Application of the superarmed glycosyl donor to chemoselective oligosaccharide synthesis

Article abstract of DOI:10.1021/ol800648d

(Figure Presented) Recently, we discovered a novel method for superarming glycosyl donors. Herein, this concept has been exemplified in one-pot oligosaccharide syntheses, whereby the superarmed glycosyl donor was chemoselectively activated over traditional armed and disarmed glycosyl acceptors. Direct side-by-side comparison of the reactivities of the classic armed and superarmed glycosyl donors further validates the credibility of the novel concept.

Full text of DOI:10.1021/ol800648d

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2107-2110
Application of the Superarmed Glycosyl
Donor to Chemoselective
Oligosaccharide Synthesis
Laurel K. Mydock and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received March 20, 2008
ABSTRACT
Recently, we discovered a novel method for “superarming” glycosyl donors. Herein, this concept has been exemplified in one-pot oligosaccharide
syntheses, whereby the superarmed glycosyl donor was chemoselectively activated over traditional “armed” and disarmed glycosyl acceptors.
Direct side-by-side comparison of the reactivities of the classic armed and superarmed glycosyl donors further validates the credibility of the
novel concept.
Thanks to the enormous progress that has been made in the
area of synthetic and analytical chemistry, many classes of
organic compounds are now accessible by widely applicable
methods. Carbohydrates of even moderate complexity,
however, still present a considerable challenge. Over the
years, glycoscientists have learned to isolate certain classes
of naturally occurring glycostructures. The availability of
pure natural isolates, however, is still too inadequate to keep
pace with the rapidly growing field of glycobiology.1
Furthermore, along with the exigent problems associated with
the isolation, purification, handling, and characterization of
glycostructures, their considerable instability frequently
results in erroneous structural assignments. Inevitably, these
errors often lead to the misinterpretation of their functions.
As a result, glycoscientists have turned to chemical and
enzymatic synthesis as a means to access complex carbo-
hydrates. Ideally, the efficient chemical synthesis of carbo-
hydrates should yield significant quantities of pure natural
analogues. Moreover, only the synthetic approach offers the
means to access unnatural mimetics that are often needed
for screening purposes. As such, the development of efficient
methods for stereoselective glycosylation2 and expeditious
assembly of complex oligomers3 remains an important area
of research.
In the expansion of our studies on how protecting groups
effect the reactivity of the anomeric leaving groups, we
discovered that the strategic placement of common protecting
groups leads to a new method for “super-arming” glycosyl
donors.4 Conceptualized from our studies on the O-2/O-5
(1) Prescher, J. A.; Bertozzi, C. R. Nat. Chem. Biol. 2005, 1, 13–21.
Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007. Seeberger, P. H.;
Werz, D. B. Nature 2007, 446, 1046–1051.
10.1021/ol800648d CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society

Cooperative Effect,5 it was determined that S-benzoxazolyl
(SBox) glycosides possessing both a participating moiety at
C-2 (benzoyl) and remote benzyl substituents that electroni-
cally arm the lone pair at O-5 (e.g., glycosyl donors 1-3,
Figure 1) are exceptionally reactive.4 Proving to be even
including thioglycosides,12–17 O-pentenyl glycosides,18,19
fluorides,16,19,20 trichloroacetimidates,21 hemiacetals,22 and
phosphates23,24 to name a few. Although these building
blocks have been probed in various expeditious12,14,23 and
one-pot16,17,20 approaches for oligosaccharide synthesis, to
the best of our knowledge no direct evidence of these
glycosyl donors being more reactive than their benzylated
counterparts has emerged. Therefore, numerous glycosyl
donors bearing this protecting group pattern have been
considered disarmed14,17,18 or “partially disarmed”.19 On a
few occasions, their reactivity has even been quantified and
determined to be lower than that of the corresponding
benzylated derivatives.18,25 It should be noted, however, that
this protecting group pattern is predominantly used due its
relatively simple synthesis via common orthoesters or glycals,
as well as for its flexibility in selectively liberating 2-OH
by deacylation for subsequent glycosylations. Application
to glycosyl donors of the D-manno series in the synthesis of
(branched) polymannans is arguably the most representa-
tive.13
In an attempt to further broaden the scope and application
of this novel superarmed concept, we proceeded to investi-
gate whether the enhanced reactivity of our superarmed
donors 1-3 was sufficient to allow for direct chemoselective
couplings. For the purpose of this study, we chose disarmed
glycosyl acceptors 5 and 6, as well as armed benzylated
building blocks 7-9, all bearing the same leaving group
(SBox). The key results of these preliminary studies are
summarized in Table 1. We already demonstrated that armed
glycosyl donor 4 can be activated over disarmed glycosyl
acceptor 5 to afford disaccharide 10 in 65% yield (entry 1,
Table 1).5 Expectedly, the superarmed glycosyl donor 1 also
smoothly reacted with acceptor 5 to afford the corresponding
disaccharide 11 in 72% yield (entry 2). Ultimately, the
superarmed concept was validated by the direct coupling of
Figure 1. Superarmed glycosyl donors.
more reactive (superarmed)6 than the traditional per-benzy-
lated (armed) glycosyl donors, these building blocks possess
the desirable quality of being both arming and participating
glycosyl donors, traits not commonly found in other systems.7
Among the most attractive strategies for oligosaccharide
synthesis is Fraser-Reid’s chemoselective (armed-disarmed)
approach, which allows for the synthesis of a cis-trans
patterned oligosaccharide sequence through the use of only
one type of anomeric leaving group. The reactivities of the
building blocks involved in such chemoselective activations
are differentiated by the electronic characteristics of their
protecting groups.8 This strategy is based on the commonly
accepted belief that benzylated derivatives are always
significantly more reactive than their benzoylated counter-
parts,9,10 and furthermore, it is thought that this effect
predominates from the neighboring substituent at C-2.10,11
Additionally, the overall glycosyl donor reactivity is pre-
sumed to be in direct correlation with the total number of
benzyl substituents.9,10
In this context, the discovery of the superarmed SBox
glycosides was somewhat surprising.4 Previously, a number
of glycosyl donors bearing the 2-O-benzoyl-3,4,6-tri-O-
benzyl protecting group pattern have been investigated,
(12) Geurtsen, R.; Cote, F.; Hahn, M. G.; Boons, G. J. J. Org. Chem.
1999, 64, 7828–7835
(13) Geng, X.; Dudkin, V. Y.; Mandal, M.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2004, 43, 2562–2565
(14) Hederos, M.; Konradsson, P. J. Org. Chem. 2005, 70, 7196–7207
(15) Sato, K.; Akai, K. S.; Kojima, M.; Murakami, H.; Idoji, T.
Tetrahedron Lett. 2005, 46, 7411–7414
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(2) Handbook of Chemical Glycosylation: AdVances in StereoselectiVity
and Therapeutic ReleVance; Demchenko, A. V., Ed.; Wiley-VCH: New
York, 2008.
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(3) Boons, G. J. Tetrahedron 1996, 52, 1095–1121. Demchenko, A. V.
Lett. Org. Chem. 2005, 2, 580–589. Codee, J. D. C.; Litjens, R. E. J. N.;
van den Bos, L. J.; Overkleeft, H. S.; van der Marel, G. A. Chem. Soc.
ReV. 2005, 34, 769–782.
(16) Tanaka, H.; Adachi, M.; Takahashi, T. Chem.-Eur. J. 2005, 11,
849–862
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(17) Wang, C.; Wang, H.; Huang, X.; Zhang, L. H.; Ye, X. S. Synlett
2006, 2846–2850
(18) Fraser-Reid, B.; Lopez, J. C.; Radhakrishnan, K. V.; Nandakumar,
M. V.; Gomez, A. M.; Uriel, C. Chem. Commun. 2002, 2104–2105
(19) Lopez, J. C.; Uriel, C.; Guillamon-Martin, A.; Valverde, S.; Gomez,
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(4) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2103–2106.
(5) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
(6) Previously, the term “superarmed” was introduced by Bols and co-
workers in their recent publications dedicated to conformationally modified
glycosyl donors:Pedersen, C. M.; Nordstrom, L. U.; Bols, M J. Am. Chem.
Soc. 2007, 129, 9222–9235. Jensen, H. H.; Pedersen, C. M.; Bols, M.
Chem.-Eur. J. 2007, 13, 7576–7582.
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(20) Hashihayata, T.; Ikegai, K.; Takeuchi, K.; Jona, H.; Mukaiyama,
T Bull. Chem. Soc. Jpn. 2003, 76, 1829–1848. Tanaka, H.; Adachi, M.;
Takahashi, T. Tetrahedron Lett. 2004, 45, 1433–1436
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(7) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem.,
Int. Ed. 2005, 44, 7123–7126.
(21) Okada, Y.; Nagata, O.; Taira, M.; Yamada, H. Org. Lett. 2007, 9,
2755–2758. Jayaprakash, K. N.; Chaudhuri, S. R.; Murty, C. V. S. R.; Fraser-
Reid, B. J. Org. Chem. 2007, 72, 5534–5545. Rising, T. W. D. F.; Heidecke,
C. D.; Fairbanks, A. J. Synlett 2007, 1421–1425.
(8) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583–5584. Fraser-Reid, B.; Udodong, U. E.; Wu,
Z. F.; Ottosson, H.; Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R.
Synlett 1992, 92, 7–942.
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(9) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155–173
(10) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry and
Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim,
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(23) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H.
J. Am. Chem. Soc. 2001, 123, 9545–9554
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Org. Lett., Vol. 10, No. 11, 2008

Table 1. Chemoselective Activation of Superarmed Donors 1-3 over Glycosyl Acceptors 4-827
the superarmed glycosyl donor 1 and benzylated (“armed”)
acceptor 7. As in the previous coupling, no self-condensation
products were detected, and disaccharide 12 was isolated in
70% yield (entry 3).
Additionally, sequential trisaccharide syntheses were car-
ried out with the use of the superarmed glycosyl donor 1,
thus allowing us to introduce a 1,2-trans linkage prior to
otherlinkages.Thisisnotpossibleintheclassicarmed-disarmed
approach. In the first sequence, we performed a stepwise
coupling of building blocks 1 and 7, and the isolated
disaccharide 12 was reacted with glycosyl acceptor 1626 at
room temperature, to afford trisaccharide 17 in 60% overall
yield (Scheme 1). The same sequencing could also be
performed in a one-pot fashion without isolating the inter-
mediate. In this case, trisaccharide 17 was isolated in a 74%
yield. Similarly, a one-pot synthesis of the trans-trans-linked
trisaccharide 18, from building blocks 1, 5, and 16, was
accomplished in 83% overall yield.
The superarmed galactosyl donor 2 corroborated the
previous result: its coupling with benzylated galactosyl
acceptor 8 afforded the corresponding disaccharide 13 in 80%
yield (entry 4). To ensure successful coupling, the reaction
temperature was lowered to -20 °C, so as to minimize the
competing side reaction of the isomerization of galactosyl
donor 2 into its corresponding unreactive N-linked (NBox)
counterpart.5 Coupling between the superarmed mannosyl
donor 3 and benzylated mannosyl acceptor 9 was somewhat
less efficient. Although no self-condensation products were
observed, the disaccharide 14 could only be isolated in 51%
yield (entry 5). The only additional compound recovered after
2 h was the unreacted glycosyl acceptor 9 (30%). We believe
that this complication derives from the less significant
difference of the reactivity between mannosyl donor 3 and
its per-benzylated counterpart.4 In lieu of this result, the
additional glycosylation of the disarmed mannosyl acceptor
6 with the superarmed mannosyl donor 3 was performed.
This reaction was straightforward and afforded the anticipated
disaccharide 15 in 90% yield.
As a verification of these results, we also deemed it
necessary to carry out a series of competitive glycosylations,
wherein both the armed and superarmed donor, 4 and 1,
respectively, would be placed in the same reaction vessel
(26) Kuester, J. M.; Dyong, I. Justus Liebigs Ann. Chem. 1975,
2179-2189.
(27) Glycosyl acceptors 7-9 have been obtained from known corre-
sponding 6-O-trityl thioglycosides:Ottosson, H Carbohydr. Res. 1990, 197,
101–107. Houdier, S.; Vottero, P. J. A. Carbohydr. Res. 1993, 248, 377–
384. Ruda, K.; Lindberg, J.; Garegg, P. J.; Oscarson, S.; Konradsson, P.
J. Am. Chem. Soc. 2000, 122, 11067–11072.
Org. Lett., Vol. 10, No. 11, 2008
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Scheme 1. Chemoselective Sequential Synthesis of Trisaccharides 17 and 18
with the glycosyl acceptor 16. Upon addition of the promoter
(DMTST), the two glycosyl donors would then compete to
react with the glycosyl acceptor 16. As depicted in Scheme
2, the superarmed glycosyl donor 1 was clearly significantly
more reactive than its per-benzylated analogue 4 and led to
the formation of the corresponding disaccharide 19 which
contained only trace (<5%) amounts of disaccharide 20 for
a combined yield of 95%. In addition, the unreacted glycosyl
donor 4 was recovered in 87% yield.
armed-disarmed strategy. These easily accessible super-
armed glycosyl donors offer an entirely 1,2-trans stereose-
lective glycosidation. Consequently, the novelty of having
both an armed and a 1,2-trans directing glycosyl donor
makes this approach a very useful concept in many practical
applications. Although not covered by the scope of these
preliminary studies, it is expected that these super-reactive
glycosyl donors can be applied in cases of difficult glyco-
sylations, wherein classic per-acylated glycosyl donors fail.
In combination with our previous studies on the O-2/O-5
cooperative effect, this superarmed glycosyl donor offers
further significance, as it has allowed for the development
of a versatile tool kit, consisting of both R- and ꢀ-directing
armed glycosyl donors, as well as both R- and ꢀ-directing
disarmed glycosyl donors, respectively. Future studies on the
superarmed glycosyl donor concept are currently underway
in our laboratory.
In conclusion, we have discovered that this new concept
for superarming glycosyl donors through the use of common
protecting groups allows for the expansion of the classic
Scheme 2
. Competitive Glycosidations of Glycosyl Donors 1
and 4 with Glycosyl Acceptor 16 in the Presence of DMTST
Acknowledgment. The authors thank NIGMS (GM077170)
for financial support of this research and NSF for grants to
purchase the NMR spectrometer (CHE-9974801) and the
mass spectrometer (CHE-9708640) used in this work. Dr.
R. E. K. Winter and Mr. J. Kramer (Department of Chemistry
and Biochemistry, University of MissourisSt. Louis) are
thanked for HRMS determinations.
Supporting Information Available: Experimental pro-
cedures for the synthesis of all new compounds and their
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800648D
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Org. Lett., Vol. 10, No. 11, 2008