A versatile and stereocontrolled route to pyranose and furanose C-glycosides

Article abstract of DOI:10.1021/ol0490678

(Matrix Presented) The α,β-unsaturated-γ,δ- epoxyester 1 is a novel and versatile precursor to a wide variety of C-glycosides. For instance, treatment of Z-1 or E-1 with palladium(0) affords, stereospecifically, β- or α-C-furanosides, respectively. In con

Full text of DOI:10.1021/ol0490678

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2611-2614
A Versatile and Stereocontrolled Route
to Pyranose and Furanose C-Glycosides
,†
Joanne E. Harvey,* Steven A. Raw, and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, UK
rjkt1@york.ac.uk
Received May 20, 2004
ABSTRACT
The r,â-unsaturated-γ,δ-epoxyester 1 is a novel and versatile precursor to a wide variety of C-glycosides. For instance, treatment of Z-1 or
E-1 with palladium(0) affords, stereospecifically, â- or r-C-furanosides, respectively. In contrast, reaction of Z-1 or E-1 with base gives,
stereoselectively, the â- or r-C-pyranosides, respectively.
C-Glycosides are important as analogues of naturally oc-
curring heteroatom-linked glycosides as a result of their
hydrolytic stability toward enzymes that normally catalyze
cleavage of the anomeric bond. Such compounds can
therefore act as small-molecule inhibitors of, inter alia,
processes that involve cell-surface glycoside cleavage. The
design of new C-glycosides is therefore driven by the need
to probe the mode of action of enzymes that are implicated
in disease and to inhibit these enzymes in the form of
pharmaceutical drugs. C-Glycosides are also found in a
number of natural products and, as such, represent attractive
synthetic targets.1 A number of routes to C-glycosides have
been published,1-3 but they are usually specific for a single
type of product. We have previously described a synthetic
route to C-glycosides, including C-disaccharides, using the
Ramberg-Ba¨cklund reaction as a key step.3,4 We now wish
to report the preparation of building blocks Z- and E-1
(Scheme 1), prepared from D-glucose in five steps, which
can be utilized in a novel and particularly versatile approach
to C-glycosides. Depending on the conditions used, C-
furanosides or C-pyranosides can be synthesized in a
chemoselective and stereocontrolled manner.
The key precursors for this approach, i.e. R,â-unsaturated-
γ,δ-epoxyesters E- and Z-1, appeared to be accessible from
D-glucose (Scheme 2). Thus, the known diol 35 was prepared
from D-glucose (2) in two steps, comprising anomeric
allylation followed by 4,6-O-benzylidene acetal formation.
The epoxide of compound 4 was installed by double
deprotonation of the diol, followed by selective tosylation
at O-2 and spontaneous displacement of the resulting leaving
group.6,7 Removal of the allyl group with Pd(PPh3)4, prepared
in situ from Pd(OAc)2 and PPh3, in the presence of both
(2) For recent reviews of C-glycoside synthesis see: (a) Palomo, C.;
Oiarbide, M.; Landa, A.; Gonza´lez-Rego, M. C.; Garc´ıa, J. M.; Gonza´lez,
A.; Odriozola, J. M.; Mart´ın-Pastor, M.; Linden, A. J. Am. Chem. Soc. 2002,
124, 8637-8643. (b) Zamojski, A. Polish J. Chem. 2002, 76, 1053-1084.
(c) Vogel, P. Chimia 2001, 55, 359-365. (d) Compain, P.; Martin, O. R.
Bioorg. Med. Chem. 2001, 9, 3077-3092. (e) Toshima, K. Carbohydr. Res.
2000, 327, 15-26. (f) Dondoni, A.; Marra, A. Chem. ReV. 2000, 100, 4395-
4421. (g) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103-2112.
(h) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913-
9959. (i) Kozlowski, J. S.; Marzabadi, C. H.; Rath, N. P.; Spilling, C. D.
Carbohydr. Res. 1997, 300, 301-313.
† Current address: School of Chemical and Physical Sciences, Victoria
University of Wellington, PO Box 600, Wellington, New Zealand. E-mail:
joanne.harvey@vuw.ac.nz
(1) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
Postema, M. H. D. C-Glycoside Synthesis; CRC: Boca Raton, FL, 1995.
(c) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Oxford, 1995.
(3) McAllister, G. D.; Paterson, D. E; Taylor, R. J. K. Angew. Chem.,
Int. Ed. 2003, 42, 1387-1391 and references therein.
(4) Paterson, D. E.; Griffin, F. K.; Alcaraz, M.-L.; Taylor, R. J. K. Eur.
J. Org. Chem. 2002, 1323-1336.
(5) Mehta, S.; Jordan, K. L.; Weimar, T.; Kreis, U. C.; Batchelor, R. J.;
Einstein, F. W. B.; Pinto, B. M. Tetrahedron: Asymmetry 1994, 5, 2367-
2396.
10.1021/ol0490678 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004

Scheme 1. Cyclization of Z-1 and E-1 to Afford C-Furanoside and C-Pyranoside Products
methanol and diethylamine afforded the hemiacetal 5 as a
trapped by the internal hydroxyl moiety to form a five-
membered ring.9 Although a 1.5:1 mixture of stereoisomers
6 and 7 (Scheme 3) was obtained upon treatment of
pale yellow solid in 78% yield. This common intermediate
could be transformed either exclusively to the E-alkene E-1
by Horner-Wadsworth-Emmons (HWE) reaction with
triethyl phosphonoacetate and KHMDS or to the Z-alkene
Z-1 by Z-selective stabilized Wittig reaction8 with (ethoxy-
carbonylmethylene)triphenylphosphorane in methanol in the
presence of triethylamine (Z:E ) 4:1).
Scheme 3. Stereospecific Synthesis of C-Furanosides 6 and 7
Scheme 2. Preparation of Cyclization Precursors Z-1 and E-1
compound Z-1 with a catalytic quantity of Pd2(dba)3/dppf,
the use of Pd(PPh3)4, prepared in situ from Pd(OAc)2/PPh3,
provided solely the â-C-furanoside 6 in 70% yield as the
E-alkene (3Ja,b 15.7 Hz). The “anomeric” stereochemistry was
established by NOE studies, which showed a through-space
interaction between H-1 and H-2 (using furanoside number-
ing scheme).10 Under identical conditions, the E-isomer also
reacted stereospecifically to afford the R-C-furanoside 7 in
77% yield. The stereochemical assignment was confirmed
by an NOE interaction between H-2 and H-b. Related
compounds have been prepared before2i by a number of
groups as precursors to, inter alia, C-nucleoside analogues,11
the antibiotic elfamycins aurodox and efrotomycin,12 and the
antitumor polyether macrolide halichondrin B.13 The novel
(8) Aldehydes bearing a substituent with a lone pair at the â-position
give higher-than-expected amounts of the Z-isomer on treatment with
stabilized ylids; see: Tronchet, J. M. J.; Gentile, B. HelV. Chim. Acta 1979,
62, 2091-2098. Fine-tuning of the solvent may then provide good
Z-selectivity; see: Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265-276. Minami, N.; Ko, S. S.; Kishi, Y. J. Am.
Chem. Soc. 1982, 104, 1109-1111.
(9) Similar Pd(0)-catalyzed cyclizations have been carried out on simpler
substrates: Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990, 31,
4747-4750. Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2927-
2930. Using Rh(I) catalysis: Ha, J. D.; Shin, E. Y.; Kang, S. K.; Ahn, J.
H.; Choi, J.-K. Tetrahedron Lett. 2004, 45, 4193-4195.
(10) The assignments made here were further confirmed by conversion
of compound 6 to the p-bromobenzoate derivative, in which all of the NMR
signals from the furanoside ring protons were well defined; there were NOE
interactions between H-1 and H-2, H-1 and H-4, and H-2 and H-4, thus
confirming the â-“anomeric” stereochemistry.
The allyl epoxide functionality present within E- and
Z-alkenes 1 undergoes reaction with Pd(0) to provide the
corresponding palladium π-allyl intermediates, which can be
(6) Magnusson, G.; Ahlfors, S.; Dahme´n, J.; Jansson, K.; Nilsson, U.;
Noori, G.; Stenvall, K.; Tjo¨rnebo, A. J. Org. Chem. 1990, 55, 3932-
3946.
(7) A similar sequence had been used successfully on the corresponding
1-O-benzylglucoside, involving reaction at room temperature.6 These
conditions gave the epoxide 4 in only 31% yield (see also Pasetto, P.; Franck,
R. W. J. Org. Chem. 2003, 68, 8042-8060.) By heating the reaction to 50
°C, the yield of 4 was improved to 75%. It is likely that the ring-flip
necessary for epoxide formation occurs at ambient temperature for the bulky
1-O-benzylglucoside but is sluggish for the 1-O-allylglucoside unless heating
is applied.
2612
Org. Lett., Vol. 6, No. 15, 2004

chemistry described in this Letter produces building blocks
of this type in a particularly efficient and inexpensive manner.
Furthermore, the ability to access, in a fully stereocon-
trolled manner, either anomer of the C-furanoside is note-
worthy.14
Scheme 5. Deprotection of C-Furanoside 7
We next investigated Michael-type cyclizations of the
alkenes 1.15 When compound Z-1 was treated with NaH, the
â-C-pyranoside 8 (Scheme 4) was obtained in excellent yield.
Scheme 4. Stereoselective Synthesis of C-Pyranosides 8 and 9
functionalization. For instance, epoxide opening of R-isomer
9 with NaN3 gave the azide 12 (Scheme 6) in excellent yield.
Hydrogenolysis of the azide and benzylidene acetal re-
moval followed by global acetylation afforded the novel
3-acetamido-3-deoxy-C-glycoside 13.
Scheme 6. Deprotection of C-Pyranoside 9
The stereochemistry at C-1 was assigned on the basis of a
NOE interaction between H-1 and H-5. At lower temperature
(0 °C), alkene Z-1 reacted only extremely slowly with NaH,
but the E-isomer E-1 underwent conjugate cyclization to
afford a 1:1.4 mixture of the novel epoxide-containing R-
and â-C-pyranosides 9 and 8. Chilling the reaction to -40
°C improved the R-selectivity to 2.5:1. The isomers were
partially separable by chromatography, but the R-isomer 9
could be crystallized out of a mixture containing 8 using
hot MeOH. An NOE between the exocyclic methylene
protons (Ha) and H-5 confirmed the assignment of the
product stereochemistry.
The presence of the benzylidene acetal, hydroxyl, alkene,
and ester in the C-furanosides 6 and 7 should enable further
functionalization or differential protection, if required for
future applications. Indeed, it was demonstrated that depro-
tection of 7 could be carried out by hydrogenation in the
presence of acetic acid to afford the saturated triol 10
(Scheme 5), which was isolated as the peracetylated deriva-
tive 11.
As the above results show, the versatility of alkenes of
type 1 is particularly noteworthy in terms of the range of
products accessible. Thus, R- and â-C-furanosides 7 and 6
and â-C-pyranoside 8 can be prepared in a stereocontrolled
fashion from the γ,δ-epoxy-R,â-unsaturated esters Z- and
E-1. The R-C-pyranoside 9 can be isolated by crystalli-
zation from a mixture containing the â-anomer 8. Further-
more, the resulting products may be further functionalized
at the ring and/or aglycon positions. Alternatively, it is
proposed that reaction of hemiacetal 5 with other Wittig or
HWE reagents would give a number of other interesting and
useful alkenes whose cyclizations could be investigated. We
plan to report our results in this area in due course, together
with a fuller rationalization for the origin of the observed
stereocontrol.
The presence of the epoxide in C-pyranoside products 8
and 9 also provides a useful synthetic handle, allowing further
(11) Krishna, P. R.; Reddy, V. V. R.; Sharma, G. V. M. Synlett 2003,
1619-1622. Dondoni, A.; Massi, A.; Minghini, E. Synlett 2002, 89-92.
Popsavin, M.; Torovicˇ, L.; Spaic´, S.; Stankov, S.; Kapor, A.; Tomic´, Z.;
Popsavin, V. Tetrahedron 2002, 58, 569-580. Fleet, G. W. J.; Seymour,
L. C. Tetrahedron Lett. 1987, 28, 3015-3018.
(12) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691-
1694.
(13) Horita, K.; Hachiya, S.; Yamazaki, T.; Naitou, T.; Uenishi, J.;
Yonemitsu, O. Chem. Pharm. Bull. 1997, 45, 1265-1281.
(14) The R-C-furanoside, 7, is presumably formed by overall retention
in the Pd(0)-catalyzed cyclization, as is typical with E-allylic substrates. It
is likely that the â-configuration of 6 is due to a π-σ-π rearrangement of
the intermediate palladium complex prior to cyclization, with concomitant
Z- to E-isomerisation. See: Vares, L.; Rein, T. Org. Lett. 2000, 2, 2611-
2614 and references therein.
(15) Similar reactions, albeit without an epoxide group, are known; See
ref 1 and Dawe, R. D.; Fraser-Reid, B. J. Org. Chem. 1984, 49, 522-528.
Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.; Ram´ırez, M.
A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570-4583. Mart´ın, V. S.;. Nun˜ez,
M. T.; Ram´ırez, M. A.; Soler, M. A. Tetrahedron Lett. 1990, 31,
763-766. Giannis, A.; Sandhoff, K. Carbohydr. Res. 1987, 171, 201-
210.
Org. Lett., Vol. 6, No. 15, 2004
2613

Acknowledgment. The authors thank the Anglo-Austra-
lian Fellowships Trust and the Ramsay Memorial Fellow-
ships Trust (J.E.H.) and the BBSRC (S.A.R.) for funding.
6-9. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Experimental
procedures and spectral data for compounds Z-1, E-1, and
OL0490678
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