Why are the hydroxy groups of partially protected N-acetylglucosamine derivatives such poor glycosyl acceptors, and what can be done about it? A comparative study of the reactivity of N-acetyl-, N-phthalimido-, and 2-azido-2-deoxy-glucosamine derivatives

Article abstract of DOI:10.1021/ja010086b

Competition experiments were used to determine that the 4-OH of a 2-deoxy-2-azidoglucose derivative is more reactive than that of the corresponding N-phthalimido glucose derivative which, in turn, is more easily glycosylated than the N-acetyl derivative.

Full text of DOI:10.1021/ja010086b

J. Am. Chem. Soc. 2001, 123, 6819-6825
6819
Why Are the Hydroxy Groups of Partially Protected
N-Acetylglucosamine Derivatives Such Poor Glycosyl Acceptors, and
What Can Be Done about It? A Comparative Study of the Reactivity
of N-Acetyl-, N-Phthalimido-, and 2-Azido-2-deoxy-glucosamine
Derivatives in Glycosylation. 2-Picolinyl Ethers as
Reactivity-Enhancing Replacements for Benzyl Ethers
David Crich* and Vadim Dudkin
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
ReceiVed January 9, 2001
Abstract: Competition experiments were used to determine that the 4-OH of a 2-deoxy-2-azidoglucose derivative
is more reactive than that of the corresponding N-phthalimido glucose derivative which, in turn, is more easily
glycosylated than the N-acetyl derivative. Glycosylation of the 4-OH groups of the N,N-diacetyl and N-acetyl-
N-benzyl glucosamine was also found to be superior to that of the simple N-acetyl substance. The 3-O-picolinyl
ether of a 4,6-O-benzylidene-protected N-acetylglucosamine was shown to have a strong intramolecular hydrogen
bond to the adjacent acetamide group. This interaction does not persist in the 3-O-picolinyl-6-O-benzyl
N-acetylglucosamine derivative, owing to a probable competing hydrogen bond between the 4-OH and the
picolinyl ether. However, in the 3-O-picolinyl-4-O-benzyl N-acetylglucosamine regioisomer the picolinyl-
acetamide hydrogen bond persists and leads to an enhancement of reactivity of the 6-OH, over and above that
in the corresponding 3-O-benzyl ether, due to disruption of the typical intermolecular amide hydrogen bonding
scheme. It is demonstrated that the picolinyl ether is readily removed by hydrogenolysis at atmospheric pressure
and room temperature.
Introduction
which necessitate adjustment of the amino functionality after
glycosylation. Interestingly, given the very widespread applica-
tion of these two derivatives,7 there appears to have been no
systematic comparison of their reactivity.8 The aims of the in-
vestigations set out here were multiple and included: (i) deter-
mination of the relative reactivities of 1, 2, and 3, (ii) under-
standing why 1 is such a poor nucleophile, and (iii) using that
understanding to design and develop simpler, better surrogates
for 1.
Part of the perceived wisdom in preparative carbohydrate
chemistry is that the 4-hydroxy group of N-acetyl glucosamine
derivatives (e.g., 1) is a very poor nucleophile (glycosyl
acceptor) in glycosylation reactions.1 We have no reason to
doubt this principle. Indeed in our own work on â-mannosy-
lation, methyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-â-D-glu-
copyranoside (the anomer of 1) was by far the least reactive of
a spectrum of primary, secondary, and tertiary alcohols assayed.2
This lack of reactivity is unfortunate and severely hampers the
synthesis of a very broad spectrum of biologically important
oligosaccharides and glycoconjugates in which glycosidic bonds
to the N-acetyl glucosamine 4-OH are an essential component.3-6
Not the least of these is the common core pentasaccharide of
the N-linked glycoproteins, the very heart of which is an
exceptionally difficult â-mannoside of N-acetylglucosamine
4-OH.3-6 In view of the importance of such linkages numerous
strategies have evolved with the aim of circumventing the lack
of reactivity of the said hydroxy group. Chief among these has
been the use of 2-azido-2-deoxy-glucopyranosides (e.g., 2) and
of N-phthalimido glucosaminopyranosides (e.g., 3), both of
Results and Discussion
We began our study with the preparation of the two known
acceptors 1,9 and 3.10,11 and a third very readily prepared one
2, which was accessible by standard methods.12 Each was
coupled under a set of standard conditions with the mannosyl
sulfoxide 4,2 which was activated to triflate 513 prior to addition
(7) For some of the many examples see the chapters by Schmidt, R. R.;
Jung, K.-H., by Nicolaou, K. C.; Ueno, H., and by Fraser-Reid, B.; Madsen,
R. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997.
(8) Debendham, J.; Rodebaugh, R.; Fraser-Reid, B. Liebigs Ann./Recl.
1997, 791-802.
(9) Rana, S. S.; Barlow, J. J.; Matta, K. L. Carbohydr. Res. 1983, 113,
257-271.
(1) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-224.
(2) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(3) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(4) Varki, A. Glycobiology 1993, 3, 97-130.
(5) Lehmann, J. Carbohydratres. Structure and Biology; Thieme: Stut-
tgart, 1998.
(10) Alais, J.; David, S. Carbohydr. Res. 1990, 201, 69-77.
(11) van der Ven, J. G. M.; Kerekgyarto, J.; Kamerling, J. P.; Liptak,
A.; Vliegenthart, J. F. G. Carbohydr. Res. 1994, 264, 45-62.
(12) Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV. Chim.
Acta 1991, 74, 2073-2077.
(6) Bioorganic Chemistry: Carbohydrates; Hecht, S. M., Ed.; OUP: New
York, 1999; p 624.
(13) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
10.1021/ja010086b CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/21/2001

6820 J. Am. Chem. Soc., Vol. 123, No. 28, 2001
Crich and Dudkin
Scheme 1
Scheme 2
Scheme 3
of the acceptors (Scheme 1). In each case the saccharides were
isolated and shown to be the â-anomers, as anticipated, on the
basis of the mannose H-5 chemical shift and the mannose 1JCH
anomeric coupling constant.2 The byproducts from these reac-
tions were not quantified but did consist in the main of 2,3-di-
O-benzyl-4,6-O-benzylidene-R/â-D-mannopyranose as is typical
in couplings to less reactive alcohols by this method.
and resulted in the isolation of disaccharide 15 in 39% yield
(Scheme 3). An experiment in which equimolar quantities of 1
and 14 were allowed to compete for triflate 5 produced
disaccharides 6 and 15, respectively, in the ratio 1/2.2. No such
competition experiment could be conducted between 1 and 12,
owing to the partial deacetylation of the disaccharide derived
from 12 (vide supra). It is nevertheless evident that both 12
and 14 are superior to 1 and somewhat comparable to phthal-
imide 3 in terms of reactivity as glycosyl acceptors, but inferior
to azide 2. Unfortunately, both harbor undesirable characteris-
tics: the instability of the imide function in 12 and the
complication of NMR spectra due to the presence of two amide
rotamers in 14, which render them less attractive in general than
3 and, especially, 2.
With authentic samples of 6, 7, and 8 in hand a competition
experiment was conducted in which 4 was allowed to react,
via 5, with an equimolar mixture of 1, 2, and 3. Analysis of the
crude reaction mixture by HPLC determined the ratio of 6:7:8
to be 0.1:1.0:0.3 with good agreement from two separate
experiments. These simple experiments demonstrate that with
a reactive glycosyl donor, such as 5, the azido acceptor 2 is
some 10 times more reactive than the N-acetyl acceptor 1, with
the phthalimido-protected glucosamine acceptor 3 falling be-
tween the two. The azide 2 is therefore clearly the acceptor of
choice for such couplings.
A final option, the 1,6-anhydro-2-deoxy-2-azido glucose
derivative 16 was excluded from our study as, although it is a
moderately reactive mannosyl acceptor, the â/R-selectivity was
a less than optimal 5/1.2 Moreover, the preparation of 16 is
somewhat lengthy and detracts from its overall usefulness.14,15
All in all, it is clear that among the spectrum of N-acetylglu-
cosamine derivatives currently available as acceptors the
2-azido-2-deoxy-system is the most reactive one, at least in
â-mannosylations as practiced in this laboratory.
It is patently obvious that 1 differs from its more reactive
surrogates 2, 3, 12, 14, and 16 by the possession of an amide
N-H capable of hydrogen bonding. Similarly, it requires no
great leap of imagination to surmise that it is hydrogen bonding
that is in some way responsible for the lack of reactivity of 1.
Following this line of thought we reasoned that disrupting any
N,N-Diacetylglucosamine derivatives and N-benzyl-N-acetyl-
glucosamines have been previously employed as glycosyl donors
but not as acceptors. Accordingly, we prepared the imide 12
and tertiary amide 14 as set out in Scheme 2.
Coupling of 12 with sulfoxide 4 under the standard conditions
gave a crude reaction mixture that was complicated by partial
imide hydrolysis, both at the level of unreacted 12 (giving 1)
and in terms of the coupled product. The crude reaction mixture
was therefore treated with sodium methoxide in methanol to
complete hydrolysis of the imides to the acetamides. Subsequent
treatment of the reaction mixture with succinic anhydride, to
render any alcohols present more polar, and chromatography
on silica gel enabled isolation of disaccharide 6 in 47% yield
(Scheme 3). Coupling of 14 and sulfoxide 4 was more
straightforward, although it was again necessary to derivatize
the residual alcohols as hemisuccinates to facilitate separation,
(14) Tailler, D.; Jacquinet, J.-C.; Noirot, A.-M.; Beau, J.-M. J. Chem.
Soc., Perkin Trans. 1 1992, 3163-3164.
(15) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989,
54, 1346-1353.

ReactiVity-Enhancing Replacements for Benzyl Ethers
J. Am. Chem. Soc., Vol. 123, No. 28, 2001 6821
Figure 1. Concentration dependence of the NH chemical shift of 1 in
CDCl3 at room temperature.
Figure 3.
both DMSO and water.20 It seems apparent that there is neither
a pure intermolecular nor a pure intramolecular hydrogen-
bonding scheme in CDCl3 solutions of 1. Rather it is likely that
a dynamic situation, incorporating both, exists and that this will
increasingly favor the intermolecular system at the lower
temperatures and higher concentrations of the glycosylation
reaction.
We therefore focused on a method of disrupting an intermo-
lecular hydrogen-bonding network. The addition of simple
heterocycles, capable of binding amides, to the reaction medium
was briefly considered and dismissed on the grounds that any
group sufficiently exposed to bind the amide would almost
certainly also be a competing nucleophile in glycosylation
reactions. We therefore turned to the design of novel protecting
groups incorporating hydrogen-bond acceptors. Specifically we
hypothesized that a 3-O-(2-picolinyl) ether, replacing a benzyl
ether, would be ideally poised to form a hydrogen bond with
the adjacent acetamide NH, thereby disrupting the intermolecular
hydrogen-bonding system. Toward this end a solution of alcohol
9 in THF was treated with an excess of sodium hydride followed
by o-picolinyl chloride hydrochloride. The resulting 3-O-Pic
ether 17 was isolated in 96% yield as a crystalline solid. In
CDCl3 solution at room temperature a 0.04 M solution of 17
had δNH of 7.60, which, when contrasted with that of δNH of
5.35 for 10 under the same conditions of temperature and
concentration, was suggestive of the formation of a strong
intramolecular hydrogen bond (Figure 3). Reduction of 17 with
sodium cyanoborohydride and HCl in ether, according to the
standard Garegg conditions,21 afforded 6-O-benzyl derivative
18 in 75% yield. Unfortunately, the intramolecular hydrogen
bond was not nearly as strong in 18 as demonstrated by the
δNH of 6.20. We attribute this to both the 4-OH and the 2-NH
competing to form a hydrogen bond with the picolinyl group
which has the effect of restoring the intermolecular hydrogen-
bonding capabilities of the amide (Figure 3). This, in retrospect,
obvious problem was confirmed by reduction of 17 with
Figure 2. Chemical shift temperature dependence of the NH in a 0.05
M CDCl3 solution of 1.
hydrogen bonding would increase the reactivity of 1 and thus,
perhaps, enable us to design a simple reactive N-acetylglu-
cosamine derivative. Ideally, such a derivative would not require
deprotection of any latent amide after coupling, such as is
required with each of the surrogates studied above. An essential
prerequisite to design is understanding, and therefore, we first
investigated the nature of any hydrogen bonding, intra- or
intermolecular, in 1. Vasella has conducted an extensive study
of hydrogen bonding in a wide range of N-acetylglycosamine
derivatives and has found examples of both intra- and inter-
molecular hydrogen bonding, in nonpolar solvents, depending
on the configuration at the two flanking ring carbons.16,17 We
therefore investigated the concentration and temperature de-
pendence of the NH in CDCl3 solution for 1. At room
temperature δNH of 1 fell off almost linearly with concentration
(Figure 1) which strongly suggests an intermolecular phenom-
enon. Linear regression of the ∆δ/∆T plot (Figure 2) taken for
a 0.05 M solution of 1 gave a “reduced temperature coefficient”
of -2.1. In nonpolar solvents such as CDCl3 a coefficient of
this magnitude is usually interpreted as being characteristic of
an intramolecular hydrogen bond or of a non-hydrogen-bonded
state.16-19 We note that the interpretation of ∆δ/∆T values is
not as straightforward in relatively nonpolar solvents as it is in
(16) Fowler, P.; Bernet, B.; Vasella, A. HelV. Chim. Acta 1996, 79, 269-
287.
(20) For application of ∆δ/∆T relationships to carbohydrates in polar
solvents see: Buffington, L. A.; Blackburn, D. W.; Hamilton, C. L.; Jarvis,
T. C.; Knowles, J. J.; Lodwick, P. A.; McAllister, L. M.; Neidhart, D. J.;
Serumgard, J. L. J. Am. Chem. Soc. 1989, 111, 2451-2454.
(21) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108,
97-101.
(17) Vasella, A.; Witzig, C. HelV. Chim. Acta 1995, 78, 1971-1982.
(18) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R. J. Am.
Chem. Soc. 1991, 113, 1164-1173.
(19) Stevens, E. S.; Sugawara, N.; Bonora, G. M.; Toniolo, C. J. Am.
Chem. Soc. 1980, 102, 7048-7050.

6822 J. Am. Chem. Soc., Vol. 123, No. 28, 2001
Crich and Dudkin
Scheme 4
catalyst in methanol/dioxane at room temperature and pressure.
As befits a replacement for a benzyl ether, the 3-O-Pic group
was cleanly removed under these conditions along with the
benzyl and benzylidene groups. To facilitate isolation on the
small scale employed the disaccharide hexol obtained from the
hydrogenolysis was immediately converted to the heptabenzoate
24, which was isolated in 66% overall yield for the two steps.
All of the couplings employed in the proof of concept
experiments described above were made using our â-manno-
side adaptation2 of Kahne’s sulfoxide method.23,24 This was not
only because â-mannosylation continues to be a focus of our
research25,26 but also because the Kahne method enables gly-
cosylation of some of the most delicate and unreactive accep-
tors,23,27 yet does not fare well with the N-acetylglucosamines,
as we have demonstrated. Nevertheless, it was felt that a brief
investigation of another popular glycosylation method, namely
Schmidt’s trichloroacetimidate method,28 was justified. To this
end, in parallel reactions, the trichloroacetimidate 25 was
activated in dichloromethane with catalytic TMSOTf in the
presence of 19 and 20. Coupling with 20 was smooth, and
disaccharide 26 was isolated in 26% yield as a 1/1 R/â mix-
ture. With acceptor 19, however, no reaction was observed, and
the trichloroacetimidate was found to be essentially un-
changed in the recovered reaction mixture. We rationalize this
observation in terms of the picolinyl group in 19 binding the
TMSOTf and so preventing activation of the donor. We
conclude that the picolinyl ethers will not be compatible with
glycosylation methods requiring donor activation by Lewis
acids. On the other hand any method conducted in the presence
of excess base should be compatible with the picolinyl ether.
One such method is the new dehydrative glycosylation, intro-
duced by Gin and co-workers, in which a glycopyranose is
activated with a combination of diphenyl sulfoxide, triflic
anhydride, and a hindered base.29,30 To test this hypothesis 27
was coupled in separate flasks with 1 equiv of 19 or 20 with
activation by the diphenyl sulfoxide/Tf2O combination in the
presence of 2,4,6-tri-tert-butylpyrimidine (TTBP). With 19 an
87% isolated yield of disaccharide 28 was obtained, whereas
with 20 the yield of disaccharide 26 was only 18% after the
same reaction time. It is therefore clear that the reactivity-
enhancing advantages of the picolinyl ether are not confined to
the sulfoxide method. We also stress here the application of
the crystalline, hindered base TTBP that we have very re-
cently introduced as cost-effective replacement for the very
widely used, but expensive, low-melting and hygroscopic
DTBMP.31
dibutylboron triflate‚THF.22 This reaction provided the regio-
isomer 19 in 87% yield, whose δNH of 7.40 at the same
temperature and concentration again suggested a strong in-
tramolecular hydrogen bond (Figure 3). This chemical shift is
to be contrasted with that of 5.30 determined for the 3-O-benzyl
analogue 20 under the standard conditions.
The lack of effectiveness of the 3-O-Pic ether in 18 was
confirmed on attempted coupling to 4 under the standard
conditions when the disaccharide 21 was isolated in only 8%
yield. Evidently, 18 is neither better nor worse than 1 as a
glycosyl acceptor in the sulfoxide-mediated â-mannosylation
sequence.
Although the 6-OH group is somewhat further removed than
the 4-OH from the 2-NHAc, it might reasonably be expected
that the hydrogen-bonding acetamide NH might still have a
detrimental, albeit reduced, effect on the reactivity of N-
acetylglucosamine 6-OH in glycosylation. Indeed, in our initial
work on â-mannosylations we noted that methyl 2-acetamido-
3,4-di-O-acetyl-2-deoxy-R-D-glucopyranoside was significantly
less reactive than methyl 2,3,4-tri-O-acetyl-R-D-glucopyrano-
side.2 This being the case the 3-O-Pic derivative 19 should be
a better glycosyl acceptor than the 3-O-benzyl analogue 20. In
the event, in separate couplings under the standard conditions,
the isolated yields of disaccharides 22 and 23 were 63 and 39%,
respectively (Scheme 4). The approximately 50% increase in
yield with the 3-O-Pic acceptor does not reveal the full extent
of the advantages that 19 presents over 20. These reside, in
addition to the increased yield, in the cleaner reaction mixture,
resulting from higher conversion, and thus greatly facilitated
isolation. As with acceptors 1-3 a set of reactions were
conducted in which the glycosyl triflate 5 derived from 4 was
invited to compete for coupling with an equimolar mixture of
19 and 20. In each of three separate competition experiments
19 was found to be approximately twice as reactive as 20. We
consider these experiments with 19 and 20, together with the
NH chemical shifts set out in Figure 3, to be a proof of the
principle that successful disruption of intermolecular hydrogen
bonding in N-acetylglucosamine derivatives renders them better
glycosyl acceptors.
(23) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc.
1989, 111, 6881-6882.
(24) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.
(25) Crich, D.; Dudkin, V. Org. Lett. 2000, 2, 3941-3943.
(26) Crich, D.; Smith, M. Org. Lett. 2000, 2, 4067-4069.
(27) Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999, 121,
1237-1244.
(28) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212-235.
(29) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597-7598.
(30) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269-
4279.
(31) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
There is little to be gained from the introduction of a novel
protecting group if it cannot be removed readily. Disaccharide
22 was therefore subjected to hydrogenolysis over Pearlman’s
(22) Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 355-358.

ReactiVity-Enhancing Replacements for Benzyl Ethers
J. Am. Chem. Soc., Vol. 123, No. 28, 2001 6823
solution of the glycosyl acceptor (0.4 mmol) in CH2Cl2 (2 mL)
dropwise. The reaction mixture was stirred at -78 °C for 2 h and then
allowed to warm to 0 °C over 2 h and maintained there for a further
0.5 h before quenching with saturated aqueous NaHCO3, washing with
brine, drying, concentrating, and purifying by chromatography on silica
gel.
Methyl 2-Acetamido-2-deoxy-3,6-di-O-benzyl-[2,3-di-O-benzyl-
4,6-O-benzylidene-â-D-mannopyranosyl]-(1f4)-r-D-glucopyrano-
side (6). Alcohol 19 was coupled to donor 4, according to the general
protocol to give 6 as a white foam in 9% yield. [R]D ) +22.8° (c )
1
0.50, CHCl3); H NMR (300 MHz) δ 1.84 (s, 3H), 3.10 (dt, J ) 4.8,
9.7 Hz, 1H), 3.40 (s, 3H), 3.36 (s, 3H), 3.36-3.42 (m, 1H), 3.50-
3.63 (m, 5H), 3.71 (d, J ) 3.0, 10.7 Hz, 1H), 3.99 (t, J ) 9.7 Hz, 1H),
4.08 (t, J ) 9.5 Hz, 1H), 4.11-4.22 (m, 2H), 4.36 (d, J ) 12.0 Hz,
1H), 4.46 (s, 1H), 4.57 (d, J ) 12.1 Hz, 1H), 4.59 (d, J ) 12.0 Hz,
1H), 4.65 (d, J ) 12.1 Hz, 1H), 4.73 (d, J ) 3.7 Hz, 1H), 4.76 (d, J
) 11.6 Hz, 1H), 4.84 (d, J ) 11.7 Hz, 1H), 4.89 (d, J ) 11.7 Hz, 1H),
4.95 (d, J ) 12.1 Hz, 1H), 5.23 (br d, J ) 8.4 Hz, 1H), 5.52 (s, 1H),
7.21-7.50 (m, 25H); 13C NMR (75 MHz) δ 52.4, 55.3, 67.4, 68.6,
68.7, 70.5, 72.8, 73.7, 74.4, 75.1, 77.3, 78.0, 78.3, 78.5, 78.9, 98.6,
101.5, 101.9, 128.3, 128.4, 128.5, 128.7, 128.9, 137.8, 138.8, 138.9,
139.4, 169.9; FAB-HRMS: Calcd for C50H55NO11 [M + H]+ 846.3853,
Found: 846.3696.
Methyl 2-Azido-2-deoxy-3,6-di-O-benzyl-[2,3-di-O-benzyl-4,6-O-
benzylidene-â-D-mannopyranosyl]-(1f4)-â-D-glucopyranoside (7).
Alcohol 2 was coupled to donor 4 according to the general protocol to
give 7 as a colorless oil in 70% yield. [R]D ) -38.8° (c ) 2.0, CHCl3);
1H NMR (300 MHz) δ 3.08 (dt, J ) 4.7, 9.7 Hz, 1H), 3.31 (m, 1H),
3.36 (s, 3H), 3.37-3.45 (m, 3H), 3.50 (t, J ) 10.4 Hz, 1H), 3.58 (s,
3H), 3.65 (dd, J ) 1.8, 11.1 Hz, 1H), 3.78 (m, 1H), 3.97 (t, J ) 9.0
Hz, 1H), 4.01-4.17 (m, 3H), 4.39 (d, J ) 12.3 Hz, 1H), 4.49 (s, 1H),
4.56-4.68 (m, 4H), 4.76 (d, J ) 12.5 Hz, 1H), 4.80 (d, J ) 12.8 Hz,
1H), 4.89 (d, J ) 12.5 Hz, 1H), 5.11 (d, J ) 10.7 Hz, 1H), 5.53 (s,
1H), 7.23-7.54 (m, 25H); 13C NMR (75 MHz) δ 57.3, 65.8, 67.5, 68.6,
72.8, 73.8, 74.9, 75.3, 77.2, 78.5, 78.9, 81.7, 101.50, 101.53, 103.0,
126.2, 127.5, 127.7, 128.0, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6,
128.7, 129.0, 129.2, 137.8, 138.6, 138.7; FAB-HRMS: Calcd for
C48H51N3O10 [M + H]+ 830.3653, Found: 830.3727.
Methyl 3,6-Di-O-benzyl-2-phthalimido-[2,3-di-O-benzyl-4,6-O-
benzylidene-â-D-mannopyranosyl]-(1f4)-â-D-glucopyranoside (8).
Alcohol 310,11 was coupled to donor 4 according to the general protocol
to give 8 as a colorless oil in 53% yield. [R]D ) +7.4° (c ) 0.78,
CHCl3); 1H NMR (300 MHz) δ 3.14 (dt, J ) 4.2, 9.8 Hz, 1H), 3.40 (s,
3H), 3.42 (m, 1H), 3.50 (m, 1H), 3.58 (m, 2H), 3.69 (dd, J ) 2.8, 10.7
Hz, 1H), 3.75 (d, J ) 3.0 Hz, 1H), 4.05 (m, 2H), 4.15 (m, 2H), 4.25
(m, 2H), 4.42 (d, J ) 12.1 Hz, 1H), 4.44 (d, J ) 12.1 Hz, 1H), 4.54
(br s, 1H), 4.59 (d, J ) 12.4 Hz, 1H), 4.68 (d, J ) 12.8 Hz, 1H), 4.75
(d, J ) 12.4 Hz, 1H), 4.87 (d, J ) 12.0 Hz, 1H), 4.88 (d, J ) 12.6 Hz,
1H), 4.91 (d, J ) 11.8 Hz, 1H), 5.05 (d, J ) 8.4 Hz, 1H), 5.52 (s, 1H),
6.82-6.87 (m, 3H), 6.91-6.96 (m, 2H), 7.21-7.52 (m, 20H), 7.60-
7.80 (m, 4H); 13C NMR (75 MHz) δ 55.7, 56.8, 67.4, 68.6, 68.7, 72.7,
73.7, 74.8, 74.9, 75.1, 77.3, 78.5, 78.9, 79.6, 99.4, 101.5, 102.0, 107.0,
123.4, 126.2, 127.1, 127.5, 127.7, 127.9, 128.0, 128.2, 128.3, 129.5,
128.7, 129.5, 131.9, 131.8, 137.8, 137.9, 138.7, 138.9; FAB-HRMS:
Calcd for C56H55NO12 [M + 2H]+ 935.3881, Found: 935.3922.
Competition Experiment. The mixture of acceptors 1, 2, and 3,
(0.2 mmol each) was mannosylated as described in general protocol
using 0.2 mmol of sulfoxide 4. The resulting mixture of products was
analyzed using HPLC. The ratio of mannosides 6:7:8 was determined
as 0.1:1.0:0.3
The experiments presented here establish the principle of
using 2-picolinyl ethers to disrupt intermolecular hydrogen
bonding of adjacent amides and so of enhancing the reactivity
of N-acetylglucosamine hydroxyl groups. The method falls down
when the picolinyl ether is sandwiched immediately between
the amide and the reactive hydroxyl group, as in 18 owing to a
competition for the hydrogen bond accepting pyridine nitrogen.
This renders the method ineffective in terms of enhancing the
reactivity of the N-acetylglucosamine 4-OH, the most important
of the cases considered, by means of a 3-O-picolinyl ether. In
principle this situation can be overcome by locating a suitable
hydrogen bond acceptor at the anomeric position of N-
acetylglucosamine from where hydrogen bonding with the 4-OH
group is unlikely to compete. It is unlikely, however, that a
simple 2-picolinyl glycoside will suffice since, to form a
hydrogen bond with the 2-acetamido group, the exo-anomeric
effect must be overcome. Indeed, picolinyl 2-acetamido-3,4,6-
tri-O-acetyl-â-D-glucoside showed no evidence for the formation
of hydrogen bond between the pyridine and the acetamide.
Studies directed toward the design and implementation of a
suitable anomeric group are currently underway and will be
reported in due course.
Experimental Section
General Procedures. 1H and 13C NMR spectra were run at 500 and
125 MHz, respectively, unless otherwise stated. All solvents were dried
and distilled by standard procedures. All reactions were run under a
dry argon atmosphere. Triflic anhydride was distilled from phosphorus
pentoxide.
Methyl 2-Azido-2-deoxy-3,6-di-O-benzyl-â-D-glucopyranoside (2).
Methyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-â-D-glucopyranoside
(3)10,11 (471 mg, 0.94 mmol) and ethylenediamine (2.76 mL, 46 mmol)
were dissolved in ethanol (10 mL), and the reaction mixture was
refluxed for 15 h and concentrated. The residue was dissolved in
acetonitrile (10 mL) together with DMAP (116 mg, 0.94 mmol), cooled
to 0 °C, and TfN3 (5.88 mL of 0.4 M solution, 2.35 mmol) was added
dropwise. The reaction mixture was stirred for 20 h at room temperature
and concentrated. The residue was purified by flash chromatography
to give azide (2) as colorless oil (364 mg, 97%). [R]D ) -4.0° (c )
Methyl N,N-Diacetyl-2-amino-2-deoxy-3,6-di-O-benzyl-r-D-glu-
copyranoside (12). Benzylation of 99 gave the known amide 10,9 of
which 230 mg, (0.56 mmol) and Hunig’s base (0.5 mL) were placed
in 50 mL flask, and acetyl chloride (1.0 mL) was added, followed by
30 mL of dichloromethane. The resulting solution was stirred for 12 h
and then poured into saturated aqueous NaHCO3, extracted with
dichloromethane, washed with brine, and concentrated. Short column
chromatography afforded methyl N,N-diacetyl-2-amino-2-deoxy-4,6-
O-benzylidene-3-O-benzyl-R-D-glucopyranoside (11) (220 mg, 86%),
1
2.00, CHCl3); H NMR (300 MHz) δ 2.73 (br s, 1H), 3.28 (dd, J )
10.0, 11.5 Hz, 1H), 3.35-3.43 (m, 2H), 3.57 (s, 3H) 3.66 (t, J ) 11.0
Hz, 1H), 3.74-3.79 (m, 2H), 4.19 (d, J ) 8.3 Hz, 1H), 4.57 (d, J )
12.8 Hz, 1H), 4.65 (d, J ) 12.8 Hz, 1H), 4.80 (d, J ) 11.0 Hz, 1H),
4.93 (d, J ) 11.0 Hz, 1H), 7.30-7.52 (m, 10H); FAB-HRMS: Calcd
for C21H25N3O5 [M + Na]+ 422.1692, Found: 422.1693.
General Mannosylation Protocol. To a stirred solution of sulfoxide
42 (0.2 mmol) and DTBMP (82.1 mg, 0.4 mmol) in CH2Cl2 (8.0 mL)
at -78 °C was added Tf2O (37.0 mL, 0.22 mmol) and, 5 min later, the
1
which was immediately used in the next step. H NMR (300 MHz) δ
2.27 (s, 6H), 3.36 (s, 3H), 3.72-3.85 (m, 2H), 3.88 (dd, J ) 4.6, 9.8

6824 J. Am. Chem. Soc., Vol. 123, No. 28, 2001
Crich and Dudkin
Hz, 1H), 4.30 (dd, J ) 4.6, 10.0 Hz, 1H), 4.50-4.65 (m, 2H), 4.71 (d,
J ) 11.4 Hz, 1H), 4.73 (d, J ) 3.5 Hz, 1H), 4.91 (d, J ) 11.4 Hz,
1H), 5.59 (s, 1H), 7.23-7.51 (m, 10H). The above diacetate (11) and
NaBH3CN (250 mg, 4 mmol) were dissolved in 15 mL of THF and
cooled to 0 °C, and a 1 M solution of HCl in diethyl ether was added
dropwise until gas evolution ceased. The reaction mixture was stirred
at this temperature for 1 h, quenched with saturated aqueous NaHCO3,
extracted with dichloromethane, washed with brine, and concentrated.
Column chromatography gave monoacetate 1 (110 mg, 50%) and title
diacetate 12 (87 mg, 39%) as colorless oil, which decomposed on
standing and was therefore used immediately in the next step. 1H NMR
(300 MHz) δ 2.30 (s, 6H), 2.49 (br s, 1H), 3.35 (s, 3H), 3.66-3.78
(m, 4H), 4.26 (dd, J ) 3.6, 10.9 Hz, 1H), 4.47 (dd, J ) 7.6, 10.9 Hz,
1H), 4.55 (d, J ) 12.1 Hz, 1H), 4.62 (d, J ) 12.1 Hz, 1H), 4.73 (d, J
) 3.6 Hz, 1H), 4.75 (d, J ) 11.6 Hz, 1H), 4.80 (d, J ) 11.6 Hz, 1H),
7.25-7.38 (m, 10H); 13C NMR (75 MHz) δ 26.6, 55.5, 59.9, 69.8,
70.3, 73.2, 73.6, 73.9, 78.8, 99.8, 127.9, 128.1, 128.7, 138.5, 139.4,
175.9.
chloride hydrochloride in DMF (15 mL) was then added slowly with
vigorous stirring during 1 h. Stirring was continued for 3 h at which
point the reaction was quenched with methanol, concentrated to about
half of the volume, and diluted with water. Extraction with ethyl acetate,
drying, and concentration afforded a solid residue which, after flash
chromatography, gave the title compound 17 as a white solid (796 mg,
96%): mp 232-233 °C; [R]D ) +84.1° (c ) 2.0, CHCl3); 1H NMR δ
2.05 (s, 3H), 3.39 (s, 3H), 3.76-3.85 (m, 3H), 3.97 (dd, J ) 8.6, 10.0
Hz, 1H), 4.15-4.19 (m, 1H), 4.28-4.31 (m, 1H), 4.93 (d, J ) 15.0
Hz, 1H), 5.05 (d, J ) 3.6 Hz, 1H), 5.06 (d, J ) 15.0 Hz, 1H), 5.61 (s,
1H), 7.22 (dd, J ) 5.5, 6.8 Hz, 1H), 7.30 (t, J ) 7.5 Hz, 1H), 7.37-
7.42 (m, 3H), 7.48-7.52 (m, 2H), 7.61 (d, J ) 6.2 Hz, 1H), 7.68 (dt,
J ) 1.7, 7.5 Hz, 1H), 8.57 (d, J ) 5.0 Hz, 1H); 13C NMR δ 23.7, 52.4,
55.1, 70.0, 70.4, 71.4, 72.8, 73.6, 84.0, 99.0, 121.9, 123.0, 127.7, 128.6,
137.5, 138.5, 148.8, 158.5, 170.2; FAB-HRMS: Calcd for C28H30N2O6
[M + H]+ 491.2182, Found: 491.2226.
Methyl 2-Acetamido-2-deoxy-6-O-benzyl-3-O-(2-picolinyl)-r-D-
glucopyranoside (18). 4,6-O-Benzylidene-protected compound 17 was
treated with NaBH3CN as described for 14 to produce alcohol 18 in
75% yield as a white solid: mp 122-124 °C; [R]D ) +50.1° (c ) 1.0,
Methyl N-Acetyl-N-benzyl-2-amino-2-deoxy-3-O-benzyl-4,6-O-
benzylidene-r-D-glucopyranoside (13). Alcohol 99 (3.89 g, 12.0 mmol)
was dissolved in DMF (100 mL) and treated with NaH (1.0 g, 25 mmol)
followed by benzyl bromide (3.0 mL, 25 mmol). The reaction mixture
was stirred for 15 h at room temperature and poured into saturated
aqueous NaHCO3, extracted with chloroform, washed with brine, and
concentrated. The residue was separated by column chromatography
to give acetate 10 (860 mg, 16%) and title compound 13 (4.230 g,
1
CHCl3); H NMR δ 2.06 (s, 3H), 3.39 (s, 3H), 3.66-3.89 (m, 6H),
4.23-4.30 (m, 1H), 4.63 (s, 2H), 4.75 (d, J ) 15.0 Hz, 1H), 4.78 (d,
J ) 3.8 Hz, 1H), 4.95 (d, J ) 15.0 Hz, 1H), 6.21 (d, J ) 8.9 Hz, 1H),
7.17 (d, J ) 7.7 Hz, 1H), 7.20-7.39 (m, 6H), 7.68 (dt, J ) 1.7, 8.0
Hz, 1H), 8.54 (d, J ) 5.1 Hz, 1H); 13C NMR δ 23.7, 52.4, 55.1, 70.0,
70.4, 71.4, 72.8, 73.6, 84.0, 98.8, 122.0, 123.0, 127.7, 128.5, 137.5,
138.5, 148.8, 158.5, 170.2; FAB-HRMS: Calcd for C22H28N2O6 [M +
H]+ 417.2026, Found: 417.2047.
1
71%). [R]D ) +184.8° (c ) 1.25, CHCl3); H NMR δ 1.94 and 2.35
(s, 3H), 2.84 and 2.94 (s, 3H), 3.76-3.95 and 4.01-4.21 (m, 5H),
4.23-4.42 (m, 3H), 4.61-4.88 and 5.16-5.22 (m, 3H), 5.62 (s, 3H),
7.00-7.55 (m, 15H); 13C NMR (75 MHz) δ 22.0, 45.6, 48.2, 52.1,
54.7, 55.8, 62.0, 62.5, 69.1, 72.7, 73.1, 74.5, 84.0, 100.0, 100.7, 101.2,
125.2-128.9, 137.5, 138.0, 139.0, 138.5, 172.8, 173.0; FAB-HRMS:
Calcd for C30H33NO6 [M + H+] 504.2386, Found: 504.2372.
Methyl 2-Acetamido-2-deoxy-4-O-benzyl-3-O-(2-picolinyl)-r-D-
glucopyranoside (19). 4,6-O-Benzylidene-protected compound 17 (750
mg, 1.8 mmol) was placed in 100 mL flask and treated with solution
of BH3 in THF (1.0 M, 18 mL, 18 mmol). After 5 min stirring the
reaction mixture was cooled to 0 °C, and a solution of Bu2BOTf in
dichloromethane (1.0 M, 1.8 mL, 1.8 mmol) was added dropwise.
Stirring was continued for 1 h at 0 °C, and then a solution of HCl in
diethyl ether (1.0 M, 30 mL) was carefully added; the reaction mixture
was left stirring overnight at room temperature, concentrated, redis-
solved in dichloromethane, and washed with saturated aqueous
NaHCO3, dried, and concentrated. Column chromatography of the
residue afforded alcohol 19 as a white solid (653 mg, 87%): mp
Methyl N-Acetyl-N-benzyl-2-amino-2-deoxy-3,6-di-O-benzyl-r-
D-glucopyranoside (14). 4,6-O-Benzylidene-protected compound 13
(1.11 g, 2.21 mmol) and NaBH3CN (1.39 g, 22.1 mmol) were dissolved
in THF (70 mL) and cooled to 0 °C, and a 1 M solution of HCl in
diethyl ether was added dropwise until gas evolution ceased. The
reaction mixture was stirred at this temperature for 2 h, quenched with
saturated aqueous NaHCO3, extracted with dichloromethane, washed
with brine, and concentrated. Column chromatography gave title alcohol
1
158-160 °C; [R]D ) +84.0° (c ) 0.4, CHCl3); H NMR δ 1.99 (s,
1
14 (810 mg, 73%). [R]D ) +200.3° (c ) 1.05, CHCl3); H NMR δ
3H), 2.34 (br s, 1H), 3.35 (s, 3H), 3.66 (dt, J ) 9.5, 3.3 Hz, 1H), 3.73
(t, J ) 9.5 Hz, 1H), 3.79 (m, 1H), 3.85 (dd, J ) 1.7, 11.7 Hz, 1H),
3.91 (dd, J ) 8.8, 10.7 Hz, 1H), 4.09 (m, 1H), 4.74 (d, J ) 10.8 Hz,
1H), 4.89 (d, J ) 11.8 Hz, 1H), 4.99 (dt, J ) 14.3 Hz, 1H), 4.97 (d,
J ) 3.8 Hz, 1H), 5.01 (d, J ) 14.3 Hz, 1H), 7.23 (dd, J ) 5.0, 7.1 Hz,
1H), 7.28-7.38 (m, 6H), 7.43 (d, J ) 6.9 Hz, 1H), 7.69 (dt, J ) 1.3,
7.7 Hz, 1H), 8.58 (br d, J ) 5.1 Hz, 1H); 13C NMR δ 23.8, 54.4, 55.5,
62.0, 71.7, 75.1, 75.4, 79.2, 80.8, 98.6, 122.0, 122.9, 128.3, 128.4, 128.9,
137.4, 138.4, 149.1, 159.1, 170.9, FAB-HRMS: Calcd for C22H28N2O6
[M + H]+ 417.2026, Found: 417.2029.
1.90 and 2.31 (s, 3H), 2.71 and 2.82 (s, 3H), 2.95 (br s, 1H), 3.62-
3.83 (m, 2H), 4.12 and 4.25 (d, J ) 17.1, 15.5 Hz, 1H), 4.45-4.61
(m, 3H), 4.62-4.68 and 5.16 (m, 2H), 4.82 and 4.96 (d, J ) 11.9,
15.5 Hz, 7.01-7.40 (m, 15H); 13C NMR (75 MHz) δ 22.5, 22.8, 46.1,
48.3, 54.7, 54.79, 54.83, 61.3, 65.3, 69.9, 70.8, 72.2, 72.7, 73.85, 73.90,
74.06, 74.9, 76.5, 76.9, 99.5, 99.7, 125.3-128.8, 137.8-139.6, 172.8,
173.9; FAB-HRMS: Calcd for C30H35NO6 [M + Na+] 528.2362,
Found: 528.2369.
Methyl N-Acetyl-N-benzyl-2-amino-2-deoxy-3,6-di-O-benzyl-[2,3-
di-O-benzyl-4,6-O-benzylidene-â-D-mannopyranosyl]-(1f4)-r-D-
glucopyranoside (15). Alcohol 14 was coupled to donor 4 according
to the general protocol, and the crude residue was dissolved in
dichloromethane (5 mL) together with succinic anhydride (2.0 mmol),
MgBr‚OEt2 (258 mg, 1.0 mmol), and triethylamine (0.2 mL, 1.5 mmol).
The resulting mixture was stirred for 3 days, filtered, and subjected to
column chromatography to afford title disaccharide 15 (73 mg, 39%).
Methyl 2-Acetamido-2-deoxy-6-O-benzyl-3-O-(2-picolinyl)-[2,3-
di-O-benzyl-4,6-O-benzylidene-â-D-mannopyranosyl]-(1f4)-r-D-
glucopyranoside (21). Alcohol 18 was coupled to donor 4 according
to the general protocol to give 21 as a colorless oil in 8% yield. [R]D
1
) +7.4° (c ) 0.74); H NMR δ 2.05 (s, 3H), 3.17 (dt, J ) 4.8, 9.5
Hz, 1H), 3.39 (s, 3H), 3.43 (dd, J ) 3.0, 10.0 Hz, 1H), 3.57-3.62 (m,
2H), 3.69 (d, J ) 3.0 Hz, 1H), 3.73-3.85 (m, 3H), 3.91-3.97 (m,
1H), 4.01 (t, J ) 9.1 Hz, 1H), 4.11-4.17 (m, 1H), 4.28 (dd, J ) 4.7,
10.2 Hz, 1H), 4.39 (d, J ) 12.2 Hz, 1H), 4.46 (br s, 1H), 4.62 (d, J )
12.4 Hz, 1H), 4.68 (d, J ) 14.6 Hz, 1H), 4.75 (d, J ) 11.3 Hz, 1H),
4.79 (d, J ) 12.6 Hz, 1H), 4.83 (d, J ) 11.7 Hz, 1H), 4.94 (d, J )
15.7 Hz, 1H), 5.07 (d, J ) 15.5 Hz, 1H), 5.20 (d, J ) 3.4 Hz, 1H),
5.62 (s, 1H), 6.99 (d, J ) 7.8 Hz, 1H), 7.20-7.45 (m, 20H), 7.52 (dd,
J ) 2.1, 8.1 Hz, 1H), 7.61 (dt, J ) 1.4, 7.7 Hz, 1H), 8.43 (d, J ) 4.6
Hz, 1H), 8.57 (d, J ) 4.6 Hz, 1H); 13C NMR δ 23.6, 54.6, 55.6, 67.4,
68.5, 68.9, 70.4, 72.8, 73.9, 75.4, 77.4, 78.1, 78.5, 78.6, 79.0, 98.1,
101.6, 101.7, 122.0, 122.6, 126.3, 127.5, 127.6, 127.7, 127.8, 128.0,
128.3, 128.4, 128.5, 128.6, 128.8, 129.1, 137.8, 137.9, 138.8, 170.9;
FAB-HRMS: Calcd for C49H54N2O11 [M+Na+] 869.3625, Found:
869.3700.
1
[R]D ) +39.4° (c ) 1.47, CHCl3); H NMR δ 1.86 and 2.29 (s, 3H),
2.77 and 2.86 (s, 3H), 3.08 (m, 1H), 3.30-3.71 (m, 6H), 3.84-4.14
(m, 5H), 4.16-4.48 (m, 4H), 4.55-5.20 (m, 8H), 5.48 and 5.51 (s,
1H), 6.98-7.53 (m, 30H); 13C NMR δ 22.3, 22.8, 29.1, 29.7, 54.7,
54.8, 67.2, 67.3, 68.2, 68.4, 69.8, 70.3, 72.5, 73.3, 73.6, 73.8, 74.3,
74.86, 74.91, 75.0, 75.2, 78.16, 78.22, 78.6, 79.0, 79.3, 99.4, 99.7,
101.25, 101.31, 101.7, 125.2-128.9, 137.6-139.8, 172.7, 173.7; FAB-
HRMS: Calcd for C57H61NO11 [M + H]+ 936.4323, Found: 936.4384.
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2-picolinyl)-
r-D-glucopyranoside (17). To the suspension of NaH (400 mg, 10.0
mmol) in THF (5 mL) was added dropwise the solution of alcohol 9
(647 mg, 2 mmol) in the mixture of THF (15 mL) and DMF (15 mL),
and the whole was stirred to homogeneity. A solution of 2-picolinyl

ReactiVity-Enhancing Replacements for Benzyl Ethers
J. Am. Chem. Soc., Vol. 123, No. 28, 2001 6825
Methyl 2-Acetamido-2-deoxy-4-O-benzyl-3-O-(2-picolinyl)-[2,3-
di-O-benzyl-4,6-O-benzylidene-â-D-mannopyranosyl]-(1f6)-r-D-
glucopyranoside (22). Alcohol 19 was coupled to donor 4 according
to the general protocol to give 22 as a white solid in 63% yield: mp
J ) 12.0 Hz, 1H), 5.39 (dd, J ) 4.5, 14.0 Hz, 1H), 5.59 (dd, J ) 4.0,
13.0 Hz, 1H), 5.97-6.03 (m, 2H), 6.39 (dd, J ) 12.0, 14.0 Hz, 1H),
7.22-7.58 (m, 21H), 7.74-8.08 (m, 14H); 13C NMR (75 MHz) δ 29.8,
54.8, 57.3, 63.0, 67.0, 69.7, 69.8, 71.0, 71.8, 72.1, 72.6, 77.3, 98.7,
100.0, 128.4, 128.6, 129.0, 129.2, 129.6, 129.8, 129.9, 130.0, 130.2,
133.0, 133.1, 133.3, 133.4, 133.6, 135.7, 142.8, 165.0, 165.4, 165.5,
165.7, 165.9, 166.2, 169.9, 173.6; FAB-HRMS: Calcd for C64H55NO18
[M + H]+ 1126.3498, Found: 1126.3670.
1
215-217 °C; H NMR δ 1.97 (s, 3H), 3.27-3.33 (m, 1H), 3.31 (s,
3H), 3.50-3.57 (m, 3H), 3.82 (ddd, J ) 1.5, 5.5, 10.0 Hz, 1H), 3.84
(d, J ) 3.5 Hz, 1H), 3.91 (dd, J ) 9.0, 11.0 Hz, 1H), 3.97 (t, J ) 10.0
Hz, 1H), 4.16-4.23 (m, 3H), 4.25 (br s, 1H), 4.31 (dd, J ) 4.5, 10.5
Hz, 1H), 4.56 (d, J ) 11.5 Hz, 1H), 4.63 (d, J ) 12.5 Hz, 1H), 4.74
(d, J ) 12.5 Hz, 1H), 4.86 (d, J ) 11.5 Hz, 1H), 4.88 (d, J ) 12.0 Hz,
1H), 4.93 (d, J ) 3.0 Hz, 1H), 4.94 (d, J ) 14.0 Hz, 1H), 4.99 (d, J
) 12.0 Hz, 1H), 5.03 (d, J ) 14.0 Hz, 1H), 5.64 (s, 1H), 7.09 (d, J )
8.0 Hz, 1H), 7.22-7.52 (m, 21H), 7.53 (dd, J ) 1.5, 8.0 Hz, 1H), 7.72
(dt, J ) 1.5, 8.0 Hz, 1H), 8.59 (m, 1H); 13C NMR δ 23.9, 54.1, 55.4,
68.0, 68.9, 69.0, 70.7, 72.9, 75.1, 75.4, 76.1, 78.2, 79.1, 79.5, 81.5,
98.4, 101.8, 102.7, 122.1, 123.0, 126.5, 128.1, 128.2, 128.3, 128.4,
128.6, 128.7, 128.8, 128.9, 129.0, 129.3, 137.4, 138.0, 138.4, 138.8
149.2, 159.0, 170.7; FAB-HRMS: Calcd for C49H54N2O11 [M + H]+
847.3806, Found: 847.3887.
Methyl 2-Acetamido-2-deoxy-4-O-benzyl-3-O-(2-picolinyl)-[2,3,4,6-
tetra-O-benzyl-â-D-mannopyranosyl]-(1f6)-r-D-glucopyranoside (28).
Triflic anhydride (24 µL, 0.14 mmol) was added to a solution of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose33 (54 mg, 0.1 mmol) and diphenyl
sulfoxide (57 mg, 0.28 mmol) in a mixture of toluene and dichlo-
romethane (3:1, 1.0 mL) at -78 °C. After stirring at this temperature
for 10 min and then at -40 °C for 1 h, TTBP (124 mg, 0.5 mmol) in
dichloromethane (0.5 mL) and a solution of acceptor 19 (42 mg, 0.1
mmol) in dichloromethane (1.0 mL) were added sequentially at -40
°C. The solution was then stirred at this temperature for 30 min and
then at 0 °C for 25 min and finally at room temperature for 4 h before
the addition of excess triethylamine (0.1 mL). The reaction was diluted
with dichloromethane and washed sequentially with saturated aqueous
NaHCO3 and brine, dried, and concentrated. The residue was purified
by column chromatography to give the title disaccharide as a 1/1.2
R/â mixture of anomers (81.5 mg, 87%). 1H NMR δ 1.88 (s, 3H), 3.28
and 3.31 (s, 3H), 3.46-3.89 (m, 10H), 3.96-4.13 (m, 2H), 4.40-5.06
(m, 14H), 5.33 (d, J ) 8.5 Hz, 1H), 7.11-7.42 (m, 30H); 13C NMR δ
23.9, 30.1, 52.9, 53.1, 53.4, 69.1, 69.4, 70.7, 70.8, 71.1, 73.2, 73.8,
73.9, 75.1, 75.2, 75.28, 75.33, 75.4, 75.9, 76.9, 78.0, 78.2, 78.3, 79.1,
79.12, 80.3, 80.7, 80.8, 82.2, 82.5, 85.2, 97.6, 98.8, 98.9, 104.2, 127.9-
128.9, 138.3-138.9, 170.3; FAB-HRMS: Calcd for C56H62N2O11 [M
+ Na+] 961.4251, Found: 961.4291.
Methyl 2-Acetamido-2-deoxy-3,4-di-O-benzyl-[2,3-di-O-benzyl-
4,6-O-benzylidene-â-D-mannopyranosyl]-(1f6)-r-D-glucopyrano-
side (23). Alcohol 2032 was coupled to donor 4 according to the general
protocol to give 8 as a colorless oil in 39% yield: mp ) 230 °C; [R]D
1
) +30.1° (c ) 1.0, CHCl3); H NMR δ 1.87 (s, 3H), 3.28 (dt, J )
4.6, 9.5 Hz, 1H), 3.31 (s, 3H), 3.49-3.57 (m, 3H), 3.72 (dd, J ) 8.9,
10.6 Hz, 1H), 3.79-3.83 (m, 2H), 3.96 (t, J ) 10.2 Hz, 1H), 4.17 (dd,
J ) 1.8, 10.3 Hz, 1H), 4.20-4.29 (m, 3H), 4.32 (dd, J ) 5.3, 11.1 Hz,
1H), 4.55 (d, J ) 11.8 Hz, 1H), 4.62 (d, J ) 12.6 Hz, 1H), 4.65-4.70
(m, 2H), 4.73 (d, J ) 12.4 Hz, 1H), 4.83-4.89 (m, 3H), 4.99 (d, J )
11.9 Hz, 1H), 5.47 (d, J ) 9.5 Hz, 1H), 5.64 (s, 1H), 7.42-7.50 (m,
25H); 13C NMR δ: 23.9, 53.0, 55.3, 68.0, 68.9, 69.0, 70.7, 72.8, 75.2,
75.3, 75.4, 76.1, 78.1, 78.4, 79.0, 81.1, 98.8, 101.8, 102.6, 126.5, 128.0,
128.3, 128.5, 128.6, 128.7, 128.8, 128.9, 128.96, 129.0, 129.3, 138.0,
138.4, 138.7, 170.1; FAB-HRMS: Calcd for C50H55NO11 [M + H]+
846.3853, Found: 846.3696.
Methyl 2-Acetamido-2-deoxy-3,4-di-O-benzyl-[2,3,4,6-tetra-O-
benzyl-â-D-mannopyranosyl]-(1f6)-r-D-glucopyranoside (26). Ac-
ceptor 20 was reacted with 2,3,4,6-tetra-O-benzyl-D-glucopyranose33
exactly as in previous experiment to give the 1/2.4 R/â anomeric mixture
Methyl N-Acetyl-N-benzoyl-3,4-di-O-benzoyl-[2,3,4,6-tetra-O-
benzoyl-â-D-mannopyranosyl]-(1f6)-r-D-glucopyranoside (24). Dis-
accharide 22 (4.5 mg, 0.0053 mmol) was dissolved in the mixture of
1,4-dioxane (2 mL), and methanol (10 mL) and 10% Pd(OH)2/C (5.0
mg) was added. The reaction mixture was stirred for 20 h under
atmospheric pressure of hydrogen and then concentrated. The residue
was dried carefully and then dissolved in pyridine (0.5 mL) and treated
with benzoyl chloride (0.2 mL). After overnight stirring the reaction
mixture was poured into saturated aqueous NaHCO3, extracted with
chloroform, washed with brine, and concentrated. Preparative TLC of
the residue provided perbenzoylated compound 24 (4.0 mg, 66%). [R]D
1
of 26 (17.0 mg, 18%). H NMR δ 2.0 (s, 3H), 3.32 and 3.35 (s, 3H),
3.42-3.87 (m, 10H), 3.95-4.23 (m, 2H), 4.40-4.62 (m, 5H), 4.67-
4.83 (m, 4H), 4.85-5.20 (m, 5H), 7.10-7.44 (m, 33H), 7.70-7.77
(m, 1H), 8.56-8.59 (m, 1H); 13C NMR δ 23.9, 30.1, 54.0, 54.2, 55.5,
66.1, 68.9, 68.94, 69.5, 70.7, 70.72, 71.2, 73.1, 73.9, 74.1, 75.1, 75.3,
75.33, 75.4, 75.5, 75.9, 76.2, 78.0, 78.3, 79.4, 79.6, 80.3, 80.31, 81.3,
81.3, 82.2, 82.5, 85.2, 97.6, 98.5, 98.6, 104.2, 122.8, 122.9, 123.3,
127.8-128.8, 138.4-139.2, 147.5, 147.6, 158.3, 170.8; FAB-HRMS:
Calcd for C57H63NO11 [M + Na+] 960.4300, Found: 960.4330.
1
Acknowledgment. We thank the NIHGMS for support of
this work (GM 57335).
) -10.5° (c ) 0.2, CHCl3); H NMR δ 1.75 (s, 3H), 2.84 (s, 3H),
3.79 (dd, J ) 11.0, 14.0 Hz, 1H), 4.04 (dd, J ) 2.0, 14.0 Hz, 1H),
4.08 (m, 1H), 4.15 (m, 1H), 4.44 (dd, J ) 5.5, 15.0 Hz, 1H), 4.64 (dd,
J ) 3.0, 15.0 Hz, 1H), 4.92 (d, J ) 4.5 Hz, 1H), 5.04 (s, 1H), 5.23 (t,
JA010086B
(32) Falcone-Hindley, M. L.; Davis, J. T. J. Org. Chem. 1998, 63, 5555-
5561.
(33) Perrine, T. D.; Glaudemans, C. P. J.; Ness, R. K.; Kyle, J.; Fletcher,
H. J. Org. Chem. 1967, 32, 664-669.