Linker influence on the stereochemical outcome of glycosylations utilizing solid support-bound glycosyl phosphates

Article abstract of DOI:10.1021/ol026276o

(Matrix presented) Glycosyl phosphates can be readily accessed on a solid support via a three-step procedure from support-bound glycals. These resin-bound glycosyl phosphates were successfully used as glycosylating agents for coupling with a series of nuc

Full text of DOI:10.1021/ol026276o

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2751-2754
Linker Influence on the Stereochemical
Outcome of Glycosylations Utilizing
Solid Support-Bound Glycosyl
Phosphates
Diana K. Hunt and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
seeberg@mit.edu
Received June 1, 2002
ABSTRACT
Glycosyl phosphates can be readily accessed on a solid support via a three-step procedure from support-bound glycals. These resin-bound
glycosyl phosphates were successfully used as glycosylating agents for coupling with a series of nucleophiles. The stereochemical outcome
of disaccharide formation was dependent on the nature of the linker connecting the saccharide to the polymer. Interestingly, other glycosyl
donors such as thioglycosides and trichloroacetimidates did not exhibit such a dependence, indicating a different reaction mechanism for
glycosylation.
Different strategies for the assembly of oligosaccharides on
polymeric supports have recently received much attention.1
The solid-phase approach is attractive due to increased yields
resulting from the use of excess reagents and the ease of
product purification. Recent success with automated solid-
phase oligosaccharide synthesis offers additional benefits.2
bound glycosyl donor.1,2a,3 Although the acceptor-bound
method is most commonly employed, a variety of polymer-
supported glycosyl donors have been explored. Effective
glycosylations with resin-bound glycosyl fluorides, trichlo-
roacetimidates, thioglycosides, and glycals have been dem-
onstrated, whereby the latter two methods provided the best
yields and purity.3,4
Polymer-supported oligosaccharide synthesis may be ap-
proached from two different directions: linker attachment
at the reducing end resulting in an immobilized acceptor or
attachment at a “nonreducing” position providing a resin-
Glycosyl phosphates have proven to be competent donors
that couple rapidly and in high yield in solution and in
acceptor-bound glycosylations.5 On the basis of the synthesis
(1) (a) Solid Support Oligosaccharide Synthesis and Combinatorial
Carbohydrate Libraries; Seeberger, P. H., Ed.; Wiley: New York, 2001.
For recent reviews, see: (b) Ito, Y.; Manabe, S. Curr. Opin. Chem. Biol.
1998, 2, 701-708. (c) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000,
100, 4349-4393.
(2) (a) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001,
291, 1523-1527. (b) Sears, P.; Wong, C. H. Science 2001, 291, 2344-
2350.
(3) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685-
695.
(4) (a) Doi, T.; Sugiki, M.; Yamada, H.; Takahashi, T. Tetrahedron Lett.
1999, 40, 2141-2144. (b) Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1997,
119, 5562-5566. (c) Kononov, L. O.; Ito, Y.; Ogawa, T. Tetrahedron Lett.
1997, 38, 1599-1602. (d) Manabe, S.; Ito, Y. Chem. Pharm. Bull. 2001,
49, 1234-1235. (e) Zhu, T.; Boons, G.-J. Angew. Chem., Int. Ed. 1998,
37, 1898-1900.
10.1021/ol026276o CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/09/2002

of glycosyl phosphates from glycals, an efficient route to
resin-bound glycosyl phosphates was envisioned.3,5
Choice of an appropriate linker is an important consider-
ation for any polymer-supported synthesis. The linker should
be inert to all required manipulations, yet easily installed
and readily cleaved to release the product. Donor-bound
strategies have employed a variety of linkers, including
trialkylsilyl3,4a and p-alkoxybenzyl4b,d groups, as well as base-
labile succinic ester4c and succinamyl4e linkers.
Here, we report the synthesis and use of polymer-bound
glycosyl phosphates for oligosaccharide synthesis. The nature
of the linker was observed to have a profound influence on
the stereochemical outcome of the glycosylation reactions.
This dependence was found to stand in stark contrast to
glycosylations involving other commonly used glycosyl
donors such as glycosyl trichloroacetimidates and thiogly-
cosides.
With glycosyl phosphate 5 in hand, activation of the
support-bound donor for union with a series of nucleophiles
was explored. Coupling with glycosyl acceptors 7, 10, and
13, exhibiting C6, C2, and C4 hydroxyl groups, respectively,
followed by cleavage from the resin with sodium methoxide
provided disaccharides 8, 11, and 14, respectively (Table 1).
Table 1. Disaccharide Synthesis Using Resin-Bound
Phosphates and a Solution-Phase Model with a Succinamyl
Linker
Glycal 1 was equipped on the C6 hydroxyl group with a
base-labile4e,6 succinate linker to furnish 2. Immobilization
of 2 on aminomethyl polystyrene provided resin-bound glycal
3. Coupling of 2 with benzylamine provided solution-phase
model 4 to facilitate reaction analysis (Scheme 1).
Scheme 1. Synthesis of Resin-Bound and Solution-Phase
Model Glycosyl Phosphate Donor with a Succinamyl Linker
a Resin-bound phosphate 5 (1.0 equiv) was swelled in CH2Cl2; R′OH
(2.5-6.5 equiv) was added, followed by TMSOTf (1.1 equiv) at -15 °C,
and the reaction was shaken for 2 h. The procedure was repeated twice.
b Phosphate 6 (1.1 equiv) and R′OH (1.0 equiv) were dissolved in CH2Cl2;
TMSOTf (1.3 equiv) was added at -78 °C and the reaction warmed to
-10 °C over 2 h. c Phosphate 6 (1.1 equiv) and R′OH (1.0 equiv) were
dissolved in CH2Cl2, and TMSOTf (1.3 equiv) was added at -78 °C,
followed by another 1.3 equiv of activator after warming to -30 °C over
1 h. d Resin-bound phosphate 5 (1.0 equiv) was swelled in CH2Cl2; R′OH
(2.0 equiv) was added, followed by slow warming from -78 °C with
addition of 3 × 1.1 equiv of TMSOTf added on 1 h delays at -78, -30,
and -10 °C.
Surprisingly, despite the presence of a pivaloyl ester at C2,
the resulting disaccharides were obtained as anomeric
mixtures (Table 1). Solution-phase couplings employing
glycosyl phosphate 6 and acceptors 7, 10, and 13 also
produced anomeric mixtures, suggesting that the nature of
the linker was responsible for these unexpected results (Table
1).
A three-step, one-pot procedure we had previously devel-
oped5 for access to glycosyl phosphates provided 6 from 4
in excellent yield. The sequence of epoxidation with dim-
ethyldioxirane (DMDO) followed by treatment with a
phosphoric acid diester and pivaloylation was readily adapted
to the synthesis of resin-bound glycosyl phosphate 5 (Scheme
1). A 1:1 mixture of R- and â-glycosyl phosphates in solution
and on a solid support was observed by 31P NMR and high-
resolution magic angle spinning (HR-MAS) 31P NMR.
Previous work, including couplings with glycosyl phos-
phates containing a 6-O-levulinate ester, had not indicated
any interference of the C6 hydroxyl protecting group with
the anomeric selectivity.2a,5b On the basis of these consid-
erations, a levulinate-type linker was not expected to erode
the stereoselectivity of the glycosylations, while hydrazine
cleavage would allow rapid removal of the products from
the resin under nonbasic conditions. A 3-benzoylpropionic
ester linker, previously utilized at the anomeric position for
(5) (a) Palmacci, E. R.; Plante, O. J.; Seeberger, P. H. Eur. J. Org. Chem.
2002, 585-589. (b) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.;
Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545-9554.
(6) (a) Adinolfi, M.; Barone, G.; De Napoli, L.; Iadonisi, A.; Piccialli,
G. Tetrahedron Lett. 1998, 39, 1953-1956. (b) Adinolfi, M.; Barone, G.;
De Napoli, L.; Iadonisi, A.; Piccialli, G. Tetrahedron Lett. 1996, 37, 5007-
5010.
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Org. Lett., Vol. 4, No. 16, 2002

the assembly of di-, tri-, and tetrasaccharides,7 was selected
to remedy the problem at hand.
Table 2. Disaccharide Synthesis Using Glycosyl Phosphates
Union of glucal 1 and 3-benzoylpropionic acid 16 afforded
protected glucal 18 that was converted to the corresponding
glycosyl â-phosphate 20 (Scheme 2).
Containing a 4-Oxo-5-phenyl-valeric Ester at C6
Scheme 2. Synthesis of 3-Benzoylpropionic Linker Model
Phosphate from the Glycal and Coupling with the 6-OH
Acceptor
coside and glycosyl trichloroacetimidate donors, containing
a C2 pivaloyl ester and each of the three C6 model linkers,
were prepared according to standard protocols (Scheme
Scheme 3. Synthesis of Thioglycosides and Glycosyl
Trichloroacetimidates Containing Various Linkers
Subsequent coupling with 7 produced exclusively the
expected â-disaccharide 22 (Scheme 2). Cleavage of the
3-benzoylpropionic ester with either excess hydrazine or
hydrazine acetate proved to be very slow, requiring prolonged
reaction times (18 h) even at elevated temperatures (80 °C).
Addition of a methylene group to separate the phenyl ketone
and relieve steric crowding was proposed to alleviate this
problem. To assess this strategy, a 4-oxo-5-phenyl-valeric8
ester on the C6 hydroxyl of a galactose model was cleaved
with 2 equiv of hydrazine at ambient temperature in 90 min.
On the basis of these initial observations, glycal 1 was
equipped with the 4-oxo-5-phenyl-valeric ester at C6 and
converted to the corresponding glycosyl phosphate 21.
Subsequent coupling with the acceptors 7, 10, and 13
unexpectedly produced an anomeric mixture of disaccharides
23-25 (Table 2).
3).4e,9-11 Glycosylating agents 26-31 were then coupled with
galactose acceptor 7 (Table 3).
To explore the generality of the observed linker effect for
different anomeric leaving groups, the corresponding thiogly-
(7) (a) Excoffier, G.; Gagnaire, D.; Utille, J.-P. Carbohydr. Res. 1975,
39, 368-373. (b) Excoffier, G.; Gagnaire, D. Y.; Vignon, M. R. Carbohydr.
Res. 1976, 46, 201-213.
(8) Tschantz, M. A.; Burgess, L. E.; Meyers, A. I. Org. Synth. 1996, 73,
215-220.
(9) (a) Demchenko, A.; Stauch, T.; Boons, G. J. Synlett 1997, 7, 818-
820. (b) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179.
(10) Schmidt, R. R. AdV. Carbohydr. Chem. Biochem. 1994, 50, 21.
(11) Thioglycoside 28 was prepared by an alternate route; see Supporting
Information.
Org. Lett., Vol. 4, No. 16, 2002
2753

three-step procedure. These glycosyl phosphates served as
resin-bound glycosyl donors in the formation of several
disaccharides. The nature of the linker connecting the C6
hydroxyl group to the support was found to fundamentally
influence the stereoselectivity of glycosylations involving
these donors. Influence of the linker on glycosylation with
glycosyl phosphates will have to be considered during
synthetic planning of oligosaccharide assembly under the
donor-bound regime.
Table 3. Glycosylations with Thioglycosides and Glycosyl
Trichloroacetimidates Containing Various Linkers
Acknowledgment. Financial support from Boehringer-
Ingelheim for partial support of this research is gratefully
acknowledged. P.H.S. is a Glaxo-Smith-Kline Research
Scholar and an Alfred P. Sloan Scholar. Funding for MIT-
DCIF Inova 501 and 5 mm Broadband CP/MAS probe was
provided by NSF (Grant CHE-9808061). Funding for the
MIT-DCIF Inova 500 was provided by NSF (Grant DBI-
9729592). Funding for MIT-DCIF Avance (DPX) 400 was
provided by NIH (Grant ISIORR13886-01). Funding for the
MIT-DCIF Mercury 300 was provided by NSF (Grants CHE-
9808061 and DBI-9729592).
Both donor types exhibited complete â-selectivity in all
cases. The influence of a C6 linker on glycosylation
stereoselectivity for glycosyl phosphates and the absence of
such a dependence for thioglycosides and glycosyl trichlo-
roacetimidates suggest the presence of different intermediates
along the reaction pathway. The exact nature of the linker
interference during glycosylation is not understood at this
time but must be taken into consideration in the development
of new linkers for the synthesis of oligosaccharides and
carbohydrate libraries on a solid support.
Supporting Information Available: Detailed experi-
mental procedures, including synthesis of 28, and compound
characterization data, including 1H, 13C, and 31P NMR
spectral data for all described compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have demonstrated the preparation of
glycosyl phosphates from support-bound glycals using a
OL026276O
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Org. Lett., Vol. 4, No. 16, 2002