Disarming, non-participating 2-O-protecting groups in manno- and rhamnopyranosylation: Scope and limitations of sulfonates, vinylogous esters, phosphates, cyanates, and nitrates

Article abstract of DOI:10.1016/j.tetasy.2004.11.032

A series of d-mannopyranosyl and l-rhamnopyranosyl thioglycosides protected with electron-withdrawing, non-participating protecting groups on O-2 have been prepared and investigated for their potential as β-glycosyl donors. Both α- and β-thioglycosides we

Full text of DOI:10.1016/j.tetasy.2004.11.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 105–119
Disarming, non-participating 2-O-protecting groups in manno- and
rhamnopyranosylation: scope and limitations of sulfonates,
vinylogous esters, phosphates, cyanates, and nitrates
David Crich,* Thomas K. Hutton, Abhisek Banerjee, Prasanna Jayalath and John Picione
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 25 October 2004; accepted 17 November 2004
Abstract—A series of D-mannopyranosyl and L-rhamnopyranosyl thioglycosides protected with electron-withdrawing, non-partic-
ipating protecting groups on O-2 have been prepared and investigated for their potential as b-glycosyl donors. Both a- and b-thio-
glycosides were investigated and the latter preferred on the grounds of enhanced stability at room temperature. A 2-O-nitro-L-
rhamnosyl fluoride was also prepared and investigated. Moderate b-selectivities were observed with some of these donors. With
the more powerfully electron-withdrawing groups reduced donor reactivity leads to a requirement for higher reaction temperatures
and reduced selectivities. Decomposition temperatures of the intermediate glycosyl triflates were determined by variable temperature
NMRspectroscopy and generally correlate with the disarming propensity of the protecting group system.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tion involves the direct SN2 attack of the acceptor alco-
hol on the covalently bound a-glycosyl donor, but the
problem is compounded by the likelihood of the reac-
tion actually taking place via the intermediacy of a tran-
sient contact ion pair, or even a solvent separated ion
pair. Nucleophilic attack on a contact ion pair, in which
the counterion is intimately associated with and blocks
one face of the oxacarbenium ion, is functionally equiv-
alent to the direct SN2 attack. However, the dictates of
the anomeric effect are such that any reaction proceed-
ing through the solvent-separated ion pair is likely to
lead at least in part to the axial glycoside, which is
Neighboring group participation by esters and related
groups is one of the most fundamental and widely ap-
plied concepts of modern organic chemistry.1 This is
especially the case in carbohydrate chemistry2 where
the concept is very widely invoked, applied, and stud-
ied.3 The high level of awareness arises from the central
nature of neighboring group participation in the stereo-
controlled synthesis of 1,2-trans-glycosidic bonds, which
facilitates the preparation of the b-glucopyranosides and
the a-mannopyranosides among others. In the absence
of neighboring group participation, stereocontrolled
glycosylation is inherently more difficult, being subject
to the vagaries of the anomeric effect and the complex
interplay between covalently bound donors and ion
pairs, whether contact or solvent separated. Accord-
ingly, the 1,2-cis-glycosidic bonds, as exemplified by
the a-glucopyranosides and especially the b-mannopyr-
anosides,4 are considerably more difficult to prepare in
a highly stereocontrolled manner than their 1,2-trans-
counterparts. The problem is illustrated in Scheme 1
for the 1,2-cis-equatorial glycosidic bonds found in the
b-manno- and b-rhamnopyranosides. The ideal situa-
P
P
P
P
O
O
O
O
O
O
O
O
X
X
X
CIP
free
covalent
donor
SSIP
oxacarbenium ion
P
P
O
O
O
O
OR
OR
α-glycoside
β-glycoside
*
Corresponding author. Tel.: +1 312 996 5189; fax: +1 312 996
0431; e-mail: dcrich@uic.edu
Scheme 1. Abbreviated glycosylation mechanism.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.032

106
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
obviously the predominant product from any free
oxacarbenium ions. In attempting any stereoselective
1,2-cis-glycosidic bond forming reaction it is imperative,
therefore, to shift the complete series of equilibria in
Scheme 1 as far to the left as possible such that the
chemistry is dictated either by the covalently bound do-
nor or the transient contact ion pair. At least in theory,
this may be achieved by the use of non-polar solvents,
weaker leaving groups, and the use of protecting groups
likely to destabilize the oxacarbenium ion by their elec-
tron-withdrawing nature. Of course nothing is quite so
simple: strongly covalently bound donors are inherently
unreactive, and the use of electron-withdrawing protect-
ing groups is widely recognized as being disarming,5 that
is leading to a further reduction in reactivity. Even more
problematic in this regard is the fact that by far the most
common and convenient disarming protecting groups
are the carboxylate esters with their unavoidable predis-
position for neighboring group participation.6 Cyclic
carbonates,7 and related groups,8 are strongly disarming
and are stereoelectronically barred from participating,
but only afford b-mannosides in heterogeneous, as
opposed to homogeneous,9 glycosylation reactions due
to a conformational effect.
of cyanate esters, vinylogous esters, phosphates, and
nitrates17,18 as non-participating, disarming protecting
groups.
BnO
BnO
SO2R
Cl
O
O
O
BnO
Ph
BnO
BnO
Cl
O
SO2Me
1: R = Me
2: R = Bn
3
SO2Bn
BnO
O
SO2Bn
X
O
O
O
O
O
BnO
BnO
BnO
OC(=NH)CCl3
4: X = OC(=NH)CCl3
5: X = S-2-pyr
6
1.1. 2-O-sulfonyl protected thiomannosides
In recent years we have developed a powerful method
for the stereocontrolled formation of b-mannopyrano-
sides using 4,6-O-benzylidene blocked thiomannoside
donors 7, and/or their sulfoxides, protected by disarm-
ing ether groups on O-2 and O-3.19–21 In this chemistry
the thioglycoside and sulfoxide donors are transformed
into glycosyl triflates 8,19c,22,23 the actual donor, by
means of the combination of 1-benzenesulfinyl piperi-
dine BSP19c and triflic anhydride or, for the sulfoxides,
triflic anhydride alone.24 The high b-selectivity in these
glycosylations, which proceed via the intermediacy of
transient contact ion pairs,25 is attributed to the disarm-
ing nature26–28 of the 4,6-O-benzylidene group, which
serves to destabilize the oxacarbenium ion and shift
the whole series of equilibria in Scheme 1 very strongly
toward the left.
The potential of sulfonate esters as non-participating
but powerfully electron-withdrawing protecting groups
in carbohydrate chemistry was recognized by Schuerch
et al., who reasoned that a powerfully electron-with-
drawing, non-participating 2-O-sulfonate group on a
mannosyl or rhamnosyl donor would lead to greater sta-
bility of the a- over the b-donor, by increasing the dipo-
lar repulsion in the b-donor.10,11 The Schuerch group
further reasoned that the electron-withdrawing, non-
participating 2-O-sulfonate group would increase the
tightness of any transient ion pair arising from an a-do-
nor, thereby leading to high b-selectivity in the difficult
manno and rhamnopyranoside series. These expecta-
tions were borne out with a series of 2-O-sulfonyl pro-
tected mannosyl and rhamnosyl chlorides, 1–3, which
were transformed in to the corresponding anomeric sul-
fonates by metathesis with silver sulfonate salts prior to
introduction of the glycosyl acceptor, and which took
part in b-selective couplings with primary, and to a
lesser extent secondary, alcohols.10,12–14 Despite the
promising nature of these glycosylations, this work lay
dormant in the literature for many years, possibly be-
cause of the authors insistence on the high water sensi-
tivity of the intermediate glycosyl sulfonates, the need
for Schlenk line techniques, and the limited number of
examples, until the description of a single b-selective
mannosylation with each of the donors 4–6 by the
Schmidt group in 200215 and our own work on b-selec-
tive 2-O-sulfonyl rhamnosyl thioglycosides in 2003.16
R'
R'
O
O
Ph
O
Ph
O
O
O
O
O
O
O
"R
"R
S(O)nR
OTf
8
7
R = alkyl, aryl; R' = R" = allyl, benzyl; n = 0, 1
While the 4,6-O-benzylidene acetal, or its congenors,
possess many advantages, they are not entirely devoid
of limitations. Most pertinently, it is obviously not pos-
sible to employ this type of cyclic protecting group in the
synthesis of the b-L-rhamnopyranosides, owing to the 6-
deoxy functionality. Slightly less obvious, but equally
pertinent to ongoing research, is the need for the selec-
tive cleavage of the 4,6-O-benzylidene acetal to the 6-
O-benzyl ether-4-OH compound following glycosylation
in the synthesis of the b-(1!4)-linked mannans and
associated substances with alternating b-(1!3) and b-
(1!4)-linkages. There are well-established methods to
affect this cleavage selectively29 but the conditions are
harsh and, as we have found, rarely applicable to tri-
and higher saccharides. In the synthesis of these b-
(1!4)-linked mannans by the glycosyl triflate method
a two step sequence involving hydrolytic cleavage of
the benzylidene acetal and selective reprotection of the
Herein we extend our earlier investigations on the use of
2-O-sulfonates in the formation of b-rhamnopyrano-
sides16 to the closely analogous b-mannosides. We ad-
dress the previously neglected issue of the dependence
of donor stability on the anomeric configuration, and
the influence of the electron-withdrawing effect of these
various groups on both reactivity and anomeric selectiv-
ity in coupling reactions. We also survey the potential

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
107
6-OH, is therefore typically required.20e,k,l With these
problems in mind, and cognizant of the work of Schu-
erch, we were attracted to the possibility that the use
of a 2-O-sulfonyl protecting group might allow us to dis-
pose with the need for the benzylidene acetal, thereby
broadening our triflate-based approach to the 1,2-cis-
equatorial glycosidic bonds.
vicinal diaxial configuration of the nucleophilic thio-
ether and the sulfonate esters, as is clear from the iso-
lation of the rearrangement product 14. Migrations
related to the rearrangement of 12–14 are well known
in the carbohydrate literature,32 have found application
in total synthesis,33 and, beyond the bounds of carbohy-
drate chemistry, underpin many elegant syntheses of sat-
urated heterocycles.34 We therefore directed our
attention at the synthesis of an analogous series of b-
phenyl thioglycosides. Thus, acetobromomannose was
exposed to thiophenol and sodium hydride in HMPA,
followed by deacetylation, to first give the b-thioglyco-
side 15 and then the known thioglycoside 16.35 Intro-
duction of the benzylidene group gave 17, which was
selectively converted to the 3-O-benzyl ether 18 in the
usual manner by means of the dibutylstannylene acetal,
benzyl bromide, and cesium fluoride. Sulfonylation with
tosyl chloride, silver oxide, potassium iodide, and coll-
idine then gave the stable donor 19 in 94% yield. Finally,
exposure of 19 to excess sodium cyanoborohydride and
HCl in ether afforded 74% of 20, which was converted to
the 4-O-trimethylsilyl derivative 21 in 95% yield with
trimethylsilyl triflate.
We first demonstrated that the 3,4-di-O-benzyl-2-O-sul-
fonyl-rhamnosyl donor 9 was an adequate donor for
coupling to a simple model acceptor, 3b-cholestanol,
by the BSP/Tf2O method when a b:a ratio of 5.5:1 was
obtained. However, further deactivation was required
to obtain useful a:b ratios with more complex acceptors.
Ultimately, the 4-O-benzoyl-3-O-benzyl-2-O-sulfonyl
donor 10 was developed for this purpose and gave
acceptable b:a ratios on coupling to a number of carbo-
hydrate based acceptors.16
O
SPh
O
O
SPh
CF3
BnO
BzO
BnO
BnO
O
O
O
S
S
O
O
9
10
Y
CF3
O
X
X
BnO
O
O
OTs
O
O
Ph
O
O
X
X
O
O
O
SPh
SPh
SPh
O
BnO
O
X
X
In attempting to transfer these results to the mannose
series it was not clear to what extent the extra disarming
effect of the C-6–O-6 bond would negate the need for the
ester protecting group on O-4.30 We therefore began with
the preparation of set of simple 2-O-sulfonyl protected
mannosyl thioglycosides, working first in the more read-
ily available a-series. Thus, reaction of thioglycoside
1131 with tosyl chloride in the presence of silver nitrate
and triethylamine afforded the sulfonate 12 in 81% yield.
While it was possible to isolate and characterize this
compound, and store it in the refrigerator, it was not
indefinitely stable at room temperature and decomposed
over a period of several days. Attempted conversion of
12 to the 6-O-benzyl-4-hydroxy analog 13, such as
may be useful for eventual use in the synthesis of a b-
(1!4)-mannan, under the standard sodium cyanoboro-
hydride/HCl conditions for this transformation, resulted
only in the formation of the 1,2-dideoxy-2-phenylthio-
glucopyranose derivative 14.
17: X = Y = H
20: X = H
15: X = Ac
16: X = H
18: X = Bn, Y = H
19: X = Bn, Y = Ts
21: X = TMS
The synthesis of 19 as an intermediate en route to 21
provided us with the opportunity to test the combined
disarming effect of the 4,6-O-benzylidene group and of
the 2-O-sulfonate. In the event, while activation was
possible with the usual BSP/Tf2O combination and
under the DPSO/Tf2O conditions, no coupling was ever
observed, even to the relatively reactive acceptor, choles-
tanol (Table 1). This failure provided a first indication
that it is possible for a donor to be too strongly
disarmed.
Coupling of donor 21 to 1-adamantanol by the diphenyl
sulfoxide method gave the b-mannoside 25 in excellent
yield, with no indication of formation of the corre-
sponding a-anomer. However, as we have discussed pre-
viously,36 1-adamantanol routinely gives very high b-
selectivity in our glycosyl triflate protocols19b,19c and is
therefore an unreliable model. With the more demand-
ing, but typical, glucose 4-OH acceptor 26 the selectivity
fell to 2:1 in favor the unwanted a-anomer. We therefore
fell back on the introduction of a second electron-with-
drawing protecting group. Mindful of the need for max-
imum orthogonality of protection in any donor we
elected to introduce a carboxylate ester, rather than a
further sulfonate group, to fulfill this function. It was
previously shown that 3-O-acyl groups are strongly
a-directing in mannosylation by the glycosyl triflate
method,9,20f,37 presumably through neighboring group
participation, therefore the only option was a 4-O-car-
boxylate ester or, possibly, a 6-O-carboxylate in the
X
BnO
BnO
O
OTs
O
Ph
O
O
O
O
HO
HO
BnO
BnO
BnO
PhS
SPh
SPh
11: X = H
12: X = Ts
14
13
O
S
N
Ph
N
N
BSP
TTBP
The basis of the instability of the 2-O-sulfonyl protected
a-thiomannosides, which was also observed earlier with
the analogous a-thiorhamnosides, arises from the trans-

108
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
Table 1. Coupling of 2-O-sulfonyl mannosyl donors to selected acceptors
Donor
Acceptor
HO
Product (% yield; a:b ratio)
1JC1,H1 (Hz)
OTs
O
Ph
O
19
—
—
O
SPh
SPh
BnO
BnO
BnO
OTs
OTs
O
O
21
25 (82; b-only)a,b
b: 155.5
HO
TMSO
HO
O
BnO
BnO
BnO
OTs
O
OBn
HO
BnO
OTs
O
OBn
O
BnO
O
21
26
28
27 (77; 2:1)a,c
a: 176.1d
b: 158.9d
HO
TMSO
BnO
O
SPh
BnO
BnO
BnO
OMe
BnO
OMe
O
OMe
S
O
BnO
O
O
OMe
O
24
24
29 (75; 1:10)c
a: 173.4d
b: 159.1d
CF3
O
S
HO
O
AcO
BnO
O
O
BnO
O
CF3
SPh
O
O
O
O
O
AcO
BnO
O
OBn
O
S
O
BnO
O
O
CF3
HO
S
O
26
30 (76; 2:1)c
a: 172.0d
b: 155.1d
AcO
OBn
O
BnO
O
BnO
O
BnO
CF3
SPh
O
BnO
AcO
O
OMe
BnO
BnO
BnO
OMe
a A treatment with Bu4NF was included in the work-up.
b Conducted with the DPSO protocol.
c Directly analogous results were obtained by the DPSO method.
1
d Only the JCH coupling constants for the mannose residue are reported in this table.
mannose series. Thus, a 4-O-acetyl-2-O-(o-trifluoro-
methylbenzenesulfonyl) donor 24 was also prepared as
illustrated in Scheme 2.
as non-participating, electron-withdrawing and, so, b-
directing groups. A vinylogous ester 32 was obtained
from 3116 in 64% yield by reaction with ethyl propiolate
and N-methylmorpholine,38 while bis(2,2,2-trichloro-
ethyl)phosphate 33 was accessed from the corresponding
phosphoryl chloride in 85% yield. A further donor, the
2-O-cyanate ester 34, was obtained in 35% yield directly
from 31 on treatment with potassium hexamethyldisilaz-
ide, then cyanogen bromide. Alternatively, 34 was ob-
tained in 56% yield on dehydration of carbamate 35,
itself formed quantitatively from 31 with trichloroacetyl
isocyanate, with triphenylphosphine and carbon tetra-
bromide.39 Coupling of these donors to 3b-cholestanol
was achieved by the standard BSP method leading to
the results of Table 2. To our knowledge neither vinylo-
gous esters, nor phosphates or cyanates have been
employed in this manner previously in glycosylation
reactions.
O
X
NaCNBH3, HCl,
Et2O, 83%
O
Ph
O
S
O
BnO
O
O
O
O
SPh
CF3
SPh
BnO
X
O
BnO
RSO2Cl,
Ag2O, KI,
89%
Ac2O,
96%
18: X = H
22: X = o-C6H4CF3
23: X = H
24: X = Ac
Scheme 2. Synthesis of a mannosyl donor.
With the relatively unhindered rhamnose derivative 28
as acceptor, donor 24 gave a satisfactory 75% yield of
a 10:1 b:a mixture of glycosides 29. Unfortunately, how-
ever, with the more demanding glucose 4-OH derivative
26, the anomeric ratio was a disappointing 2:1 in favor
of the a-anomer. Apparently, in the mannose series,
the introduction of the extra electron-withdrawing
group at O-4 has no significant effect on the outcome
of the reaction with these already strongly disarmed
donors.
O
SPh
O
SPh
BnO
BnO
BnO
BnO
OH
31
O
CO2Et
32
O
SPh
O
SPh
BnO
BnO
1.2. Investigation of alternative non-participating,
electron-withdrawing protecting groups at O-2
BnO
BnO
O
O
P(OCH2CCl3)2
X
O
34: X = CN
In addition to the 2-O-sulfonate esters, we have investi-
gated several other protecting groups for their potential
33
35: X = CONH2

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
109
Table 2. Coupling to alternate donors
Donor
Acceptor
Product (% yield; a:b ratio)
1JC1,H1 (Hz)
O
SPh
SPh
BnO
a: 169.7
b: 153.8
O
O
BnO
32
33
36 (49; 1:1)a
BnO
BnO
O
HO
HO
BnO
BnO
EtO2C
O
CO2Et
O
BnO
O
O
37 (73; 1:2.6)a
a: 170.3
b: 153.5
BnO
O
O
(Cl3CH2CO)2P
O
P(OCH2CCl3)2
O
O
SPh
N
BnO
O
38 (42; b-only)a
b: 154.2
O
BnO
BnO
BnO
O
34
34
C
C
BnO
BnO
HO
HO
O
C
N
OMe
O
OMe
O
SPh
N
O
BnO
O
39 (19; a-only)a
173.7b
O
BnO
O
28
O
O
O
O
O
C
N
O
O
O
O
O
N
O
SPh
N
BnO
O
41 (21; a-only)a
170.0b
O
34
34
40
BnO
O
O
O
HO
C
C
O
O
O
BnO
BnO
O
C
OBn
O
O
SPh
N
BnO
HO
26
—
—
BnO
O
BnO
BnO
OMe
a Comparable results were obtained when these couplings were conducted by the DPSO method.
1
b Only the JCH coupling constants for the rhamnose residue are reported in this table.
Among the vinylogous esters, phosphates, and cyanates
(Table 2) only the latter (34) was deemed sufficiently
selective on coupling to cholestanol to warrant further
investigation. Unfortunately our hopes for this moder-
ately disarmed but sterically unencumbered rhamnosyl
donor were short lived, as coupling reactions to the
rhamnosyl acceptor 28 and to the glucofuranose accep-
tor 40 gave only the a-anomeric products in low yield
(Table 2). With the less reactive glucosyl 4-OH acceptor
26 the situation was even worse with no coupling, and
only decomposition of the donor being observed (Table
2). Obviously, the minimal steric bulk of the cyanate
ester is insufficient to compensate for the only moder-
ately disarming effect of this group (pKa HOCN = 3.5).
While the reason for the inefficient coupling with the
cyanate donor is unclear at this point, it is possible that
the cyanate itself is acting as a competing intermolecular
nucleophile toward the intermediate glycosyl triflate in
much the same way that acetonitrile participates in gly-
cosylation reactions.14 Alternatively, it may be that the
cyanate group itself is undergoing nucleophilic attack
by the acceptor alcohol in competition with the glycosyl-
ation reaction.
glycosyl triflates by means of TMS triflate,40 glycosyl
fluorides41 were considered as potentially suitable do-
nors for use in conjunction with this novel protecting
group. In the event, a 2-O-nitrate protected rhamnosyl
fluoride 45 was prepared as outlined in Scheme 3.42
Unfortunately, the nitrate ester (pKa HNO3 = À1.3)
was found to be so disarming as to prevent activation
by TMS triflate until the reaction temperature was
raised to 0 °C, at which point decomposition was ob-
served. Hafnocene dichloride in combination with silver
triflate43 was found, however, to activate the nitrate to-
ward coupling, albeit slowly as the reaction mixture was
allowed to warm to room temperature. The slow activa-
tion and high coupling temperature were then reflected
in the poorly selective coupling to cholestanol when an
unsatisfactory a:b ratio of 1:1 was observed (Scheme
3). On the basis of the slow activation and the inade-
quate selectivity, this direction of investigation was not
pursued further.
1.3. Variable temperature NMR studies and glycosyl
triflate decomposition
Variable-temperature NMR-derived decomposition
temperatures for several of the intermediate glycosyl tri-
flates employed in this study were determined with a
view to checking the central premise of this paper:
non-participating, electron-withdrawing protecting
groups should stabilize covalent glycosyl triflates. As is
Finally, the powerfully disarming 2-O-nitrate ester was
investigated. Methods for the introduction of nitrate
esters are generally oxidizing and were considered
incompatible with the presence of a thioglycoside. How-
ever, with the rapid conversion of glycosyl fluorides to

110
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
F
F
DDQ,
54%
O
SPh
O
O
BnO
DAST,
NBS
BnO
BnO
BnO
BnO
BnO
O
O
ONap
X
X
43: 86%
44: X = H
HNO3,
Ac2O,
91%
31: X = H
42: X = Nap
NaH,
NapBr,
79%
45: X = NO2
Cp2HfCl2, AgOTf,
CH2Cl2, -60°C - rt, 5 h
O
O
BnO
BnO
ONO2
46: 60%, α:β = 1:1
HO
Scheme 3. Synthesis and coupling of a nitrate protected rhamnosyl donor.
apparent from the results presented in Table 3, this over-
arching principle generally holds with the more dis-
armed triflates decomposing at higher temperatures.
The triflate derived from thioglycoside 19 is of particular
interest as it illustrates the combined effect of the tor-
sionally disarming 4,6-O-benzylidene protecting group
and that of the more classically inductively disarming
2-O-sulfonyl group. The combination is obviously pow-
erful as it results both in a substantial deactivation of the
thioglycoside itself toward activation and an increased
decomposition temperature of approximately 20 °C.
2. Conclusion
2-O-Sulfonyl protected mannosyl thioglycosides are
readily prepared, stable glycosyl donors, provided b-
thioglycosides are employed. These donors are moder-
ately selective for the formation of the b-glycosides with
simple alcohols, and less hindered carbohydrate accep-
tors. However, with the more demanding glucose
4-OH acceptor the selectivity is considerably reduced.
A number of other non-participating, electron-with-
drawing protecting groups were investigated but none
Table 3. Thioglycoside activation times and glycosyl triflate decomposition temperatures
Thioglycoside
Act. time, temp (°C)
dH1 for glycosyl triflate
Decomp. temp (°C)
À30
MeO
MeO
OMe
O
47a,b
<3 min, À78
6.17, br s
MeO
S(O)Ph
OMe
O
Ph
O
48a,b
<3 min, À78
<1 min, À60
<1 min, À60
6.20, br s
À10
10
O
MeO
S(O)Ph
O
SPh
CF3
BzO
BnO
O
O
10
6.26, d (J = 1.8 Hz)
S
O
O
S
24
6.28, s
À10
BnO
O
O
CF3
O
AcO
SPh
BnO
O
SPh
BnO
BnO
34
<1 min, À60
1 h, À60
6.24, s
À30
O
C
N
OTs
O
Ph
O
19
6.24, d (J = 1.8 Hz)
20
O
SPh
BnO
a Taken from Ref. 22 for comparison purposes.
b Activation with Tf2O.

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
111
compared favorably with the 2-O-sulfonates. An impor-
tant lesson, gleaned from the relative lack of reactivity
of the 4,6-O-benzylidene-2-O-sulfonyl protected system
19, and the 2-O-nitrate 45, is that it is possible for a sys-
tem to be disarmed to a point at which it is insufficiently
reactive. This leads to a need for increased reaction tem-
peratures and, ultimately, to reduced selectivities.
J = 9.5 Hz, 1H), 3.96–3.93 (dd, J = 3.5, 9.5 Hz, 1H),
3.87 (t, J = 9.5 Hz, 1H), 2.39 (s, 3H); 13C NMR d:
144.9, 137.5, 137.3, 133.1, 132.5, 132.3, 129.7, 129.3,
128.9, 128.3, 128.27, 128.26, 128.2, 127.7, 126.0, 101.6,
87.4, 78.9, 78.3, 73.4, 72.5, 68.3, 65.4, 21.7; ESIHRMS
Calcd for C33H33O7S2Na [M+H]+: 605.1668. Found:
605.1684.
3.4. 3,6-Di-O-benzyl-1,2-dideoxy-2-phenylthioglucopyra-
nose 14
3. Experimental
3.1. General
To a stirred solution of 12 (1.35 g, 2.2 mmol) in THF
(25 mL) was added NaBH3CN (2.09 g, 33.3 mmol) and
a pinch of methyl orange at 0 °C. After 15 min a
2.0 M solution of HCl in Et2O (20 mL) was added
slowly until the color of the solution became perma-
nently pink. The reaction mixture was stirred at rt for
12 h and diluted with EtOAc, washed with saturated
aqueous NaHCO3 solution, water, and brine. The
organic layer was separated, dried, and concentrated.
Unless otherwise stated, 1H and 13C NMRspectra were
recorded in CDCl3 solution. Optical rotations were re-
corded in CHCl3 solution, unless otherwise stated. All
solvents were dried and distilled by standard protocols.
All reactions were conducted under a blanket of dry
nitrogen or argon. All organic extracts were dried over
sodium sulfate, and concentrated under aspirator vac-
uum at room temperature. Chromatographic purifica-
tions were carried out over silica gel. Room
temperature is referred to as rt.
Chromatographic purification (12% ethyl acetate in hex-
26
D
ane) afforded 14 (0.82 g, 85%). ½aŠ ¼ À10:8 (c 0.3,
1
CHCl3); H NMR d: 7.48–7.46 (m, 2H), 7.43–7.41 (m,
2H), 7.38–7.24 (m, 11H), 5.03–5.01 (d, J = 11.0 Hz,
1H), 4.83–4.80 (d, J = 11.0 Hz, 1H), 4.60–4.57 (d,
J = 11.5 Hz, 1H), 4.55–4.52 (d, J = 12.5 Hz, 1H), 4.02–
3.99 (m, 1H), 3.68–3.64 (m, 3H), 3.39–3.35 (m, 4H);
13C NMR d: 138.4, 137.9, 133.7, 132.1, 129.2, 128.8,
128.6, 128.4, 128.2, 127.9, 127.5, 84.2, 79.1, 77.6, 77.2,
76.8, 75.6, 73.8, 72.9, 70.6, 70.2, 49.6; ESIHRMS Calcd
for C26H28O4SNa [M+Na]+: 459.1572. Found 459.1571.
3.2. General procedure for coupling to thioglycosides
To a solution of substrate in CH2Cl2 (0.03 M in sub-
strate), containing activated molecular sieves BSP
(1.1 equiv), and TTBP (2 equiv) were added and the
reaction mixture cooled to À60 °C, after which Tf2O
(1.2 equiv) was added slowly. After stirring for the pre-
scribed activation time at À60 °C, the acceptor (2 equiv)
in CH2Cl2 (2 M in substrate) was added slowly over a
period of 1 min. The cloudy reaction mixture was stirred
for further 30 min at À60 °C, then was removed from
the cooling bath and left to stir for a further 15 min.
The clear orange solution was then quenched by adding
saturated aqueous NaHCO3. Brine was then added and
the contents were extracted with CH2Cl2. The combined
organic layer was dried and the solvent removed. Chro-
matographic purification (eluting with mixtures of hex-
ane and ethyl acetate) afforded the coupled products.
The DPSO protocol is identical save for the replacement
of BSP by DPSO.
3.5. S-Phenyl 4,6-O-benzylidene-b-D-thiomannopyrano-
side 17
To a solution of S-phenyl b-D-thiomannopyranoside 16
(3.4 g, 12.5 mmol)35 and catalytic camphorsulfonic acid
in THF (150 mL) was added benzaldehyde dimethyl ace-
tal (2.0 mL, 2.1 g). The reaction mixture was heated to
reflux for 1 h then concentrated. Chromatographic puri-
fication (EtOAc/hexane, 1/1) gave 17 (3.2 g, 71%) as
20
D
white solid. ½aŠ ¼ À46:4 (c, 1.1); mp 195 °C; 1H
NMR d: 7.20 (m, 10H), 5.43 (s, 1H), 4.81 (d,
J = 1.2 Hz, 1H), 4.21 (dd, J = 5.1, 10.5 Hz, 1H), 4.10
(d, J = 2.7 Hz, 1H), 4.04 (br s, 2H), 3.79 (t, J = 9.6 Hz,
1H), 3.72 (t, J = 10.5 Hz, 1H), 3.63 (dd, J = 3.6,
9.6 Hz, 1H), 3.29 (dt, J = 5.1, 9.9 Hz, 1H); 13C NMR
d:130.9, 129.0, 128.2, 127.4, 126.2, 120.1, 88.4, 78.3,
72.7, 71.5, 71.0, 68.4. Anal. Calcd for C19H20O5SÆ0.33-
H2O: C, 62.29; H, 5.68. Found: C, 62.33; H, 5.62.
3.3. S-Phenyl 3-O-benzyl-4,6-O-benzylidene-2-O-(p-tolu-
enesulfonyl)-a-D-thiomannopyranoside 12
To a solution of 11 (1.31 g, 2.9 mmol) in CH2Cl2
(20 mL) was added Et3N (1.2 mL, 8.7 mmol) and tosyl
chloride (1.48 g, 5.8 mmol) followed by AgNO3
(0.99 g, 5.8 mmol). The reaction mixture was stirred at
rt for 12 h after which it was filtered through Celite.
The filtrate was washed with saturated aqueous NaH-
CO3 solution and brine. The organic layer was sepa-
rated, dried, and concentrated. Chromatographic
purification (10% ethyl acetate in hexane) afforded 12
3.6. S-Phenyl 3-O-benzyl-4,6-O-benzylidene-b-D-thio-
mannopyranoside 18
Diol 17 (70 mg, 0.19 mmol) and Bu2SnO (72 mg,
0.29 mmol) were heated to reflux with stirring in a mix-
ture of benzene (5 mL) and MeOH (0.5 mL) for 3 h.
After cooling to rt and concentration, the residue was
taken up in toluene (10 mL), benzyl bromide (24 lL
43.0 mg, 0.2 mmol) and Bu4NI (80 mg, 0.4 mmol) were
added, and the reaction mixture heated to 100 °C for
8 h. After concentration, chromatographic purification
of the residue (EtOAc/hexane, 1/3) gave 18 (43 mg,
25
1
(1.42 g, 81%). ½aŠ ¼ þ31:9 (c 1.6, CHCl3); H NMR
D
d: 7.79–7.78 (d, J = 7.0 Hz, 2H), 7.49–7.48 (dd, J = 2.0,
8.0 Hz, 2H), 7.42–7.26 (m, 11H), 7.21–7.16 (m, 4H),
5.63 (d, J = 1.5 Hz, 1H), 5.62 (s, 1H), 5.02–5.01 (m,
1H), 4.57–4.55 (d, J = 12.0 Hz, 1H), 4.47–4.45 (d,
J = 12.0 Hz, 1H), 4.27–4.21 (m, 2H), 4.13 (t,

112
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
20
D
50%). ½aŠ ¼ À18:5 (c 0.4, CHCl3); 1H NMR d: 7.39 (m,
À20 °C. The reaction mixture was stirred for 1 h at
À20 °C then was diluted with CH2Cl2 and washed with
saturated aqueous NaHCO3 solution and brine. The
organic layer was separated, dried, and concentrated.
15H), 5.62 (s, 1H), 4.89 (s, 1H), 4.86 and 4.75 (2d,
J = 12.0 Hz, 2H), 4.33 (dd, J = 5.1, 10.8 Hz, 1H), 4.31
(s, 1H), 4.18 (t, J = 9.3 Hz, 1H), 3.93 (t, J = 10.5 Hz,
1H), 3.69 (dd, J = 3.4, 9.6 Hz, 1H), 3.43 (dt, J = 5.1,
9.9 Hz, 1H); 13C NMR d: 138.8, 136.2, 131.4, 129.2,
128.7, 128.4, 128.2, 128.1, 127.7, 126.2, 101.7, 87.8,
78.4, 77.9, 73.0, 71.6, 71.2, 68.7. Anal. Calcd for
C26H26O5S: C, 69.31; H, 5.82. Found: C, 69.50; H, 6.08.
Chromatographic purification (8% ethyl acetate in hex-
24
ane) afforded 21 (0.123 g, 95%). ½aŠ ¼ À55:8 (c 1.1,
D
CHCl3); 1H NMR d: 7.88–7.87 (d, J = 7.0 Hz, 2H),
7.52–7.50 (m, 2H), 7.41–7.39 (m, 2H), 7.35–7.26 (m,
8H), 7.22–7.20 (m, 5H), 5.46 (d, J = 2.5 Hz, 1H), 4.89–
4.87 (d, J = 11.5 Hz, 1H), 4.84 (s, 1H), 4.57 (d,
J = 2.5 Hz, 2H), 4.48–4.46 (d, J = 11.5 Hz, 1H), 3.84–
3.80 (t, J = 8.5 Hz, 1H), 3.78–3.75 (dd, J = 2.0,
11.0 Hz, 1H), 3.68–3.65 (dd, J = 6.5, 11.0 Hz, 1H),
3.48–3.47 (m, 1H), 3.44–3.42 (dd, J = 3.0, 9.0 Hz, 1H),
2.40 (s, 3H), 0.01 (s, 9H); 13C NMR d: 144.2, 138.5,
137.1, 134.9, 134.5, 131.1, 129.3, 128.9, 128.3, 128.2,
128.0, 127.7, 127.6, 127.5, 127.4, 85.3, 81.1, 78.9,
73.4, 72.3, 69.6, 67.5, 21.6, 0.4; ESIHRMS Calcd
for C36H42O7S2SiNa [M+Na]+: 701.2039. Found
701.2007.
3.7. S-Phenyl 3-O-benzyl-4,6-O-benzylidene-2-O-(p-tolu-
enesulfonyl)-b-D-thiomannopyranoside 19
To a stirred solution of 18 (280 mg, 0.62 mmol) in
CH2Cl2 (4 mL) were added sym-collidine (1 mL), KI
(206 mg, 1.22 mmol), Ag2O (288 mg, 1.24 mmol) and
tosyl chloride (178 mg, 0.93 mmol) at 0 °C. The reaction
mixture was stirred for 1 h at 0 °C, and for 16 h at rt be-
fore it was diluted with CH2Cl2 and filtered. The filtrate
was washed with aqueous CuSO4 then satd. NaHCO3.
The organic layer was separated, dried, and concen-
trated. Chromatographic purification (hexane/ethyl ace-
3.10. S-Phenyl 3-O-benzyl-4,6-O-benzylidene-2-O-(2-
trifluoromethylbenzenesulfonyl)-b-D-thiomannopyrano-
side 22
tate, 5:1) then gave 19 (344 mg, 94%) as white solid.
26
D
½aŠ ¼ À52:3 (c 1.0, CHCl3); mp 140 °C; 1H NMR:
7.94–7.92 (d, J = 8.0 Hz, 2H), 7.86–7.84 (d, J = 8.5 Hz,
1H), 7.47–7.25 (m, 16H), 5.58 (s, 1H), 5.49–5.48 (d,
J = 3.0 Hz, 1H), 4.88 (s, 1H), 4.85–4.83 (d,
J = 12.0 Hz, 1H), 4.71–4.69 (d, J = 12.5 Hz, 1H), 4.29–
4.25 (dd, J = 5.0, 10.0 Hz, 1H), 4.04–4.01 (t,
J = 9.5 Hz, 1H), 3.89–3.85 (t, J = 10.0 Hz, 1H), 3.75–
3.72 (dd, J = 3.0, 10.0 Hz, 1H), 3.43–3.38 (m, 1H),
2.42 (s, 3H); 13C NMR d: 144.5, 137.5, 137.2, 134.4,
133.5, 131.8, 131.5, 130.4, 129.4, 129.1, 128.9, 128.4,
128.3, 128.2, 128.1, 127.9, 127.7, 126.0, 101.5, 86.8,
79.9, 77.6, 77.0, 75.9, 72.4, 71.9, 68.2, 22.0, 21.7; ESI-
HRMS Calcd for C33H32O7S2Na [M+Na]+: 627.1487.
Found 627.1500. Anal. Calcd for C33H32O7S2: C,
65.54; H, 5.33: Found: C, 65.31; H, 5.48.
Following the procedure applied for the preparation of
19, 22 was obtained from 18 and o-trifluoro-
24
D
methylbenzenesulfonyl chloride (89%). ½aŠ ¼ À37:2
1
(c 1.8, CHCl3); H NMR d: 8.26–8.24 (d, J = 7.5 Hz,
1H), 7.84–7.83 (d, J = 7.5 Hz, 1H), 7.63–7.60 (t,
J = 7.5 Hz, 1H), 7.58–7.54 (t, J = 7.5 Hz, 1H), 7.46–
7.25 (m, 15H), 5.60 (s, 1H), 5.45–5.44 (d, J = 3.5 Hz,
1H), 4.87 (d, J = 0.5 Hz, 1H), 4.68–4.65 (d,
J = 12.5 Hz, 1H), 4.56–4.53 (d, J = 12.5 Hz, 1H), 4.33–
4.29 (dd, J = 4.5, 10.5 Hz, 1H), 4.07–4.03 (t,
J = 10.0 Hz, 1H), 3.91–3.87 (t, J = 10.5 Hz, 1H), 3.71–
3.69 (dd, J = 3.0, 9.5 Hz, 1H), 3.43–3.38 (m, 1H); 13C
NMR d: 137.3, 131.6, 131.4, 129.2, 128.9, 128.3, 128.2,
128.0, 127.8, 127.7, 126.0, 101.5, 86.6, 82.1, 77.9, 75.6,
72.5, 71.7, 68.4; ESIHRMS Calcd for C33H30F3O7S2
[M+H]+: 659.1385. Found 659.1378.
3.8. S-Phenyl 3,6-di-O-benzyl-2-O-(p-toluenesulfonyl)-b-
D-thiomannopyranoside 20
Compound 19 was converted to 20 (74%) by the proto-
26
D
3.11. S-Phenyl 3,6-di-O-benzyl-2-O-(2-trifluoromethyl-
benzenesulfonyl)-b-D-thiomannopyranoside 23
col used for the formation of 14 from 12. ½aŠ ¼ À57:3
1
(c 1.2, CHCl3); H NMR d: 7.93–7.91 (d, J = 8.5 Hz,
2H), 7.52–7.50 (m, 2H), 7.43–7.23 (m, 15H), 5.48 (d,
J = 2.5 Hz, 1H), 4.98–4.95 (d, J = 12.0 Hz, 1H), 4.85
(s, 1H), 4.55 (d, J = 1.5 Hz, 2H), 4.53–4.51 (d,
J = 11.5 Hz, 1H), 3.86–3.83 (m, 2H), 3.76–3.73 (dd,
J = 6.5, 11.0 Hz, 1H), 3.54–3.51 (m, 1H), 3.50–3.48
(dd, J = 2.5, 9.0 Hz, 1H), 2.72 (br s, 1H), 2.41 (s, 3H);
13C NMR d: 144.5, 138.2, 137.2, 134.4, 134.2, 131.2,
129.4, 129.1, 128.6, 128.4, 128.3, 128.2, 128.1, 127.7,
127.64, 127.62, 85.3, 80.3, 79.5, 78.1, 73.6, 72.1, 70.4,
67.2, 21.7; ESIHRMS Calcd for C33H34O7S2Na
[M+Na]+: 629.1644. Found 629.1619.
Compound 22 was converted to 23 in 83% yield analo-
26
D
gously to the preparation of 14 from 12. ½aŠ ¼ À61:5
1
(c 2.4, CHCl3); H NMR d: 8.27–8.25 (d, J = 7.5 Hz,
1H), 7.86–7.85 (d, J = 8.0 Hz, 1H), 7.67–7.64
(t, J = 7.5 Hz, 1H), 7.60–7.57 (t, J = 7.5 Hz, 1H),
7.45 (d, J = 2.0 Hz, 1H), 7.44–7.43 (d, J = 4.0 Hz,
1H), 7.34–7.21 (m, 13H), 5.46–5.45 (d, J = 2.5 Hz,
1H), 4.83–4.80 (d, J = 11.5 Hz, 1H), 4.82 (s, 1H),
4.61–4.59 (d, J = 11.5 Hz, 1H), 4.58–4.56 (d,
J = 12.0 Hz, 1H), 4.46–4.43 (d, J = 11.5 Hz, 1H), 3.93–
3.89 (t, J = 9.5 Hz, 1H), 3.86–3.83 (dd, J = 3.5,
10.5 Hz, 1H), 3.79–3.76 (dd, J = 6.0, 11.0 Hz, 1H),
3.51–3.49 (m, 1H), 3.47–3.44 (dd, J = 3.0, 9.5 Hz, 1H),
2.62 (br s, 1H); 13C NMR d: 138.0, 137.0, 136.0,
133.9, 133.3, 131.8, 131.4, 131.2, 129.0, 128.8, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 85.1,
80.1, 79.9, 79.3, 73.6, 72.1, 70.4, 67.7; ESIHRMS
3.9. S-Phenyl 3,6-di-O-benzyl-2-O-(p-toluenesulfonyl)-4-
O-(trimethylsilyl)-b-D-thiomannopyranoside 21
To a solution of 20 (0.116 g, 0.19 mmol) in CH2Cl2
(5 mL) was added Et3N (67 lL, 0.48 mmol). After
15 min, TMSOTf (42 lL, 0.23 mmol) was added at

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
113
Calcd for C33H31F3O7S2Na [M+Na]+: 683.1361.
Found 683.1354.
(d, J = 11.5 Hz, 1H), 4.93–4.92 (t, J = 2.5 Hz, 1H),
4.80–4.78 (d, J = 12.0 Hz, 1H), 4.67–4.65 (d,
J = 12.0 Hz, 1H), 4.59–4.58 (d, J = 4.0 Hz, 1H), 4.55–
4.52 (d, J = 11.5 Hz, 1H), 4.54–4.51 (d, J = 12.0 Hz,
1H), 4.52 (s, 1H), 4.46–4.41 (t, J = 12.5 Hz, 2H), 4.32–
4.30 (d, J = 11.0 Hz, 1H), 4.20–4.18 (d, J = 11.0 Hz,
1H), 3.88–3.78 (m, 5H), 3.72–3.69 (m, 2H), 3.66 (d,
J = 2.5 Hz, 1H), 3.65 (s, 1H), 3.64–3.63 (d, J = 2.5 Hz,
1H), 3.56–3.53 (dd, J = 3.5, 9.0 Hz, 1H), 3.38 (s, 3H),
2.61 (br s, 1H), 2.29 (s, 3H); 13C NMR d: 144.4, 138.8,
138.1, 137.9, 137.8, 137.5, 133.8, 129.6, 128.5, 128.4,
128.3, 127.9, 127.8, 127.78, 127.76, 127.68, 127.6,
127.5, 127.3, 127.0, 99.7 (1JCH = 176.1 Hz), 97.8
(1JCH = 166.9 Hz), 80.8, 80.1, 77.4, 76.4, 74.9, 74.8,
73.6, 73.3, 73.2, 72.1, 71.4, 70.4, 69.7, 68.9, 67.6, 55.3,
3.12. S-Phenyl 4-O-acetyl-3,6-di-O-benzyl-2-O-(2-tri-
fluoromethylbenzenesulfonyl)-b-D-thiomannopyranoside
24
To a stirred solution of 23 (0.422 g, 0.64 mmol) and
DMAP (0.008 g, 0.06 mmol) in pyridine (10 mL) was
added Ac2O (97 lL, 0.96 mmol). After 6 h, the reaction
mixture was concentrated, dissolved in EtOAc, washed
with saturated aqueous NaHCO3 solution and brine.
The organic layer was separated, dried, and concen-
trated. Chromatographic purification (20% ethyl acetate
26
in hexane) afforded 24 (0.432 g, 96%). ½aŠ ¼ À83:1 (c
D
0.8, CHCl3); 1H NMR d: 8.21–8.19 (d, J = 7.5 Hz,
1H), 7.76–7.75 (d, J = 8.0 Hz, 1H), 7.53–7.48 (m, 4H),
7.34–7.20 (m, 11H), 7.08–7.06 (m, 2H), 5.50–5.49 (d,
J = 3.5 Hz, 1H), 5.21–5.17 (t, J = 10.0 Hz, 1H), 4.88 (s,
1H), 4.56–4.53 (d, J = 11.0 Hz, 1H), 4.52–4.49 (d,
J = 12.0 Hz, 1H), 4.51 (s, 1H), 4.33–4.31 (d,
J = 12.0 Hz, 1H), 3.69–3.67 (m, 1H), 3.62–3.58 (m,
3H), 1.86 (s, 3H); 13C NMR d: 169.5, 138.1, 136.9,
136.0, 133.9, 133.1, 131.8, 131.2, 129.1, 128.3, 128.1,
128.08, 128.03, 127.8, 127.7, 127.68, 127.6, 127.5, 85.1,
80.3, 78.5, 77.9, 73.6, 72.1, 69.9, 67.9, 20.8; ESIHRMS
Calcd for C35H33F3O8S2Na [M+Na]+: 725.1467. Found
725.1451.
21.6; ESI-HRMS Calcd for C55H60O13SNa [M+Na]+:
25
983.3653. Found 983.3630. 27b: ½aŠ ¼ À39:0 (c 0.6,
D
CHCl3); 1H NMR d: 7.76–7.74 (d, J = 6.5 Hz, 2H),
7.41–7.15 (m, 27H), 4.96–4.95 (d, J = 3.0 Hz, 1H),
4.81–4.79 (d, J = 12.0 Hz, 1H), 4.76–4.74 (d,
J = 11.5 Hz, 1H), 4.71–4.68 (d, J = 12.0 Hz, 1H), 4.63–
4.61 (d, J = 11.5 Hz, 1H), 4.60–4.57 (d, J = 12.5 Hz,
1H), 4.56 (s, 1H), 4.44–4.42 (d, J = 12.0 Hz, 1H), 4.41
(s, 2H), 4.39–4.38 (d, J = 3.5 Hz, 1H), 4.37–4.35 (d,
J = 12.0 Hz, 1H), 4.26–4.23 (d, J = 12.0 Hz, 1H), 3.82–
3.79 (t, J = 9.5 Hz, 1H), 3.73–3.70 (m, 2H), 3.63–3.59
(m, 2H), 3.55–3.51 (t, J = 9.5 Hz, 1H), 3.49–3.45 (dd,
J = 5.0, 10.5 Hz, 1H), 3.40 (s, 3H), 3.39–3.34 (m, 2H),
3.17–3.15 (m, 1H), 3.12–3.10 (dd, J = 3.0, 9.5 Hz, 1H),
2.77 (br s, 1H), 2.36 (s, 3H); 13C NMR d: 144.3, 139.7,
138.3, 137.9, 137.7, 137.5, 134.9, 129.3, 128.6, 128.5,
128.4, 128.1, 128.07, 128.04, 127.99, 127.95, 127.9,
127.7, 127.6, 127.4, 126.9, 98.5 (1JCH = 169.2 Hz), 97.9
(1JCH = 158.9 Hz), 79.9, 78.9, 78.8, 77.7, 76.6, 74.9,
74.4, 73.7, 73.6, 73.5, 71.8, 70.8, 69.3, 68.7, 68.5, 55.4,
21.6; ESIHRMS Calcd for C55H60O13SNa [M+Na]+:
983.3653. Found 983.3621.
3.13. (1-Adamantanyl) 3,6-di-O-benzyl-2-O-(p-toluene-
sulfonyl)-b-D-mannopyranoside 25
Coupling of 21 with 1-adamantanol, with a 20 min acti-
24
vation period, gave 25b in 82% yield. ½aŠ ¼ À28:2 (c
D
0.3, CHCl3); 1H NMR d: 7.86–7.84 (d, J = 9.0 Hz,
2H), 7.45–7.43 (d, J = 8.5 Hz, 2H), 7.34–7.21 (m,
10H), 5.02–5.01 (d, J = 2.5 Hz, 1H), 4.91–4.89 (d,
J = 11.0 Hz, 1H), 4.86 (d, J = 1.5 Hz, 1H), 4.56–4.54
(d, J = 12.0 Hz, 1H), 4.52–4.50 (d, J = 11.5 Hz, 1H),
4.48–4.45 (d, J = 11.0 Hz, 1H), 3.93–3.90 (dd, J = 4.0,
10.0 Hz, 1H), 3.89–3.87 (t, J = 8.0 Hz, 1H), 3.65–3.62
(dd, J = 7.0, 10.5 Hz, 1H), 3.47–3.44 (m, 1H), 3.38–
3.36 (dd, J = 3.0, 8.5 Hz, 1H), 2.40 (s, 3H), 2.09 (br s,
2H), 1.99 (br s, 2H), 1.74–1.72 (d, J = 12.0 Hz, 2H),
1.69–1.66 (d, J = 11.5 Hz, 2H), 1.62–1.51 (m, 6H),
1.44–1.42 (d, J = 11.5 Hz, 2H); 13C NMR d: 143.7,
138.7, 137.8, 135.4, 129.2, 128.2, 128.1, 128.0, 127.5,
127.3, 91.0 (1JCH = 155.5 Hz), 79.4, 78.5, 76.5, 75.0,
74.7, 73.1, 72.3, 70.3, 65.9, 42.6, 42.2, 36.2, 36.1, 30.8,
30.6, 29.6, 21.5; FABHRMS Calcd for C37H43O8S
[MÀH]+: 647.2678. Found 647.2672.
3.15. Methyl 4-O-[4-O-acetyl-3,6-di-O-benzyl-2-O-(2-
trifluoromethylbenzenesulfonyl)-a-D-mannopyranosyl]-
2,3-O-isopropylidene-a-L-rhamnopyranoside 29a and the
b-mannosyl anomer 29b
Coupling of 24–28, with a 1 h activation period, gave
29a and 29b in 7% and 68% yield, respectively. 29a:
24
D
1
½aŠ ¼ þ2:4 (c 0.1, CHCl3); H NMR d: 8.21–8.19 (d,
J = 8.0 Hz, 1H), 7.70–7.69 (d, J = 7.5 Hz, 1H), 7.54–
7.50 (t, J = 7.0 Hz, 1H), 7.44–7.41 (t, J = 8.0 Hz, 1H),
7.34–7.26 (m, 8H), 7.08–7.06 (m, 2H), 5.42–5.38 (t,
J = 10.0 Hz, 1H), 5.24 (d, J = 1.5 Hz, 1H), 4.97–4.96
(dd, J = 2.0, 3.0 Hz, 1H), 4.84 (s, 1H), 4.58–4.56 (d,
J = 11.5 Hz, 1H), 4.46–4.43 (d, J = 12.0 Hz, 1H), 4.36–
4.34 (d, J = 12.5 Hz, 1H), 4.31–4.28 (d, J = 12.5 Hz,
1H), 4.12–4.04 (m, 3H), 3.84–3.81 (dd, J = 2.5,
10.0 Hz, 1H), 3.66–3.62 (dd, J = 6.5, 10.5 Hz, 1H),
3.58–3.56 (m, 2H), 3.44–3.40 (dd, J = 7.0, 10.0 Hz,
1H), 3.38 (s, 3H), 1.84 (s, 3H), 1.49 (s, 3H), 1.32–1.31
(s, J = 7.0 Hz, 3H), 1.27 (s, 3H); 13C NMR d: 169.5,
138.0, 137.3, 133.4, 131.9, 131.7, 128.3, 128.2, 128.1,
128.0, 127.9, 127.6, 127.5, 127.3, 109.4, 98.1
(1JCH = 173.4 Hz), 97.9 (1JCH = 169.6 Hz), 80.8, 76.7,
76.6, 75.9, 74.3, 73.6, 71.9, 69.9, 69.3, 68.3, 64.6, 54.9,
27.9, 26.3, 20.8, 17.4; ESI-HRMS Calcd for
3.14. Methyl 2,3,6-tri-O-benzyl-4-O-[3,6-di-O-benzyl-2-
O-(p-toluenesulfonyl)-a-D-mannopyranosyl]-a-D-gluco-
pyranoside 27a and the b-manno-isomer 27b
Coupling of 21 with to alcohol 26, with a 20 min activa-
tion period, gave 27a and 27b in 51% and 26% yield,
25
D
respectively. 27a: ½aŠ ¼ À7:0 (c 1.5, CHCl3); 1H
NMR d: 7.60–7.58 (d, J = 6.5 Hz, 2H), 7.44–7.43 (d,
J = 7.0 Hz, 2H), 7.39–7.36 (t, J = 7.5 Hz, 2H), 7.32–
7.26 (m, 19H), 7.16–7.14 (d, J = 7.5 Hz, 2H), 7.01–6.99
(d, J = 8.0 Hz, 2H), 5.37 (d, J = 2.0 Hz, 1H), 5.04–5.02

114
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
C39H45F3O13SNa [M+Na]+: 833.2431. Found 833.2430.
1H), 3.83–3.80 (t, J = 9.5 Hz, 1H), 3.73–3.71 (dd,
J = 2.5, 11.0 Hz, 1H), 3.62–3.57 (m, 2H), 3.53–3.49 (t,
J = 9.5 Hz, 1H), 3.41–3.36 (br s, 5H), 3.26–3.23 (m,
2H), 3.20–3.18 (dd, J = 3.0, 9.5 Hz, 1H), 1.83 (s, 3H);
13C NMR d: 169.5, 139.5, 138.3, 138.2, 137.8, 137.3,
136.7, 132.9, 131.8, 131.2, 128.6, 128.4, 128.3, 128.2,
128.1, 128.08, 128.03, 128.0, 127.94, 127.9, 127.8,
127.7, 127.6, 127.4, 127.2, 127.1, 98.5 (1JCH = 163.4 Hz),
97.8 (1JCH = 155.1 Hz), 79.9, 78.7, 78.3, 78.1, 77.3, 75.1,
73.9, 73.64, 73.61, 73.5, 71.5, 70.2, 69.2, 68.7, 68.5, 55.3,
20.8; ESI-HRMS Calcd for C57H59F3O14SNa [M+Na]+:
1079.3476. Found 1079.3439.
24
D
29b: ½aŠ ¼ À61:5 (c 1.2, CHCl3); 1H NMR d: 8.18–8.17
(d, J = 7.5 Hz, 1H), 7.77–7.75 (d, J = 6.5 Hz, 1H), 7.56–
7.48 (m, 2H), 7.34–7.24 (m, 8H), 7.19–7.13 (m, 2H), 5.27
(d, J = 3.0 Hz, 1H), 5.16–5.12 (t, J = 9.5 Hz, 1H), 5.02
(s, 1H), 4.82 (s, 1H), 4.57–4.55 (d, J = 12.0 Hz, 1H),
4.54–4.52 (d, J = 12.0 Hz, 1H), 4.51–4.49 (d,
J = 11.5 Hz, 1H), 4.35–4.33 (d, J = 12.0 Hz, 1H), 4.06–
4.05 (dd, J = 2.5, 5.5 Hz, 2H), 3.63–3.55 (m, 4H),
3.51–3.48 (m, 1H), 3.35 (s, 3H), 3.27–3.24 (dd, J = 6.0,
10.0 Hz, 1H), 1.87 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H),
1.14–1.13 (d, J = 6.5 Hz, 3H); 13C NMR d: 169.5,
137.9, 137.1, 132.8, 131.7, 131.2, 128.33, 128.29,
128.25, 128.22, 127.9, 127.9, 127.7, 127.5, 109.5, 97.6
(1JCH = 169.4 Hz), 96.1 (1JCH = 159.1 Hz), 78.2, 78.0,
77.9, 76.5, 76.0, 74.1, 73.6, 71.4, 69.9, 68.6, 63.8, 54.7,
27.9, 26.4, 20.8, 17.2; ESI-HRMS Calcd for
C39H45F3O13SNa [M+Na]+: 833.2431. Found 833.2433.
3.17. S-Phenyl 3,4-di-O-benzyl-2-O-(3-ethoxycarbonyl-1-
E-vinyl)-thio-b-L-rhamnopyranoside 32
To alcohol 31 (0.36 g, 0.82 mmol) in CH2Cl2 (7 mL) N-
methyl morpholine (0.14 mL, 1.2 mmol) was added fol-
lowed by ethyl propiolate (0.13 mL, 1.2 mmol), after
which the reaction mixture was stirred for 4 h. Concen-
tration followed by column chromatography afforded 32
3.16. Methyl 2,3,6-tri-O-benzyl-4-O-[4-O-acetyl-3,6-di-
O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-a-D-
mannopyranosyl]-a-D-glucopyranoside 30a and the
b-mannosyl anomer 30b
25
D
1
(0.28 g, 64%). ½aŠ ¼ þ36:2 (c 0.9, CHCl3); H NMR d:
7.57–7.54 (d, J = 11.2 Hz, 1H), 7.48–7.29 (m, 15H),
5.55–5.52 (d, J = 12.4 Hz, 1H) 4.87 (d, J = 10.0 Hz,
1H), 4.77 (s, 1H), 4.72 (s, 2H), 4.64 (d, J = 10.8 Hz,
1H), 4.35 (d, J = 2.4 Hz, 1H), 4.24–4.16 (m, 2H), 3.63
(dd, J = 3.2, 9.6 Hz, 1H), 3.54 (t, J = 9.2 Hz, 1H),
3.44–3.37 (m, 1H), 1.40 (d, J = 5.6 Hz, 3H), 1.29 (t,
J = 7.6 Hz, 3H); 13C NMR d: 167.8, 163.4, 137.9,
137.3, 134.1, 131.3, 129.1, 128.9, 128.6, 128.4, 128.3,
128.2, 128.18, 128.1, 127.97, 127.91, 127.7, 124.8, 98.6,
85.7, 82.7, 81.8, 79.5, 76.3, 75.7, 73.1, 59.8, 18.1, 14.5;
ESIHRMS Calcd for C31H34O6NaS [M+Na]+:
557.1974. Found: 557.1987.
Coupling of 24–26, with a 1 h activation period, gave
30a and 30b in 25% and 51% yield, respectively. 30a:
½aŠ ¼ À2:9 (c 1.9, CHCl3); H NMR d: 7.63–7.61 (d,
24
D
1
J = 8.0 Hz, 1H), 7.43–7.35 (m, 6H), 7.32–7.19 (m,
20H), 6.92–6.90 (m, 2H), 5.46 (d, J = 2.5 Hz, 1H),
5.18–5.14 (t, J = 10.0 Hz, 1H), 5.06–5.04 (d,
J = 11.5 Hz, 1H), 5.01–5.00 (t, J = 3.0 Hz, 1H), 4.79–
4.77 (d, J = 11.5 Hz, 1H), 4.67–4.65 (d, J = 12.0 Hz,
1H), 4.58–4.57 (d, J = 3.5 Hz, 1H), 4.55–4.52 (d,
J = 12.5 Hz, 1H), 4.54–4.52 (d, J = 12.0 Hz, 1H), 4.47–
4.45 (d, J = 11.5 Hz, 1H), 4.44–4.41 (d, J = 12.0 Hz,
1H), 4.43–4.40 (d, J = 11.5 Hz, 1H), 4.08–4.05 (d,
J = 11.5 Hz, 1H), 4.04–4.01 (d, J = 11.5 Hz, 1H), 3.94–
3.92 (m, 1H), 3.87–3.85 (dd, J = 2.5, 7.0 Hz, 2H),
3.83–3.80 (dd, J = 4.5, 11.0 Hz, 1H), 3.79–3.77 (dd,
J = 3.0, 9.5 Hz, 1H), 3.70–3.69 (m, 1H), 3.66–3.64 (dd,
J = 2.0, 11.0 Hz, 1H), 3.56–3.53 (m, 1H), 3.52–3.49
(dd, J = 5.5, 10.5 Hz, 1H), 3.46–3.43 (dd, J = 3.5,
11.0 Hz, 1H), 3.38 (s, 3H), 1.84 (s, 3H); 13C NMR d:
169.5, 138.7, 138.0, 137.9, 137.8, 137.2, 133.1, 131.7,
131.3, 129.0, 128.8, 128.5, 128.4, 128.3, 128.26, 128.22,
128.19, 128.15, 128.1, 127.97, 127.9, 127.8, 127.7,
127.6, 127.5, 127.3, 127.1, 126.9, 99.6 (1JCH = 172.0 Hz),
97.9 (1JCH = 167.0 Hz), 80.6, 79.9, 78.1, 74.9, 74.4, 73.5,
73.3, 71.5, 71.2, 69.9, 69.8, 68.9, 68.2, 68.1, 55.3, 20.8;
ESI-HRMS ESI-HRMS Calcd for C57H59F3O14SNa
[M+Na]+: 1079.3476. Found 1079.3464. 30b:
3.18. S-Phenyl 3,4-di-O-benzyl-2-O-[bis(2,2,2-trichloro-
ethyl)phosphoryl]-thio-b-L-rhamnopyranoside 33
To a stirred solution of 31 (0.22 g, 0.50 mmol) in
CH2Cl2 (6 mL) at 0 °C Et3N (0.22 mL, 1.5 mmol) was
added followed by bis(2,2,2-trichloroethyl) phosphoro-
chloridate (0.38 g, 1.0 mmol). The reaction mixture
was stirred for 3 h at 0 °C, then was quenched by addi-
tion of saturated aqueous NaHCO3, and extracted with
CH2Cl2. The combined organic layers were washed with
brine and dried, and the solvent removed. Column chro-
matography (hexanes/ethyl acetate, 8:1) afforded 33
25
1
(0.33 g, 85%) ½aŠ ¼ þ47:2 (c 0.6, CHCl3); H NMR d:
D
7.53–7.29 (m, 15H), 5.31–5.29 (dd, J = 9.0, 3.0 Hz,
1H), 4.96–4.94 (d, J = 10.5 Hz, 1H), 4.93–4.91 (d,
J = 11.0 Hz, 1H), 4.87–4.83 (dd, J = 6.5, 11.0 Hz, 1H),
4.80 (d, J = 2.5 Hz, 1H), 4.77–4.74 (dd, J = 6.0,
11.0 Hz, 1H), 4.68–4.65 (d, J = 11.0 Hz, 1H), 4.63–4.60
(d, J = 10.5 Hz, 1H), 4.55–4.52 (dd, J = 6.0, 11.5 Hz,
1H), 4.42–4.38 (dd, J = 5.5, 11.0 Hz, 1H), 3.65–3.63
(ddd, J = 1.0, 3.0 and 9.5 Hz, 1H), 3.52–3.48 (t,
J = 9.5 Hz, 1H), 3.44–3.41 (m, 1H), 1.39 (d,
J = 6.0 Hz, 3H); 13C NMR d: 138.2, 137.2, 134.0,
132.1, 129.6, 129.2, 129.0, 128.9, 128.7, 128.5, 128.3,
95.14 (d, J = 17.0 Hz), 86.2 (d, J = 6.25 Hz), 82.0, 79.1,
78.7 (d, J = 5.0 Hz), 77.7, 76.8, 76.1, 73.3, 30.1, 18.6.
24
D
1
½aŠ ¼ À15:8 (c 0.3, CHCl3); H NMR d: 8.12–8.11 (d,
J = 8.0 Hz, 1H), 7.75–7.73 (d, J = 8.0 Hz, 1H), 7.55–
7.52 (t, J = 7.5 Hz, 1H), 7.44–7.41 (t, J = 8.0 Hz, 1H),
7.34–7.19 (m, 23H), 7.11–7.10 (d, J = 8.0 Hz, 2H),
5.09–5.06 (t, J = 9.5 Hz, 1H), 4.99–4.98 (d, J = 3.0 Hz,
1H), 4.77–4.75 (d, J = 13.0 Hz, 1H), 4.76–4.74 (d,
J = 10.5 Hz, 1H), 4.71–4.69 (d, J = 12.0 Hz, 1H), 4.60–
4.58 (d, J = 12.5 Hz, 1H), 4.54–4.53 (d, J = 3.5 Hz,
1H), 4.50–4.49 (d, J = 4.5 Hz, 1H), 4.47–4.46 (d,
J = 3.0 Hz, 1H), 4.45 (s, 1H), 4.41–4.39 (d,
J = 12.0 Hz, 1H), 4.32–4.29 (d, J = 12.0 Hz, 1H), 4.25–
4.23 (d, J = 12.5 Hz, 1H), 4.14–4.12 (d, J = 11.0 Hz,

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
115
Anal. Calcd for C30H31Cl6O7 PS: C, 46.24 H, 4.01.
Found: C, 46.51 H, 4.15.
J = 6.0, 9.5 Hz, 1H), 1.41 (d, J = 6.0 Hz, 3H); 13C
NMR: 156.0, 138.3, 138.6, 134.1, 131.5, 129.1, 128.5,
128.4, 128.1, 127.9, 127.8, 127.7, 85.6, 81.3, 71.4, 76.2,
75.6, 71.8, 71.2, 18.3; ESIHRMS Calcd for C27H29NO5-
NaS [M+Na]+ 502.1664. Found 502.1650.
3.19. S-Phenyl 3,4-di-O-benzyl-2-O-cyano-thio-b-L-
rhamnopyranoside 34
To a solution of 31 (0.30 g, 0.69 mmol) in toluene
(7 mL) was added KHMDS (0.5 M solution in toluene,
2.4 mL) at À78 °C. Cyanogen bromide (0.11 g,
1.03 mmol in 2.8 mL of toluene) was then added over
1 h via syringe pump. The reaction mixture was then al-
lowed to slowly warm to rt and was then stirred for 36 h
before it was quenched with saturated aqueous NaH-
CO3 and extracted with EtOAc. The combined organic
layer was dried, concentrated, and purified by column
chromatography (hexanes/ethyl acetate, 9:1) to give 35
as a white solid (112 mg, 0.24 mmol, 35%). Alterna-
tively, 34 was obtained by dehydration of 35: To a stir-
red solution at À20 °C of 35 (430 mg, 0.90 mmol), PPh3
(590 mg, 2.25 mmol), and Et3N (250 lL, 1.80 mmol) in
CH2Cl2 (15 mL) was added dropwise a solution of
CBr4 (895 mg, 2.70 mmol) in CH2Cl2 (5 mL). The resul-
tant solution was stirred À20 °C for 3 h then concen-
trated. The crude product was triturated by addition
of hexanes/CH2Cl2 (10:1, 22 mL) then filtered. Concen-
tration of the filtrate and chromatographic purification
3.21. (3b-Cholestanyl) 3,4-di-O-benzyl-2-O-(3-ethoxy-
carbonyl-1-E-vinyl)-a-L-rhamnopyranoside 36a and the
b-anomer 36b
Coupling of 32 to 3b-cholestanol, with a 20 min activa-
tion, gave 36a and 36b, both in 24% yield. 36a:
25
D
½aŠ ¼ À15:1 (c 0.7, CHCl3); 1H NMR d: 7.51–7.30
(m, 11H), 5.37–5.34 (d, J = 12.4 Hz, 1H), 4.94 (s, 1H),
4.88–4.86 (d, J = 11.2 Hz, 1H), 4.69 (s, 2H), 4.62–4.59
(d, J = 11.2 Hz, 1H), 4.22–4.14 (m, 2H), 3.98–3.95 (dd,
J = 2.8, 9.6 Hz, 1H), 3.84–3.77 (m, 1H), 3.56–3.44 (m,
2H), 1.98–0.59 (m, 53H); 13C NMR d: 166.1, 160.2,
138.0, 137.1, 133.2, 132.4, 129.7, 129.1, 128.9, 128.8,
128.7, 128.6, 128.5, 99.9, 88.9, 84.5, 80.9, 79.0, 76.8,
76.3, 73.3, 56.9, 56.7, 54.8, 45.3, 43.0, 40.5, 39.9, 37.3,
36.6, 35.8, 35.6, 35.5, 33.9, 32.0, 29.1, 28.8, 28.3, 28.0,
24.2, 23.8, 22.8, 22.6, 21.3, 18.7, 17.7, 12.4, 12.1. 36b:
25
D
½aŠ ¼ þ32:4 (c 0.6, CHCl3); 1H NMR d: 7.52–7.29
(m, 11H), 5.36 (d, J = 12.3 Hz, 1H), 4.87 (d,
J = 11.0 Hz, 1H), 4.78 (s, 1H), 4.69 (s, 2H), 4.62 (d,
J = 11.2 Hz, 1H), 4.22–4.18 (m, 2H), 3.98 (dd, J = 3.0,
10.0 Hz, 1H), 3.86–3.80 (m, 1H), 3.56–3.44 (m, 2H),
1.98–0.58 (m, 53H); 13C NMR d: 166.1, 160.1, 138.0,
137.1, 133.2, 132.4, 129.7, 129.1, 128.9, 128.8, 128.7,
128.6, 128.5, 99.9, 91.4, 84.5, 80.9, 79.0, 76.7, 76.3,
73.3, 56.7, 56.7, 54.8, 45.3, 43.0, 40.5, 39.9, 37.3, 36.6,
35.8, 35.6, 35.5, 33.9, 32.0, 29.1, 28.8, 28.3, 28.0, 24.2,
23.8, 22.8, 22.6, 21.3, 18.7, 17.7, 12.4, 12.1.
(eluting with 25% EtOAc in hexanes) afforded 34
25
D
(233 mg, 0.51 mmol, 56%). ½aŠ ¼ þ38:4 (c 0.6, CHCl3);
1
mp 112 °C; H NMR d: 7.50–7.28 (m, 15H), 4.95 (d,
J = 3.0 Hz, 1H), 4.90 (d, J = 11.0 Hz, 1H), 4.87 (d,
J = 11.5 Hz, 1H), 4.73 (s, 1H), 4.70 (d, J = 11.5 Hz,
1H), 4.65 (d, J = 11.0 Hz, 1H), 3.70 (dd, J = 3.0,
9.0 Hz, 1H), 3.51 (t, J = 9.5 Hz, 1H), 3.40–3.34 (m,
1H), 1.37 (d, J = 6.5 Hz, 3H); 13C NMR d: 138.0,
137.1, 133.2, 132.4, 129.7, 129.1, 128.9, 128.8, 128.7,
128.6, 128.5, 113.4, 88.9, 84.5, 80.9, 79.0, 76.8, 76.3,
73.3, 18.4. IR(thin film) m (cmÀ1) 2235; ESIHRMS
Calcd for C27H27NO4NaS [M+Na]+: 484.1559. Found:
484.1563.
3.22. (3b-Cholestanyl) 3,4-di-O-benzyl-2-O-[bis(2,2,2-tri-
chloroethyl)phosphoryl]-a-L-rhamnopyranoside 37a and
the b-anomer 37b
Coupling of 33 to 3b-cholestanol, with a 20 min activa-
tion, gave 37a and 37b in 20% and 53% yield, respec-
tively. 37a: ½aŠ ¼ À14:8 (c 0.8, CHCl3); H NMR d:
25
D
1
3.20. S-Phenyl 3,4-di-O-benzyl-2-O-carbamoyl-thio-b-L-
rhamnopyranoside 35
7.57–7.31 (m, 10H), 5.10 (d, J = 1.5 Hz, 1H), 4.93–4.92
(d, J = 6.5 Hz, 1H), 4.91–4.89 (m, 1H), 4.87–4.85 (d,
J = 11.5 Hz, 1H), 4.66 (dd, J = 5.0, 10.0 Hz, 1H), 4.61
(d, J = 6.5 Hz, 2H), 4.56–4.52 (dd, J = 6.5, 11.0 Hz,
1H), 4.45–4.42 (dd, J = 5.5, 11.0 Hz, 1H), 3.99–3.96
(m, 1H), 3.87–3.81 (m, 1H), 3.58–3.53 (m, 1H), 3.48–
3.44 (t, J = 9.5 Hz, 1H), 1.98–0.58 (m, 50H); 13C
NMR d: 143.3, 138.5, 137.9, 137.0, 135.8, 134.0, 131.9,
131.8, 129.8, 129.7, 129.3, 129.2, 128.9, 128.9, 128.7,
128.5, 128.4, 128.3, 128.2, 127.9, 124.7, 95.9 (d,
J = 5.1 Hz), (JCH = 170.3 Hz), 95.1 (q, J = 8.1 Hz,
J = 4.0 Hz), 80.2, 78.8–78.7 (d, J = 3.0 Hz), 77.6–77.6
(d, J = 3.5 Hz), 77.5, 77.0, 76.5–76.5 (d, J = 5.4 Hz),
76.0, 73.0, 56.8, 56.6, 54.7, 45.0, 43.0, 40.4, 39.9, 37.4,
36.6, 36.2, 35.9, 35.9, 34.5, 32.4, 29.5, 29.2, 28.6, 28.4,
24.6, 24.2, 23.2, 23.0, 21.6, 19.1, 18.2, 12.7, 12.5; ESI-
To a stirred solution at 0 °C of 31 (500 mg, 1.15 mmol)
in CH2Cl2 (10 mL) was added Cl3CC(O)NCO (275 lL,
2.30 mmol). The resulting solution was stirred for
30 min then concentrated. The residue was dissolved in
MeOH (20 mL) and H2O (2 mL) and cooled to 0 °C be-
fore addition of K2CO3 (477 mg, 3.45 mmol), followed
by stirring for 1 h at 0 °C, then 1 h at rt. The reaction
mixture was then concentrated, diluted with water
(10 mL), and extracted with CH2Cl2. The combined or-
ganic layers were washed with brine, dried, and concen-
trated. Purification by flash column chromatography
(40% EtOAc in Hexanes) then yielded pure 35
25
(550 mg, >99%). ½aŠ ¼ þ62:6 (c 1.0, CHCl3); mp 140–
D
1
142 °C; mmax (KBr)/cmÀ1 1731; H NMR d: 7.53–7.49
(m, 2H), 7.35–7.26 (m, 13H), 5.69 (dd, J = 1.0, 3.5 Hz,
1H), 4.94 (br s, 2H), 4.92 (d, J = 10.5 Hz, 1H), 4.87 (d,
J = 11.0 Hz, 1H), 4.84 (d, J = 5.1 Hz, 1H), 4.63 (d,
J = 10.5 Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 3.65 (dd,
J = 3.5, 9.0 Hz, 1H), 3.50 (t, J = 9.5, 1H), 3.42 (dq,
HRMS Calcd for C51H73Cl6O8NaP [M+Na]+:
25
1077.3072 Found: 1077.3069. 37b: ½aŠ ¼ þ29:7 (c 0.8,
D
CHCl3), 1H NMR d: 7.46–7.29 (m, 10H), 5.04 (dd,
J = 3.0, 9.5 Hz, 1H), 4.94 (d, J = 11.0 Hz, 2H), 4.81–
4.77 (dd, J = 6.0, 11.0 Hz, 1H), 4.75–4.71 (dd, J = 6.0,

116
D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
10.5 Hz, 1H), 4.67–4.65 (d, J = 11.0 Hz, 1H), 4.62–4.60
(m, 2H), 4.59–4.58 (d, J = 11.5 Hz, 1H), 4.42–4.39 (dd,
J = 5.5, 11.0 Hz, 1H), 3.68–3.60 (m, 2H), 3.43–3.33 (t,
J = 9.0 Hz, 1H), 3.37–3.34 (m, 1H), 1.99–0.59 (m,
50H); 13C NMR d: 138.3, 137.5, 128.9, 128.9, 128.8,
128.6, 128.5, 128.4, 96.8–96.8 (d, J = 3.5 Hz),
(JCH = 153.5 Hz), 95.4 (d, J = 13.6 Hz), 81.0, 79.4,
78.9, 77.4–77.3 (d, J = 4.8 Hz), 76.8–76.8 (d,
J = 6.4 Hz), 75.9, 72.6, 72.0, 56.9, 56.7, 54.7, 45.3,
43.0, 40.4, 39.9, 37.2, 36.5, 36.2, 35.9, 35.9, 32.4, 29.0,
28.6, 28.4, 28.3, 24.6, 24.2, 23.2, 23.0, 21.6, 19.1, 18.4,
12.7, 12.5. Anal. Calcd for C51H73Cl6O8P: C, 57.91 H,
6.96. Found: C, 58.20 H, 6.97.
(d, J = 3.5 Hz, 1H), 4.34 (d, J = 2.5 Hz, 1H), 4.12–4.08
(m, 4H), 3.94–3.91 (m, 1H), 3.42 (dd, J = 3.0, 9.5 Hz,
1H), 3.41 (t, J = 9.5 Hz, 1H), 1.50 (s, 3H), 1.37 (s,
3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.24 (d, J = 6.6 Hz,
3H); 13C NMR d: 138.2, 137.0, 128.6, 128.4, 128.3,
127.7, 127.6, 112.5, 112.3, 109.4, 105.2, 93.4
(JCH = 170.0 Hz), 85.7, 81.5, 80.8, 78.9, 77.4, 77.2,
75.3, 73.0, 71.8, 68.6, 68.0, 26.8, 26.7, 26.2, 25.2, 17.3;
ESIHRMS Calcd for C33H41NO10Na [M+Na]+
634.2628, found 634.2629.
3.26. S-Phenyl 3,4-di-O-benzyl-2-O-(2-naphthylmethyl)-
b-L-thiorhamnopyranoside 42
3.23. (3b-Cholestanyl) 3,4-di-O-benzyl-2-O-cyano-b-L-
rhamnopyranoside 38
To a stirred solution of 31 (2.00 g, 4.58 mmol) in THF
(30 mL) at 0 °C was added NaH (60% in mineral oil,
367 mg, 9.2 mmol). After 10 min stirring, NapCH2Br
(1.52 g, 6.9 mmol) was added, and the solution was
heated to reflux and stirred for 14 h. Addition of NH4Cl
(satd. aq.) was followed by extraction with EtOAc, and
the combined organic extracts were then washed with
brine, dried, then concentrated. Purification by flash col-
Coupling of 34 to 3b-cholestanol, with a 20 min activa-
25
tion, gave 38 in 42% yield. ½aŠ ¼ þ28:7 (c 0.5, CHCl3);
D
1H NMR d: 7.43–7.26 (m, 10H), 4.90 (d, J = 11.0 Hz,
1H), 4.83 (d, J = 11.5 Hz, 1H), 4.70–4.66 (m, 2H), 4.63
(d, J = 11.0 Hz, 1H), 4.60 (s, 1H), 3.66–3.56 (m, 1H),
3.64 (dd, J = 2.7, 9.0, 1H), 3.43–3.38 (t, J = 9.2 Hz,
1H), 3.34–3.27 (m, 1H), 1.97–0.56 (m, 50H); 13C NMR
d: 138.7, 138.4, 128.3, 128.1, 127.5, 127.4, 113.1, 97.6
(JCH = 154.2 Hz), 80.7, 80.3, 75.7, 75.5, 75.4, 72.8,
72.1, 67.9, 45.3, 43.0, 40.5, 39.9, 37.3, 36.6, 35.8, 35.6,
35.5, 33.9, 32.0, 29.1, 28.8, 28.3, 28.0, 24.2, 23.8, 22.8,
22.6, 21.2, 18.7, 18.0, 12.2, 12.1; ESIHRMS Calcd for
C48H69NO5Na [M+Na]+: 762.5073. Found: 762.5077.
umn chromatography (20% EtOAc in hexanes) afforded
25
D
pure 42 (2.08 g, 79%). ½aŠ ¼ þ18:9 (c 1.0, CHCl3); mp
1
98–100 °C; H NMR d: 7.89–7.80 (m, 4H), 7.69–7.65
(m, 1H), 7.50–7.45 (m, 4H), 7.38–7.21 (m, 13H), 5.19
(d, J = 11.5 Hz, 1H), 5.06 (d, J = 11.5 Hz, 1H), 4.96
(d, J = 10.5 Hz, 1H), 4.76–4.69 (m, 4H), 4.20 (d,
J = 2.0 Hz, 1H), 3.76 (t, J = 9.0 Hz, 1H), 3.61 (dd,
J = 3.0, 9.5 Hz, 1H), 3.42–3.39 (m, 1H), 1.41 (d,
J = 6.0 Hz, 3H); 13C NMR d: 135.8, 135.6, 133.2,
133.1, 130.8, 128.9, 128.5, 128.4, 128.2, 128.0, 127.9,
127.8, 127.7, 127.6, 127.1, 127.0, 126.7, 125.9, 125.8,
87.6, 84.2, 79.9, 77.6, 76.3, 75.6, 75.1, 72.7, 18.3. Anal.
Calcd for C37H36O4S: C, 77.05; H, 6.29. Found: C,
77.18; H, 6.29.
3.24. Methyl 4-O-[3,4-di-O-benzyl-2-O-cyano-a-L-
rhamnopyranosyl]-2,3-O-isopropylidene-a-L-rhamnopyr-
anoside 39
Coupling of 34 to rhamnoside 28, with 20 min activa-
25
tion, gave 39 in 19% yield. ½aŠ ¼ À40:9 (c 0.8, CHCl3);
D
1
mmax (thin film)/cmÀ1 2235, 1092; H NMR d: 7.46–7.41
(m, 2H), 7.39–7.26 (m, 8H), 5.49 (d, J = 2.0 Hz, 1H),
4.87 (d, J = 11.0 Hz, 1H), 4.85 (s, 1H), 4.82 (d,
J = 11.5 Hz, 1H), 4.76 (t, J = 2.2 Hz, 1H), 4.69 (d,
J = 11.5 Hz, 1H), 4.62 (d, J = 11.0 Hz, 1H), 4.10 (d,
J = 5.5 Hz, 1H), 4.04 (dd, J = 1.5, 5.5 Hz, 1H), 3.90
(dd, J = 3.0, 9.0 Hz, 1H), 3.76–3.73 (m, 1H), 3.61–3.57
(m, 1H), 3.45 (t, J = 9.5 Hz, 1H), 3.43 (t, J = 9.5 Hz,
1H), 3.37 (s, 3H), 1.64 (s, 3H), 1.35 (s, 3H), 1.28 (d,
J = 6.5 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR d:
137.8, 137.1, 128.6, 128.5, 128.2, 128.0, 112.6, 109.6,
97.9, 95.5 (JCH = 173.7), 85.8, 79.3, 79.0, 78.1, 77.5,
76.1, 75.8, 72.8, 68.6, 63.6, 55.0, 27.9, 26.3, 17.8, 17.6;
FABHRMS Calcd for C31H39NO9Na [M+Na]+
592.2522. Found 592.2465.
3.27. 3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-a-L-
rhamnopyranosyl fluoride 43
To a stirred solution of 42 (1.5 g, 2.60 mmol) in CH2Cl2
(10 mL) at rt was added dropwise DAST (515 lL,
3.90 mmol), and the solution cooled to À78 °C and stir-
red for 10 min before the addition of NBS (602 mg,
3.38 mmol). The solution was stirred and allowed to
warm to rt over 6 h. The reaction mixture was then di-
luted with CH2Cl2 (20 mL), poured into NaHCO3 (satd.
aq.) and the organic layer washed with NaHCO3 (satd.
aq.) then NaCl (satd. aq.). The organic extracts were
dried then concentrated. Purification by flash column
chromatography (10% EtOAc in hexanes) afforded 43
25
D
1
(1.08 g, 86%). ½aŠ ¼ À18:0 (c 0.4, CHCl3); H NMR
d: 7.88–7.78 (m, 4H), 7.55–7.50 (m, 3H), 7.37–7.34 (m,
10H), 5.54 (dd, J = 1.8, 50.7 Hz, 1H), 4.99 (d,
J = 10.5 Hz, 1H), 4.98 (d, J = 12.3 Hz, 1H), 4.87
(d, J = 12.3 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.69
(d, J = 10.5 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1H), 3.93–
3.85 (m, 3H), 3.73 (t, J = 9.5 Hz, 1H), 1.40 (d,
J = 6.3 Hz, 3H); 13C NMR d: 138.4, 138.3, 135.3,
133.3, 133.2, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0,
127.9, 127.8, 127.1, 126.4, 126.3, 126.1, 106.0 (d,
J = 221.6 Hz, JCH = 183.2 Hz), 79.7, 79.2, 77.3, 75.5,
73.7, 73.4, 72.8, 70.6, 18.1; 19F NMR d: À64.71 (d,
3.25. 3-O-(3,4-Di-O-benzyl-2-O-cyano-a-L-rhamnopyr-
anosyl)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose 41
Coupling of 35 to acceptor 40, with 20 min activation,
25
gave the a-glycoside 41 in 21% yield. ½aŠ ¼ À52:4 (c
D
1.8, CHCl3); mmax (thin film)/cmÀ1 2236, 1075;
1H NMR d: 7.32–7.25 (m, 10H), 5.86 (d, J = 3.5 Hz,
1H), 5.14 (d, J = 1.5 Hz, 1H), 4.87 (d, J = 11.0 Hz, 1H),
4.77 (d, J = 11.5 Hz, 1H), 4.69 (d, J = 11.5 Hz, 1H),
4.63 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 3.0 Hz, 1H), 4.50

D. Crich et al. / Tetrahedron: Asymmetry 16 (2005) 105–119
117
J = 50.7 Hz); ESIHRMS Calcd for C31H31FO4Na
with CH2Cl2 and washing of the combined organic ex-
tracts with brine, followed by drying and concentration
gave the crude product mixture. Purification by flash
column chromatography (10% EtOAc in hexanes)
[M+Na]+ 509.2104. Found 509.2122.
3.28. 3,4-Di-O-benzyl-a-L-rhamnopyranosyl fluoride 44
yielded 46a (28 mg, 29%) and 46b (30 mg, 31%). 46a:
25
To a stirred solution of 43 (50 mg, 0.10 mmol) in
CH2Cl2 (2 mL) and H2O (0.2 mL) at rt was added
DDQ (35 mg, 0.16 mmol), and the resultant solution
was stirred for 5 h. Addition of NaHCO3 (satd. aq.)
was followed by extraction with CH2Cl2, and the com-
bined organic extracts were dried, then concentrated to
yield the crude product. Purification by flash column
½aŠ ¼ À8:4 (c 0.5, CHCl3); mp 124–126 °C; mmax
D
(KBr)/cmÀ1 1633, 1279, 861, 737, 694; 1H NMR
d: 7.35–7.26 (m, 10H), 5.34 (dd, J = 1.5, 1.5 Hz, 1H),
5.02 (d, J = 1.5 Hz, 1H), 4.88 (d, J = 10.5 Hz,
1H), 4.70 (d, J = 11.5 Hz, 1H), 4.63 (d, J = 10.5 Hz,
1H), 4.60 (d, J = 10.5 Hz, 1H), 4.05 (dd, J = 3.0,
9.5 Hz, 1H), 3.84–3.74 (m, 1H), 3.58–3.50 (m, 1H),
3.41 (t, J = 9.5 Hz, 1H), 1.95–0.55 (m, 50H); 13C
NMR d: 138.2, 137.7, 128.5, 128.1, 127.9, 127.8, 94.0
(1JCH = 170.0 Hz), 80.1, 78.4, 77.9, 77.25, 76.6, 75.7,
72.6, 67.8, 56.5, 56.3, 54.3, 44.6, 42.6, 40.0, 39.5, 37.0,
36.2, 35.8, 35.6, 35.5, 34.0, 32.1, 31.6, 29.1, 28.8, 28.3,
28.1, 24.2, 23.9, 22.9, 22.7, 22.6, 21.2, 18.7, 17.8, 12.3,
chromatography (20% EtOAc in hexanes) afforded pure
25
D
44 (23 mg, 64%). ½aŠ ¼ À10:4 (c 1.0, CHCl3); 1H NMR
d: 7.36–7.26, (m, 10H), 5.58 (dd, J = 1.5, 49.0 Hz, 1H),
4.90 (d, J = 10.5 Hz, 1H), 4.74 (d, J = 11.5 Hz,
1H), 4.69 (d, J = 11.5 Hz, 1H), 4.66 (d, J = 10.5 Hz,
1H), 4.11–4.10 (m, 1H), 3.93–3.85 (m, 1H), 3.84 (dd,
J = 1.0, 3.5 Hz, 1H), 3.5 (t, J = 9.5 Hz, 1H), 2.62 (br s,
1H), 1.35 (d, J = 6.5 Hz, 3H); 13C NMR d: 138.1,
137.6, 128.7, 128.5, 128.2, 128.1, 128.0, 127.9, 107.0 (d,
J = 216.5 Hz, JCH = 181.3 Hz), 79.05, 78.9, 75.5, 72.5,
69.9, 67.6, 67.2, 17.8; 19F NMR d: À67.40 (d,
J = 49.0 Hz); ESIHRMS Calcd for C20H23FO4Na
[M+Na]+ 369.1478. Found 369.1465.
12.1; FABHRMS Calcd for C47H69NO7Na [M+Na]+
25
782.4972. Found 782.4916. 46b: ½aŠ ¼ þ31:1 (c 0.4,
D
CHCl3); mp 130–132 °C; mmax (KBr)/cmÀ1 1634, 1282,
876, 751, 696; 1H NMR d: 7.35–7.26 (m, 10H), 5.57
(d, J = 2.5 Hz, 1H), 4.89 (d, J = 10.5 Hz, 1H), 4.73 (d,
J = 11.5 Hz, 1H), 4.65 (d, J = 1.0 Hz, 1H), 4.62
(d, J = 10.5 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 3.69
(dd, J = 3.5, 9.5 Hz, 1H), 3.65–3.57 (m, 1H), 3.40 (t,
J = 9.5 Hz, 1H), 3.36–3.29 (m, 1H), 2.00–0.52 (m,
50H); 13C NMR d: 138.1, 137.2, 128.8, 128.6, 128.5,
128.2, 128.1, 127.9, 95.9 (1JCH = 156.0 Hz), 79.8, 79.7,
78.1, 77.9, 75.6, 72.2, 71.6, 56.5, 56.3, 54.4, 44.9, 40.1,
39.5, 36.8, 36.2, 35.8, 35.6, 35.5, 32.1, 28.7, 28.1, 28.3,
28.1, 27.6, 24.2, 23.9, 22.9, 22.6, 21.3, 18.7, 17.9, 12.3,
12.1; ESIHRMS Calcd for C47H69NO7Na [M+Na]+
782.4972, found 782.4942.
3.29. 3,4-Di-O-benzyl-2-O-nitro-a-L-rhamnopyranosyl
fluoride 45
To a stirred solution of 44 (285 mg, 0.82 mmol) in
CH2Cl2 (10 mL) at 0 °C was added 20 drops of a solu-
tion of Ac2O (2 mL) and HNO3 (0.1 mL), and the result-
ing solution was stirred for 3 h. Addition of NaHCO3
(satd. aq.) was followed by extraction with CH2Cl2,
and the combined organic extracts were dried, then con-
centrated to yield 45 (293 mg, 91%), which was used
25
without further purification. ½aŠ ¼ þ6:5 (c 1.0, CHCl3);
D
Acknowledgements
mmax (thin film)/cmÀ1 1651, 1279, 854, 746, 698; 1H
NMR d: 7.32–7.26 (m, 10H), 5.63 (dd, J = 1.5,
49.0 Hz, 1H), 5.45 (dd, J = 1.5, 1.5 Hz, 1H), 4.90
(d, J = 10.5 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.68
(d, J = 11.5 Hz, 1H), 4.64 (d, J = 10.5 Hz, 1H), 4.01
(ddd, J = 1.0, 2.5, 9.5 Hz, 1H), 3.93–3.90 (m, 1H), 3.47
(t, J = 9.5 Hz, 1H), 1.34 (d, J = 6.5 Hz, 3H); 13C NMR
d: 137.9, 137.2, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9,
104.1 (d, J = 220.3 Hz, JCH = 184.5 Hz), 78.9, 76.8,
75.9, 75.7, 75.6, 73.1, 70.1, 17.7; 19F NMR d: À64.07
(d, J = 49.0 Hz); ESIHRMS Calcd for C20H22FNO6Na
[M+Na]+ 414.1329. Found 414.1347.
We thank the NIH (GM 57335) for support of this
work.
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6. Neighboring group participation by esters is not easily
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pate strongly,a as demonstrated by the isolation of
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tered as the pyranose ring flattens to the sofa-conform-

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