Novel Strategy for Oligosaccharide Synthesis Featuring Reiterative Alkynol Cycloisomerization

Full text of DOI:10.1021/ja980196r

4246
J. Am. Chem. Soc. 1998, 120, 4246-4247
Scheme 1. Preparation and Cycloisomerization of Alkynolsa
Novel Strategy for Oligosaccharide Synthesis
Featuring Reiterative Alkynol Cycloisomerization
Frank E. McDonald* and Hugh Y. H. Zhu
Department of Chemistry, Northwestern UniVersity
2145 Sheridan Road, EVanston, Illinois 60208-3113
ReceiVed January 20, 1998
In recent years many significant advances have been made in
the synthesis of oligosaccharides. Virtually all of these ap-
proaches link two or more cyclic monosaccharide components
via glycoside bond formation.1 Several classes of biologically
active natural products possess polysaccharide domains composed
of highly deoxygenated sugars. The most common patterns
feature deoxygenation at the 2- and 6-positions and occasionally
at the 3-position, and both D and L enantiomeric forms are known
for many of these deoxy sugars.2 Herein we describe a novel
strategy for the preparation of oligosaccharides of 2,3,6-trideoxy-
hexoses, in which glycosylation with an acyclic alkynyl alcohol
glycosyl acceptor is followed by transition-metal-promoted
alkynol cycloisomerization to the glycal,3 forming a polysaccha-
ride in which the reducing terminus is activated as a glycosyl
donor for subsequent glycosylation.
The absolute chirality for the deoxycarbohydrate target arose
from the stereochemistry of the lactate precursor to aldehydes
1a,b (Scheme 1).4 Although addition of allenylmagnesium
bromide to 1a,b was not stereoselective, the 1:1 mixture of
diastereomeric products could be chromatographically separated.5
Compounds 2a6 and 3a were separately converted into 4 and 6,
which each underwent tungsten-induced cyclization followed by
triethylamine treatment to afford the pyranoid 1,2-glycals of
L-amicetose (5)7 and L-rhodinose (7), respectively.8
a Reagents: (a) (i) H2CdCdCHMgBr, Et2O (73-84%). For series a:
(ii) silica gel chromatographic separation. For series b: (ii) Ac2O, py,
cat. DMAP, CH2Cl2. (iii) Silica gel chromatographic separation. (iv)
K2CO3, CH3OH/H2O. (b) (i) NaH, PhCH2Br, THF. (ii) Bu4NF, THF (87-
92%). (c) (THF)W(CO)5, THF. (d) Et3N, Et2O/THF (28-32%, two steps).
Our first demonstration of the reiterative application of alkynol
cycloisomerization to oligosaccharide synthesis began with ste-
reoselective N-iodosuccinimide-promoted glycosylation of glycal
5 with the acyclic alkynol 3a (R ) TBDMS), followed by
triphenylstannane-promoted dehalogenation9 to afford the alkynyl
glycoside 8 (Scheme 2).10-12 Desilylation and tungsten-promoted
cycloisomerization of the alkynol 9 provided the disaccharide
glycal 10. Although iodoglycosylation of 10 with 3a proceeded
in low yield, the direct acid-catalyzed glycosylation11 of 10 with
compound 3a gave glycoside 1112 as a single diastereomer, due
to the large L-amicetose substituent attached to C-4 of the glycal
10. Desilylation and cycloisomerization steps as before furnished
the L-amicetose-R-L-rhodinose-R-L-rhodinose trisaccharide glycal
(13) in a straightforward manner.
(1) Recent reviews: (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93,
1503. (b) Halcomb, R. L.; Wong, C.-H. Curr. Opin. Struct. Biol. 1993, 3,
694. (c) Boons, G. J. Tetrahedron 1996, 52, 1095. (d) Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380.
To test this new strategy in a more challenging system, we
engaged in syntheses of the disaccharide and trisaccharide glycals
17 and 20 (Scheme 3), which are reasonable synthetic precursors
to the aquayamycin class of platelet aggregation inhibitor natural
products exemplified by PI-080 (Figure 1).2d,13,14
(2) For representative lead references, see the following. (a) Vineomy-
cins: Imamura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka, H.; Omura, S. J.
Antibiot. 1981, 34, 1517. Ohta, K.; Mizuta, E.; Okazaki, H.; Kishi, T. Chem.
Pharm. Bull. 1984, 32, 4350. (b) Digitoxin: Wiesner, K.; Tsai, T. Y. R.; Jin,
H. HelV. Chim. Acta 1985, 68, 300. (c) Saquayamycins: Uchida, T.; Imoto,
M.; Watanabe, Y.; Miura, K.; Dobashi, T.; Matsuda, T.; Naganawa, H.;
Hamada, M.; Takiuchi, T.; Umezawa, H. J. Antibiot. 1985, 38, 1171. (d) PI-
080: Kawashima, A.; Kishimura, Y.; Tamai, M.; Hanada, K. Chem. Pharm.
Bull. 1989, 37, 3429. (e) Landomycin: Weber, S.; Zolke, C.; Rohr, J.; Beale,
J. M. J. Org. Chem. 1994, 59, 4211. (f) Amicenomycin A: Kamamura, N.;
Sawa, R.; Takahashi, Y.; Sawa, T.; Kinoshita, N.; Naganawa, H.; Hamada,
M.; Takeuchi, T. J. Antibiot. 1995, 48, 1521. (g) Reviews: Rohr, J.; Thiericke,
R. Nat. Prod. Rep. 1992, 9, 103. Kirschning, A.; Bechthold, A. F.-W.; Rohr,
J. Top. Curr. Chem. 1997, 188, 1.
The base-sensitive L-aculose donor 1415 could be stereoselec-
tively glycosylated by ZnCl2-catalyzed reaction16 with alkynol
3a. Desilylation of glycoside 1512 was accomplished under mildly
(9) (a) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696. (b) Thiem,
J.; Klaffke, W. Top. Curr. Chem. 1990, 154, 285. (c) Ko¨pper, S.; Thiem, J.
Carbohydr. Res. 1994, 260, 219. (d) Suzuki, K.; Sulikowski, G. A.; Friesen,
R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 8895.
(10) Toluenesulfonic acid-catalyzed glycosylation (ref 11) of glycal 5 with
alkynol 3a gave compound 8 as the major diastereomer of a 3:1 anomeric
mixture in 57% combined yield.
(3) (a) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc. 1996, 118,
6648. (b) McDonald, F. E.; Bowman, J. L. Tetrahedron Lett. 1996, 37, 4675.
(c) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061.
(4) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180. (b) Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima,
S. Tetrahedron 1989, 45, 5767. (c) Kobayashi, Y.; Takase, M.; Ito, Y.;
Terashima, S. Bull. Chem. Soc. Jpn. 1989, 62, 3038.
(11) (a) Daniels, P. J. L.; Mallams, A. K.; Wright, J. J. J. Chem. Soc.,
Chem. Commun. 1973, 675. (b) Arcamone, F.; Bargiotti, A.; Cassinelli, G.;
Redaelli, S.; Hanessian, S.; DiMarco, A.; Casazza, A. M.; Dasdia, T.; Necco,
A.; Reggiani, P.; Supino, R. J. Med. Chem. 1976, 19, 733. (c) Tu, C. J.;
Lednicer, D. J. Org. Chem. 1987, 52, 5624. (d) Wakamatsu, T.; Nakamura,
H.; Naka, E.; Ban, Y. Tetrahedron Lett. 1986, 27, 3895. (e) Bolitt, V.;
Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org. Chem. 1990, 55, 5812.
(12) Coupling constants for anomeric hydrogens are consistent with
formation of axial glycosides: 8 (4.86 ppm, doublet, J ) 3.1 Hz); 11 (4.74
ppm, apparent single; 4.56 ppm, doublet, J ) 3.2 Hz); 15 (5.35 ppm, doublet,
J ) 3.6 Hz); 19 (5.25 ppm, doublet, J ) 3.5 Hz; 4.97 ppm, apparent singlet).
(13) The L-aculose-R-L-rhodinose-R-L-rhodinose trisaccharide of PI-080 has
been synthesized: Sobti, A.; Kim, K.; Sulikowski, G. A. J. Org. Chem. 1996,
61, 6.
(5) Attempts to induce chelate-controlled addition to MEM-protected
analogues of 1 also proceeded with low stereoselectivity.
(6) Compound 2a exhibited a proton NMR spectrum identical to that of
its enantiomer, prepared by addition of lithium acetylide to the TBDMS-ether
of (2S,3R)-3-hydroxy-1,2-epoxybutane: (a) White, J. D.; Kang, M.-C.;
Sheldon, B. G. Tetrahedron Lett. 1983, 24, 4539. (b) Kang, M.-C. Ph.D.
Dissertation, Oregon State University, 1984. We thank Prof. White for
providing a detailed procedure for preparation of (2S,3R)-3-hydroxy-1,2-
epoxybutane.
(7) Glycal 5 is identical to the product obtained from the published three-
step synthesis from 3,4-diacetoxy-L-rhamnal: (a) Martin, A.; Pais, M.;
Monneret, C. Carbohydr. Res. 1983, 113, 21. (b) Suzuki, K.; Sulikowski, G.
A.; Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 8895.
(8) For recent syntheses of rhodinose and amicetose, see: (a) Dondoni,
A.; Fantin, G.; Fugagnolo, M.; Pedrini, P. Tetrahedron 1989, 45, 5141. (b)
Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1995, 36, 4193. (c) Itoh, T.;
Yoshinaka, A.; Sato, T.; Fujisawa, T. Chem. Lett. 1985, 1679.
(14) The L-aculose-R-L-rhodinose disaccharide is also present in vineomycin
and saquayamycin-type natural products (refs 2a and 2c).
(15) Prepared in 95% ee by the published procedure: Kusakabe, M.; Kitano,
Y.; Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085.
(16) (a) Mucha, B.; Hoffmann, H. M. R. Tetrahedron Lett. 1989, 30, 4489.
(b) Kolb, H. C.; Hoffmann, H. M. R. Tetrahedron 1990, 46, 5127.
S0002-7863(98)00196-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/18/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 17, 1998 4247
Scheme 2. Synthesis of Trisaccharide 13 via Alkynol
Scheme 3. Short Synthesis of Oligosaccharide Glycals 17 and
Cycloisomerizationsa
20a
a Reagents: (a) NIS, CH3CN, 3 Å molecular sieves, 0 °C. (b) Ph3SnH,
cat. AIBN, C6H6, 80 °C (58%, two steps). (c) Bu4NF, THF (94-97%).
(d) (THF)W(CO)5, THF. (e) Et3N, Et2O/THF (45-47%, two steps). (f)
cat. p-TsOH-H2O, C6H6 (90%).
a Reagents: (a) cat. ZnCl2-OEt2, CH2Cl2/ClCH2CH2Cl (80%). (b)
HOAc, THF, H2O (70%). (c) (THF)W(CO)5, THF. (d) Et3N, Et2O/THF
(for 17, 34%; for 20, 23% yield). (e) cat. p-TsOH-H2O, C6H6. (f) DDQ,
H2O/CH2Cl2 (49%, two steps).
deprotected under oxidative conditions to yield the disaccharide-
substituted alkynol 19,12 and cycloisomerization provided the
glycal 20 corresponding to the L-aculose-R-L-rhodinose-R-L-
rhodinose trisaccharide of PI-080.
The principal advantage of our strategy for oligosaccharide
synthesis is the relatively inert nature of alkynes to the polar
reaction conditions required for glycosylation and the minimal
protective group manipulations, particularly the absence of
anomeric deprotection and activation steps generally required with
traditional glycosylation strategies. Note also that the affinity of
the transition-metal-promoted transformation for the π-system of
the alkyne readily accommodates acid-sensitive glycoside linkages
as well as base- and nucleophile-sensitive aculose sugar. Al-
though the challenge of yield optimization still remains, this novel
strategy provides significant step savings toward the efficient
synthesis of oligosaccharides of deoxygenated carbohydrates.
Figure 1. Structure of PI-080.
Acknowledgment. This research was supported by the National
Institutes of Health (CA-59703). F.E.M. also acknowledges additional
funding as an Alfred P. Sloan Foundation Reseach Fellow, a grantee of
Lilly Research Laboratories and Novartis Pharmaceuticals, and a Camille
Dreyfus Teacher-Scholar Awardee. This manuscript is dedicated to Prof.
Charles D. Hurd on the occasion of his 100th birthday.
acidic conditions to afford 16, which underwent tungsten-
promoted cycloisomerization to the L-aculose-R-L-rhodinose dis-
accharide glycal 17 in the presence of the sensitiVe aculose sugar.
The electron-rich enol ether of 17 could also be stereoselectively
glycosylated with silyl ether-alkynol 3a under acidic catalysis
to afford the axial glycoside 18a, but at this stage, we could not
remove the silyl ether protective group without hydrolysis of the
newly formed glycosidic bond. However, the p-methoxybenzyl-
protected glycoside 18b (from alkynol 3b and glycal 17) was
Supporting Information Available: Preparation and characterization
data for compounds 2-20 (19 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
JA980196R