724
LETTERS
SYNLETT
enol triflate was prepared using 1.2 equiv of potassium
(9) Lipsky, P. E.; Tao, X. L.; Cai, J.; Kovacs, W. J.; Olsen, N. J., U.S.
hexamethyldisilazide and 1.2 equiv of N-phenyltrifluoro-
Patent 5616458, 1997; Chem. Abstr. 1997, 126 , 246818h.
18,19
methanesulfonimide at -78°C.
The carboxylic esters were then
(10) Typically this type of process suffers from polyalkylation of the
enolate derived from the monoalkylated product. A notable
example relied on eneamine chemistry to efficiently
monomethylate a closely analogous keto-ketal. See Piers, E.;
Friesen, R. W. Can. J. Chem. 1992, 70, 1204.
reduced with 2.2 equiv of diisobutylaluminium hydride in
tetrahydrofuran at -78°C to deliver diol 8. Carbonylation of the triflate
using 0.10 equiv of tetrakis(triphenylphosphine) palladium(0) with 10
equiv of triethylamine under an atmosphere of carbon monoxide in
acetonitrile at room temperature provided the butenolide of 9 in high
(11) Jung, M. E. Tetrahedron 1976, 32, 3.
20, 21
yield.
(12) Ellis, J. E.; Dutcher, J. S.; Heathcock, C. H. Synth. Commun.
1974, 4, 71.
At this point all that remained was an apparently straightforward
oxidation to complete the synthesis. A wide variety of oxidants were
22
(13) Bodalski, R.; Pietrusiewicz, K. M.; Monkiewicz, J.; Koszuk, J.
employed with varying degrees of success, and of these, the Swern
Tetrahedron Lett. 1980, 21, 2287.
oxidation proved to be optimal. Alcohol 9 was thereby cleanly oxidized
1
13
(14) Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974, 39, 2648.
to provide synthetic (±) wilforonide. H NMR and C NMR spectra of
23
the synthetic material were identical with those of the natural product.
(15) Ohta, S.; Shimabayashi, A.; Hatano, S.; Okamoto, M. Synthesis
1983, 715.
Studies investigating the mode of immunosuppressant action, the GR-
mediated effects, as well as structure-activity relationships of analogs
will be published elsewhere.
(16) Zibuck, R.; Streiber, J. Org. Synth. 1993, 71, 236; see also
references therein.
1
d ) 4.97 (m, 1H), 3.65 (s,
(17) Spectral data for 7: H NMR (DMSO-
6
References and Notes:
3H), 3.36 (d, J = 12.6 Hz, 1H), 2.65 (m, 1H), 2.20 (dq, J = 4.5, 15
(1) Kutney, J. P.; Hewitt, G. M.; Kurihara, T.; Salisbury, P. J.;
Sindelar, R. D.; Stuart, K. L.; Townsley, P. M.; Chalmers, W.T;.
Jacoli, G. Can. J. Chem. 1981, 59, 2677.
Hz, 1H), 1.9-1.4 (series of m, 9H), 1.22 (s, 3H), 1.15 (s, 9H) ppm.
13
C NMR (DMSO-d ) 205.4, 176.8, 169.9, 68.8, 59.2, 51.4, 45.6,
6
42.4, 39.3, 38.2, 36.9, 32.0, 29.2, 26.8(3C), 21.9, 17.2 ppm.
(18) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(19) Crisp, G. T.; Scott, W. J. Synthesis 1985, 335.
(2) Kutney, J. P.; Constabel, F.; Vasil, I. K. Cell Cult. Somatic Cell
Genet. Plants 1988, 5, 159.
(3) Kutney, J. P.; Han, K. Recl. Trav. Chim. Pays-Bas 1996, 115, 110.
(20) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972.
(21) Molander, G. A.; Carey, J. S. J. Org. Chem. 1995, 60, 4845.
(4) Buckanin, R. S.; Chen, S. J.; Frieze, D. M.; Sher, F. T.; Berchtold,
G. A. J. Am. Chem. Soc. 1980, 102, 1200.
(22) Ruthenium, sulfurane, and chromium-based oxidants returned or
decomposed alcohol 9. Swern conditions provided the natural
product albeit in low yield.
(5) Lai, C. K.; Buckanin, R. S.; Chen, S. J.; Zimmerman, D. F.; Sher,
F. T.; Berchtold, G. A. J. Org. Chem. 1982, 47, 2364.
(6) Garver, L. C.; Van Tamelen, E. E. J. Am. Chem. Soc. 1982, 104,
(23) We are indebted to Prof. Peter Lipsky from the Department of
Internal Medicine at the University of Texas Southwest Medical
867.
1
13
(7) Van Tamelen, E. E.; Demers, J. P.; Taylor, E. G.; Koller, K. J. Am.
Chem. Soc. 1980, 102, 5424.
Center at Dallas for providing authentic H NMR, IR, and
C
NMR spectra of natural wilforonide. Spectra of the synthetic
sample were also identical to those reported by Chen, K.; Yang,
R.; Wang, C. Zhongcaoyao 1986, 17, 242.
(8) Van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104,
1785.