Synthesis and glycosylation of a series of 6-mono-, di-, and trifluoro S-phenyl 2,3,4-tri-O-benzyl-thiorhamnopyranosides. Effect of the fluorine substituents on glycosylation stereoselectivity

Article abstract of DOI:10.1021/ja0730258

A series of 6-mono-, di-, and trifluoro analogs of S-phenyl 2,3,4-tri-O-benzyl-D- or L-thiorhamnopyranoside has been synthesized and used as donors in glycosylation reactions, with activation by the 1-benzenesulfinyl piperidine/triflic anhydride system. T

Full text of DOI:10.1021/ja0730258

Published on Web 08/29/2007
Synthesis and Glycosylation of a Series of 6-Mono-, Di-, and
Trifluoro S-Phenyl 2,3,4-Tri-O-benzyl-thiorhamnopyranosides.
Effect of the Fluorine Substituents on Glycosylation
Stereoselectivity
David Crich*,† and Olga Vinogradova
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago, 845 West
Taylor Street, Chicago, Illinois 60607-7061
Received April 30, 2007; E-mail: dcrich@chem.wayne.edu
Abstract: A series of 6-mono-, di-, and trifluoro analogs of S-phenyl 2,3,4-tri-O-benzyl-D- or L-thiorham-
nopyranoside has been synthesized and used as donors in glycosylation reactions, with activation by the
1-benzenesulfinyl piperidine/triflic anhydride system. The stereochemical outcome of the glycosylation
reactions was found to depend on the electron-withdrawing capability of the disarming substituent at the
6-position, i.e., on the number of fluorine atoms present. The results are explained with regard to the
increased stability of the glycosyl triflates, shown to be intermediates in the reaction by low-temperature
1H NMR experiments, with increased fluorine content.
Scheme 1. Mechanism of Glycosylation
Introduction
â-Linked rhamnopyranosides, important structural units of
many naturally occurring oligosaccharides, especially bacterial
capsular polysaccharides,1 constitute important synthetic targets.
Consequently, methods of stereoselective â-rhamnopyranosyl-
ation are greatly desired. Similar to â-mannopyranosylation,2-4
stereocontrolled â-rhamnopyranosylation is challenging due to
the simultaneous occurrence of the anomeric effect and steric
repulsion between the axial C-2 substituent on the rhamnosyl
donor and the approaching nucleophile, both favoring the
formation of the R-isomer. In a broader sense, the stereoselective
construction of such 1,2-cis glycosylic linkages depends on a
number of factors which influence the equilibrium between the
proposed intermediates of the reaction: covalent donors and
ion pairs, contact (CIP) or solvent separated (SSIP) (Scheme
1).5,6
selectivity observed in 4,6-O-benzylidene-directed glycosyla-
tions on going from highly â-selective mannopyranoside7-12
donors to the R-selective glucopyranoside donors10,12-16 is
attributed to a shift in the equilibria toward the covalent donor
in the manno series, largely due to the compression of the O2-
C2-C3-O3 torsion angle on going from the covalent glycosyl
triflate to the oxacarbenium ion, as compared to the relaxation
of this torsion angle in the gluco series.17,18 The problem of the
chemical synthesis of â-rhamnosides parallels that of the
â-mannosides but is indisputably more difficult, owing to the
â-Selectivity results from the attack on the covalent triflate
or the associated CIP, whereas R-selectivity arises from attack
on the SSIP. Destabilization of the oxacarbenium ion results in
a diminished concentration of the SSIP and, therefore, in
increased â-selectivity. For instance, the striking difference in
† Current address: Chemistry Department, Wayne State University, 5101
Cass Avenue, Detroit, Michigan 48202.
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Fluoro-Substituted Rhamnopyranosides
A R T I C L E S
Scheme 2. Effect of the C5-C6 Conformation
directed away from the electron-deficient center of the oxa-
carbenium ion, thereby destabilizing this key glycosyl transfer
intermediate, whereas in the gg and gt conformers, this dipole
is gauche to the developing positive charge, making the
oxacarbenium ion more stable.30 Third, the â-directing effect
of electron-withdrawing groups at the 5-position is displayed
in the synthesis of D-mannuronic acid oligomers, where thio-
mannuronic acid ester donors were shown to give excellent
â-selectivities.31
Accordingly, we set out to probe 6-mono-, di-, and trifluoro-
substituted rhamnopyranosides as donors in glycosylation reac-
tions, foreseeing an improvement in the â-selectivity caused
by the destabilization of the intermediate oxacarbenium ion by
the presence of the strongly electron-withdrawing substituent(s)
at the 6-position and the consequent shift of the key equilibria
(Scheme 1) toward the covalent donor. Furthermore, fluorine-
substituted carbohydrates have been a topic of interest for many
years,34-40 owing to the fact that fluorine, strategically positioned
in target molecules, may greatly modify their chemical and
biological properties and biological activity. Moreover, the
excellent NMR properties of 19F labels allow the detection of
the position, conversion, or other interactions of the labeled
compounds by in vivo or in vitro 19F NMR measurements.41-45
The fluorine atom can mimic either a hydrogen atom or a
hydroxyl group and thus can turn a substrate into an inhibitor
of a critical enzyme, improve stability of a drug, and/or protect
crucial bonds from hydrolytic cleavage.40 Thus, fluorinated
carbohydrates can be used as cores in the development of drugs
against viral infections and cancer,39,40,46-48 as well as to probe
biochemical processes.49 For example, the ability of the electron-
withdrawing fluorine substituents to decelerate a particular
reaction is used in the elucidation of enzyme mechanisms or in
the inhibition of a process of interest. Thus, a fluorine substituent
in the carbohydrate moiety of the clofarabine, a medicine
marketed for the treatment of leukemia,50 increases the hydro-
lytic stability of the drug by disfavoring positive charge
development on the anomeric carbon, required for the hydrolytic
cleavage of nucleosides.40 Similarly, the mechanism-based
fluorinated glycoside inhibitors designed by Withers and co-
workers51-53 for identification of the active site residues of
6-deoxy functionality. In effect, the absence of the electron-
withdrawing C-O bond at C6 influences the equilibrium
between the intermediates of the reaction and, therefore,
impinges directly on the reaction mechanism. Furthermore, the
use of disarming 4,6-O-benzylidene-protected donors,9,11,19-22
as in our recent solution to the â-mannosylation problem, is
not possible because of the deoxy nature of the system.
Cognizant of the â-directing effect of disarming, nonpartici-
pating substituents at the 2-position,23-25 as well as of the 3,4-
O-carbonate group26 in homogeneous rhamnosylation reactions,
we were drawn to the potential influence of the substituents at
the 6-position on the selectivity of the rhamnosylation reaction.
Indeed, several examples of the directing effect of electron-
withdrawing groups at the 6-position on glycosylation reactions
have been reported in the literature.27-31 First, in their studies
of the influence of the reactant structure on galactopyranosyl-
ation with galactosyl sulfonates, Schuerch and co-workers
reported a remarkably high â-selectivity in the methanolysis of
6-O-(N-phenylcarbamoyl)-2,3,4-tri-O-benzyl-D-galactopyrano-
syl triflate28,29 and, more generally, a noticeable enhancement
in â-selectivity on going from less to more electron-withdrawing
protective groups at the 6-position of 2,3,4-tri-O-benzyl-D-
galactopyranose derivatives.28 Second, the well-known deacti-
vating effect of 4,6-O-acetal protecting groups on glycosyl
transfers and hydrolyses, utilized, for example, in 4,6-O-
benzylidene-directed â-mannopyranosylation reactions,7-12 was
demonstrated not to be wholly “torsional disarmament”,32,33 but
in part to be an electronic effect, associated with locking C5-
C6 in the tg conformation (Scheme 2).30 In the tg conformer,
the C6-O6 bond acts as a dipole with the negative terminus
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A R T I C L E S
Crich and Vinogradova
“retaining” glysosidases, function through destabilization of the
putative oxacarbenium intermediate of the studied enzymatic
reaction by the electron-withdrawing fluorine substituent.51-53
Similar characteristics are to be expected from the 6-mono-,
di-, and trifluoro-substituted rhamnopyranosides, thereby making
them candidates for inhibitors of glycoside processing enzymes,
in addition to potential â-selective rhamnosyl donors.
fluorine-containing building block for the introduction of the
trifluoromethyl moiety into the arabinose precursor (Scheme
5). The trifluoromethyl analog of an L-rhamnopyranoside donor
was selected as target on account of the low cost and availability
of L-arabinose. Thus, derivative 760 was converted to 8 and 9
by a two-step, one-pot protocol, starting with TBAF-catalyzed
nucleophilic addition of CF3TMS to the aldehyde,61,62 followed
by the cleavage of the intermediate TMS ether. The undesired
diastereomer 8 failed to undergo Mitsunobu inversion63,64 but
was successfully transformed to 9 by a method involving
displacement of the derived triflate with nitrite anion.65-70
2-Naphthyl-methylation of 9, followed by the removal of the
trityl group in acidic media, gave 10.
Results
Preparation of Donors. Preparation of the D-monofluoro
donor 3 was straightforward and followed the protocol outlined
in Scheme 3, starting from the known 1,2,3,4-tetra-O-acetyl-
6-deoxy-6-fluoro-â-D-mannopyranose 1,54 easily available through
the reaction of 1,2,3,4-tetra-O-acetyl-â-D-mannopyranose55 with
N,N-diethylaminosulfur trifluoride (DAST),54 and proceeding
via the intermediacy of the corresponding tri-O-acetyl thiogly-
coside 2.
Scheme 5. Synthesis of a Trifluoro Donor
Scheme 3. Synthesis of a Monofluoro Donor
The difluoro derivative 5 was synthesized in a similar manner
by deoxofluorination with DAST, following conversion of the
6-OH group of the mannopyranoside derivative 456 to the
corresponding aldehyde57 (Scheme 4). One-pot hydrolysis of
the anomeric OMe group and acetylation of the pyranose in
acidic media,58 followed by Lewis acid-promoted substitution
with thiophenol, gave 6 as a mixture of R and â isomers, easily
separable by means of chromatography.
Scheme 4. Synthesis of a Difluoro Donor
Differential protection of 10 in this manner allows potential
difficulties related to the increase of the furanose content as
the methyl group is replaced with the trifluoromethyl group,
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In this proof of principle study, D-mannose was selected as
a precursor for the synthesis of the mono- and difluoromethyl
analogs 3 and 6 in view of its low cost and availability and the
rapid access to the target donors. The trifluorinated donor 12
required the development of an entirely different strategy, in
which the Ruppert-Prakash reagent59 was utilized as a suitable
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Fluoro-Substituted Rhamnopyranosides
A R T I C L E S
Table 1. Variable-Temperature 1H NMR Experiments
Table 2. Glycosylation of the Donor 3
a Determined from 1H NMR spectrum of the crude reaction mixture.
b Total isolated yield.
known to occur in the L-fucose series,62 to be avoided. Swern
oxidation, followed by oxidative cleavage of the 2-methylnaph-
thyl ether gave 11 predominantly as the R-isomer. Obvious
routes for the conversion of the pyranose derivative 11 to the
donor 12 via reaction of the anomeric hydroxyl group with
tributylphosphine and sulfur nucleophiles (e.g., diphenyl di-
sulfide), or via acetylation of 11 followed by the Lewis acid-
promoted reaction with thiophenol, failed. This is presumably
due to the strong electron-withdrawing nature of the CF3
substituent at the 5-position, diminishing the nucleophilicity of
the hydroxyl group or, in the case of the acetate, prohibiting its
effective activation with the Lewis acid. Therefore, pyranose
derivative 11 was treated with N-phenyltrifluoroacetimidoyl
chloride71 to give the more reactive N-phenyltrifluoroacetimidate
derivative,72-77 which was instantly converted to donor 12 with
thiophenol under Lewis acid-catalyzed conditions.
Table 3. Glycosylation of the Donor 6r
Investigation of the Key Intermediates. Variable-temper-
1
ature H NMR experiments were conducted for donors 3, 6r,
and 12â, in which activation was performed by the BSP/Tf2O
couple in CD2Cl2 (Table 1).
a Determined from 1H NMR spectrum of the crude reaction mixture.
b Total isolated yield.
Glycosylation Reactions. In light of the results obtained from
the low-temperature NMR experiments, the glycosylation reac-
tions (Tables 2-4) were performed by the following modus
operandi: donors were first activated at -60 °C by the BSP/
Tf2O couple in the presence of TTBP, the solution of the
acceptor was then added, and the reaction mixture was allowed
to warm slowly to room temperature. The assignment of the
In all three cases, the thioglycosides followed the typical
pattern previously observed in our laboratory:10,13,25,78,79 clean
activation at -60 °C directly gave putative glycosyl triflate
intermediates, which underwent decomposition on warming.
Interestingly, the stability of the observed intermediates 13, 14,
and 15 exhibited a direct correlation with the number of fluorine
substituents at the 6-position. Thus, the decomposition of 13
was completed by 0 °C, whereas the decomposition of 14 and
15 required higher temperatures (+10 °C and room temperature,
respectively).
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A R T I C L E S
Crich and Vinogradova
Table 5. Glycosylations under the Modified Conditions
Table 4. Glycosylation of the Donor 12â
a Total isolated yield. b Determined from 1H NMR spectrum of the crude
reaction mixture.
stereochemistry of the so-formed glycosidic products was made
1
on the basis of the magnitude of the JC1,H1 coupling con-
stants.80,81
Glycosylation of the monofluoro donor 3 proceeded in good
yield, but poor selectivity. In all but one case, a preference for
the R- over â-isomer was observed (Table 2). A significant
change in selectivity was detected going to the difluoro
thioglycoside donor 6r, with which the desired â-isomer was
the major product of the glycosylation reactions, reaching a
maximum of 3/1 â/R with a primary alcohol as acceptor (Table
3). A further improvement in â-selectivity was observed going
from the difluoro donor 6r to the trifluoro analog 12â, with
the exception of glycosylation of acceptor 22 for which the R/â
ratio was only 1/1.2 (Table 4).
The formation of significant amounts of the pyranose
byproduct 11 was observed in coupling reactions with trifluoro
donor 12â, which led us to examine further glycosylation
reactions under the modified conditions. Thus, 12â was activated
at -60 °C by the BSP/Tf2O couple in the presence of TTBP,
followed by addition of the acceptor, and the reaction mixture
was maintained at -60 °C for an extended period of time (18
h or, for the acceptor 22, 24 h) before it was quenched.
Application of this modified procedure gave a significant
improvement in the yield and selectivity for the reaction of donor
12â with acceptor 16 (Table 5) and decreased the amount of
the byproduct 11 in the majority of cases.
a Total isolated yield. b Determined from 1H NMR spectrum of the crude
reaction mixture.
which preactivation of donors 3284 or 3315 was performed at
-78 °C. In accordance with the general pattern, each of these
donors showed a high preference for the formation of R-linked
products.
Deprotection of Disaccharides. In order to ascertain whether
or not introduction of the fluorine atoms into rhamnopyranosides
in this manner complicates deprotection, disaccharides 26â, 27â,
28â, and 29â were submitted to the transformations described
in Scheme 6. Hydrogenolysis of 28â proceeded efficiently and
resulted in a quantitative yield of 36.
Cleavage of the acetonide protecting groups,85 followed by
the hydrogenolysis over Pd(OH)2, enabled 37 and 38 to be
obtained from 26â and 29â, respectively. Hydrogenolysis of
the benzyl ethers in 27â was uneventful and gave 39 in
quantitative yield.
To further probe the effect of the fluorine substituent(s) at
the 6-position, glycosylation reactions with the analogous
nonfluorinated substrates, the rhamno- (30)82 and mannopyra-
noside derivatives (31),83 were examined for comparison. The
results of these coupling reactions under the original conditions
with the acceptor 16 are presented in Table 6 (entries 1 and 2)
along with pertinent literature examples (entries 3 and 4), in
Discussion
It is evident that introduction of fluorine atoms at the
6-position of the rhamnopyranoside donor enhances the â-se-
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(85) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem.
Soc. 1975, 97, 4056-4062.
9
11760 J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007

Fluoro-Substituted Rhamnopyranosides
A R T I C L E S
Table 6. Glycosylation Reactions with Rhamno- and
Mannopyranoside Donors
as compared to oxygen and obvious steric factors. Poor
selectivity in the glycosylation of acceptor 19 with difluoro and
trifluoro donors 6r and 12â, as compared with the good
â-selectivity in reactions with acceptors 16, 17, and 18, is
attributable to the sterically hindered nature of this acceptor and
the stereochemical matching/mismatching phenomenon.86,87
The effect of the electron-withdrawing group at the 6-position
on the stability of the covalent triflate was further demonstrated
by low-temperature 1H NMR experiments, in which decomposi-
tion temperatures increase with the number of fluorine atoms
at C6. Surprisingly, introduction of the disarming substiuents
to the rhamnosyl donors did not significantly influence the
activation step (Table 1): in all cases putative glycosyl triflate
intermediates were obtained from all thioglycosyl donors within
minutes upon treatment with the BSP/Tf2O pair at -60 °C.
Experimental Section
General. Unless otherwise noted, reactions were conducted under
1
an inert atmosphere of argon or nitrogen. All H, 13C, and 19F spectra
were recorded in CDCl3, except for the spectra of the compounds 36,
37, and 38 where CD3OD was used as a solvent. All 19F spectra were
referenced to CFCl3.
General Procedure for Variable-Temperature 1H NMR Experi-
ments. A solution of 3, 6r, or 12â (0.02 to 0.05 mmol, 1 equiv) in
CD2Cl2 (1 g) containing BSP (1 equiv) and TTBP (2 equiv) was placed
into an NMR tube and cooled to -60 °C in the NMR probe. The first
1H spectrum was obtained, then the sample was quickly removed from
the probe and kept cool in a -60 °C acetone/dry ice bath during the
addition of Tf2O (1.1 equiv). The sample was returned to the NMR
probe, and the 1H spectrum was recorded again. The temperature was
a Total isolated yield. b Determined from 1H NMR spectrum of the crude
reaction mixture.
Scheme 6. Deprotection of Trifluororhamnopyranosides
1
increased by 10 °C increments every 10 min, and H NMR spectra
were acquired at each temperature.
General Coupling Protocol (Method A). To a stirred solution of
donor 3, 6r, or 12â (1 equiv) in CH2Cl2 (∼0.03 M), containing BSP
(1 equiv), TTBP (2 equiv), and activated 3 Å powdered molecular
sieves, Tf2O (1.1 equiv) was added at -60 °C. The reaction mixture
was stirred for 5 min at this temperature, and solution of acceptor 16,
17, 18, or 22 (1.2 equiv) in CH2Cl2 (∼0.09 M) was added dropwise.
The reaction mixture was stirred for an additional 2 min at this
temperature, then slowly warmed to room temperature, filtered, washed
(saturated aq NaHCO3), dried (Na2SO4), and concentrated. The crude
was filtered through a pad of silica gel (with ethyl acetate as an eluent)
and chromatographed using SiO2.
General Coupling Protocol (Method B). To a stirred solution of
donor 3, 6r, or 12â (1 equiv) in CH2Cl2 (∼0.03 M), containing BSP
(1 equiv), TTBP (2 equiv), and activated 3 Å powdered molecular
sieves, Tf2O (1.1 equiv) were added at -60 °C. The reaction mixture
was stirred for 5 min at this temperature, and solution of acceptor (1.2
equiv) in CH2Cl2 (∼0.09 M) was added dropwise. The reaction mixture
was stirred for an additional 18 h (for acceptors 16, 17, and 18) or
24 h (for 22) at -60 to -65 °C, then filtered, washed (saturated aq
NaHCO3), dried (Na2SO4), and concentrated. The crude reaction mixture
was filtered through a pad of silica gel (with ethyl acetate as an eluent)
and chromatographed using SiO2.
2,3,4-Tri-O-benzyl-6-fluoro-r-D-rhamnopyranosyl-(1f3)-1,2:5,6-
di-O-iso-propylidene-r-D-glucofuranose (19r) and 2,3,4-Tri-O-ben-
zyl-6-fluoro-â-D-rhamnopyranosyl-(1f3)-1,2:5,6-di-O-isopropylidene-
r-D-glucofuranose (19â). Prepared by method A or method B (18 h
at -60 to -65 °C) from 3 (50 mg, 0.092 mmol) and 16 (29 mg, 0.113
mmol). Purification by radial chromatography (SiO2, hexanes to 1/4
ethyl acetate/hexanes) gave 19r (41 mg, 64%, method A or 36 mg,
lectivity of the rhamnosylation reaction. This is in agreement
with the hypothesis of the dependence of the stereochemical
outcome of the glycosylation reaction on the nature of the
substituents at the 6-position, their influence on the stability of
the intermediate oxacarbenuim ion and, consequently, on the
key equilibria (Scheme 1). The â/R ratio of the disaccharide
products increases going from nonfluorinated substrates to
monofluoro donor 3 to difluoro donor 6r, and further to trifluoro
donor 12â. The increase in formation of the â-linked products
with the monofluro donor as compared to the mannopyranoside
donor can be attributed to the higher electronegativity of fluorine
(86) Fraser-Reid, B.; Lopez, J. C.; Gomez, A. M.; Uriel, C. Eur. J. Org. Chem.
2004, 1387-1395.
(87) Crich, D.; Patel, M. Carbohydr. Res. 2006, 341, 1467-1475.
9
J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007 11761

A R T I C L E S
Crich and Vinogradova
57%, method B) and 19â (15 mg, 24%, method A or 13 mg, 21%,
21r and 21â (51 mg, 84%, R/â ) 1/1.6). 21r: [R]23 +42.9 (c 0.21,
CHCl3); H NMR (501 MHz) δ 7.26-7.40 (m, 15H), 4.97 (d, J )
D
1
method B). 19r: [R]24D +11.6 (c 0.55, CHCl3); H NMR (501 MHz)
1
δ 7.28-7.41 (m, 15H), 5.80 (d, J ) 3.5 Hz, 1H), 5.26 (d, J ) 1.3 Hz,
1H), 4.97 (d, J ) 10.6 Hz, 1H), 4.76 (d, J ) 12.5 Hz, 1H), 4.52-4.76
(m, 7H), 4.27 (s, 1H), 4.08-4.13 (m, 1H), 3.98-4.07 (m, 4H), 3.85
(dd, J ) 9.4, 2.9 Hz, 1H), 3.72-3.82 (m, 2H), 1.49 (s, 3H), 1.41 (s,
3H), 1.34 (s, 3H), 1.29 (s, 3H); 13C NMR (126 MHz) δ 138.2, 138.04,
138.00, 128.6, 128.4, 128.2, 128.0, 127.9, 127.8, 127.73, 127.70, 112.1,
109.5, 105.2 (1JCH ) 182.6 Hz), 98.8 (1JCH ) 172.5 Hz), 83.8, 82.3 (d,
J ) 172.9 Hz), 81.4, 80.3, 79.5, 75.5, 73.9, 73.7 (d, J ) 6.5 Hz), 72.5,
72.4, 72.11, 72.09 (d, J ) 18.5 Hz), 67.8, 27.0, 26.9, 26.2, 25.6; 19F
(282 MHz) δ -233.8 (td, J ) 47.7, 26.7 Hz, 1F); FABHRMS calcd
10.6 Hz, 1H), 4.86 (d, J ) 1.3 Hz, 1H), 4.49-4.82 (m, 8H), 4.11 (t, J
) 9.8 Hz, 1H), 4.04 (d, J ) 5.7 Hz, 1H), 3.95-4.06 (m, 1H), 3.93
(dd, J ) 7.2, 5.8 Hz, 1H), 3.86 (dd, J ) 9.4, 3.0 Hz, 1H), 3.73 (dd, J
) 2.8, 1.8 Hz, 1H), 3.46-3.55 (m, 1H), 3.33 (s, 3H), 3.29 (dd, J )
10.1, 7.5 Hz, 1H), 1.50 (s, 3H), 1.27 (s, 3H), 1.00 (d, J ) 6.2 Hz, 3H);
13C NMR (126 MHz) δ 138.5, 138.4, 138.1, 128.5, 128.2, 128.1, 127.9,
127.8, 127.7, 127.6, 109.1, 99.3 (1JCH ) 171.4 Hz), 98.0 (1JCH ) 166.2
Hz), 82.2 (d, J ) 172.0 Hz), 80.3, 80.1, 75.9, 75.5, 73.9 (d, J ) 5.6
Hz), 73.8, 72.9, 72.4, 71.1 (d, J ) 18.5 Hz), 64.7, 54.9, 28.1, 26.4,
17.2; 19F (282 MHz) δ -236.6 (td, J ) 48.3, 30.9 Hz, 1F); FABHRMS
calcd for C37H45FNaO9 [M + Na]+, 675.2945; found, 675.2932. 21â:
for C39H47FNaO10 [M + Na]+, 717.3051; found, 717.3041. 19â: [R]23
D
1
[R]23 -71.2 (c 0.16, CHCl3); H NMR (501 MHz) δ 7.41-7.45 (m,
-41.9 (c 0.32, CHCl3); H NMR (501 MHz) δ 7.39-7.42 (m, 2H),
1
D
7.27-7.36 (m, 13H), 5.91 (d, J ) 3.3 Hz, 1H), 4.93 (d, J ) 10.6 Hz,
1H), 4.88 (d, J ) 12.1 Hz, 1H), 4.77 (d, J ) 12.1 Hz, 1H), 4.42-4.67
(m, 8H), 4.31-4.33 (m, 1H), 4.28-4.29 (m, 1H), 4.13 (t, J ) 7.5 Hz,
1H), 4.03-4.07 (m, 1H), 3.89 (t, J ) 9.5 Hz, 1H), 3.84-3.87 (m, 1H),
3.52-3.55 (m, 1H), 3.40-3.49 (m, 1H), 1.50 (s, 3H), 1.43 (s, 3H),
1.32 (s, 3H), 1.31 (s, 3H); 13C NMR (126 MHz) δ 138.3, 138.0, 128.53,
128.48, 128.3, 128.22, 128.17, 128.0, 127.8, 127.7, 127.6, 112.0, 108.6,
105.0 (1JCH ) 182.6 Hz), 99.9 (1JCH ) 155.3 Hz), 83.1, 82.23 (d, J )
172.9 Hz), 82.17, 81.2, 80.6, 75.3, 75.1 (d, J ) 18.5 Hz), 74.2, 74.1,
73.6 (d, J ) 6.5 Hz), 73.2, 71.8, 66.1, 26.8, 26.6, 26.4, 25.2; 19F (282
MHz) δ -232.3 (td, J ) 47.3, 23.7 Hz, 1F); FABHRMS calcd for
C39H47FNaO10 [M + Na]+, 717.3051; found, 717.3033.
2H), 7.25-7.36 (m, 13H), 4.91-4.98 (m, 3H), 4.87 (s, 1H), 4.78 (d, J
) 12.5 Hz, 1H), 4.66 (d, J ) 3.7 Hz, 1H), 4.58 (d, J ) 10.8 Hz, 1H),
4.56 (d, J ) 3.7 Hz, 1H), 4.53 (d, J ) 11.9 Hz, 1H), 4.44 (d, J ) 11.7
Hz, 1H), 4.14 (dd, J ) 7.2, 5.7 Hz, 1H), 4.09 (d, J ) 5.5 Hz, 1H),
3.95 (d, J ) 3.1 Hz, 1H), 3.85 (t, J ) 9.5 Hz, 1H), 3.68-3.73 (m,
1H), 3.61-3.68 (m, 1H), 3.57 (dd, J ) 9.3, 3.0 Hz, 1H), 3.40-3.48
(m, 1H), 3.39 (s, 3H), 1.48 (s, 3H), 1.35 (d, J ) 6.2 Hz, 3H), 1.32 (s,
3H); 13C NMR (126 MHz) δ 138.8, 138.2, 138.1, 128.5, 128.4, 128.2,
128.1, 127.9, 127.7, 127.6, 127.5, 109.4, 99.8 (1JCH ) 157.2 Hz), 97.9
(1JCH ) 168.3 Hz), 82.44 (d, J ) 173.9 Hz), 82.38, 78.5, 77.8, 76.1,
75.2, 75.0 (d, J ) 18.5 Hz), 74.00, 73.97, 73.9 (d, J ) 7.4 Hz), 71.3,
64.3, 54.9, 27.8, 26.5, 17.7; 19F (282 MHz) δ -231.9 (td, J ) 47.7,
23.7 Hz, 1F); FABHRMS calcd for C37H45FNaO9 [M + Na]+, 675.2945;
found, 675.2921.
2,3,4-Tri-O-benzyl-6-fluoro-r-D-rhamnopyranosyl-(1f6)-1,2:3,4-
di-O-iso-propylidene-r-D-galactopyranose (20r) and 2,3,4-Tri-O-
benzyl-6-fluoro-â-D-rhamnopyranosyl-(1f6)-1,2:3,4-di-O-isopro-
pylidene-r-D-galactopyranose (20â). Prepared by method A from 3
(50 mg, 0.092 mmol) and 17 (29 mg, 0.113 mmol). Purification by
radial chromatography (SiO2, hexanes to 1/4 ethyl acetate/hexanes) gave
20r (28 mg, 43%) and 20â (28 mg, 43%). 20r: [R]2D4 -10.2 (c 0.58,
CHCl3); 1H NMR (400 MHz) δ 7.27-7.40 (m, 15H), 5.52 (d, J ) 5.0
Hz, 1H), 4.99 (d, J ) 1.6 Hz, 1H), 4.95 (d, J ) 10.8 Hz, 1H), 4.51-
4.78 (m, 8H), 4.32 (dd, J ) 5.0, 2.4 Hz, 1H), 4.16 (dd, J ) 8.0, 1.8
Hz, 1H), 3.90-4.03 (m, 3H), 3.83 (dd, J ) 2.9, 1.9 Hz, 1H), 3.73-
3.81 (m, 2H), 3.66-3.72 (m, 1H), 1.51 (s, 3H), 1.44 (s, 3H), 1.34 (s,
3H), 1.33 (s, 3H); 13C NMR (101 MHz) δ 138.4, 138.3, 138.2, 128.44,
128.35, 128.1, 127.9, 127.8, 127.64, 127.62, 127.56, 109.4, 108.6, 97.6
(1JCH ) 169.4 Hz), 96.3 (1JCH ) 178.3 Hz), 82.3 (d, J ) 173.2 Hz),
80.0, 75.3, 74.4, 73.8 (d, J ) 6.6 Hz), 72.5, 72.1, 71.4 (d, J ) 17.7
Hz), 71.0, 70.7, 70.6, 65.7, 65.4, 26.1, 26.0, 24.9, 24.6; 19F (282 MHz)
δ -234.2 (td, J ) 47.5, 27.9 Hz, 1F); FABHRMS calcd for C39H47-
2,3,4-Tri-O-benzyl-6,6-difluoro-r-D-rhamnopyranosyl-(1f3)-1,2:
5,6-di-O-iso-propylidene-r-D-glucofuranose (23r) and 2,3,4-Tri-O-
benzyl-6,6-difluoro-â-D-rhamnopyranosyl-(1f3)-1,2:5,6-di-O-iso-
propylidene-r-D-glucofuranose (23â). Prepared by method A from
6r (50 mg, 0.089 mmol) and 16 (28 mg, 0.107 mmol) or by method
B (18 h at -60 to -65 °C) from 23r (25 mg, 0.044 mmol) and 16 (14
mg, 0.054 mmol). Purification by radial chromatography (SiO2, hexanes
to 1/4 ethyl acetate/hexanes) gave 23r (17 mg, 26%, method A or 8
mg, 25%, method B) and 23â (34 mg, 54%, method A or 17 mg, 53%,
method B). 23r: [R]24D +2.7 (c 0.26, CHCl3); 1H NMR (500 MHz) δ
7.28-7.39 (m, 15H), 6.01 (t, J ) 54.4 Hz, 1H), 5.80 (d, J ) 3.7 Hz,
1H), 5.29 (d, J ) 1.7 Hz, 1H), 4.94 (d, J ) 10.5 Hz, 1H), 4.74 (d, J
) 12.3 Hz, 1H), 4.64 (d, J ) 12.5 Hz, 1H), 4.63 (d, J ) 10.6 Hz, 1H),
4.53-4.59 (m, 3H), 4.26 (d, J ) 1.8 Hz, 1H), 3.99-4.12 (m, 5H),
3.78-3.87 (m, 2H), 3.76 (t, J ) 2.4 Hz, 1H), 1.49 (s, 3H), 1.41 (s,
3H), 1.33 (s, 3H), 1.29 (s, 3H); 13C NMR δ 138.0, 137.8, 137.7, 128.6,
128.44, 128.42, 128.2, 128.1, 127.8, 127.7, 113.9 (t, J ) 244.1 Hz),
112.1, 109.4, 105.2 (1JCH ) 182.6 Hz), 99.0 (1JCH ) 172.5 Hz), 83.6,
81.3, 81.0, 79.0, 75.4, 73.7, 73.6, 72.5, 72.4, 72.1, 71.2 (t, J ) 20.4
Hz), 67.8, 26.9, 26.8, 26.1, 25.6; 19F (471 MHz) δ -132.9 (ddd, J )
285.0, 54.0, 9.4 Hz, 1F), -133.8 (ddd, J ) 285.0, 54.3, 15.0 Hz, 1F);
ESIHRMS calcd for C39H46F2NaO10 [M + Na]+, 735.2957, found,
735.2947. 23â: [R]24D -52.8 (c 0.07, CHCl3); 1H NMR (501 MHz) δ
7.25-7.40 (m, 15H), 6.09 (td, J ) 54.7, 3.1 Hz, 1H), 5.85 (d, J ) 3.7
Hz, 1H), 4.82 (d, J ) 10.8 Hz, 1H), 4.80 (d, J ) 12.1 Hz, 1H), 4.72
(d, J ) 12.1 Hz, 1H), 4.62-4.68 (m, 2H), 4.58 (d, J ) 11.9 Hz, 1H),
4.52 (d, J ) 11.9 Hz, 1H), 4.45 (d, J ) 3.9 Hz, 1H), 4.39 (q, J ) 6.0
Hz, 1H), 4.29 (d, J ) 2.9 Hz, 1H), 4.24-4.27 (m, 1H), 3.98-4.07 (m,
3H), 3.88 (dd, J ) 2.6, 1.7 Hz, 1H), 3.57-3.64 (m, 2H), 1.49 (s, 3H),
1.42 (s, 3H), 1.29 (s, 3H), 1.28 (s, 3H); 13C NMR δ 138.1, 137.9, 137.6,
128.6, 128.5, 128.4, 128.2, 128.13, 128.09, 128.06, 127.82, 127.79,
127.5, 113.8 (t, J ) 244.1 Hz), 112.0, 108.7, 105.0 (1JCH ) 182.6 Hz),
99.3 (1JCH ) 157.4 Hz), 82.9, 81.3, 80.8, 79.6, 74.5, 74.2 (t, J ) 22.7
Hz), 73.7, 73.6, 72.8, 72.2, 66.4, 26.8, 26.7, 26.3, 25.0; 19F (471 MHz)
δ -129.5 (dd, J ) 287.9, 51.8 Hz, 1F), -131.2 (dd, J ) 287.9, 54.8
Hz, 1F); ESIHRMS calcd for C39H46F2NaO10 [M + Na]+, 735.2957;
found, 735.2952.
FNaO10 [M + Na]+, 717.3051; found, 717.3045. 20â: [R]24 -78.4
D
1
(c 0.62, CHCl3); H NMR (400 MHz) δ 7.48-7.53 (m, 2H), 7.22-
7.36 (m, 13H), 5.60 (d, J ) 5.0 Hz, 1H), 5.02 (d, J ) 12.4 Hz, 1H),
4.98 (d, J ) 10.8 Hz, 1H), 4.92 (d, J ) 12.4 Hz, 1H), 4.70 (d, J ) 3.2
Hz, 1H), 4.56-4.65 (m, 3H), 4.49 (s, 1H), 4.45 (d, J ) 12.0 Hz, 1H),
4.31-4.36 (m, 2H), 4.19-4.25 (m, 2H), 4.10-4.14 (m, 1H), 4.02 (d,
J ) 2.9 Hz, 1H), 3.92 (t, J ) 9.6 Hz, 1H), 3.62 (dd, J ) 10.7, 8.5 Hz,
1H), 3.49 (dd, J ) 9.4, 3.0 Hz, 1H), 3.36-3.48 (m, 1H), 1.49 (s, 3H),
1.45 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H); 13C NMR (101 MHz) δ 138.4,
138.2, 137.9, 128.8, 128.44, 128.35, 128.2, 128.1, 127.8, 127.6, 127.5,
109.6, 108.8, 102.4 (1JCH ) 155.1 Hz), 96.4 (1JCH ) 179.9 Hz), 82.2
(d, J ) 173.9 Hz), 81.6, 75.3, 74.8 (d, J ) 18.4 Hz), 73.7, 73.5 (d, J
) 7.4 Hz), 72.4, 71.6, 71.0, 70.8, 70.5, 70.0, 68.0, 26.04, 25.99, 25.1,
24.4; 19F (282 MHz) δ -232.7 (td, J ) 47.5, 24.8 Hz, 1F); FABHRMS
calcd for C39H47FNaO10 [M + Na]+, 717.3051; found, 717.3064.
Methyl 2,3,4-Tri-O-benzyl-6-fluoro-r-D-rhamnopyranosyl-(1f4)-
2,3-O-iso-propylidene-r-L-rhamnopyranoside (21r) and Methyl
2,3,4-Tri-O-benzyl-6-fluoro-â-D-rhamnopyranosyl-(1f4)-2,3-O-iso-
propylidene-r-L-rhamnopyranoside (21â). Prepared from 3 (50 mg,
0.092 mmol) and 18 (25 mg, 0.113 mmol) by method A. Purification
by radial chromatography (SiO2, hexanes to 1/4 ethyl acetate/hexanes),
followed by HPLC (SiO2, hexanes to 1/4 ethyl acetate/hexanes) gave
9
11762 J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007

Fluoro-Substituted Rhamnopyranosides
A R T I C L E S
2,3,4-Tri-O-benzyl-6,6-difluoro-r-D-rhamnopyranosyl-(1f6)-1,2:
3,4-di-O-iso-propylidene-r-D-galactopyranose (24r) and 2,3,4-Tri-
O-benzyl-6,6-difluoro-â-D-rhamnopyranosyl-(1f6)-1,2:3,4-di-O-
isopropylidene-r-D-galactopyranose (24â). Prepared by method A
from 6r (50 mg, 0.089 mmol) and 17 (28 mg, 0.107 mmol). Purification
by radial chromatography (SiO2, hexanes to 1/4 ethyl acetate/hexanes)
3H), 3.32-3.39 (m, 1H), 3.29 (dd, J ) 9.0, 2.9 Hz, 1H); 13C NMR δ
139.3, 138.6, 138.3, 138.1, 137.8, 128.5, 128.44, 128.41, 128.14, 128.07,
127.97, 127.95, 127.9, 127.84, 127.81, 127.75, 127.5, 127.4, 127.3,
114.3 (t, J ) 244.6 Hz), 100.7 (1JCH ) 157.6 Hz); 98.3 (1JCH ) 165.6
Hz), 81.3, 80.0, 79.5, 77.6, 75.4, 74.9, 74.4, 73.92, 73.85 (t, J ) 22.7
Hz), 73.6, 72.5, 73.4 (d, J ) 2.8 Hz), 71.8, 69.6, 68.8, 55.3; 19F (471
MHz) δ -128.8 (ddd, J ) 286.5, 54.0, 13.7 Hz, 1F), -131.6 (ddd, J
) 286.5, 54.9, 8.8 Hz, 1F); ESIHRMS calcd for C55H58F2NaO10 [M +
Na]+, 939.3896; found, 939.3923.
gave 24r (12 mg, 19%) and 24â (36 mg, 57%). 24r: [R]23 -9.3 (c
D
1
0.20, CHCl3); H NMR (501 MHz) δ 7.25-7.39 (m, 15H), 5.97 (t, J
) 54.5 Hz, 1H), 5.53 (d, J ) 5.0 Hz, 1H), 5.04 (d, J ) 1.7 Hz, 1H),
4.92 (d, J ) 10.6 Hz, 1H), 4.74 (d, J ) 12.5 Hz, 1H), 4.70 (d, J )
12.5 Hz, 1H), 4.59-4.64 (m, 2H), 4.58 (s, 2H), 4.32 (dd, J ) 5.0, 2.5
Hz, 1H), 4.15 (dd, J ) 7.9, 1.8 Hz, 1H), 4.05 (t, J ) 9.6 Hz, 1H),
3.94-3.98 (m, 1H), 3.92 (dd, J ) 9.3, 3.0 Hz, 1H), 3.84-3.91 (m,
1H), 3.76-3.82 (m, 2H), 3.69 (dd, J ) 10.8, 6.1 Hz, 1H), 1.51 (s,
3H), 1.43 (s, 3H), 1.33 (s, 6H); 13C NMR (126 MHz) δ 138.2, 138.1,
138.0, 128.5, 128.4, 128.1, 127.90, 127.87, 127,73, 127.68, 127.5, 114.0
2,3,4-Tri-O-benzyl-6,6,6-trifluoro-r-L-rhamnopyranosyl-(1f3)-
1,2:5,6-di-O-isopropylidene-r-D-glucofuranose (26r) and 2,3,4-Tri-
O-benzyl-6,6,6-trifluoro-â-L-rhamnopyranosyl-(1f3)-1,2:5,6-di-O-
isopropylidene-r-D-glucofuranose (26â). Prepared by method A or
method B (18 h at -60 to -65 °C) from 12â (25 mg, 0.043 mmol)
and 16 (14 mg, 0.052 mmol). Purification by radial chromatography
(SiO2, hexanes to 3/17 ethyl acetate/hexanes) gave 26r (3 mg, 10%,
method A), 26â, and 11r,â (combined yield 16 mg, 26â/11r,â )
1/0.42, 26â 40%, 11r,â 17%, method A) or only 26r (3 mg, 10%,
(t, J ) 243.6 Hz), 109.5, 108.7, 97.5 (1JCH ) 170.0 Hz), 96.4 (1JCH
)
180.0 Hz), 79.6, 75.2, 74.1, 73.8, 72.5, 72.2, 71.0, 70.7, 70.58 (t, J )
19.9 Hz), 70.55, 65.9, 65.3, 26.1, 26.0, 25.0, 24.6; 19F (471 MHz) δ
-133.2 (ddd, J ) 285.0, 54.0, 9.4 Hz, 1F), -134.5 (ddd, J ) 285.0,
method B) and 26â (24 mg, 77%, method B). 26r: white solid; mp
1
100-102 °C; [R]18 -42.0 (c 0.20, CHCl3); H NMR (400 MHz) δ
D
54.0, 16.6 Hz, 1F); ESIHRMS calcd for C39H46F2NaO10 [M + Na]+,
7.24-7.40 (m, 15H), 5.77 (d, J ) 3.7 Hz, 1H), 4.87 (s, 1H), 4.85 (d,
J ) 2.9 Hz, 1H), 4.82 (s, 1H), 4.62-4.69 (m, 4H), 4.52-4.62 (m,
1H), 4.31 (d, J ) 2.9 Hz, 1H), 4.15 (d, J ) 3.7 Hz, 1H), 4.02-4.12
(m, 4H), 3.89-3.95 (m, 1H), 3.78 (dd, J ) 9.2, 3.1 Hz, 1H), 3.67-
1
735.2957; found, 735.2947. 24â: [R]23 -95.2 (c 0.65, CHCl3); H
D
NMR (501 MHz) δ 7.48-7.51 (m, 2H), 7.23-7.35 (m, 13H), 6.02
(td, J ) 54.4, 1.9 Hz, 1H), 5.59 (d, J ) 5.0 Hz, 1H), 4.99 (d, J ) 12.3
Hz, 1H), 4.92 (d, J ) 10.6 Hz, 1H), 4.88 (d, J ) 12.3 Hz, 1H), 4.60-
4.63 (m, 1H), 4.63 (d, J ) 10.8 Hz, 1H), 4.56 (s, 1H), 4.48 (d, J )
11.9 Hz, 1H), 4.36 (d, J ) 11.9 Hz, 1H), 4.33-4.35 (m, 1H), 4.23
(dd, J ) 8.0, 1.7 Hz, 1H), 4.19 (dd, J ) 10.8, 2.4 Hz, 1H), 4.10-4.13
(m, 1H), 4.04 (t, J ) 9.0 Hz, 1H), 4.01 (d, J ) 2.6 Hz, 1H), 3.64 (dd,
J ) 10.8, 8.3 Hz, 1H), 3.50-3.58 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H),
1.34 (s, 3H), 1.32 (s, 3H); 13C NMR (126 MHz) δ 138.4, 137.9, 137.8,
128.7, 128.5, 128.4, 128.3, 128.1, 127.9, 127.71, 127.66, 127.6, 113.9
3.69 (m, 1H), 1.49 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H), 1.23 (s, 3H); 13
C
NMR (101 MHz) δ 138.1, 138.0, 137.9, 128.5, 128.4, 128.2, 128.1,
127.9, 127.78, 127.76, 124.3 (q, J ) 280.9 Hz), 112.1, 109.6, 105.3
(1JCH ) 182.6 Hz), 95.7 (1JCH ) 170.0 Hz), 81.7, 80.8, 79.0, 77.0,
74.9, 74.5, 73.8, 73.3 72.9, 71.9, 69.8 (q, J ) 30.2 Hz), 67.9, 26.8,
26.6, 26.2, 24.9; 19F (376 MHz) δ -74.6 (d, J ) 6.3 Hz, 3F); ESIHRMS
calcd for C39H45F3NaO10 [M + Na]+, 735.2863; found, 735.2855.
1
26â: white solid; mp 87-89 °C; [R]18 +30.5 (c 0.80, CHCl3); H
D
(t, J ) 244.2 Hz), 109.6, 108.8, 102.3 (1JCH ) 157.4 Hz), 96.4 (1JCH
)
NMR (500 MHz) δ 7.40-7.45 (m, 2H), 7.27-7.37 (m, 13H), 5.84 (d,
J ) 3.5 Hz, 1H), 4.88-4.93 (m, 2H), 4.84 (d, J ) 12.5 Hz, 1H), 4.76
(d, J ) 3.5 Hz, 1H), 4.68 (d, J ) 10.1 Hz, 1H), 4.60 (s, 1H), 4.57 (d,
J ) 11.7 Hz, 1H), 4.54 (d, J ) 11.9 Hz, 1H), 4.18 (d, J ) 2.8 Hz,
1H), 4.15 (t, J ) 9.4 Hz, 1H), 4.02-4.10 (m, 2H), 3.93-4.00 (m, 2H),
3.87 (d, J ) 2.8 Hz, 1H), 3.71-3.78 (m, 1H), 3.52 (dd, J ) 9.4, 2.8
Hz, 1H), 1.49 (s, 3H), 1.37 (s, 3H), 1.31 (s, 3H), 1.21 (s, 3H); 13C
NMR (126 MHz) δ 138.2, 137.62, 137.59, 128.5, 128.4, 127.3, 128.24,
128.20, 128.0, 127.9, 127.6, 123.5 (q, J ) 280.2 Hz), 112.0, 109.2,
105.4 (1JCH ) 183.5 Hz), 102.6 (1JCH ) 157.8 Hz), 83.9, 83.3, 81.5,
81.0, 75.5, 74.1, 73.6, 73.23, 73.21 (q, J ) 30.5 Hz), 72.5, 72.2, 67.9,
26.84, 26.82, 26.1, 25.4; 19F (471 MHz) δ -75.4 (d, J ) 6.5 Hz, 3F);
ESIHRMS calcd for C39H45F3NaO10 [M + Na]+, 735.2863; found,
735.2863.
180.0 Hz), 80.7, 75.0, 74.0 (t, J ) 21.8 Hz), 73.63, 76.57, 72.3, 71.5,
71.3, 70.8, 70.5, 70.1, 68.0, 26.1, 26.0, 25.1, 24.4; 19F (471 MHz) δ
-131.1 (ddd, J ) 286.5, 54.6, 15.7 Hz, 1F), -132.2 (ddd, J ) 286.5,
54.3, 15.2 Hz, 1F); ESIHRMS calcd for C39H46F2NaO10 [M + Na]+,
735.2957; found, 735.2953.
Methyl 2,3,4-Tri-O-benzyl-6,6-difluoro-r-D-rhamnopyranosyl-
(1f4)-2,3,6-tri-O-benzyl-r-D-glucopyranoside (25r) and Methyl
2,3,4-Tri-O-benzyl-6,6-difluoro-â-D-rhamnopyranosyl-(1f4)-2,3,6-
tri-O-benzyl-r-D-glucopyranoside (25â). Prepared by method A from
6r (50 mg, 0.089 mmol) and 22 (50 mg, 0.107 mmol). Purification by
radial chromatography (SiO2, elution consecutive plates with hexanes
to 1/4 ethyl acetate/hexanes and then with 1/9 to 1/3 diethyl ether/
hexanes) gave 25r (22 mg, 27%) and 25â (33 mg, 41%). 25r: [R]24
+4.9 (c 0.39, CHCl3); H NMR (500 MHz) δ 7.19-7.38 (m, 28H),
D
1
2,3,4-Tri-O-benzyl-6,6,6-trifluoro-r-L-rhamnopyranosyl-(1f6)-
1,2:3,4-di-O-isopropylidene-r-D-galactopyranose (27r) and 2,3,4-
Tri-O-benzyl-6,6,6-trifluoro-â-L-rhamnopyranosyl-(1f6)-1,2:3,4-di-
O-isopropylidene-r-D-galactopyranose (27â). Prepared by method A
or method B (18 h at -60 to -65 °C) from 12â (25 mg, 0.043 mmol)
and 17 (14 mg, 0.052 mmol). Purification by radial chromatography
(SiO2, hexanes to 1/4 ethyl acetate/hexanes) gave 27r (4 mg, 11%,
method A), 27â, and 11r,â (combined yield 24 mg, 27â/11r,â )
1/0.08, 27â 72%, 11r,â 6%, method A) or only 27r (4 mg, 11%,
7.11-7.15 (m, 2H), 5.84 (t, J ) 54.6 Hz, 1H), 5.32 (d, J ) 2.0 Hz,
1H), 5.10 (d, J ) 11.7 Hz, 1H), 4.88 (d, J ) 10.8 Hz, 1H), 4.67 (d, J
) 12.1 Hz, 1H), 4.53-4.64 (m, 6H), 4.46-4.51 (m, 2H), 4.26 (d, J )
12.1 Hz, 1H), 4.21 (d, J ) 12.1 Hz, 1H), 4.00 (t, J ) 9.4 Hz, 1H),
3.80-3.89 (m, 3H), 3.66-3.75 (m, 5H), 3.54 (dd, J ) 9.5, 3.5 Hz,
1H), 3.39 (s, 3H); 13C NMR δ 138.8, 138.4, 138.2, 138.0, 137.8, 128.5,
128.4, 128.3, 128.2, 128.12, 128.06, 128.0, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.1, 126.6, 114.1 (t, J ) 244.1 Hz), 100.5 (1JCH
) 172.7 Hz), 97.7 (1JCH ) 171.3 Hz), 81.4, 79.9, 79.2, 78.2, 75.7,
75.02, 74.97, 73.6, 73.3, 73.2, 72.3, 72.0, 71.4 (t, J ) 20.4 Hz), 69.7,
69.0, 55.3; 19F (471 MHz) δ -132.2 (ddd, J ) 285.0, 53.6, 6.8 Hz,
1F), -133.2 (ddd, J ) 285.0, 53.3, 11.5 Hz, 1F); ESIHRMS calcd for
method B) and 27â (23 mg, 72%, method B). 27r: [R]15 -35.6 (c
D
1
0.18, CHCl3); H NMR (501 MHz) δ 7.24-7.40 (m, 15H), 5.50 (d, J
) 5.1 Hz, 1H), 4.99 (d, J ) 1.1 Hz, 1H), 4.85 (d, J ) 10.3 Hz, 1H),
4.72 (s, 2H), 4.66 (d, J ) 10.3 Hz, 1H), 4.57-4.61 (m, 3H), 4.32 (dd,
J ) 5.0, 2.6 Hz, 1H), 4.19-4.26 (m, 1H), 4.09-4.15 (m, 2H), 3.83-
3.93 (m, 3H), 3.80 (dd, J ) 2.9, 2.0 Hz, 1H), 3.55 (dd, J ) 8.8, 5.9
Hz, 1H), 1.51 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H); 13C
NMR (126 MHz) δ 138.2, 138.1, 128.4, 128.3, 128.0, 127.9, 127.74,
127.70, 124.4 (q, J ) 280.2 Hz), 109.5, 108.6, 97.9 (1JCH ) 173.7
Hz), 96.2 (1JCH ) 180.0 Hz), 79.1, 75.1, 73.94, 73.87, 72.6, 72.4, 70.7,
70.5, 69.8 (q, J ) 29.6 Hz), 66.5, 65.8, 26.2, 25.8, 25.0, 24.4; 19F (471
C55H58F2NaO10 [M + Na]+, 939.3896; found, 939.3887. 25â: [R]24
-26.0 (c 0.57, CHCl3); H NMR (500 MHz) δ 7.20-7.43 (m, 30H),
D
1
5.81 (t, J ) 54.5 Hz, 1H), 5.06 (d, J ) 11.0 Hz, 1H), 4.85 (d, J ) 10.6
Hz, 1H), 4.76-4.82 (m, 4H), 4.59-4.67 (m, 3H), 4.58 (d, J ) 12.1
Hz, 1H), 4.44-4.51 (m, 3H), 4.33 (d, J ) 12.1 Hz, 1H), 4.02 (t, J )
9.0 Hz, 1H), 3.88-3.97 (m, 2H), 3.70-3.74 (m, 1H), 3.68 (d, J ) 2.8
Hz, 1H), 3.62 (dd, J ) 11.0, 1.8 Hz, 1H), 3.52-3.57 (m, 2H), 3.40 (s,
9
J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007 11763

A R T I C L E S
Crich and Vinogradova
MHz) δ -75.8 (d, J ) 6.5 Hz, 3F); ESIHRMS calcd for C39H45F3-
4.84-4.89 (m, 2H), 4.79 (d, J ) 12.4 Hz, 1H), 4.74 (d, J ) 12.4 Hz,
1H), 4.66 (d, J ) 10.2 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.57 (d, J
) 11.7 Hz, 1H), 4.15 (t, J ) 9.2 Hz, 1H), 3.98-4.11 (m, 3H), 3.79-
3.85 (m, 2H), 3.54-3.62 (m, 1H), 3.48-3.53 (m, 1H), 3.38 (s, 3H),
1.54 (s, 3H), 1.36 (s, 3H), 1.26 (d, J ) 6.1 Hz, 3H);13C NMR (126
MHz) δ 138.1, 138.0, 137.8, 128.4, 128.3, 128.0, 127.8, 127.73, 127.68,
127.6, 124.1 (q, J ) 280.2 Hz), 109.7, 98.0 (1JCH ) 167.4 Hz), 97.2
(1JCH ) 175.9 Hz), 79.1, 78.7, 78.3, 76.1, 75.3, 74.3, 73.8, 72.42, 72.36,
70.6 (q, J ) 29.6 Hz), 63.6, 54.9, 27.9, 26.4, 18.0; 19F (471 MHz) δ
-75.8 (d, J ) 5.8 Hz, 3F); ESIHRMS calcd for C37H43F3NaO9 [M +
Na]+, 711.2757; found, 711.2765. 29â: [R]15D +40.6 (c 0.29, CHCl3);
1H NMR (400 MHz) δ 7.40-7.45 (m, 2H), 7.26-7.35 (m, 13H), 4.98
(d, J ) 12.6 Hz, 1H), 4.89 (d, J ) 9.9 Hz, 1H), 4.83 (s, 1H), 4.81 (d,
J ) 12.7 Hz, 1H), 4.64-4.69 (m, 2H), 4.46-4.56 (m, 3H), 4.10-4.16
(m, 2H), 3.92 (d, J ) 2.9 Hz, 1H), 3.70-3.79 (m, 2H), 3.54 (dd, J )
9.2, 2.9 Hz, 1H), 3.40 (dd, J ) 9.7, 7.1 Hz, 1H), 3.37 (s, 3H), 1.47 (s,
3H), 1.30 (s, 3H), 1.28 (d, J ) 6.3 Hz, 3H); 13C NMR (101 MHz) δ
138.3, 137.8, 137.7, 128.4, 128.3, 128.2, 127.9, 127.8, 127.6, 127.5,
NaO10 [M + Na]+, 753.2863; found, 753.2851. 27â: [R]15 +29.1 (c
D
1
0.43, CHCl3); H NMR (500 MHz) δ 7.44-7.49 (m, 2H), 7.24-7.35
(m, 13H), 5.52 (d, J ) 5.0 Hz, 1H), 4.96 (d, J ) 12.5 Hz, 1H), 4.89
(d, J ) 10.1 Hz, 1H), 4.88 (d, J ) 12.3 Hz, 1H), 4.66 (d, J ) 9.9 Hz,
1H), 4.59 (dd, J ) 8.0, 2.3 Hz, 1H), 4.52 (d, J ) 11.7 Hz, 1H), 4.484
(s, 1H), 4.479 (d, J ) 11.7 Hz, 1H), 4.32 (dd, J ) 5.0, 2.4 Hz, 1H),
4.19 (dd, J ) 8.1, 1.8 Hz, 1H), 4.13 (t, J ) 9.4 Hz, 1H), 4.04 (ddd, J
) 8.0, 6.2, 1.6 Hz, 1H), 3.98 (dd, J ) 9.4, 6.0 Hz, 1H), 3.92 (d, J )
2.9 Hz, 1H), 3.74 (dd, J ) 9.4, 8.4 Hz, 1H), 3.66-3.73 (m, 1H), 3.52
(dd, J ) 9.5, 2.9 Hz, 1H), 1.55 (s, 3H), 1.45 (s, 3H), 1.34 (s, 3H), 1.32
(s, 3H); 13C NMR (126 MHz) δ 138.4, 137.74, 137.67, 128.43, 128.39,
128.3, 128.2, 127.9, 127.8, 127.62, 127.55, 123.6 (q, J ) 281.1 Hz),
109.1, 108.6, 102.0 (1JCH ) 156.5 Hz), 96.2 (1JCH ) 179.6 Hz), 81.4,
75.5, 73.8, 73.7, 73.2 (q, J ) 30.5 Hz), 72.9, 71.9, 70.7, 70.5, 68.1,
65.6, 26.0, 24.9, 24.4; 19F (471 MHz) δ -75.3 (d, J ) 5.8 Hz, 3F);
ESIHRMS calcd for C39H45F3NaO10 [M + Na]+, 753.2863; found,
753.2835.
123.6 (q, J ) 280.9 Hz), 109.0, 101.2 (1JCH ) 155.2 Hz), 98.4 (1JCH
)
Methyl 2,3,4-Tri-O-benzyl-6,6,6-trifluoro-r-L-rhamnopyranosyl-
(1f4)-2,3,6-tri-O-benzyl-r-D-glucopyranoside (28r) and Methyl
2,3,4-Tri-O-benzyl-6,6,6-trifluoro-â-L-rhamnopyranosyl-(1f4)-2,3,6-
tri-O-benzyl-r-D-glucopyranoside (28â). Prepared by method A from
12â (50 mg, 0.086 mmol) and 22 (48 mg, 0.103 mmol) or by method
B (24 h at -60 to -65 °C) from 12â (25 mg, 0.043 mmol) and 22 (24
mg, 0.052 mmol). Purification by radial chromatography (SiO2, hexanes
to 3/17 ethyl acetate/hexanes) gave 28r, 28â, and 11r,â (combined
yield 56 mg, 28r/28â/11r,â ) 1/1.2/0.02, 28r 31%, 28â 38%, 11r,â
<1%, method A or 31 mg, 28r/28â/11r,â ) 1/1.29/0.41, 28r 31%,
28â 39%, 11r,â 12%, method B). Analytical samples were obtained
167.2 Hz), 83.9, 82.0, 76.2, 75.7, 75.5, 73.9, 73.7, 73.5, 73.1 (q, J )
30.2 Hz), 71.9, 63.7, 54.9, 28.0, 25.9, 17.9; 19F (376 MHz) δ -74.4
(d, J ) 6.3 Hz, 3F); ESIHRMS calcd for C37H43F3NaO9 [M + Na]+,
711.2757; found, 711.2769.
2,3,4-Tri-O-benzyl-r-L-rhamnopyranosyl-(1f3)-1,2:5,6-di-O-iso-
propylidene-r-D-glucofuranose (34r) and 2,3,4-Tri-O-benzyl-â-L-
rhamnopyranosyl-(1f3)-1,2:5,6-di-O-isopropylidene-r-D-glucofura-
nose (34â). Prepared by method A from 3082 (50 mg, 0.095 mmol)
and 16 (30 mg, 0.115 mmol). Purification by radial chromatography
(SiO2, hexanes to 3/17 ethyl acetate/hexanes) gave 34r (42 mg, 65%)
and 34â (6 mg, 10%). 34r: [R]2D3 -68.1 (c 0.80, CHCl3); H NMR
1
by further purification by radial chromatography (SiO2, 1/7 to 3/17
1
ethyl acetate/hexanes). 28r: [R]18 -2.7 (c 1.12, CHCl3); H NMR
(501 MHz) δ 7.25-7.41 (m, 15H), 5.77 (d, J ) 3.9 Hz, 1H), 4.93 (d,
J ) 11.4 Hz, 1H), 4.86 (d, J ) 12.3 Hz, 1H), 4.75 (d, J ) 1.5 Hz,
1H), 4.63-4.69 (m, 4H), 4.28 (d, J ) 3.1 Hz, 1H), 4.14-4.19 (m,
2H), 4.05-4.09 (m, 2H), 3.94-4.01 (m, 1H), 3.90 (dd, J ) 8.4, 5.9
Hz, 1H), 3.75 (dd, J ) 9.2, 3.1 Hz, 1H), 3.69 (dd, J ) 3.0, 1.9 Hz,
1H), 3.60 (t, J ) 9.4 Hz, 1H), 1.49 (s, 3H), 1.38 (s, 3H), 1.31 (s, 3H),
1.28 (s, 3H), 1.28 (d, J ) 6.2 Hz, 3H); 13C NMR (126 MHz) δ 139.1,
138.6, 138.5, 128.64, 128.59, 128.4, 128.04, 127.98, 127.9, 127.8, 127.6,
112.2, 109.4, 105.4 (1JCH ) 182.7 Hz), 96.1 (1JCH ) 168.2 Hz), 82.0,
81.2, 80.5, 80.1, 76.9, 75.5, 75.1, 73.6, 72.8, 72.2, 68.8, 68.0, 27.0,
D
(500 MHz) δ 7.18-7.37 (m, 30H), 5.23 (d, J ) 1.5 Hz, 1H), 4.92 (d,
J ) 10.5 Hz, 1H), 4.84 (d, J ) 10.3 Hz, 1H), 4.70-4.77 (m, 2H), 4.62
(d, J ) 10.3 Hz, 1H), 4.54-4.58 (m, 6H), 4.52 (d, J ) 9.4 Hz, 1H),
4.41 (d, J ) 12.1 Hz, 1H), 4.33-4.40 (m, 1H), 4.10 (t, J ) 9.4 Hz,
1H), 3.79-3.88 (m, 3H), 3.61-3.65 (m, 2H), 3.52-3.57 (m, 2H), 3.43
(dd, J ) 11.1, 3.4 Hz, 1H), 3.35 (s, 3H); 13C NMR (126 MHz) δ 138.3,
138.11, 138.07, 138.03, 137.97, 137.8, 128.5, 128.4, 128.24, 128.22,
128.1, 128.0, 127.73, 127.67, 127.5, 127.4, 124.3 (q, J ) 281.1 Hz),
97.9 (1JCH ) 168.7 Hz), 97.2 (1JCH ) 170.0 Hz), 80.6, 79.8, 78.5, 75.4,
75.2, 74.3, 74.1, 73.8, 73.6, 73.4, 72.33, 72.31, 70.4 (q, J ) 29.6 Hz),
69.7, 68.8, 55.3; 19F (471 MHz) δ -75.8 (d, J ) 6.5 Hz, 3F); ESIHRMS
calcd for C55H57F3NaO10 [M + Na]+, 957.3802; found, 957.3778.
28â: [R]17D +35.3 (c 0.85, CHCl3); 1H NMR (500 MHz) δ 7.18-7.42
(m, 28H), 7.11-7.15 (m, 2H), 4.99 (d, J ) 11.6 Hz, 1), 4.82 (d, J )
9.9 Hz, 1H), 4.72-4.80 (m, 3H), 4.58-4.68 (m, 5H), 4.48 (d, J )
12.3 Hz, 1H), 4.35 (d, J ) 11.6 Hz, 1H), 4.25 (d, J ) 11.6 Hz, 1H),
4.22 (d, J ) 11.7 Hz, 1H), 4.02 (t, J ) 9.5 Hz, 1H), 3.90 (dd, J )
11.0, 2.0 Hz, 1H), 3.87 (t, J ) 9.4 Hz, 1H), 3.76-3.82 (m, 1H), 3.51-
3.61 (m, 5H), 3.45 (s, 3H), 3.14 (dd, J ) 9.4, 2.8 Hz, 1H); 13C NMR
(126 MHz) δ 138.7, 138.5, 138.4, 137.88, 137.85, 137.6, 128.5, 128.42,
128.39, 128.3, 128.20, 128.15, 128.1, 127.9, 127.73, 127.67, 127.4,
127.34, 127.29, 123.6 (q, J ) 281.1 Hz), 102.2 (1JCH ) 158.3 Hz),
97.7 (1JCH ) 165.6 Hz), 82.01, 81.97, 79.8, 76.9, 75.5, 75.4, 73.7, 73.4,
73.1, 72.9 (q, J ) 29.6 Hz), 72.8, 71.9, 69.6, 69.3, 55.4; 19F (471 MHz)
δ -75.4 (d, J ) 5.8 Hz, 3F); ESIHRMS calcd for C55H57F3NaO10 [M
+ Na]+, 957.3802; found, 957.3787.
26.4, 25.5, 17.9; ESIHRMS calcd for C39H48NaO10 [M + Na]+,
1
699.3145; found, 699.3107. 34â: [R]22 +13.3 (c 0.06, CHCl3); H
D
NMR (501 MHz) δ 7.22-7.45 (m, 15H), 5.87 (d, J ) 3.5 Hz, 1H),
4.96 (d, J ) 10.6 Hz, 1H), 4.91 (d, J ) 12.6 Hz, 1H), 4.84 (d, J )
12.6 Hz, 1H), 4.80 (d, J ) 3.7 Hz, 1H), 4.66 (d, J ) 10.8 Hz, 1H),
4.56 (d, J ) 12.0 Hz, 1H), 4.49-4.53 (m, 2H), 4.16 (d, J ) 2.6 Hz,
1H), 4.01-4.08 (m, 2H), 3.92-3.99 (m, 2H), 3.86 (d, J ) 2.8 Hz,
1H), 3.62 (t, J ) 9.4 Hz, 1H), 3.46 (dd, J ) 9.0, 2.6 Hz, 1H), 3.30-
3.37 (m, 1H), 1.50 (s, 3H), 1.39 (d, J ) 6.1 Hz, 3H), 1.37 (s, 3H),
1.31 (s, 3H), 1.21 (s, 3H); 13C NMR (126 MHz) δ 138.8, 138.7, 138.4,
128.7, 128.6, 128.41, 128.37, 128.0, 127.94, 127.86, 127.8, 112.1, 109.3,
105.7 (1JCH ) 183.5 Hz), 102.8 (1JCH ) 155.8 Hz), 84.5, 83.0, 82.6,
81.4, 80.3, 75.7, 74.3, 74.2, 72.8, 72.4, 72.1, 68.2, 27.12, 27.09, 26.5,
25.7, 18.3; ESIHRMS calcd for C39H48NaO10 [M + Na]+, 699.3145;
found, 699.3122.
2,3,4,6-Tri-O-benzyl-r-D-mannopyranosyl-(1f3)-1,2:5,6-di-O-iso-
propylidene-r-D-glucofuranose (35r) and 2,3,4,6-Tri-O-benzyl-â-
D-mannopyranosyl-(1f3)-1,2:5,6-di-O-isopropylidene-r-D-gluco-
furanose (35â). Prepared by method A from 3183 (50 mg, 0.079 mmol)
and 16 (25 mg, 0.095 mmol). Purification by radial chromatography
(SiO2, hexanes to 1/4 ethyl acetate/hexanes) gave 35r (44 mg, 71%)
and 35â (5 mg, 8%). 35r: [R]2D4 +16.3 (c 0.10, CHCl3); lit. [R]D
+15.9 (c 0.08, CHCl3);88 1H NMR (501 MHz) δ 7.21-7.40 (m, 18H),
7.15-7.20 (m, 2H), 5.81 (d, J ) 3.5 Hz, 1H), 5.25 (s, 1H), 4.90 (d, J
Methyl 2,3,4-Tri-O-benzyl-6,6,6-trifluoro-r-L-rhamnopyranosyl-
(1f4)-2,3-O-isopropylidene-r-L-rhamnopyranoside (29r) and Meth-
yl 2,3,4-Tri-O-benzyl-6,6,6-trifluoro-â-L-rhamnopyranosyl-(1f4)-
2,3-O-isopropylidene-r-L-rhamnopyranoside (29â). Prepared from
12â (25 mg, 0.043 mmol) and 18 (11 mg, 0.052 mmol) by method B.
Purification by radial chromatography (SiO2, hexanes to 3/17 ethyl
acetate/hexanes) gave 29r (5 mg, 15%), 29â (15 mg, 52%), and 11r,â
(1 mg, 4%). 29r: [R]15D -11.3 (c 0.08, CHCl3); 1H NMR (400 MHz)
δ 7.40-7.45 (m, 2H), 7.29-7.38 (m, 13H), 5.57 (d, J ) 1.2 Hz, 1H),
(88) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320, 61-69.
9
11764 J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007

Fluoro-Substituted Rhamnopyranosides
A R T I C L E S
) 10.5 Hz, 1H), 4.76 (d, J ) 12.3 Hz, 1H), 4.65-4.70 (m, 3H), 4.49-
4.61 (m, 4H), 4.28 (s, 1H), 3.97-4.11 (m, 5H), 3.75-3.86 (m, 5H),
1.49 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H); 13C NMR (126
MHz) δ 138.6, 138.50, 138.47, 138.4, 128.63, 128.58, 128.55, 128.4,
128.1, 128.0, 127.92, 127.86, 127.8, 112.2, 109.5, 105.5 (1JCH ) 182.9
Hz), 99.1 (1JCH ) 170.4 Hz), 83.9, 81.6, 80.8, 79.8, 75.5, 75.0, 74.5,
73.7, 72.9, 72.8, 72.5, 72.3, 69.5, 67.9, 27.14, 27.05, 26.3, 25.8. Spectral
5H), 3.26 (dd, J ) 9.2, 7.9 Hz, 1H); 13C NMR (101 MHz) δ 125.3 (q,
J ) 280.4 Hz), 102.2 (1JCH ) 162.2 Hz), 102.0 (1JCH ) 161.8 Hz),
97.7 (1JCH ) 159.6 Hz, C1â), 93.5 (1JCH ) 168.1 Hz. C1R), 86.0, 83.3,
77.8, 75.0 (q, J ) 29.5 Hz), 74.6, 74.4, 73.0, 72.2, 71.8, 71.7, 71.4,
71.3, 67.3, 62.5, 62.4; 19F (377 MHz) δ -75.6 (d, J ) 6.3 Hz, 3F),
-75.7 (d, J ) 6.3 Hz, 3F); ESIHRMS calcd for C12H19F3NaO10 [M +
Na]+, 403.0828; found, 403.0817.
data recorded in C6D6 matched that reported in literature.88 35â: [R]23
Methyl 6,6,6-Trifluoro-â-L-rhamnnopyranosyl-(1f4)-r-L-rham-
nopyranoside (38). A mixture of 29â (10 mg, 0.015 mmol), trifluo-
roacetic acid (1.8 mL), and water (0.2 mL) was stirred for 15 min at
room temperature, and then rapidly concentrated under reduced pressure.
The reaction mixture was filtered through a pad of silica gel (with 3/7
mixture of hexanes/ethyl acetate as an eluent) and concentrated. The
residue was dissolved in MeOH/ethyl acetate (2 mL/1 mL), and Pd-
(OH)2/C (50% H2O, 15 wt %, 6 mg, 0.004 mmol) was added. The
reaction mixture was shaken overnight in the pressure vessel under an
atmosphere of hydrogen (50 psi) and then concentrated. Purification
by column chromatography (SiO2, 3/17 to 1/4 MeOH/CHCl3) gave 38
(5 mg, 84%, two steps). Mp 86 °C (decomp); [R]1D6 -20.9 (c 0.23,
D
1
-41.9 (c 0.32, CHCl3); H NMR (501 MHz) δ 7.20-7.43 (m, 20H),
5.92 (d, J ) 3.7 Hz, 1H), 4.90 (d, J ) 12.1 Hz, 1H), 4.89 (d, J ) 10.6
Hz, 1H), 4.79 (d, J ) 11.9 Hz, 1H), 4.72 (d, J ) 11.9 Hz, 1H), 4.55-
4.60 (m, 3H), 4.53 (d, J ) 11.9 Hz, 1H), 4.49 (s, 1H), 4.45-4.48 (m,
2H), 4.35 (d, J ) 2.9 Hz, 1H), 4.31 (dd, J ) 5.1, 3.1 Hz, 1H), 4.10-
4.13 (m, 1H), 4.03-4.07 (m, 1H), 3.96 (t, J ) 9.5 Hz, 1H), 3.85 (d, J
) 2.8 Hz, 1H), 3.77-3.83 (m, 2H), 3.52 (dd, J ) 9.4, 2.9 Hz, 1H),
3.43 (ddd, J ) 9.6, 4.7, 2.4 Hz, 1H), 1.50 (s, 3H), 1.39 (s, 3H), 1.31
(s, 3H), 1.22 (s, 3H); 13C NMR (126 MHz) δ 138.80, 138.75, 138.5,
138.4, 128.64, 128.61, 128.56, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8,
112.2, 108.8, 105.3 (1JCH ) 182.9 Hz), 99.9 (1JCH ) 154.1 Hz), 83.2,
82.6, 80.89. 80.85, 76.8, 75.5, 74.9, 74.7, 74.3, 74.0, 73.5, 72.1, 69.6,
66.4, 27.1, 26.9, 26.6, 25.5; ESIHRMS calcd for C46H54NaO11 [M +
Na]+, 805.3564; found, 805.3522.
1
MeOH); H NMR (400 MHz) δ 4.78 (s, 1H), 4.57 (d, J ) 1.6 Hz,
1H), 3.96 (d, J ) 3.1 Hz, 1H), 3.80-3.90 (m, 3H), 3.77 (dd, J ) 9.1,
3.3 Hz, 1H), 3.63-3.72 (m, 1H), 3.59 (t, J ) 9.3 Hz, 1H), 3.53 (dd, J
Methyl 6,6,6-Trifluoro-â-L-rhamnnopyranosyl-(1f4)-r-D-glu-
copyranoside (36). A mixture of 28â (16 mg, 0.017 mmol) and Pd/C
(15 wt %, 14 mg, 0.02 mmol) in MeOH/ethyl acetate (1 mL/2 mL)
was shaken overnight in a pressure vessel under an atmosphere of
hydrogen (50 psi). The reaction mixture was filtered twice through a
) 8.8, 3.1 Hz, 1H), 3.34 (s, 3H), 1.29 (d, J ) 6.1 Hz, 3H);
13C NMR
(126 MHz) δ 125.3 (q, J ) 280.2 Hz), 102.5 (1JCH ) 158.6 Hz), 102.4
(1JCH ) 168.7 Hz), 84.8, 74.9 (q, J ) 29.6 Hz), 74.4, 71.8, 71.5, 70.7,
67.9, 67.1, 55.2, 17.9; 19F (377 MHz) δ -75.7 (d, J ) 6.3 Hz, 3F);
ESIHRMS calcd for C13H21F3NaO9 [M + Na]+, 401.1035; found,
401.1030.
pad of Celite (with MeOH as an eluent) and concentrated to give 36
1
(7 mg, quantitative). [R]16 +107.0 (c 0.29, MeOH); H NMR (400
6,6,6-Trifluoro-â-L-rhamnnopyranosyl-(1f6)-1,2:3,4-di-O-iso-
propylidene-r-D-galactopyranose (39). A mixture of 27â (13 mg,
D
MHz) δ 4.92 (s, 1H), 4.67 (d, J ) 3.8 Hz, 1H), 4.01 (d, J ) 2.9 Hz,
1H), 3.90-3.97 (m, 1H), 3.84 (t, J ) 9.5 Hz, 1H), 3.76 (t, J ) 9.4 Hz,
1H), 3.66-3.73 (m, 1H), 3.59-3.66 (m, 2H), 3.43-3.50 (m, 2H), 3.37-
3.43 (m, 4H); 13C NMR (101 MHz) δ, 125.4 (q, J ) 280.1 Hz), 102.8
(1JCH ) 162.1 Hz), 101.0 (1JCH ) 172.4 Hz), 79.2, 75.0, 74.9 (q, J )
29.3 Hz), 74.5, 73.6, 72.1, 71.5, 67.3, 63.2, 55.6; 19F (377 MHz) δ
-75.9 (d, J ) 6.3 Hz, 3F); ESIHRMS calcd for C13H21F3NaO10 [M +
Na]+, 417.0985; found, 417.0983.
0.017 mmol) and Pd(OH)
2/C (50% H2O, 15 wt %, 15 mg, 0.01 mmol)
in MeOH/ethyl acetate (1 mL/2 mL) was shaken for 24 h in the pressure
vessel under an atmosphere of hydrogen (50 psi). The reaction mixture
was filtered twice through a pad of Celite (with MeOH and then with
ethyl acetate as an eluent) and concentrated to give 39 (8 mg,
1
quantitative). [R]16
-17.0 (c 0.37, CHCl3); H NMR (500 MHz) δ
D
5.52 (d, J ) 5.1 Hz, 1H), 4.59-4.65 (m, 2H), 4.33 (dd, J ) 5.0, 2.4
Hz, 1H), 4.29 (dd, J ) 7.9, 1.5 Hz, 1H), 4.09 (br s, 1H), 3.96-4.06
(m, 3H), 3.82 (dd, J ) 9.5, 6.8 Hz, 1H), 3.54-3.68 (m, 2H), 3.24 (br
6,6,6-Trifluoro-â-L-rhamnopyranosyl-(1f3)-r,â-D-glucopyra-
nose (37). A mixture of 26â and 11r,â (40 mg, 26â/11r,â ) 6/1, 26â
0.049 mmol), trifluoroacetic acid (1.8 mL), and water (0.2 mL) was
stirred for 15 min at room temperature and then rapidly concentrated
under reduced pressure. Purification by radial chromatography (SiO2,
CHCl3 to 1/9 MeOH/CHCl3), collecting only the more polar fractions,
gave the product as a clear oil (29 mg, 90%). A mixture of the product
and Pd(OH)2/C (50% H2O, 15 wt %, 38 mg, 0.027 mmol) in MeOH/
ethyl acetate (2 mL/1 mL) was shaken for 24 h in a pressure vessel
under an atmosphere of hydrogen (50 psi). The reaction mixture was
filtered twice through a pad of Celite (with MeOH as an eluent),
concentrated, and washed with CH2Cl2 to give 37 (17 mg, 90%, two
steps, R/â ∼ 1/1). White solid; mp 141 °C (decomp); [R]19D +55.7 (c
s, 3H), 1.52 (s, 3H), 1.45 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H); 13
C NMR
(126 MHz) δ 123.3 (q, J ) 280.6 Hz), 109.5, 108.8, 100.0 (1JCH
)
159.2 Hz), 96.2 (1JCH ) 180.6 Hz), 73.5, 73.4 (q, J ) 30.7 Hz), 70.7,
70.6, 70.5, 69.5, 67.8, 66.9, 65.6, 26.0, 24.8, 24.5;
19F (471 MHz) δ
-75.8 (d, J ) 5.8 Hz, 3F); ESIHRMS calcd for C
18H27F3NaO10 [M +
Na]+, 483.1454; found, 483.1437.
Acknowledgment. We thank the NIH (GM62160) for support
of this work.
Supporting Information Available: Details of the preparation
of all donors and copies of NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
0.30, MeOH); H NMR (500 MHz) δ 5.16 (d, J ) 3.7 Hz, 1H, H1R),
5.04 (dd, J ) 4.5, 0.6 Hz, 2H), 4.55 (d, J ) 7.7 Hz, 1H, H1â), 4.04 (d,
J ) 3.1 Hz, 2H), 3.92 (t, J ) 9.2 Hz, 1H), 3.87 (t, J ) 9.5 Hz, 2H),
3.84 (dd, J ) 11.9, 2.4 Hz, 1H), 3.58-3.82 (m, 8H), 3.45-3.53 (m,
JA0730258
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J. AM. CHEM. SOC. VOL. 129, NO. 38, 2007 11765