Rhenium(V)-Catalyzed Synthesis of 2-Deoxy-α-glycosides

Article abstract of DOI:10.1021/ja031895t

A mild method for the synthesis of 2-deoxysugars from the coupling of glycals with a range of nucleophiles is described. The method employs 1 mol % of an air- and moisture-tolerant rhenium?oxo complex [ReOCl₃(SMe₂)(Ph₃PO)] as a catalyst for the formation of O-, N-, and S-α-glycosides. The catalytic system tolerates a number of commonly employed protecting groups, including isopropylidene acetals, alkyl and silyl ethers, acetates, and benzoates. Furthermore, the high-oxidation-state complex selectively catalyzes the coupling with the glycal acceptor in preference to oxidation of the glycals, alcohols, and even thiols. Copyright

Full text of DOI:10.1021/ja031895t

Published on Web 03/16/2004
Rhenium(V)-Catalyzed Synthesis of 2-Deoxy-r-glycosides
Benjamin D. Sherry, Rebecca N. Loy, and F. Dean Toste*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California, Berkeley,
Berkeley, California 94720
Received December 22, 2003; E-mail: fdtoste@uclink.berkeley.edu
Table 1. Re(V)-Catalyzed O-Glycosylationa
The formation of carbon-heteroatom bonds through acid-
mediated electrophilic activation of an olefin has a rich history in
organic chemistry.1,2 The harsh reaction conditions often required
for the acid-mediated process prompted the development of
alternative strategies involving stoichiometric reagents (Hg2+, I+,
PhSe+) for alkene activation.2 These methods generate carbon-
heteroatom bonds from olefins under mild conditions, but suffer
from the requirement for a stoichiometric activating reagent and
the need for reductive removal from the substrate. A mild catalytic
method that allows for addition of nucleophiles to olefins is
therefore highly desirable.
Our interest3 in the use of high-oxidation-state metal complexes
as catalysts for organic reactions led us to consider mechanisms
related to the microscopic reverse of the well-studied acetate
pyrolysis4 (eq 1) as a means to add nucleophiles across a carbon-
carbon multiple bond. We reasoned that a protonated metal-oxo,5
generated by the activation of a nucleophile (Nu-H) by the metal-
oxygen multiple bond, could replace the hydroxyl group of acetic
acid (eq 2). This approach presents several advantages. The use of
high-oxidation-state complexes as catalysts should render the
reaction tolerant of air and moisture. Additionally, the mild reaction
conditions of the metal-oxo-catalyzed reaction could allow for the
activation of sensitive olefins, such as glycals. However, successful
use of metal-oxo complexes for preparation of 2-deoxyglycosides6
requires that the traditional behavior of these complexes as oxidizing
agents of the nucleophile7 and glycal8 be suppressed. Furthermore,
the competing Ferrier rearrangement,9 generally mediated by Lewis
acids, must be avoided.
a Reaction conditions: 0.4 M glycosyl acceptor in PhMe, 1.5 equiv of
glycal, 1 mol % 1, 0 °C to room temperature. b Isolated yield after
chromatography. c Determined from 1H NMR of isolated material. d 4-OAc
was hydrolyzed to allow purification; reported yield is over two steps.
A survey of a number of high-valent metal complexes uncovered
a Re(V)-oxo complex, [ReOCl3(SMe2)(Ph3PO)] 1,10 as the catalyst
of choice. We found that 1 was a competent catalyst for the
glycosylation in a variety of solvents; however, nonpolar solvents
proved most effacious.11 With optimized reaction conditions in hand,
the scope of the Re(V)-catalyzed glycosylation was examined. The
reaction was found to be compatible with a large variety of both
glycosyl donors and acceptors (Table 1). Glucal and galactal donors
function well in the glycosylation, the latter preceding with high
anomeric R-selectivity. The catalytic system tolerated a number of
commonly employed protecting groups, including isopropylidene
acetals, silyl ethers, acetates, and benzoates. Importantly, the
disaccharide product (13) from entry 9 served as a viable donor,
thus demonstrating the synthetic utility of this method for the
preparation of 2-deoxyoligosaccharides (entry 10).
Having demonstrated the ability to efficiently generate O-
glycosides using metal-oxo complex 1, we chose to examine other
heteroatom nucleophiles in the reaction. Toward that end, the
coupling of tri-O-benzyl-D-galactal 2 with p-toluenesulfonamide
proceeded efficiently, providing the desired amino-glycoside in 81%
yield.12 Catalytic addition of thiols to olefins is particularly
challenging because thiols often serve as poisons for transition metal
complexes and are readily oxidized to disulfides.13 We were
therefore pleased to find that complex 1 readily catalyzes the
addition of thiophenol and 2,3,4-tri-O-benzoyl-6-thio-R-methyl-D-
glucopyranoside to galactal 2 to selectively afford R-thioglycosides14
15 and 16 in 94% and 81% yield, respectively (eq 3).
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C O M M U N I C A T I O N S
and allows for the use of alcohols, sulfonamides, thiols, and glycals
as nucleophiles. Traditionally, these high-valent metal-oxo com-
plexes have been associated with oxidative transformations of
olefins; however, adjusting the reactivity of these systems to
promote alternative reactions is of fundamental importance in
expanding the repertoire of transition metal catalysis. Application
of this catalytic system to other olefin addition reactions is currently
underway and will be reported in due course.
Our mild catalyst system allows the use of nucleophiles that
would be unstable under the conditions traditionally employed for
additions to olefins. For example, substitution of electron-withdraw-
ing groups at C-3 renders the glycal completely unreactive15 and
provides the means to couple two glycals using the Re(V)-catalyzed
method. Thus, 3,6-di-O-acetyl-D-glucal (17) was coupled with
galactal 2, catalyzed by 1 mol % 1, to afford disaccharide 18 as a
single anomer in 92% yield (eq 4). This disaccharide is now poised
for further elaboration, through employment of either an oxidative
glycosylation8 or a second Re(V)-catalyzed reaction providing an
iterative approach to the synthesis of 2-deoxyoligosaccharides. In
the event, rhenium-catalyzed coupling of 19 with thiol 20 provided
trisaccharide 21 in 74% yield as a single anomer.16,17
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, the Camille and Henry Dreyfus Foundation,
Research Corporation, Merck Research Laboratories, Amgen Inc.,
and Eli Lilly & Co. for financial support. The Center for New
Directions in Organic Synthesis is supported by Bristol-Myers
Squibb as a Sponsoring Member and Novartis Pharma as a
Supporting Member. We thank Dr. Herman van Halbeek for
assistance in NMR experiments.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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therein.
In the hopes of extending application of this method to the
synthesis of â-glycosides, we examined the effect of variation of
the rhenium-oxo complex on the selectivity of the glycosylation
(eq 5). Variation of the neutral ligands to arsine/arsine oxide or
tert-butylisocyanide slightly increased the amount of â-anomer
formed, while changing the anionic ligands from chloride to
bromide increased the selectivity for the R-anomer. Unfortunately,
these variations did not deliver the desired â-selective glycosylation.
(6) For reviews, see: (a) Marzabadi, C. H.; Franck, R. W. Tetrahedron 2000,
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Arterburn, J. B.; Liu, M.; Perry, M. C. HelV. Chim. Acta 2002, 85, 3225.
(8) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661.
Epoxidation of glycals by rhenium-oxo complexes, see: (b) Soldaini,
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(11) The reaction is reversible in polar solvents, resulting in lower yields and
formation of the thermodynamically favored R-glycoside.
To gain insight on the source of the selectivity, we examined
the facial preference of C-2 protonation. Coupling of 2-d-3,4,6-
tri-O-benzyl-D-glucal (23) with 3, catalyzed by 1 mol % 1, furnished
a 3.5:1 mixture of R- and â-dissaccharides (eq 6). Furthermore, a
2:1 ratio18 in favor of equatorial protonation was observed in both
the R- and the â-anomers, suggesting that the initial olefin activation
has very little directing influence on the anomeric selectivity. These
results suggest that the reaction is not proceeding through concerted
transfer of a proton and nucleophile from the rhenium complex.
Furthermore, it appears that the selectivity is determined not in the
olefin activation step, but in the transfer of the nucleophile.
(12) Colinas, P. A.; Bravo, R. D. Org. Lett. 2003, 5, 4509.
(13) For an example of thiol to disulfide oxidation by a rhenium(V)-oxo
complex, see: Abu-Omar, M. M.; Khan, S. I. Inorg. Chem. 1998, 37,
4979.
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(15) This effect has been noted with regard to the stability of the glycosidic
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1988, 27, 1697. (b) Geurtsen, R.; Holmes, D. S.; Boons, G.-J. J. Org.
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(18) This selectivity is substantially lower than the observed equatorial
selectivity in the acid-catalyzed glycal activation: Kaila, N.; Blumenstein,
M.; Bielawska, H.; Franck, R. W. J. Org. Chem. 1992, 57, 4576.
In conclusion, we have demonstrated that a high-oxidation-state
rhenium-oxo complex serves as an air- and moisture-tolerant
catalyst for the formation of 2-deoxy-R-glycosides from glycals.
The catalyst system tolerates a wide range of functional groups
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