Solid-phase synthesis of β-mannosides

Article abstract of DOI:10.1021/ja011406u

The linkage of S-phenyl 2,3-di-O-benzyl-α-D-thiomannopyranoside to a cross-linked polystyrene support in the form of its 4,6-O-polystyrylborinate ester is described. The activation of this polymer-supported mannosyl donor is achieved at -60 °C in dichloro

Full text of DOI:10.1021/ja011406u

Published on Web 06/28/2002
Solid-Phase Synthesis of â-Mannosides
David Crich* and Mark Smith
Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received June 7, 2001. Revised Manuscript Received May 5, 2002
Abstract: The linkage of S-phenyl 2,3-di-O-benzyl-R-D-thiomannopyranoside to a cross-linked polystyrene
support in the form of its 4,6-O-polystyrylborinate ester is described. The activation of this polymer-supported
mannosyl donor is achieved at -60 °C in dichloromethane in the presence of 2,4,6-tri-tert-butylpyrimidine
with the combination 1-benzenesulfinyl piperidine and trifluoromethanesulfonic anhydride. Addition of the
donor alcohol at -60 °C followed by warming to room temperature and subsequent cleavage from the
resin by gentle heating in aqueous acetone yields anomerically pure 2,3-di-O-benzyl-â-D-mannopyranosides
in excellent yield. Successful, diastereoselective coupling is demonstrated with a range of primary, secondary,
and tertiary glycosyl acceptors, including typical carbohydrates and threonine derivatives.
Introduction
As such, much effort has been spent on developing methods
for their synthesis, culminating in several successful strategies.13-23
Polymer-supported synthesis of oligosaccharides is a rapidly
emerging field,1-8 with remarkable successes using an auto-
mated synthesizer having been reported recently.9 Nevertheless,
the development of a truly versatile system for the automated,
supported synthesis of oligosaccharides requires that methods
for the highly diastereoselective assembly of all classes of
glycosidic bonds be transposed to the solid phase. Presently,
despite the enormous progress that has been made, we are clearly
still some way from that goal, with several classes of glycosidic
bonds still presenting a considerable challenge, even in solution.
Here, we describe the first successful polymer-supported
synthesis of the challenging â-mannopyranoside-type glycosidic
bond.
With the exception of the work conducted in our laboratory,21-23
these methods are largely indirect and consequently less than
ideal for solid-supported synthesis because of the extra steps
they introduce. The only method to have been transferred to
the solid phase so far is the Ogawa group’s adaptation of the
intramolecular aglycon delivery method which, by its very
nature, results in cleavage from the resin concomitant with
formation of the â-mannoside linkage.24
In its original form, our own direct â-mannosylation reaction,
a variation on Kahne’s sulfoxide method,25,26 involved the low-
temperature activation of a 4,6-O-benzylidene-protected man-
nopyranosyl sulfoxide, bearing additional nonparticipating
protecting groups at O2 and O3, with triflic anhydride at low
temperature to give the corresponding R-mannosyl triflate.21,22,27
Subsequent addition of the acceptor alcohol results in an SN2-
like displacement of the triflate, with selective formation of the
â-mannoside (Scheme 1). The reaction is typically conducted
in the presence of a hindered base such as DTBMP or TTBP,
which is our present choice owing to its ready availability and
crystalline, nonhygroscopic nature.28
Results and Discussion
The â-mannosides have long been recognized as one of the
more important and challenging classes of glycosidic bonds.10-12
* Address correspondence to this author. E-mail: dcrich@uic.edu.
(1) Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994,
116, 6953-6954.
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N.; Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.;
Kahne, D. Science 1996, 274, 1520-1522.
(3) Krepinsky, J. J. In Modern Methods in Carbohydrate Synthesis; Khan, S.
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(16) Ito, Y.; Ogawa, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1765-1767.
(17) Lergenmuller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa, T.; Ito,
Y. Eur. J. Org. Chem. 1999, 1367-1376.
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(21) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
(22) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435-436.
(23) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348.
(24) Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1997, 119, 5562-5566.
(25) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc. 1989,
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(12) Kaji, E.; Lichtenthaler, F. W. Trends Glycosci. Glycotechnol. 1993, 5, 121-
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(26) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239-9248.
(27) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217-11223.
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J. AM. CHEM. SOC. 2002, 124, 8867-8869
8867

A R T I C L E S
Crich and Smith
Scheme 1
as a Ley-type bis-acetal spanning the 3- and 4-positions are not
suitable and are even R-selective.33 The 4,6-O-benzylidene
group, or its functional equivalent, must therefore be incorpo-
rated into the eventual polymer-bound mannosyl donor. This
imposes limitations on the location at which the donor is bound
to the polymeric support. We considered linkage through O2
to be too close to the site of reactivity and were dissuaded from
linkers bound to O3 by the discoveries that both esters and silyl
ethers at that position are R-directing,33,34 the esters highly so,
even in the presence of the 4,6-O-benzylidene group. Accord-
ingly, immobilization via the benzylidene group, or its equiva-
lent, was selected for study.
Both Fre´chet and Hanessian have described the use of
polymer-bond benzaldehyde derivatives as protecting groups in
the glucose, but not mannose, series.35,36 Initially, therefore, we
investigated a commercial modified benzaldehyde derivative
bound to the Wang resin. Thus, diol 3, conveniently obtained
by acid hydrolysis of the corresponding 4,6-O-benzylidene
derivative, was stirred with resin 4 in DMF in the presence of
p-toluenesulfonic acid, resulting in the formation of an im-
mobilized thiomannoside 5 (Scheme 2). Unfortunately, incor-
To minimize manipulations of the hydrolytically and ther-
mally unstable triflate intermediate, it was apparent that a donor-
bound strategy should be followed in any polymer-supported
version of this reaction. However, given the problems of
monitoring stoichiometry and reaction progress commonly
associated with solid-phase chemistry, it was considered unlikely
that the key thioglycoside-to-glycosyl sulfoxide transformation
could be accomplished in sufficiently high yield on the
polymeric support. This does not, of course, exclude the use of
the sulfoxide method in acceptor-bound polymer-supported
oligosaccharide synthesis, as has been elegantly demonstrated
by Kahne and co-workers.1,2 To overcome the problem of
supported sulfide-to-sulfoxide oxidation, over the course of
several years we have consistently sought reagents for the rapid,
direct conversion of thioglycosides to glycosyl triflates at low
temperature. The first successful reagent for this purpose was
benzenesulfenyl triflate,22,23 but this suffers from its inconvenient
preparation from benzenesulfenyl chloride and silver triflate.
In particular, when this reagent is used to activate a polymer-
bound thioglycoside, the beads tend to become coated in
colloidal silver following decomposition of silver chloride, the
byproduct of in situ generation. The combination of S-(4-meth-
oxyphenyl)benzenethiosulfinate (MPBT, 1) with triflic anhydride
was found to achieve the desired transformation in solution,29
but a still more powerful combination was eventually found in
1-benzenesulfinyl piperidine (BSP, 2) and triflic anhydride,30
and it is this reagent couple that has enabled the work described
here.
Scheme 2
poration, as determined by subsequent hydrolysis and recovery
of the diol as well as by MAS NMR of the swollen beads,37
was repeatedly found to be low; therefore, this method was not
pursued further.
Following the early work of Fre´chet on the application of
polystyrylboronic acid as a protecting group for carbohydrate
diols,38 and Boons’ more recent extension to the immobilization
of thioglucoside 4,6-diols and his subsequent use of the bound
donors in coupling reactions,39,40 we turned to the investigation
of phenylboronic acid derivatives. To determine whether the
4,6-O-phenylboronate ester exhibited the same torsionally
disarming properties as the benzylidene group, diol 3 was
condensed with phenylboronic acid to give 6. This was activated
in dichloromethane at -60 °C in the presence of TTBP with
BSP and then coupled to 1-adamantanol to give the crude
â-mannoside 7. Subjection of the residue to silica gel chroma-
A requirement for high selectivity in our mannosylation
reaction is the 4,6-O-benzylidene group23,27 that serves to
torsionally disarm31,32 the intermediate mannosyl triflate and so
reduces loss of selectivity potentially caused by the formation
of free oxacarbenium ions. It is especially noteworthy that
alternatively located six-membered cyclic protecting groups such
(33) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(34) Crich, D.; Dudkin, V. Tetrahedron Lett. 2000, 41, 5643-5646.
(35) Fre´chet, J. M. J.; Pelle, G. J. Chem. Soc., Chem. Commun. 1975, 225-
226.
(36) Hanessian, S.; Huynh, H.-K. Synlett 1999, 102-104.
(37) Seeberger, P. H.; Beebe, X.; Sukenick, G. D.; Pochapsky, S.; Danishefsky,
S. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 491-493.
(38) Fre´chet, J. M. J.; Nuyens, N. J.; Seymour, E. J. Am. Chem. Soc. 1979,
101, 432-436.
(39) Belogi, G.; Zhu, T.; Boons, G.-J. Tetrahedron Lett. 2000, 41, 6965-6968.
(40) Belogi, G.; Tong, Z.; Boons, G.-J. Tetrahedron Lett. 2000, 41, 6969-
6972.
(29) Crich, D.; Smith, M. Org. Lett. 2000, 4067-4069.
(30) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(31) Fraser-Reid, B.; Wu, Z. C.; Andrews, W.; Skowronski, E. J. Am. Chem.
Soc. 1991, 113, 1434-1435.
(32) Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1996, 61,
5280-5289.
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8868 J. AM. CHEM. SOC. VOL. 124, NO. 30, 2002

Solid-Phase Synthesis of â-Mannosides
A R T I C L E S
Table 1. Polymer-Supported Synthesis of â-Mannosides with the
Polystyrylboronate 10a
tography removed the phenylboronate ester to give the diol 8
in 72% yield. The anomeric stereochemistry of 8 was confirmed
1
by the JCH coupling constant41 of 152 Hz as well as by
conversion of 8 into its known 4,6-O-benzylidene derivative,23
with which it was identical in all respects.
The viability of the 4,6-O-phenylboronates as torsionally
disarming protecting groups was thus established, and we
proceeded with the polymer-supported variant. Accordingly, diol
3 was heated in pyridine with polystyrylboronic acid (9)38,42 to
give the bound donor 10 with a loading of ∼1 mmol/g as
determined from the amount of diol liberated on cleavage.
Activation of the bound thioglycoside 10 was achieved by
stirring in dichloromethane with BSP (2) at -60 °C in the
presence of TTBP and triflic anhydride for 20 min, followed
by adding the acceptor alcohol, warming to room temperature,
and quenching. After removal of the excess reagents, alcohol,
and byproducts, the coupled â-mannosides 11 were released
from the resin by heating in aqueous acetone for 1 h to give
the 4,6-diols 12 (Scheme 3). The various â-mannosides so
Scheme 3
a All reactions were conducted in dichloromethane at -60 °C. b Anomeric
ratios of >9:1 are conservative minima; in all such cases, the minor isomer
was not detected in the NMR spectra of the reaction mixtures.
the resin is not an integral part of the coupling reaction but
rather the disaccharide is retained on the support and may, in
principle,43 be further extended. It is complementary in that after
cleavage it provides â-mannosides bearing free hydroxyl groups
at the 4- and 6-positions, whereas the Ogawa sequence affords
the â-mannoside selectively deprotected at the 2-position.
Acknowledgment. We thank the NIH (GM57335 and
GM62160) for support of this work and the NSF for instru-
mentation (Grant No. 9974802) and recognize the important
contributions of our co-workers, Jae-Taeg Hwang, Xue-Sheng
Mo, and Vadim Dudkin, in the exploratory stages of this project.
prepared are collected in Table 1, from which it will be seen
that a powerful method is at hand. The yields and selectivities
presented in Table 1 require little further discussion except,
perhaps, to draw attention to the hydrolysis of the 5,6-acetonide
of the glucofuranose residue in the course of removal from the
resin in the last entry.
All in all, a powerful method for the polymer-supported
synthesis of â-mannosides is at hand using our potent BSP (2)/
triflic anhydride combination for the activation of thioglycosides.
Only very short activation times are required at low temperature,
and the isolated yields of â-mannosides from this polymer-
supported protocol are directly comparable with those obtained
using the analogous solution-phase methodology. Finally, the
method is both different from and complementary to that of
Ogawa.16,17 It differs fundamentally insofar as cleavage from
Supporting Information Available: Full experimental details
and characterization data for all new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA011406U
(43) Further chain extension on the solid support may, in principle, take two
forms. First, it is conceivable that a glycosyl fluoride bearing a free hydroxyl
group may be used as an acceptor in the initial coupling, thereafter
permitting extrapolation of the donor-bound strategy. Second, selective
deblocking of a hydroxyl group after the initial coupling should permit
further glycosylations in an acceptor-bound strategy. To date, we have
examined only the second of these two strategies but report that we have
so far been thwarted by the relative instability of the polystyrylboronate
linker, which curtails the options for protecting group manipulation.
(41) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293-297.
(42) Fre´chet, J. M. J.; Farrall, M. J. J. Org. Chem. 1976, 41, 3877-3882.
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