Revisiting the armed-disarmed concept rationale: S-benzoxazolyl glycosides in chemoselective oligosaccharide synthesis

Article abstract of DOI:10.1021/ol050969y

(Chemical Equation Presented) It has been discovered that 2-O-benzyl-3,4,6-tri-O-acyl SBox glycosides are significantly less reactive than even "disarmed" peracylated derivatives. This finding has been applied to the synthesis of various oligosaccharides,

Full text of DOI:10.1021/ol050969y

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3215-3218
Revisiting the Armed−Disarmed Concept
Rationale: S-Benzoxazolyl Glycosides in
Chemoselective Oligosaccharide
Synthesis†
Medha N. Kamat and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received April 29, 2005
ABSTRACT
It has been discovered that 2-O-benzyl-3,4,6-tri-O-acyl SBox glycosides are significantly less reactive than even “disarmed” peracylated derivatives.
This finding has been applied to the synthesis of various oligosaccharides, the monomeric units of which are connected via cis cis, trans
cis, and cis trans sequential glycosidic linkages. Two-stage activation of the armed (benzylated) donor over moderately (dis)armed (acylated)
and, subsequently, over disarmed (2-O-benzyl-3,4-O-diacylated) acceptor has also proven to be feasible.
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−
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Carbohydrates are the most ubiquitous biomolecules on
Earth, yet their chemistry and biology has been a “Cinder-
ella” field. Our current knowledge about carbohydrates
remains incomplete. However, thanks to the explosive growth
of glycobiology in recent years, it is now recognized that
these fascinating biomolecules are involved in many vital
biological processes, such as fertilization, antiinflammation,
immunoresponse, joint lubrication, antigenic determination,
etc.1 Carbohydrates are also responsible for many damaging
processes in our cells, such as bacterial and viral infections,
development and growth of tumors, metastasis, tissue rejec-
tion, etc.2 Many of these processes are directly associated
with various deadly diseases of the 21st Century: AIDS,
cancer, meningitis, hepatitis, etc. Elucidation of the exact
mechanisms of carbohydrate involvement in disease progres-
sion would be significantly facilitated if we could rely on
the comprehensive knowledge of the structure, conformation,
and properties of the carbohydrate molecules. Although
scientists have learned to selectively cleave, isolate, purify,
and characterize certain classes of naturally occurring glyco-
structures, their accessibility in pure form is still quite limited.
It is critical to make complex carbohydrates more accessible
to the general chemical, biochemical, and industrial audience
to keep in pace with the exploding area of glycobiology.
This can only be achieved by the development of reliable
methods for glycoside synthesis and convergent oligo-
saccharide assembly that are applicable to both laboratory
and industrial-scale preparation.
† Dedicated to Professor Nickolay Kochetkov on the occasion of his 90th
birthday.
Many, if not all, known convergent strategies for oligo-
saccharide synthesis are based on the selective activation of
one leaving group (LG) over another.3 These approaches
(1) Varki, A. Glycobiology 1993, 3, 97-130. Dwek, R. A. Chem. ReV.
1996, 96, 683-720. Essentials of Glycobiology; Varki, A., Cummings, R.,
Esko, J., Freeze, H., Hart, G., Marth, J., Eds.; Cold Spring Harbor Laboratory
Press: Cold Spring Harbor, NY, 1999. Nishimura, S. I. In Glycoscience:
Chemistry and Chemical Biology; Fraser-Reid, B., Tatsuta, K., Thiem, J.,
Eds.; Springer: Berlin , 2001; Vol. 3, pp 1993-2004.
(2) Witczak, Z. J. In Carbohydrates in Drug Design; Witczak, Z. J.,
Nieforth, K. A., Eds.; Marcel Dekker: New York, 1997; pp 1-37.
10.1021/ol050969y CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/22/2005

Scheme 1. Fraser-Reid’s Armed-Disarmed Strategy Outline
Table 1. Comparative Reactivity of the Differently Protected
SBox Glycosides 1a-e in the Presence of 1 Equiv of Cu(OTf)2
entry
donor
product
yield (%)
89
no reaction
no reaction
69
R/â ratio
1
2
3
4
5
1a
1b
1c
1d
1e
3a
5.4/1
significantly shorten oligosaccharide assembly by reducing
the number of additional synthetic steps associated with the
protecting group manipulations. One of the most efficient
procedures, Fraser-Reid’s armed-disarmed approach, is
based on the chemoselectivity principle.4,5 According to this
principle, an O-benzylated (electronically activated, armed)
glycosyl donor is chemoselectively activated over an
O-acylated (electronically deactivated, disarmed) derivative
bearing the same type of LG in the presence of a mild
promoter (Scheme 1). 1,2-cis-Linked disaccharides are
preferentially obtained when nonparticipating O-2-ether-
arming substituents are employed as glycosyl donors. The
obtained disaccharide can be then used for 1,2-trans glyco-
sylation directly with the assistance of the neighboring
O-2-acyl substituent. This can be achieved in the presence
of a more potent promoter, capable of the activation of the
disarmed LG, to afford a cis-trans-linked trisaccharide. In
this context, the synthesis of cis-cis-linked derivatives is
also possible (after reprotection OAc f OBn).
The central theme in our research is the invention of new
techniques for the chemical synthesis of biologically impor-
tant glycostructures and glycomimetics and investigation of
the driving forces of the glycosylation process. We have
already demonstrated that high stability of the SBox glyco-
sides along with high stereoselectivity make these glycosyl
donors suitable for both single-step stereoselective glyco-
sylations and for the use as building blocks in sophisticated
convergent oligosaccharide syntheses.6-8 The heart of this
communication is the investigation of the chemoselective
activation of SBox glycosides and their application to
oligosaccharide synthesis. Our studies were initiated in order
to investigate the reactivity pattern of differently protected
SBox glycosides. Having decided to explore the armed-
disarmed properties of the SBox glycosides, we performed
the activation of 1a in the presence of various promoters.
To distinguish between armed and disarmed glycosides, we
needed to employ a mild promoter. In this respect, copper-
3d
3e
â only
â only
70
(II) trifluoromethanesulfonate seemed to be the most ap-
propriate. Thus, activation of 1a over glycosyl acceptor 2
proceeded smoothly, and as a result, the product 3a9 was
isolated in a good yield of 89% (entry 1, Table 1). When
essentially the same reaction conditions were applied to the
glycosidation of 2-O-benzyl-tri-3,4,6-O-acyl-protected SBox
glucosides 1b6 and 1c, no product formation was detected.
This result did not surprise us at first as we believed that
the high stability of partially benzoylated derivatives was
due to the remote disarming effect of the acyl substituents
at C-3, -4, and -6. In fact, we have previously reported that
Cu(OTf)2 is unable to promote the glycosidation of 1b.6
Unexpectedly, we discovered that supposedly “disarmed”
peracylated SBox glycosides 1d6 and 1e,7 which were
anticipated to be even less reactive than either 1b or 1c,
actually reacted readily in glycosylations. Although these
glycosylations were marginally slower in comparison to that
of the “armed” perbenzylated 1a, they nevertheless smoothly
proceeded, yet never went to completion. As a result,
disaccharides 3d10 and 3e11 were isolated in 69 and 70%
yield, respectively.
These interesting observations called for further studies,
as Lemieux’s halide stability theory,12 Fraser-Reid’s armed-
disarmed concept rationale,4,13 and Wong’s programmable
oligosaccharide synthesis concept14 all predicted that
2-O-benzylated 1b or 1c would be more reactive than their
peracylated counterparts 1d and 1e. Initially, we anticipated
that the disarming effect of the protecting groups on the
anomeric center could be rationalized by comparison of the
chemical shift of H-1 in 1H NMR spectra. Thus, H-1 would
appear at the lower field if the electron-withdrawing groups
were attached to the nearby atoms of the molecule. Indeed,
(3) Boons, G. J. Tetrahedron 1996, 52, 1095-1121. Kanie, O. In
Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay,
P., Eds.; Wiley-VCH: Weinheim, New York, 2000; Vol. 1, pp 407-426.
(4) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583-5584.
(9) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U. J.
Chem. Soc., Chem. Commun. 1988, 823-825.
(10) Kochetkov, N. K.; Khorlin, A. Y.; Bochkov, A. F. Tetrahedron 1967,
23, 693-707.
(11) Demchenko, A. V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N.
N. Angew. Chem., Int. Ed. 2004, 43, 3069-3072.
(12) Lemieux, R. U. AdV. Carbohydr. Chem. Biochem. 1954, 9, 1-57.
Lemieux, R. U. Pure Appl. Chem. 1971, 25, 527-548. Lemieux, R. U.;
Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97, 4056-
4062.
(13) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem.
1990, 55, 6068-6070.
(14) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.;
Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734-753.
(5) Fraser-Reid, B.; Udodong, U. E.; Wu, Z. F.; Ottosson, H.; Merritt,
J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942 and
references therein.
(6) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett. 2003,
5, 455-458.
(7) Demchenko, A. V.; Kamat, M. N.; De Meo, C. Synlett 2003, 1287-
1290.
(8) De Meo, C.; Kamat, M. N.; Demchenko, A. V. Eur. J. Org. Chem.
2005, 706-711.
3216
Org. Lett., Vol. 7, No. 15, 2005

Figure 1.
the H-1 signal for 1b is more shielded than that for 1e
(δ 5.54 vs 6.10 ppm). In addition, X-ray data suggested that
1b should be more reactive than 1e as the C1-S bond for
the latter is somewhat shorter and, therefore, expected to be
stronger (1.819 vs 1.803 Å).15 Overall, the above data
suggested that 1b should be more reactive than 1e. However,
these predictions were not borne out by the preliminary
activation experiments (Table 1).
Therefore, further experiments related to a direct com-
parison of these derivatives in chemoselective glycosylations
were deemed necessary. We obtained a variety of partially
protected SBox glycosides suitable for the use as glycosyl
acceptors (4-6, Figure 1). Glycosylation of the glycosyl
acceptors with armed 1a or moderately disarmed glycosyl
donor 1e was proven to be feasible (Table 2). While
Figure 2.
by the competing anomeric SBox LG isomerization of the
glycosyl donor 1a into the stable NBox moiety (7a) (Figure
2), resulting in the compromised yields (see Entries 1 and
2, Table 2). In addition, around 10-20% disaccharides with
NBox anomeric moiety (9b, 11b) (Figure 2) were formed
in some cases (see entries 2 and 5, Table 2). Prolonged
reaction times for the seemingly incomplete processes did
not result in increased yields. Instead, the increased formation
of 9b or 11b was detected. Since investigation of the
recovered acceptor has shown no traces of the NBox isomer,
we believe that a post-glycosylation isomerization took place.
In this context, reaction between the very reactive glycosyl
donor 1a and the fairly unreactive 6 did not result in the
expected disaccharide formation (see entry 6, Table 2).
Instead, 1a was rapidly hydrolyzed to the hemiacetal
derivative, 2,3,4,6-tetra-O-benzyl-D-glucopyranose, which
could be an evidence for donor/acceptor “mismatch”.16What
are the driving forces responsible for this unusual reactivity
pattern? Although direct evidence is not available yet, our
hypothesis is as follows. In the case of 1a, the LG at C-1
can be readily ejected because the O-5 lone pair is not
electronically deactivated by the adjacent oxygen substituents
Table 2. Chemoselective Activation of SBox Glycosyl Donors
over SBox Glycosyl Acceptors
SBox
disacch
NBox
isomerized
donor
(yield, %,
disacch
no. donor acceptor promoter R/â ratio) (yield, %) (yield, %)
Scheme 2. O-2/O-5 Cooperative Effect in Glycosylation
1
2
3
1a
1a
1e
4
Cu(OTf)2 8a (64, 3/1)
Cu(OTf)2 9a (51, 3/1) 9b (10)
Cu(OTf)2/ none
TfOH
7a (30)
7a (35)
5a
5a
4
5
1a
1e
5b
5b
Cu(OTf)2 10a (92,
3.5/1)
7a (5)
Cu(OTf)2/ 11a (65,
11b (20)
TfOH
â only)
6
7
1a
1e
6
6
Cu(OTf)2 none
Cu(OTf)2/ 12a (80,
TfOH
â only)
glycosidation of 1a could be accomplished in the presence
of 1 equiv of Cu(OTf)2, efficient glycosidation of 1e required
more powerful activation conditions. Cu(OTf)2 (2 equiv) in
combination with TfOH (0.2 equiv) was found to be suitable
for this purpose. In our opinion, these results serve as direct
confirmation of the preliminary observation obtained in
model glycosidations of the SBox glycosyl donors. It should
be noted that some of these glycosylations were complicated
(R ) Bn, Scheme 2). The O-5 lone pair is therefore able to
very effectively assist in the departure of the LG, and stabilize
the resulting glycosyl cation (A, R ) Bn). Although, in 1d
and 1e the O-5 lone pair is much less able to assist in LG
departure and subsequent stabilization of the C-1 glycosyl
(16) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155-173.
Spijker, N. M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. Engl. 1991,
30, 180-183. Uriel, C.; Gomez, A. M.; Lopez, J. C.; Fraser-Reid, B. Synlett
2003, 2203-2207.
(15) Note: These results will be presented in the full version of the
manuscript.
Org. Lett., Vol. 7, No. 15, 2005
3217

Scheme 3. Convergent Synthesis of the cis-cis-trans-Linked
Tetrasaccharide 16
Scheme 5. Synthesis of cis-trans and Potential cis Linkage
AgOTf to afford the trisaccharides 14 and 17, respectively.
The obtained 14 and 17 were then reacted with 1518 in the
presence of NIS/TMSOTf to afford the tetrasaccharide
derivatives 16 and 18, respectively, in high overall yields.
The ultimate demonstration of the advantages of these
findings was the synthesis of the trisaccharide 19, which was
accomplished by sequential two-step activation pathway with
the use of three SBox building blocks. For this purpose,
disaccharide 8a, obtained from 1a and 4, was then chemo-
selectively activated over 5b to afford 19 (Scheme 5).
In conclusion, we have demonstrated that perbenzylated
SBox glycosides are more reactive than their peracylated
counterparts and, therefore, can be chemoselectively activated
in accordance with the “armed-disarmed” strategy. Ad-
ditional, and perhaps the most valuable, input was the
discovery that 3,4,6-tri-O-acyl-2-O-benzyl SBox glycosides
are significantly less reactive than even “disarmed” per-
acylated derivatives. This interesting observation has allowed
us to obtain various oligosaccharides, the monomeric units
of which are connected via cis-cis, trans-cis, and cis-
trans sequential glycosidic linkages. Two-stage activation
of the armed (benzylated) donor over a moderately (dis)-
armed (acylated) acceptor and, subsequently, over a disarmed
(3,4-di-O-acyl-2-O-benzyl) acceptor, all three with the same
type of leaving group (SBox), was also proven to be feasible.
It is quite possible that this phenomenon is independent of
the nature of the leaving group and, therefore, is of general
character. Further investigation of the driving forces of this
reaction and its application to glycosyl donors of other series
is underway in our laboratory.
cation (because of the C-3, C-4, and C-6 electron-withdraw-
ing O-acyl groups), the C-2 O-acyl group can nevertheless
stabilize the cation B (Scheme 2).
Scheme 4. Convergent Synthesis of the
trans-cis-trans-Linked Tetrasaccharide 18
Acknowledgment. We thank the University of Missouris
St. Louis for financial support and the NSF for grants to
purchase the NMR spectrometer (CHE-9974801) and the
mass spectrometer (CHE-9708640) used in this work. We
also thank Dr. R. E. K. Winter and Mr. J. Kramer for HRMS
determinations.
Presumably, neither O-5 nor O-2 moieties can effectively
stabilize the glycosyl cations derived from 3,4,6-tri-O-acyl-
2-O-benzyl derivatives 1b or 1c, making the energy barrier
for their formation prohibitively high.
To test the applicability of this interesting observation to
useful oligosaccharide construction, we obtained two tetra-
saccharide derivatives 16 and 18 via convergent activation
pathways as shown in Schemes 3 and 4. For this purpose,
SBox disaccharides 10a and 11a were selectively activated
over S-ethyl glycoside acceptor 1317 in the presence of
Supporting Information Available: Experimental pro-
cedures for the synthesis of 1a,c, 4-6, 8a-12a, 14, and 16-
1
19 and their H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050969Y
(17) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
275-278.
(18) Kuester, J. M.; Dyong, I. Justus Liebigs Ann. Chem. 1975, 2179-
2189.
3218
Org. Lett., Vol. 7, No. 15, 2005