0,
24.7; MS (electrospray) m/z 567.0 (M + 1). Anal. Calcd for
was filtered on Celite and then washed with aqueous NaHSO4
and brine. After drying on Na2SO4 and concentration, chro-
matography on silica gel (eluent: hexane/EtOAc 8/1) gave 47
(115 mg, 69%): 1H NMR (CDCl3) δ 8.06 (d, J ) 8 Hz, 2 H),
7.55 (m, 1 H), 7.35-7.49 (m, 4 H), 7.25-7.35 (m, 3 H), 5.65 (s,
1 H), 5.55 (dd, J ) 3.0, 9.0 Hz, 1 H), 5.50 (dd, J ) 3.0, 12 Hz,
1 H), 4.80 (s, 1 H), 4.68 (dd, J ) 3.0, 10.0 Hz, 1 H), 4.20-4.42
(m, 6 H), 4.01 (m, 2 H), 3.86 (m, 2 H), 3.75 (t, J ) 8.0 Hz, 1 H),
1.60 (s, 3 H), 1.48 (s, 3 H), 1.40 (s, 6 H), 0.92 (s, 9 H), 0.15 (s,
3 H), -0.08 (s, 3 H); 13C NMR (CDCl3) δ 165.9, 137.3, 132.9,
130.0, 129.7, 128.8, 128.2, 128.2, 128.2, 126.0, 109.2, 108.6,
101.6, 101.5 (1J CH ) 171.1 Hz), 96.2, 76.1, 71.5, 70.7, 70.5, 70.2,
66.9, 66.2, 65.7, 65.7, 26.1, 25.9, 25.8, 24.8, 24.5, 17.9; MS
C
26H32O12‚1H2O: C, 56.31; C, 6.18. Found: C, 56.32; H, 6.35.
S-Eth yl 3-O-Ben zoyl-4,6-O-ben zyliden e-1-th ia-r-D-m an -
n op yr a n osid e (45). To a solution of diol 44 (1.0 g, 3.19 mmol)
in pyridine (10 mL) at -45 °C was added benzoyl chloride (0.41
mL, 3.50 mmol). The mixture was stirred at that temperature
for 40 min before concentration and chromatography on silica
gel (eluent: hexane/ethyl acetate ) 6/1) gave the title com-
pound 45 (615 mg, 46%): [R]20D ) +52.4 (c ) 1.85, CHCl3); 1H
NMR (CDCl3) δ 8.05 (m, 2 H), 7.50-7.60 (m, 1 H), 7.25-7.50
(m, 7 H), 5.61 (s, 1 H), 5.51 (dd, J ) 3.2 Hz, 10.0 Hz, 1 H),
5.36 (s, 1 H), 4.21-4.45 (m, 4 H), 3.91 (t, J ) 10.3 Hz, 2 H),
2.52-2.80 (m, 3 H), 1.32 (t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3)
δ 165.6, 137.3, 133.5, 129.9, 129.7, 129.2, 128.6, 128.4, 126.3,
101.9, 85.2, 76.6, 71.9, 71.4, 68.8, 64.6, 25.3, 15.0. Anal. Calcd
For C22H24O6S: C, 63.45, H5.81. Found: C, 63.63, H, 5.80.
S-E t h yl 3-O-Ben zoyl-4,6-O-b en zylid en e-2-O-(ter t-b u -
tyld im eth ylsilyl)-1-th ia -r-D-m a n n op yr a n osid e (41). A so-
lution of alcohol 45 (300 mg, 0.72 mmol), tert-butyldimethyl-
silyl triflate (0.34 mL, 1.44 mmol), and N,N-diisopropyl-
ethylamine (0.54 mL, 3.10 mmol) in CH2Cl2 (6 mL) was
stirred at -5 °C for 30 min and then 2 h at room temperture,
quenched with saturated aqueous NaHCO3 and brine, and
then dried (Na2SO4). Concentration and chromatography on
silica gel (eluent: hexane/ethyl acetate ) 25/1) gave the title
(electrospray), m/z 746.1 (M+ + 1). Anal. Calcd for C38H52O12
-
Si: C, 62.62; H, 7.19. Found: C, 62.78; H, 7.34.
6-O-[4,6-O-Ben zylid en e-r-D-m a n n op yr a n osyl]-1,2:3,4-
di-O-isopr opyliden e-r-D-galactopyr an ose (48). Fr om Car -
bon a te 46. To a solution of 46 (20 mg) and THF (2 mL) was
added three drops of LiOH in water solution. The reaction
mixture was stirred for about 2 h until all the starting material
was consumed. MgSO4 powder was added into the solution,
and then the organic solvent was filtered and concentrated to
give the diol 48.
F r om Ben zoa te 47. To a solution of 47 (20 mg) in MeOH
(2 mL) was added a catalytic amount of sodium, after which
the reaction mixture was stirred for 4 h. After the starting
material had disappeared, the solvent was removed under
vacuum. The residue was taken up in CHCl3, and then two
drops of water and brine were added into the solution. The
organic layer was dried with MgSO4 and concentrated. To the
residue were added CH2Cl2 (2 mL) and TBAF (0.05 mL),
followed by stirring for 5 h. After completion, the reaction
mixture was filtered on Celite, diluted with water, and
extracted by CH2Cl2 three times. Drying and concentration
gave compound 48: 1H NMR (CDCl3) δ 7.35-7.50 (m, 5 H),
5.55 (s, 1 H), 5.22 (d, J ) 5 Hz, 1 H), 4.89 (s, 1 H), 4.61 (dd, J
) 2.4, 8 Hz, 1 H), 4.31 (dd, J ) 2.4, 5 Hz, 1 H), 4.25 (t, J ) 8
Hz, 2 H), 4.05 (m, 2 H), 3.67-4.00 (m, 6 H), 2.90 (br.s, 2 H),
1.39 (s, 3 H), 1.33 (s, 3H), 1.25 (br.s, 6 Η), 13C NMR (CDCl3) δ
compound as an oil (284 mg, 74%): [R]20 ) +24 (c ) 0.74,
D
CH3Cl); 1H NMR (CDCl3) δ 8.05 (m, 2 H), 7.30-7.58 (m, 8 H),
5.66 (s, 1 H), 5.46 (dd, J ) 3, 9.6 Hz, 1 H), 5.20 (s, 1 H), 4.50
(dd J ) 1.2, 3.0 Hz, 1 H), 4.40 (m, 3 H), 3.98 (t, J ) 10.0 Hz,
3 H), 2.70 (m, 2 H), 1.36 (t, J ) 7.5 Hz, 3 H), 0.98 (s, 9 H), 0.09
(s, 3 H), -0.08 (s, 3H); 13C NMR (CDCl3) δ 165.8, 137.3, 132.9,
129.9, 129.7, 128.8, 128.2, 128.1, 126.1, 101.8, 86.2, 76.4, 66.7,
64.7, 25.6, 25.2, 17.9, 14.9. Anal. Calcd for C28H38O6SSi: C,
63.36; H, 7.22. Found: C, 63.58; H, 7.44.
137.4, 129.4, 128.5, 126.5, 109.6, 108.8, 102.4, 100.4 (1J CH
)
170.4 Hz), 96.5, 79.0, 71.1, 70.8, 70.7, 68.9, 68.7, 68.3, 66.6,
66.2, 63.4, 29.9, 26.3, 26.1, 25.8, 25.1, 24.7; MS (electrospray):
m/z 510, and 517.9 (M + H2O); FABHRMS found 509.2021,
calcd for C25H33O11 (M - H+) 509.2023.
6-O-[3-O-Ben zoyl-4,6-O-b en zylid en e-2-O-(ter t-b u t yl-
d im eth ylsilyl)-r-D-m a n n op yr a n osyl]-1,2,3,4-d i-O-isop r o-
p ylid en e-r-D-ga la ctop yr a n ose (47). A solution of AgOTf
(172 mg, 0.69 mmol) in CH2Cl2 (6 mL) was cooled under Ar to
-78 °C. PhSCl (100 mg, 0.69 mmol) in CH2Cl2 (2 mL) was
added dropwise over 10 min. After the mixture was stirred
for 10 min, a solution of 41 (121 mg, 0.23 mmol) and DTBMP
(141 mg, 0.69 mmol) in CH2Cl2 (3 mL) was added dropwise.
After another 10 min, a solution of acceptor 14 (120 mg, 0.46
mmol) in CH2Cl2 (3 mL) was added. The reaction was stirred
for a further 1 h and then allowed to warm to 0 °C before it
was quenched by two drops of saturated NaHSO3. The mixture
Ack n ow led gm en t. We thank the NIH (GM57335)
for support of this work and Dr. J . Brunckova for the
initial preparation of donor 41.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra of disaccharide 48. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9910482