Semi-orthogonality of O-pentenyl and S-ethyl glycosides: Application for the oligosaccharide synthesis

Article abstract of DOI:10.1016/S0040-4039(02)02235-9

Novel semi-orthogonal glycosylation strategy with the use of O-pentenyl and thioglycosides has been developed. According to this technique both armed and disarmed thioglycosides can be selectively activated with MeOTf in the presence of either armed or disarmed O-pentenyl glycosides. The applicability of this novel strategy for the synthesis of a trans-cis glycosylation pattern, not accessible via conventional armed-disarmed approach, has been demonstrated for the synthesis of a linear tetrasaccharide derivative.

Full text of DOI:10.1016/S0040-4039(02)02235-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8819–8822
Semi-orthogonality of O-pentenyl and S-ethyl glycosides:
application for the oligosaccharide synthesis
Alexei V. Demchenko* and Cristina De Meo
Department of Chemistry and Biochemistry, University of Missouri–St. Louis, 8001 Natural Bridge Road, St. Louis, MO 63121,
USA
Received 4 September 2002; revised 4 October 2002; accepted 8 October 2002
Abstract—Novel semi-orthogonal glycosylation strategy with the use of O-pentenyl and thioglycosides has been developed.
According to this technique both armed and disarmed thioglycosides can be selectively activated with MeOTf in the presence of
either armed or disarmed O-pentenyl glycosides. The applicability of this novel strategy for the synthesis of a trans–cis
glycosylation pattern, not accessible via conventional armed–disarmed approach, has been demonstrated for the synthesis of a
linear tetrasaccharide derivative. © 2002 Elsevier Science Ltd. All rights reserved.
The 1,2-cis and 1,2-trans glycosyl residues are present
as the components in a wide variety of natural gly-
cosides, glycoconjugates, oligo-, and polysaccharides,
the biological role and tremendous therapeutic poten-
tial of which has been revealed primarily during past
decade.1–3 One of the major drawbacks in the study of
these derivatives is the low availability of pure samples
from natural sources; clearly, in these cases chemical or
enzymatic synthesis would allow access to considerably
larger quantities of chirally pure material. Since the first
attempts at the turn of the 20th century, enormous
progress has been made in the area of the O-glycoside
synthesis, however only last decade or two have wit-
nessed a dramatic improvement in the methods used for
the assembly of complex oligosaccharides and glyco-
conjugates.4–9 Many new glycosyl donors, which can be
synthesized under mild reaction conditions and are
sufficiently stable to be purified, modified and stored
for a considerable period of time, have been devel-
oped.6,10 Methods for solid phase oligosaccharide syn-
Scheme 1. Armed–disarmed glycosylation strategy.
Keywords: chemoselectivity; glycosylation; novel synthetic strategy; glycosyl donors.
* Corresponding author. Tel.: +1-314-516-7995; fax: +1-314-516-5342; e-mail: demchenkoa@umsl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02235-9

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A. V. Demchenko, C. De Meo / Tetrahedron Letters 43 (2002) 8819–8822
thesis have been reported and these procedures often
shorten oligosaccharide synthesis by avoiding the neces-
sity to purify intermediate derivatives.11–14 The power
of modern supercomputers has been applied for the
conformational analysis in order to explain or even
predict the reactivity of carbohydrate molecules.15
Despite considerable progress and the extensive effort,
there is a continuous need in new versatile synthetic
methods for the oligosaccharide synthesis.
and therefore, at this point is limited to too few exam-
ples to become generally applicable.17 Typically, phenyl
thioglycosides are selectively activated over glycosyl
fluorides and vice versa.21
As a part of a program to develop versatile and
stereoselective methods for the oligosaccharide synthe-
sis, we report here a novel semi-orthogonal glycosyla-
tion strategy with the use of S-ethyl22,23 and O-pentenyl
glycosides.19,24 Both thio and O-pentenyl glycosides
fulfill the requirements for a modern glycosyl donor
(accessibility, high stability toward protecting group
manipulations, mild activation conditions) and, there-
fore, occupy an important niche among the modern
glycosylation methods, being especially useful for the
oligosaccharide synthesis. Traditionally, these glycosyl
donors are activated under similar reaction conditions
and therefore, were considered to be unsuitable for the
orthogonal synthesis when applied together. Typical
electrophilic reagents used for their activation are NIS/
TfOH, iodonium(di-g-collidine)perchlorate (IDCP), or
NBS.6 Indeed, to fulfill the requirements for the ortho-
gonality, each selected leaving group should be unaf-
fected under the conditions used to activate the other.
A number of synthetic strategies enabling the conve-
nient assembly of oligosaccharides from properly pro-
tected building blocks have recently emerged.16,17 These
strategies offer more efficient route toward complex
saccharides by reducing the number of synthetic steps
in comparison to that of conventional linear glycosyla-
tion techniques. Many modern strategies for the
oligosaccharide synthesis are based on the selective
activation of a particular glycosyl donor over another.
One of the most elegant strategies is based on the
chemoselectivity principle, so-called armed–disarmed
glycosylation approach, was rationalized by Fraser-
Reid and co-workers (Scheme 1).18,19 According to this
strategy, a benzylated (armed) glycosyl donor can be
chemoselectively activated in the presence of the acetyl-
ated (disarmed) derivative to afford a 1,2-cis-linked
disaccharide. The latter can either be used for 1,2-trans
glycosylation directly with the use of a more powerful
promoter, or 1,2-cis glycosylation after appropriate
protecting group manipulations. Similar concept was
explored for the glycosylations with ethyl thiogly-
cosides.20 Overall, the armed–disarmed glycosylation
strategy offers an efficient way to synthesize oligosac-
charides with cis–trans or cis–cis glycosylation pattern.
However, this method is not applicable for the synthesis
of trans–cis, or trans–trans-linked saccharides in its
pure fashion.
We performed a number of experiments of selective and
chemoselective activation reactions with the use of a
number of glycosyl donors. Some of these experiments
are summarized in Scheme 2. For example, we estab-
lished that armed O-pentenyl glycoside 1 can be selec-
tively activated over the disarmed ethyl thioglycoside 2
(Eq. (1)), which is presumably attributed to the general
chemoselectivity considerations. These glycosylations
were effectively promoted by IDCP25 in the presence of
26
,
molecular sieves (MS) 4 A. In this context, selective
activation of armed O-pentenyl glycosides over the
armed ethyl thioglycosides have been previously investi-
gated, however, has failed.20 Similarly, armed thiogly-
coside 4a can be chemoselectively activated in the
presence of disarmed pentenyl glycoside 5b (IDCP).
Interestingly, we have shown that armed thioglycoside
4a can be also activated over armed O-pentenyl gly-
Combination of two chemically distinct glycosylation
reactions, in which one of the leaving groups is acti-
vated while the other stays intact and vice versa, has led
to the discovery of the orthogonal glycosylation strat-
egy.21 This unique and virtually one of the most
advanced techniques for the oligosaccharides synthesis
requires the use of orthogonal glycosyl donors, which
can be independently activated in the reaction media,
cosides in the presence of MeOTf27 and MS 3 A in
,
CH2Cl2. Most importantly, similar reaction conditions
allowed the glycosylation of either armed or disarmed
,
,
Scheme 2. Reagents and conditions: (i) IDCP, MS 4 A, toluene–dioxane, 1/3, v/v; (ii) MeOTf, MS 3 A, CH2Cl2.

A. V. Demchenko, C. De Meo / Tetrahedron Letters 43 (2002) 8819–8822
8821
,
,
Scheme 3. Reagents and conditions: (i) MeOTf, MS 3 A, CH2Cl2; (ii) IDCP, MS 4 A, toluene–dioxane, 1/3, v/v.
O-pentenyl glycosides 5a or 5b with the disarmed (R=
Ac or Bz) ethyl thioglycosides 4b or 4c. It should be
noted that this result is supported by the evidence of
the selective activation of a disarmed thioglycoside
(OAc) over a disarmed O-pentenyl glycoside (NPhth).28
can be also formed via this technique. The advanta-
geous features of this approach have been explored for
the convergent synthesis of a tetrasaccharide derivative.
Further investigation of the novel glycosylation strategy
as well as application for the synthesis of biologically
important molecules is on the way.
These findings have created the firm basis for the
development of a novel efficient route toward the syn-
thesis of complex oligosaccharides. To support the
credibility of this statement, we performed the two-step
synthesis of a complex linear tetraasaccharide 9 of the
Acknowledgements
core structure b-
D
-Galp-(1“4)-b-
D
-Glcp-(1“6)-a-
D
-
This work was supported by the University of Mis-
souri–St. Louis and ‘The Foundation BLANCEFLOR
Boncompagni-Ludovisi, ne´e Bildt’
Glcp-(1“6)-a- -Galp starting from common building
D
blocks 2, 5a, and 7 (Scheme 3). According to the novel
approach, the first synthetic step involved selective acti-
vation of the fully acetylated (disarmed, glycosyl donor)
ethyl thiolactoside 7 in the presence of the pent-4-enyl
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