De novo asymmetric synthesis of All-d-, All-l-, and d-/l-oligosaccharides using atom-less protecting groups

Article abstract of DOI:10.1021/ja305321e

Oligosaccharide synthesis is hindered by the need for multiple steps as well as numerous selective protections and deprotections. Herein we report a highly efficient de novo route to various oligosaccharide motifs, of use for biological and medicinal structure activity studies. The key to the overall efficiency is the judicious use of asymmetric catalysis and synthetic design. These green principles include the bidirectional use of highly stereoselective catalysis (Pd(0)-catalyzed glycosylation/post-glycosylation). In addition, the chemoselective use of C-C and C-O π-bond functionality, as atom-less protecting groups as well as an anomeric directing group (via a Pd-π-allyl), highlights the atom-economical aspects of the route to a divergent set of natural and unnatural oligosaccharides (i.e., various d-/l-diastereomers of oligosaccharides as well as deoxysugars which lack C-2 anomeric directing groups). For example, in only 12 steps, the construction of a highly branched heptasaccharide with 35 stereocenters was accomplished from an achiral acylfuran.

Full text of DOI:10.1021/ja305321e

Communication
pubs.acs.org/JACS
De Novo Asymmetric Synthesis of All-D-, All-L-, and D-/L-
Oligosaccharides Using Atom-less Protecting Groups
Ravula Satheesh Babu,† Qian Chen,† Sang-Woo Kang,† Maoquan Zhou,† and George A. O’Doherty*
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
S
* Supporting Information
deprotection steps that makes these processes uneconomical,
not to mention un-atom-economical.8 Thus, more convenient
ABSTRACT: Oligosaccharide synthesis is hindered by
the need for multiple steps as well as numerous selective
and efficient methods are still needed.9
protections and deprotections. Herein we report a highly
efficient de novo route to various oligosaccharide motifs, of
use for biological and medicinal structure activity studies.
The key to the overall efficiency is the judicious use of
asymmetric catalysis and synthetic design. These green
principles include the bidirectional use of highly stereo-
selective catalysis (Pd(0)-catalyzed glycosylation/post-
glycosylation). In addition, the chemoselective use of C−
C and C−O π-bond functionality, as atom-less protecting
groups as well as an anomeric directing group (via a Pd-π-
allyl), highlights the atom-economical aspects of the route
to a divergent set of natural and unnatural oligosaccharides
(i.e., various D-/L-diastereomers of oligosaccharides as well
as deoxysugars which lack C-2 anomeric directing groups).
For example, in only 12 steps, the construction of a highly
branched heptasaccharide with 35 stereocenters was
accomplished from an achiral acylfuran.
Oligosaccharide motifs, like the nonasaccharide Man-9, are
involved in a variety of important biological functions (e.g.,
protein and cellular recognition and signaling).7 While
multistep synthesis and isolation and semisynthesis have
provided access to these types of oligosaccharides for biological
studies, these studies have been limited to the natural structural
motifs.10 For instance, having access to a heptasaccharide motif
with unnatural branching and its enantiomer (cf. 23, Scheme 4)
would enable structure−activity relationship (SAR) studies of
the role these complex oligosaccharide arrays (e.g., Man-9) play
in many biological processes. For instance, having access to
both D- and L-glycoconjugates could allow for the differ-
entiation of specific protein interaction from pharmacokinetic
properties.11
To address this need, we have developed a complementary
de novo approach to carbohydrates that is compatible with
diversification and oligosaccharide assembly (Scheme 1).12 Our
Scheme 1. De Novo Achmatowicz Approach to the Hexoses
f the biopolymers, the carbohydrates present the greatest
Osynthetic challenges. In contrast to peptides and nucleic
acids, there is a dearth of synthetic methods for the
incorporation of unnatural monomers into oligosaccharide
structures. While there are many methods for the de novo
asymmetric synthesis of monosaccharides, the translation of
these methods to oligosaccharides synthesis is severely limited.
Due to the stereochemical complexity, the hexoses have long
stood as targets for synthesis.1 In particular, they serve as test
substrates for asymmetric catalysis.2 As these de novo
asymmetric routes evolved from flexible, albeit laborious,
approaches to all eight hexoses2 to quite efficient approaches
to specific hexoses,3 the utility of these catalytic asymmetric
approaches has remained limited to the synthesis of unnatural
and rare monosaccharides.4
As the recognition of the importance of oligosaccharides to
biological processes has grown,5 the commensurate need for
synthetic oligosaccharide intermediates has been largely met
with traditional carbohydrate approaches, which draw from
naturally occurring carbohydrate starting materials.6 While
these approaches have been widely successful for supplying
natural oligosaccharide structural motifs for biological studies,
they have limited potential for medicinal chemistry studies.1,5,7
The obvious solution of merging of these two approaches, de
novo monosaccharide synthesis followed by oligosaccharide
assembly, is mired in the need for additional protection and
approach allows for the facile incorporation of simple pyranyl
sugars (i.e., under functionalized sugars) into various
oligosaccharide motifs without the need for any protection/
deprotection steps with complete stereocontrol.13 The appeal
of this approach is that the double bond in pyranone glycosyl
donor (2a/2b) serves as an anomeric directing group in the
Pd(0)-catalyzed glycosylation, the enone functionality of the
pyranone products (3a/3b) serves as atom-less protecting
groups for the C-2 to C-4 triol portion of the hexose (4a/4b),14
and the route has equal efficiency to access various D- and L-
isomers.11,12,15
Previously we have developed a diastereoselective Pd(0)-
catalyzed glycosylation reaction and demonstrated its use in the
de novo synthesis of all-D- or all-L-1,4- and -1,6-α-manno-
trisaccharides.11,12 Herein, we present our discovery of an
Received: June 1, 2012
© XXXX American Chemical Society
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Scheme 2. Synthesis of a Library of 1,4-Linked α-rhamno-Trisaccharides Containing Both D- and L-Pyranoses
Scheme 3. Synthesis of Branched α-rhamno/manno-Trisaccharides Containing Both D- and L-Pyranoses
expeditious route to various highly branched all-D-, all-L-, and
mixed D-/L-oligosaccharides using asymmetric and diasterose-
lective catalysis for stereocontrol. These studies resulted in a
synthesis of a library of enantiopure α-rhamno/manno-
trisaccharides (Schemes 2 and 3), as well as a 12-step synthesis
of a highly branched heptasaccharide with up to 35 stereo-
centers from achiral starting materials. This greener approach
to oligosaccharides not only reduces the number of chemical
transformations but also limits the number of protecting groups
used (one TBS group per hexose for heptasaccharide 23).
We first explored the library synthesis of 1,4-α-rhamno-
trisaccharides (i.e., D-D-D-, D-D-L-, D-L-D-, and D-L-L-trisacchar-
ides, 12−15). The route commenced with the allylic alcohol D-
5, which was prepared from commercially available achiral
acylfuran 1a (Scheme 1).16 Using a Pd-catalyzed glycosylation
with pyranone D-2a and reduction, monosaccharide D-5 was
diastereoselectively elongated into the disaccharide 6 (Scheme
2). By changing the pyranone to its enantiomer (α-Boc-
pyranone L-2a) the diasteromeric D-L-disaccharide 7 was
prepared. Repeating this divergent diastereoselective elongation
of disaccharides 6 and 7 (glycosylation/reduction) provided the
four possible D-/L-diastereomeric trisaccharides 8−11. These
four diastereomeric routes proceeded with almost the same
synthetic efficiency and with virtually complete stereocontrol. A
similarly diastereoselective osmium-catalyzed global dihydrox-
ylation of allylic alcohol 8−11 afforded the four desired
diastereomeric 1,4-linked α-rhamno-pyranoses D-D-D-12a, D-D-L-
13a, D-L-D-14a, D-L-L-15a. A final element of synthetic
divergence can be employed with a global reduction of the
double bonds in trisaccharides 8−11 with excess diimide17 to
give the α-1,4-linked 2,3-dideoxyoligosaccharides 12b, 13b,
14b, and 15b in nearly quantitative yields. An important feature
of this route is that the ketone reductions and alkene
dihydroxylations occur with complete stereocontrol with
respect to the local pyran stereochemistry and not the
stereochemistry of the adjacent pyran rings (a fundamental
requirement for atom-less protecting groups).
To further explore the stereochemical robustness of this
approach, we next explored the bidirectional glycosylation of
the C-4 and C-6 alcohols. The desired diol D-16 was prepared
from Boc-pyranone D-2b in three steps with 69% overall yield
(Scheme 3). Subjecting alcohol D-16 to our typical Pd-
catalyzed glycosylation reaction conditions provided the
trisaccharide precursor tris-pyran 17 in 75% yield. Diaster-
B
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Scheme 4. A 12-Step Synthesis of Highly Branched All-L-α-manno-Heptapyranoside
eoselective 1,2-reduction of pyranone 17 with NaBH4 and
OsO4/NMO oxidation of the resulting allylic alcohols afforded
the branched mixed D-/L-trisaccharide 18 with α-rhamno/
manno stereochemistry as a single diastereomer in 68% yield.
Alternatively, by switching the dihydroxylation conditions to
diimide reduction, the branched mixed D-/L-trisaccharide 19
with two 2,3-dideoxy-α-rhamno and one 2,3-dideoxy-manno-
pyranose rings was prepared as a single diastereomer.
sensitive deoxysugars and capable of being diversified into any
of the D- and/or L-sugar diastereomers with complete
stereocontrol. Finally, this new method enables the rapid
assembly of unnatural oligosaccharide motifs (e.g., enantiomers,
deoxysugars, D-/L-diastereomers) and in turn the possibility for
numerous mode-of-action studies in glycobiology. Efforts along
these lines are ongoing and will be reported in due course.
ASSOCIATED CONTENT
Encouraged by the results, we were emboldened to try the
application of this approach to the target hepta-oligomannoside
23 (Scheme 4). Gratifyingly, preparation of the hyperbranched
heptasaccharide occurred with the same efficiency and high
degree of stereocontrol (cf. Schemes 2 and 3). Palladium-
catalyzed glycosylation of pyranone L-2b with the enantiomeric
diol L-16, followed NaBH4 reduction, provided the allylic
alcohol 20 in 65% yield (Scheme 4). Treatment of 20 with
TBAF successfully removed the two TBS groups, and the
resulting tetraol 21 then served as a glycosyl acceptor for
perglycosylation. Simply repeating the two-step protocol
(glycosylation/reduction) on 21 gave the heptasaccharide/
tetraallylic alcohol 22 in 49% yield. To our delight, per-
dihydroxylation of 22 using the Upjohn conditions (OsO4/
NMO) gave exclusively the α-manno-heptasaccharide 23 in
86% yield, which could be purified by simple silica gel
chromatography (ether/MeOH). Similarly, global reduction
with excess diimide resulted in the 2,3-dideoxy-D-erythro-hexo-
heptasaccharide 24, which was easily isolated in 74% yield.
While a similarly short route to ent-23 (e.g., the all D-
heptasaccharide) can be envisioned using a traditional
glycosylation strategy (Scheme S1), the route would require
the use of significantly more protecting groups and offer no
practical approach to the D-/L-stereoisomers and deoxy
congeners. It is important to note the acid sensitivity of the
glycosidic bonds in deoxy heptasaccharides 23 and 24, which
might not survive the strongly acidic conditions of a traditional
glycosylation.
■
S
* Supporting Information
Detailed experimental procedures and full compound character-
ization. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
g.odoherty@neu.edu
Author Contributions
†The first four authors contributed equally to this work and are
listed alphabetically.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NIH (GM090259) and NSF (CHE-
0749451) for financial support of this research.
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