The 4,6-O-[α-(2-(2-lodophenyl)ethylthiocarbonyl)benzylidene] protecting group: Stereoselective glycosylation, reductive radical fragmentation, and synthesis of β-D-rhamnopyranosides and other deoxy sugars

Article abstract of DOI:10.1021/ol034741r

(Matrix presented) In the thioglycoside/BSP/Tf₂O glycosylation method, the 4,6-O-[α-(2-(2-iodophenyl)ethylthiocarbonyl)benzylidene] group enforces β-selectivity in mannopyranosylations. Following glycosylation, treatment with Bu₃SnH

Full text of DOI:10.1021/ol034741r

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2189-2191
The 4,6-O-[r-(2-(2-
Iodophenyl)ethylthiocarbonyl)benzylidene]
Protecting Group: Stereoselective
Glycosylation, Reductive Radical
Fragmentation, and Synthesis of
â-D-Rhamnopyranosides and Other
Deoxy Sugars
David Crich* and Qingjia Yao
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received May 2, 2003
ABSTRACT
In the thioglycoside/BSP/Tf2O glycosylation method, the 4,6-O-[r-(2-(2-iodophenyl)ethylthiocarbonyl)benzylidene] group enforces â-selectivity
in mannopyranosylations. Following glycosylation, treatment with Bu3SnH in toluene at reflux affords regioselective, reductive fragmentation
to the 6-deoxy-â-mannosides (â-rhamnosides). Applied to glucosides, the radical fragmentation provides 6-deoxyglucosides, whereas
4-deoxygalactosides are the preferred products in the galactose series. The radical fragmentation is fully compatible with the presence of
benzyl and p-methoxybenzyl ethers and with acetate esters
The â-rhamnopyranosides are frequent components of bacte-
rial polysaccharides and thus constitute important synthetic
targets. They differ from the â-mannopyranosides only by
the replacement of the 6-hydroxy group by a C-H bond
and therefore present a comparable synthetic challenge.1,2
Both enantiomeric modifications exist in nature but, by virtue
of the differing availability of the sugars themselves, present
significantly different synthetic challenges.3,4 L-Rhamnose
itself, but not L-mannose, is readily available and is therefore
the obvious starting point for the â-L-rhamnopyranosides,5
(3) â-L-Rhamnosides are components of the repeating unit of the antigenic
capsular polysaccharides from Streptococcus pneumoniae. For example,
see: Jones, C.; Whitley, C.; Lemercinier, X. Carbohydr. Res. 2000, 325,
192.
(1) Pozsgay, V. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol.
1, p 319.
(2) Recent developments: (a) Abdel-Rahman, A. A.-H.; Jonke, S.; El
Ashry, E. S. H.; Schmidt, R. R. Angew. Chem., Int. Ed. 2002, 41, 2972. (b)
Kim, K. S.; Kim, J. H.; Lee, Y. J.; Park, J. J. Am. Chem. Soc. 2001, 123,
8477.
(4) â-D-Rhamnosides are found in the repeating unit of the antigenic
exopolysaccharide common to Escherichia hermannii ATCC 33650 and
33652 isolated from human wounds, sputum, lungs, and stools: Beynon,
L. M.; Bundle, D. R.; Perry, M. B. Can. J. Chem. 1990, 68, 1456. The
ultimate challenge in terms of â-D-rhamnoside synthesis is probably the
antigenic polysaccharide from Escherichia hermannii ATCC 33651, a â-D-
rhamnan: Perry, M. B.; Richards, J. C. Carbohydr. Res. 1990, 205, 371.
10.1021/ol034741r CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003

while in the D-series the converse is true and mannose must
be used as a starting material. The direct synthesis of â-D-
mannopyranosides, both in solution and on the solid phase,
is straightforward provided that the donor is protected by
the 4,6-O-benzylidene moiety or by a surrogate such as the
4,6-O-polystyrylboronate group.6 The problem of the â-D-
rhamnopyranosides therefore reduces to that of the reductive
regioselective cleavage of the 4,6-O-benzylidene group to
the 6-deoxy system. Here, we introduce the 4,6-O-[R-(2-(2-
iodophenyl)ethylthiocarbonyl)benzylidene] group as a sur-
rogate for the 4,6-O-benzylidene group that is capable of
enforcing high â-selectivity in direct mannosylations and
which is subsequently cleaved in a single step to the â-D-
rhamnopyranoside system.
itself be stable to the glycosylation conditions; thus, 2-(2-
iodophenyl)ethylthio esters13 became the precursors of
choice.
Reaction of 16 with 214 gave the acetals 3 and 4 as a 3/1
mixture in 85% yield, favoring the less polar isomer with
the axial carbomethoxy group.15 Treatment with a reagent
formed from 2-(2-iodophenyl)ethylthiol15 and AlMe3 in
toluene at reflux then afforded the separable thioesters 5 and
6 (Scheme 1).16 It is possible to perform all of the ensuing
Scheme 1. Preparation of Glycosyl Donors
The cleavage of 4,6-O-benzylidene-protected sugars to
their 4-O-benzoyl-6-bromo-6-deoxy congeners by N-bromo-
succinimide is an established reaction in carbohydrate
chemistry.7,8 Unfortunately, the reaction is not suitable for
use in the presence of benzyl and allyl-type protecting groups
due to the competing cleavage of these groups, which
significantly reduces yields and complicates isolation.9 This
incompatibility precludes the use of the NBS cleavage in
the synthesis of â-D-rhamnosides from the corresponding
â-D-mannnosides as ethers are the protecting groups of choice
for the 2- and 3-hydroxy groups in direct â-mannosylation.
A further disadvantage of the NBS reaction is the obvious
need to remove the bromide atom in a subsequent reduction.
As recognized from the outset by Hanessian,7a-c the actual
cleavage of the 6-C-O bond in the NBS cleavage reaction
can be envisaged as proceeding by either a radical or an ionic
fragmentation. Roberts developed an alternative based on
his catalysis of radical chain reactions by thiols, which leads
directly to the 6-deoxy system, and in doing so demonstrated
the key fragmentation to be radical in nature.10 The contra-
thermodynamic regioselectivity in these radical fragmenta-
tions was explained on the basis of MO calculations as
arising from the less strained transition state for cleavage of
the 6-C-O bond.11,12 Unfortunately, in our hands, even the
very mild Roberts’ conditions proved to be incompatible with
the presence of benzyl ethers. We were therefore led to
contemplate alternative entries into the key R-benzylidene
radical and ultimately turned to cyclic acetals derived from
benzoylformic acid with the R-benzylidene radical generation
through decarbonylation. The need to minimize transforma-
tions after glycosylation indicated that the radical precursor
chemistry with the isomeric mixture, but to simplify the
spectra at the stage of the glycosylation reaction, we have
worked with pure isomers. The action of N-benzene-
sulfinyl piperidine (BSP),17,18 2,4,6-tri-tert-butylpyrimidine
(TTBP),18,19 and triflic anhydride on 5 at -60 °C in
dichloromethane followed by addition of methyl 2,3-O-
isopropylidene-R-L-rhamnopyranoside as acceptor gave 7 in
94% yield as a single anomer. It is noteworthy that the BSP/
Tf2O combination cleanly activates the thioglycoside toward
coupling but leaves the thioester unchanged. Three further
coupling reactions were similarly conducted, each providing
the desired â-mannoside in excellent yield and selectivity
(Scheme 2, Table 1).
Scheme 2. Stereoselective Formation of Mannosides
(5) Synthesis of L-rhamnosides: Crich, D.; Picione, J. Org. Lett. 2003,
5, 781.
(6) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867.
(7) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035. (b)
Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1045. (c) Hanessian,
S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1053. (d) Hullar, T. L.; Siskin,
S. B. J. Org. Chem. 1970, 35, 225. (e) Chana, J. S.; Collins, P. M.; Farnia,
F.; Peacock, D. J. J. Chem. Soc., Chem. Commun. 1988, 94.
(8) Ionic cleavage: Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J.
Org. Chem. 1984, 49, 992.
(9) Reported cleavage of benylidene acetals in the presence of benzyl
ethers: Liotta, L. J.; Dombi, K. L.; Kelley, S. A.; Targontsidis, S.; Morin,
A. M. Tetrahedron Lett. 1997, 38, 7833.
(10) Roberts, B. P.; Smits, T. M. Tetrahedron Lett. 2001, 42, 3663.
(11) Fielding, A. J.; Franchi, P.; Roberts, B. P.; Smits, T. M. J. Chem.
Soc., Perkin Trans. 2 2002, 155.
Radical fragmentation was achieved by dropwise addition
of tributyltin hydride and AIBN to the substrates in toluene
(13) Crich, D.; Yao, Q. J. Org. Chem. 1996, 61, 3566.
(14) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203.
(15) Stereochemistry of 3 and 4 was assigned by parallels in the 13C
NMR chemical shifts and the relative polarities with the pyruvate acetals.
Garegg, P. J.; Janesson, P.-E.; Lindberg, B.; Lindh, F.; Lonngren, J.;
Kvarnstrom, I.; Nimmich, W. Carbohydr. Res. 1980, 78, 127 and references
therein.
(12) Other contrathermodynamic radical ring openings and a similar
explanation: Ziegler, F. E.; Zheng, Z. L. J. Org. Chem. 1990, 55, 1416.
(16) Gennari, C.; Carcano, M.; Donghi, M.; Mongelli, N.; Vanotti, E.;
Vulpetti, A. J. Org. Chem. 1997, 62, 4746.
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Org. Lett., Vol. 5, No. 12, 2003

tion of the 4,6-O-type acetals in the mannopyranose series.
There is no reason, in view of the common fragmentation
step, why the new protecting group should not function as
an effective precursor to other deoxy sugars with the same
regioselectivity7 as the NBS-mediated cleavage of other
known benzylidene acetals. Indeed, Table 2 sets out examples
Table 1. Glycosylation and Cleavage in the Mannose Series
Table 2. Cleavage in the Glucose and Galactose Series
at reflux when the â-D-rhamnosides were obtained in high
yield (Scheme 3, Table 1). As expected, the regioselectivity
of all reactions was very high such that the alternative 6-O-
benzoyl-4-deoxy-type products were not detected. The
byproducts are the known 4,6-O-benzylidene-protected â-
mannosides20 arising from competing quenching of the
benzylidene radical by the stannane.21
Scheme 3. Reductive Radical Fragmentation
a Substrate preparation is described in Supporting Information.
of application in both the glucopyranose and galactopyranose
series, wherein the regioselectivity is consistent with that
obtained by previous workers in the field.7,10,11 Furthermore,
it is demonstrated that, as expected, the radical chemistry
may be satisfactorily conducted in the presence of acetate
esters and even p-methoxybenzyl ethers.
In summary, we have demonstrated a very direct entry
into 6-deoxy sugars using a highly stereoselective glyco-
sylation followed by a clean, regioselective, reductive radical
cleavage of an acetal. Most importantly, these radical
fragmentation reactions were compatible with the presence
of up to six benzyl ethers.
Our focus has been on the synthesis of the â-D-rhamno-
sides, and thus we have emphasized the reductive fragmenta-
Acknowledgment. We thank the NIH (GM 57335) for
support of this work.
(17) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(18) Available from Lakeview Synthesis, Chicago, IL (www.
lakeviewsynthesis.com).
(19) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(20) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(21) Formed with high selectivity for the isomer shown due to the
preferred axial quenching of the intermediate σ-type radical. Curran, D. P.;
Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, Germany, 1996.
Supporting Information Available: Full experimental
details and copies of spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034741R
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