Titanium(III)-promoted stereoselective synthesis of simple C-glycosides

Full text of DOI:10.1021/jo9702352

4204
J . Org. Chem. 1997, 62, 4204-4205
Communications
Tita n iu m (III)-P r om oted Ster eoselective
Sch em e 1
Syn th esis of Sim p le C-Glycosid es
Roxanne P. Spencer and J effrey Schwartz*
Department of Chemistry, Princeton University,
Princeton, New J ersey 08544-1009
Received February 10, 1997
1
C-Glycosides are an important class of compounds,
members of which have been noted for their antitumor,
antibacterial, or antiviral activity.1 Several methods for
C-glycoside synthesis have been described that are based
on coupling of an electrophilically activated sugar com-
ponent with a nucleophile2 or of 1-lithio sugars or glycals
with electrophiles,1b but these routes can suffer from low
stereospecificity or functional group incompatibilities.
Another method involves trapping a glycosyl radical with
an unsaturated substrate.3 While some of these radical-
based routes can give the C-glycoside stereoselectively,3e,h,i
most yield mixtures of anomers, and over-reduction can
be problematic.3a-g Classically, glycosyl radicals are
made by halogen atom abstraction from C-1 using
activated tin species derived from alkyltin hydrides and
an initiator at elevated temperature. Typically, tin
hydride-promoted reactions of mannosyl or galactosyl
halides give only the R-glycosides;3b mixtures of R- and
-coupled products are often obtained from glucosyl
derivatives.3a,b
glycoside O-protecting groups.6 Halogen atom abstrac-
tion by 1 equiv of Ti(III) gives the pyranos-1-yl radical,
which is captured by a second equivalent of Ti(III);
-elimination from the resulting Ti(IV) organometallic
gives the glycal. We now report that these glycosyl
radicals can be competitively trapped by unsaturated
organic species to produce simple hexopyranosyl C-
glycosides with R-stereochemistry (Scheme 1); acrylo-
nitrile likely reacts via a similar mechanism involving a
ketenimide-titanium intermediate. Because the radical
can be generated at relatively low temperature, R-ste-
reoselective coupling is observed, even for gluco-
pyranosyl substrates.
In a typical procedure, 50 mg of 2,3,4,6-tetra-O-acetyl-
R-D-glucopyranosyl bromide (2a ) (0.12 mmol) and 200 mg
of methyl acrylate (2.40 mmol, 20 equiv) were dissolved
in 2 mL of THF under N2 at room temperature.7 A green
solution of 130 mg of 1 in 25 mL of THF (0.30 mmol, 2.5
equiv of dimer) was added dropwise at room temperature
over 30 min. The red reaction mixture was quenched by
pouring into 15 mL of water. Extraction, drying, and
flash chromatography (Et2O) gave the C-glycoside, which
was identified by 1H NMR comparison with authentic
material.8 Only one species was observed; the charac-
teristic axial-equatorial coupling constant measured for
H4 and H5 is indicative of an R-glycoside, consistent with
expectations for radical generation and capture at room
temperature.3h,i Other representative examples of C-
glycoside synthesis are given in Table 1. In each case,
radical coupling gave only the R-glycoside;9 yields were
comparable to those reported for trapping of radicals
generated by tin species. However, in contrast to meth-
ods utilizing tin hydride that yield the final reduced
organic adduct directly, the initial product of coupling
using 1 is a titanium enolate; NMR analysis showed
The temperature-dependent stereoselectivity of reduc-
tion of glucosyl halides using tin deuterides has been
noted.4,5 It has been suggested that an equilibrium
mixture of radical conformers exists, and axial radical
capture is preferred at low temperature.5 No intermedi-
ate (C-glycosyl)alkyl organometallic has been implicated
in these olefin addition processes; instead, the adduct
radical formed reacts with additional tin hydride to give
reduced product. We recently noted that glycals can be
prepared from glycosyl halides at or below room temper-
ature using (Cp2TiCl)2 (1), a reagent that is reactive for
halogen atom abstraction yet tolerates a broad range of
(1) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press:
London, 1995. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier: Tarrytown, NY, 1995.
(2) See, Czernicki, S. In CarbohydratessSynthetic Methods and
Applications in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami,
T., Eds.; VCH: New York, 1991; pp 28-48 and references cited therein.
(3) For Sn-based reduction of glycosyl halides, see: (a) Giese, B.;
Dupuis, J .; Nix, M. Organic Syntheses; Wiley: New York, 1993; Collect.
Vol. VIII, pp 148-153. (b) Giese, B.; Dupuis, J .; Leising, M.; Nix, M.;
Lindner, H. J . Carbohydr. Res. 1987, 171, 329-341. (c) Giese, B.;
Dupuis, J . Angew. Chem., Int. Ed. Engl. 1983, 22, 622-623. (d) Araki,
Y.; Endo, T.; Tanji, M.; Nagasawa, J .; Ishido, Y. Tetrahedron Lett. 1987,
28, 5853-5856. For Sn-based reduction of phenylseleno sugars, see:
(e) Adlington, R. M.; Baldwin, J . E.; Basak, A.; Kosyrod, R. P. J . Chem.
Soc., Chem. Commun. 1983, 944-945. For Sm-based reduction, see:
(f) Maze´as, D.; Strydstrup, T.; Beau, J .-M. Angew. Chem., Int. Ed. Engl.
1995, 34, 909-912. (g) DePouilly, P.; Che´nede´, A.; Mallet, J .-M.; Sinay¨,
P. Bull. Soc. Chim. Fr. 1993, 130, 256-265. For reduction using
Vitamin B12, see: (h) Abrecht, S.; Scheffold, R. Chimia 1985, 35, 211-
212. For electrochemical generation of the anomeric radical, see: (i)
Rondinini, S.; Mussini, P. R.; Ferzetti, V.; Monti, D. Electrochim. Acta
1991, 36, 1095-1098.
(6) (a) Cavallaro, C. L.; Schwartz, J . J . Org. Chem. 1995, 60, 7055-
7057. (b) Spencer, R. P.; Schwartz, J . Tetrahedron Lett. 1996, 37, 4357-
4360.
(7) Reaction solvents were distilled prior to use using standard
methods. 2,3,4,6-Tetra-O-acetyl-R-D-glucopyranosyl bromide, 2,3,4,6-
tetra-O-acetyl-R-D-galactopyranosyl bromide, and 2-deoxyribose were
obtained from Sigma Chemical Co. All other materials were obtained
from Aldrich Chemical Co. Methyl vinyl ketone, acrylonitrile, and
methyl acrylate were evaporatively distilled before use and stored
under N2 at -40 °C.
(8) Signals for H5
J 6,7 ) 9.52 Hz), H7
(
(
5.10, J 4,5 ) 5.86 Hz, J 5,6 ) 9.52 Hz), H6 ( 5.33,
5.00, J 7,8 ) 9.52 Hz) were separate from the
glycal byproduct. The numbering is based on suggested guidelines for
C-glycoside nomenclature.1b
(4) Kahne, D.; Yang, D.; Lim, J . J .; Miller, R.; Pagvaga, E. J . Am.
Chem. Soc. 1988, 110, 8716-8717.
(5) Giese, B.; Dupuis, J . Tetrahedron Lett. 1984, 25, 1349-1352.
(9) No -glycoside was isolated or could be observed in the NMR
spectrum of the crude reaction mixture. The only byproduct observed
in all cases was the corresponding glycal.
S0022-3263(97)00235-1 CCC: $14.00 © 1997 American Chemical Society

Communications
Ta ble 1. P r ep a r a tion of C-Glycosid es
J . Org. Chem., Vol. 62, No. 13, 1997 4205
Sch em e 2
C-glycoside9 from 2a or 2b. Reports of coupling in the
2-deoxyglycosyl series14 are limited to 1-carboxylglycos-
1-yl radicals, which are stabilized by both the ring oxygen
and the carboxylate group,14b and radical allylation gave
the coupled product as a mixture of stereoisomers in
moderate yield. The 2-deoxyribosyl radical suffers from
two drawbacks not noted in the hexopyranosyl case: It
lacks stabilization, either by a -OAc substituent or by
anomeric substitution, and the pentopyranosyl ring is
more flexible and could attain conformations that could
allow rapid atom transfer. In this case, fragmentation
could be faster than coupling.15,16
substantial deuterium incorporation at C-210 when an
aliquot of the reaction mixture was quenched under N2
with D2O.
C-Glycoside synthesis using 1 to activate glycosyl
halides has several advantages compared with estab-
lished methodologies. Unlike Sm(II), 1 is inexpensively
and easily prepared17 from available starting materials.
In contrast to tin,3a-e titanium is not a toxic element, and
the Ti(IV) byproduct of coupling can be recovered readily
and recycled. Finally, the likely product of radical
capture is a C-glycosidic side chain titanium enolate (3),18
and elaboration19 of this intermediate should be possible.
Further studies to this effect are now in progress.
The anomeric radical, and not an intermediate orga-
notitanium species, is the active species for coupling.
Reaction of authentic bis(cyclopentadienyl)(3,4-di-O-
acetyl-2-deoxy- -D-erythro-pentopyranosyl)titanium(IV)
chloride (5)6a and acrylonitrile gave only the correspond-
ing anhydroalditol11 on hydrolysis; no product of conju-
gate addition was observed using the organometallic
(Scheme 2). The anhydroalditol is the expected product
from simple hydrolysis of 5. However, -coupled C-
glycoside 7 was obtained12 by reaction of 3,4-di-O-acetyl-
2-deoxy- -D-erythro-pentopyranosyl bromide (2c)13 with
1 in the presence of acrylonitrile (Scheme 2). The
stereochemistry of addition at the anomeric carbon,
assigned by 2Q-COSY NMR,12 is opposite to that found
for the hexopyranosyl case. This is unremarkable: pen-
topyranosyl radical -coupling is common.3b The ob-
served products are likely the kinetic products of trapping
by the initially formed anomeric radical and will thus
give coupled products with the same stereochemistry as
the starting glycosyl halide.
Ack n ow led gm en t. The authors acknowledge sup-
port for this research given by the National Science
Foundation. They also thank Dr. Istva´n Pelczer for
acquiring and interpreting COSY and ROESY NMR
spectra.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
COSY, and ROESY spectra of the mixture of 7 and 1,3,4-tri-
O-acetyl-2-deoxy-erythro-pentopyranose (7 pages).
J O9702352
The complexity of the reaction mixture derived from
2c stands in contrast to the relatively clean formation of
(14) (a) Wåglund, T.; Claesson, A. Acta Chem. Scand. 1992, 46, 73-
76. (b) Nagy, J . O.; Bednarski, M. D. Tetrahedron Lett. 1991, 32, 3951-
3956. (c) Paulsen, H.; Matschulat, P. Liebigs Ann. Chem. 1991, 487-
495.
(15) For examples, see: (a) Crich, D.; Sun, S.; Brunckova, J . J . Org.
Chem. 1996, 61, 605-615. (b) Crich, D.; Hwang, J .-T.; Yuan, H. J . Org.
Chem. 1996, 61, 6189-6198.
(10) Deuterium incorporation was ca. 80%, based on integration for
the C-2 proton signal ( 2.41). These protons do not exchange with
D2O as demonstrated using an authentic sample of the methyl acrylate
adduct. The adduct radical is not quenched by hydrogen atom abstrac-
tion from solvent: When a coupling procedure was carried out in THF-
d8, no deuterium incorporation was detected by NMR.
(11) (a) Cavallaro, C. L. Ph.D. Thesis, Princeton University, 1997.
(b) Cavallaro C. L.; Schwartz, J . J . Org. Chem. 1996, 61, 3863-3864.
(12) A complex mixture, including -coupled 7, 3,4-di-O-acetyl-1,5-
anhydro-2-deoxy-D-erythro-pent-1-enitol (see: Rico, M.; Santoro, J . Org.
Magn. Reson. 1976, 8, 49-55) and unidentified byproducts, was
isolated. The inseparable (1:1) mixture of 7 and residual 1,3,4-tri-O-
acetyl-2-deoxy-erythro-pentopyranose (see: Lemieux, R. U.; Stevens,
J . D. Can. J . Chem. 1965, 43, 2059-2070) was analyzed using gradient-
selected 2Q-COSY (30 ms excitation delay) connectivities and ROESY
(50 ms excitation delay) interactions at 500 MHz. 7: 1H (CDCl3)
5.37 (H6, J 5ax-6 ) J 5eq-6 ) J 7-6 ) 3 Hz), 4.82 (H7), 3.74 (H8eq), 3.68
(H4), 3.62 (H8ax), 2.45 (H2a), 2.41 (H2b), 1.82 (H5eq), 1.73 (H3a), 1.66 (H3b),
1.61 (H5ax, J ) 3, 11.4, 14.1 Hz); 13C (CDCl3) 119.37, 69.61, 67.52, 65.13,
63.69, 35.25, 30.78, 13.55; IR (neat) 2260 (CtN).
(16) Carbohydrate radicals can undergo a 1,5-hydrogen atom shift;
this route has been used for epimerization of the C-5 center in
glucopyranosides (see: De Mesmacker, A.; Waldner, A.; Hoffmann, P.;
Winkler, T. Synlett 1994, 330-332 and references therein). This radical
is reduced to the stable, coupled product in the presence of tin hydride.
(17) Coutts, R. S. P.; Wailes, P. C.; Martin, R. L. J . Organomet.
Chem. 1973, 47, 375.
(18) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994, 116,
986-997. An initially formed titanium enolate has also been suggested
for Cp2TiCl reduction of conjugated epoxides; see: Yadav, J . S.;
Shekharam, T.; Srinivas, D. Tetrahedron Lett. 1992, 33, 7973-7976.
(19) For a review of titanium aldol chemistry, see: Peterson, I. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
London, 1991; Vol. 2, Chapter 1.9. For reports of Cp2TiCl-enolates,
see: Veya, P.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics
1993, 12, 4892-4898. Murphy, P. J .; Procter, G.; Russell, A. T.
Tetrahedron Lett. 1987, 28, 2037-2040. Stille, J . R.; Grubbs, R. H. J .
Am. Chem. Soc. 1983, 105, 1664-1665.
(13) Prepared in situ from 1,3,4-tri-O-acetyl-2-deoxy- -erythro-pen-
topyranose. See: Gillard, J . W.; Israel, M. Tetrahedron Lett. 1981, 22,
513-516.