Superarming the S-benzoxazolyl glycosyl donors by simple 2-O-benzoyl-3,4,6-tri-O-benzyl protection

Article abstract of DOI:10.1021/ol800345j

(Chemical Equation Presented) The strategic placement of common protecting groups led to the discovery of a new method for "superarming" glycosyl donors. Conceptualized from our previous studies on the O-2/O-5 Cooperative Effect, it was determined that S-

Full text of DOI:10.1021/ol800345j

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2103-2106
Superarming the S-Benzoxazolyl
Glycosyl Donors by Simple
2-O-Benzoyl-3,4,6-tri-O-benzyl Protection
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 February 14, 2008
ABSTRACT
The strategic placement of common protecting groups led to the discovery of a new method for “superarming” glycosyl donors. Conceptualized
from our previous studies on the O-2/O-5 Cooperative Effect, it was determined that S-benzoxazolyl glycosyl donors possessing both a
participating moiety at C-2 and an electronically armed lone pair at O-5, such as the superarmed glycosyl donor shown above, were exceptionally
reactive.
The availability of pure natural carbohydrate isolates is still
far from being satisfactory. Hence, chemical and enzymatic
methods for the synthesis of these natural products have
become increasingly important. This has led to the develop-
ment of many excellent new methods for glycoside synthe-
sis,1 from which a variety of expeditious strategies for
oligosaccharide assembly have emerged.2 Among these
strategies, three major concepts could be identified: the
chemoselective (protecting group based),3,4 the selective
(leaving group based),5,6 and the preactivation-based ap-
proaches.7 Of particular interest is the armed-disarmed
strategy introduced by Fraser-Reid that allows for the
synthesis of a cis-trans patterned oligosaccharide sequence
with 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 the protecting groups.3 This strategy is
based on the commonly accepted belief that benzylated
derivatives are always significantly more reactive than their
(5) Koto, S.; Uchida, T.; Zen, S Bull. Chem. Soc. Jpn. 1973, 46, 2520–
2523. Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall, J. L J. Am.
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Soc. 1994, 116, 12073–12074. Kanie, O. In Carbohydrates in Chemistry
and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim,
NY, 2000; Vol. 1, pp 407-426. Demchenko, A. V.; De Meo, C.
Tetrahedron Lett. 2002, 43, 8819–8822. Tanaka, H.; Adachi, M.; Tsukamoto,
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10.1021/ol800345j CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society

benzoylated counterparts,8 and furthermore, it is thought that
this effect predominates from the neighboring substituent at
C-2.9 In addition, the overall glycosyl donor reactivity is
presumed to be in direct correlation with the total number
of benzyl substituents.8
Scheme 1. Cooperative Arming and Disarming Effects in
Glycosyl Donors of the D-Gluco Series
Although first discovered with O-pentenyl glycosides, the
armed-disarmed concept has been proven with many other
classes of compounds, including thioglycosides,10 selenogly-
cosides,6 fluorides,11 phosphoroamidates,12 substituted thio-
formimidates,13 and glycals.14 The S-benzoxazolyl (SBox)
and S-thiazolinyl (STaz) glycosyl donors developed in our
laboratory were also found to react accordingly.15,16 For
instance, we have confirmed that the armed per-benzylated
SBox glycoside 1 (Figure 1) is significantly more reactive
1). However, in the case of the per-benzoylated derivative
2, this type of stabilization is less likely due to the electron-
withdrawing substituents at C-4 and C-6. Instead, the acyl
substituent at C-2 allows for stabilization via the acyloxonium
intermediate. In combination, these two competing effects
result in an overall moderate disarming of glycosyl donor 2.
Additionally, Crich and Li recently suggested the importance
of the 1,2-trans anomeric configuration for the SBox glycosyl
donors of the D-gluco series, in order for this stabilizing
participation to occur.17 In the case of glycosyl donor 3, the
O-5 disarming effect is only slightly compensated by the
electron-donating 2-O-benzyl moiety, whose arming effect
is mild. This anticipated “lack of cooperation” is in agreement
with experimental results, which indicate an overall strong
disarming effect for compound 3.15
The studies presented herein are based on the postulate
that glycosyl donors with a participating moiety at C-2 and
electronically armed lone pair at O-5, such as 4 (Figure 1),
would have exceptionally high reactivity. In comparison to
the application of the traditional per-benzylated armed
glycosyl donor 1, the “superarmed”18 glycosyl donor 4 would
offer advantages that could significantly enhance the way
we currently obtain oligosaccharide sequences. To explore
this concept, we obtained benzoxazolyl 2-O-benzoyl-3,4,6-
tri-O-benzyl-ꢀ-D-glucopyranoside (4) as shown in Scheme
2. In addition, we generated a series of glycosyl donors of
the D-galacto and D-manno series that would further allow
us to investigate comparative superarming (7 and 10), arming
(8 and 1119), and disarming effects (919 and 12,19 Scheme
2). These relatively simple building blocks were generated
from known advanced precursors20,21 by known or slightly
modified experimental procedures.16,21,22
Figure 1. SBox glucosyl donors with varying protecting group
arrangements.
than its disarmed benzoylated counterpart 2.15 Therefore,
when glycosyl donors with the mixed protecting group
pattern, such as 2-O-benzyl-3,4,6-tri-O-acyl derivative 3,
were considered, it was believed that their reactivity would
lie between that of the armed and disarmed glycosyl donors
1 and 2, respectively. Unexpectedly, glycosyl donor 3 was
determined to be less reactive than either 1 or 2.15
This was the first indication that the reactivity of the
glycosyl donor was not limited to the electron-withdrawing/-
donating properties of its protecting groups. This finding
ultimately gave rise to the theory that we call “The O-2/O-5
Cooperative Effect,”15 wherein we experimentally deter-
mined that glycosyl donor reactivity was also dependent on
the stability of the glycosyl cation that is formed upon leaving
group departure. In the case of the armed, benzylated
glycosyl donor 1, stabilization can be efficiently achieved
through resonance with the electronically “armed” lone pair
electrons of O-5, via the oxocarbenium intermediate (Scheme
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Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97, 4056–
4062.
Having synthesized a variety of glycosyl donors, we turned
our attention to their comparative glycosidations. It is
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(11) Barrena, M. I.; Echarri, R.; Castillon, S. Synlett 1996, 675–676.
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(18) Previously, the term “superarmed” was coined 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.
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Org. Lett., Vol. 10, No. 11, 2008

Table 1. Comparative Glycosidations of Glycosyl Donors 1-4 and 7-12 in the Presence of DMTST
a All glycosylations were started at 0 °C, and then the temperature was allowed to gradually increase.
important to note that the key feature of the armed-disarmed
glycosylation is the availability of a suitable activator
(promoter) that allows for differentiation among the reactivity
levels of the various (dis)armed substrates. Upon investigat-
ing a range of activators, including mildly electrophilic
copper(II) triflate, methyl triflate, and iodonium(di-γ-col-
lidine)perchlorate (IDCP), we chose dimethyl(methylthio)
sulfonium triflate (DMTST)23 as the appropriate promoter.
The results of the DMTST (3 equiv) mediated glycosylations
in 1,2-dichloroethane are summarized in Table 1. Glycosi-
dation of the benzylated glycosyl donor 1 with glycosyl
acceptor 1324 proceeded smoothly and was completed in 2 h
Org. Lett., Vol. 10, No. 11, 2008
2105

Having investigated the glucosyl donor 4, we then
refocused our investigation to superarmed galactosyl donor
7. Similar to our previous observations, compound 7 was
found to be significantly more reactive than the armed per-
benzylated derivative 8. Thus, disaccharides 2227 and 2325
were formed in 5 min (92%) and 40 min (85%), respectively
(entries 8 and 9). As in the previous case, no reaction took
place with the per-benzoylated galactoside 9 (entry 10).
Similar observations were also made with mannosides
10-12: the disaccharides 2428 and 2529 were formed in 50
min (79%) and 90 min (79%), respectively (entries 11 and
12), whereas no glycosidation of the disarmed acceptor took
place (entry 13). To this end, we determined that not only
did the 2-O-benzoyl-3,4,6-tri-O-benzyl donors 4, 7, and 10
readily react, while the disarmed glycosyl donors (2, 3, 9,
12) did not, but also, as postulated, they proved to be more
reactive than their armed counterparts (1, 8, 11).
In conclusion, we have devised a novel method for
“superarming” glycosyl donors, through the strategic place-
ment of common protecting groups. Furthermore, these
superarmed glycosyl donors are easily obtained, through
either an orthoester or a glycal route. Complementary to the
anomeric mixture often obtained with the common per-
benzylated analogues, the superarmed glycosyl donor offers
an entirely 1,2-trans stereoselective glycosidation. This can
be achieved at ambient or slightly reduced temperatures.
Although not covered by the scope of these preliminary
studies, it is expected that these super-reactive glycosyl
donors can be useful in cases of difficult glycosylations,
wherein classic per-acylated glycosyl donors fail. Further
expansion and application of this concept to chemoselective
oligosaccharide synthesis will be discussed in the following
manuscript.30
Scheme 2. Synthesis of the SBox Glycoside 4 and its
Analogues
affording the corresponding disaccharide 1725 in 91% yield
(entry 1, Table 1). When reactions between moderately
disarmed and disarmed glycosyl donors 2 and 3, respectively,
and glycosyl acceptor 13 were set up under essentially the
same reaction conditions, no formation of the corresponding
coupling products was detected (entries 2 and 3). Encourag-
ingly, the anticipated superarmed glycosyl donor 4 reacted
nearly instantaneously, under the same reaction conditions,
to provide disaccharide 1825 in 90% yield (entry 4). The
reactivity of the superarmed glycosyl donor 4 was then tested
in reactions with less reactive secondary glycosyl acceptors
14-16.26 These couplings were also efficient, resulting in
the formation of the respective disaccharides 19,25 20,27 and
21 in high yields (88-97%, entries 5-7, Table 1).
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Acknowledgment. The authors thank NIGMS (GM077170)
for financial support of this research program 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, UMsSt. Louis) are thanked
for HRMS determinations.
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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.
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