β-glycosidation of sterically hindered alcohols

Article abstract of DOI:10.1021/ol9000735

The 2-chloro-2-methylpropanoic ester serves as a steering group in the Schmidt glycosidation reaction. Rapid and efficient glycosidation of a range of sterically hindered alcohols takes place under mild, acidic conditions to afford the glycoside products

Full text of DOI:10.1021/ol9000735

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1305-1307
ꢀ-Glycosidation of Sterically Hindered
Alcohols
Alex M. Szpilman and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie der ETH-Zu¨rich, HCI H 335, Wolfgang Pauli
Strasse 10, CH-8093 Zurich, Switzerland
carreira@org.chem.ethz.ch
Received January 14, 2009
ABSTRACT
The 2-chloro-2-methylpropanoic ester serves as a steering group in the Schmidt glycosidation reaction. Rapid and efficient glycosidation of
a range of sterically hindered alcohols takes place under mild, acidic conditions to afford the glycoside products in high yield and ꢀ-selectivity
and without formation of orthoester side products. The 2-chloro-2-methylpropanoic ester is readily cleaved under mild, basic conditions.
ꢀ-Glycosidation of sterically hindered alcohols remains a
significant challenge for the synthesis of oligosacharides and
Scheme 1
.
Glycosidation of Alcohols 2 with Donors 1a and
glycoside natural products.1 Formation of ꢀ- over R-glyco-
sides is commonly ensured by the incorporation of a C2
substituent capable of lending anchimeric assistance in the
glycoside donor. However, in the coupling of sterically
hindered alcohols, orthoesters are often formed as major
products.2 Sterically hindered steering groups, such as
pivalyl3 or isobutyryl4 esters, may repress orthoester forma-
tion, yet their removal requires harsh conditions incompatible
with base-sensitive substrates.
Subsequent Saponification
Herein, we report a protocol that enables the use of
2-chloro-2-methylpropanoic (CMP) ester as a steering group
in ꢀ-glycosylation reactions of a host of sterically hindered
a The synthesis of donors 1a and 1b is detailed in the Supporting
Information.
(1) Frontiers in Modern Carbohydrate Chemistry; Demchenko, A. V.,
Ed.; ACS Symposium Series 960; Oxford University Press: Oxford, 2007.
(2) (a) Fu¨rstner, A.; Jeanjean, F.; Razon, P.; Wirtz, C.; Mynott, R.
Chem.sEur. J. 2003, 9, 320. (b) Gung, B. W.; Fox, R. M. Tetrahedron
2004, 60, 9405. (c) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty,
T. K. J. Am. Chem. Soc. 1988, 110, 4696. (d) Kuszmann, J.; Medgyes, G.;
Boros, S. Carbohydr. Res. 2004, 339, 2407. (e) Plante, O. J.; Palmacci,
E. R.; Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545.
(3) Harreus, A.; Kunz, H. Liebigs Ann. Chem. 1986, 717.
alcohols without the observation of orthoester formation
(Scheme 1).
In the context of the synthesis of amphotericin B (AmB)
analogues, we had documented the ꢀ-glycosidation of a
protected AmB aglycon with an activated, masked my-
cosamine equivalent (Scheme 2).5 Careful optimization
studies in this case established the use of a CMP ester as a
(4) Desmares, G.; Lefebvre, D.; Renevret, G.; Le Drian, C. HelV. Chim.
Acta 2001, 84, 880.
10.1021/ol9000735 CCC: $40.75
Published on Web 02/26/2009
2009 American Chemical Society

Scheme 2
.
Glycosidation of Protected Amphoteronolide5a
Table 1. Scope of the Glycosidation Reaction (See Scheme 1)a
steering group at C2 able to provide selective ꢀ-glycosidation
and somewhat reduce formation of the orthoester biproduct.
Under optimal conditions for this substrate, protected AmB
derivative 7 was obtained in 43% yield while the corre-
sponding orthoester 8 was isolated in 23% yield. Importantly,
this required the use of excess (3 equiv) mycosamine donor.
As a consequence of this study in natural products chemistry,
we became interested in investigating whether the glycosi-
dation protocol was generally applicable to a broader range
of hindered alcohols because their glycosidation is generally
known to lead to unwanted orthoester biproducts.
The conditions we have identified involve the use of
sterically hindered Brønsted acid 5 as a catalyst in the
formation of product in high yield (Scheme 1).5a The use of
hexane as the solvent is important.2c The trichloroacetamide
formed during the reaction is poorly soluble in this solvent
and precipitates out. This facilitates the isolation of the
glycoside product 3 and minimizes the formation of gly-
cosidated trichloroacetamide byproduct.
a All reactions were carried out using 1.5 equiv of alcohol unless
otherwise noted. b Yield of unpurified product. c Yield of purified product,
over two steps. d Using 1 equiv of 2e. e Using 1.2 equiv of the alcohol.
As shown in Table 1, this protocol can be employed with
a range of sterically hindered alcohols 2a-i, leading to the
formation of ꢀ-glycosides without observation of orthoesters
biproducts. Primary and secondary cyclic alcohols, as well
as tert-butyl alcohol, are glycosidated in high yield. In each
case, the reaction is complete within 30 min. In contrast to
our work with AmB, the coupling can be conducted with
merely 1-1.5 equiv of the alcohol.
trichloroacetimidate and the sulfonic acid based Amberlyst-
15 resin proceeded in 83% yield,6 and the reaction of tetra-
O-benzoylgalactosyl trichloroacetimidate with 2e using the
strong Lewis acid tetramethylsilyl triflate proceeded in 75%
yield.7 In contrast to the protocol presented here, such
conditions may be incompatible with acid-sensitive donors
including 1a.
The glycosidation of cholesterol (2e) is noteworthy, as this
reaction is known to proceed with concomitant formation
of significant amounts of orthoester (up to 55%).3 In contrast,
glycosidation of cholesterol using 1 equiv of 1b provides
the desired product in 67% yield. Higher yields have been
achieved in the ꢀ-glycosidation of cholesterol 2e but only
using strongly acidic conditions under which any formed
orthoester would rearrange to the glycoside product. For
example, the glycosidation of 2e using tetra-O-acetyl glycosyl
Impressively, the bridged bicyclic, neopentylic secondary
alcohol borneol (2f) and the doubly neopentylic alcohol
fenchol (2g) are glycosidated by 1b in 68 and 72% yield,
respectively. No orthoester could be detected in the reaction
in either of these cases. In stark contrast, reaction of borneol
or fenchol (1 equiv) with tetra-O-pivaloylglucosyl bromide
(2 equiv) under Koenigs-Knorr conditions (AgOTf, 2,6-di-
tertbutyl-4-methylpyridine) afforded the desired glycoside
in 33-48% yield together with 27-47% orthoester.4 The
glycosidation of phenols is also possible, but yield and
(5) (a) Szpilman, A. M.; Manthorpe, J. M.; Carreira, E. M. Angew.Chem.,
Int. Ed. 2008, 47, 4339. (b) Szpilman, A. M.; Cereghetti, D. M.; Wurtz,
N. R.; Manthorpe, J. M.; Carreira, E. M. Angew.Chem., Int. Ed. 2008, 47,
4335. (c) Manthorpe, J. M.; Szpilman, A. M.; Carreira, E. M. Synthesis
2005, 3380.
(6) Tian, Q.; Zhang, S.; Yu, Q.; He, M.-B.; Yang, J.-S. Tetrahedron
2007, 63, 2142.
(7) Mbadugha, B. N. A.; Menger, F. M. Org. Lett. 2003, 5, 4041.
1306
Org. Lett., Vol. 11, No. 6, 2009

ꢀ-selectivity erode with increasing steric hindrance (compare
2h with 2i). Interestingly, glycosidation of less sterically
hindered alcohols shows a similar trend. Thus, the glycosi-
dation of benzyl alcohol (2a) by 1a proceeds with 4:1
ꢀ-selectivity in 91% yield while the more hindered cyclo-
hexyl alcohol (2b) is glycosidated in 80% yield and 6:1
ꢀ-selectivity.6 In contrast, the more hindered alcohol 2d is
glycosidated by 1a with exclusive formation of the ꢀ epimer
in 72% yield.
Subsequent to coupling, the auxiliary CMP ester is readily
hydrolyzed under mild basic conditions. Thus, saponification
was complete within 14 h at room temperature to afford
alcohols 4 in high yield (74-100%).
auxiliary removal. Simply decanting the reaction solution
from the precipitated trichloroacetamide followed by aqueous
workup leads to the isolation of glycoside 3c of sufficient
purity for submission to hydrolysis. Accordingly, reaction
of this material with potassium carbonate (2 equiv) for 14 h
and subsequent chromatographic purification leads to the
desired alcohol 4c in 88% yield over two steps.
In conclusion, in view of the unique properties of the CMP
ester disclosed herein as well as the protocol described for
coupling, it should be considered the ancillary group of
choice for ꢀ-glycosidation of sterically hindered alcohols. It
is especially attractive for applications in total synthesis of
acid- and base-sensitive natural products.
The glycosidation of tert-butyl alcohol is known to be
capricious and often proceeds in low yields.8 In contrast,
the product is formed in high yield in the reaction of 1b
with 1.5 equiv of tert-butyl alcohol and 10 mol % of the
mild acid 5. The glycoside need not be purified prior to
Acknowledgment. This research was supported by the
ETH and Swiss National Science Foundation (SNF).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Glycosidation of tert-butyl alcohol proceeds in 20-85% yield under
a variety of conditions. See, e.g.: (a) Lacombe, J. M.; Rakotomanomana,
N.; Pavia, A. A. Carbohydr. Res. 1988, 181, 246. (b) Roen, A.; Padron,
J. I.; Mayato, C.; Vazquez, J. T. J. Org. Chem. 2008, 73, 3351.
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