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Organic Chemistry Highlights

Total Synthesis

Monday, August 3, 2015
Douglass F. Taber
University of Delaware

The Hoveyda Synthesis of Disorazole C1

Disorazole C1 (3), isolated from fermentation of the myxobacterium Sorangium cellulosum, shows antifungal and anticancer activity. Amir H. Hoveyda of Boston College applied (J. Am. Chem. Soc. 2014, 136, 16136. DOI: 10.1021/ja509973r) recent advances in alkene metathesis from his group to enable the efficient assembly of 2 and so of 3.

The ester 1 was assembled from the alcohol 11 and the acid 18. The preparation of 11 began with the enantioselective addition of 5 to 4 to give 7, as described by Kalesse (Angew. Chem. Int. Ed. 2010, 49, 1619. DOI: 10.1002/anie.200906450) Leighton allylation led to 8, that was then coupled with 9 to give 10 with high Z selectivity. Iodination of 10 followed by deprotection then completed the assembly of 11.

The starting material for the acid 18 was the allylic alcohol 13. As reported by Cramer (Angew. Chem. Int. Ed. 2008, 47, 6483. DOI: 10.1002/anie.200802043), exposure of the racemic alcohol 12 to vinyl acetate in the presence of Amano lipase PS converted one enantiomer to the acetate, leaving 13. Methylation of the secondary alcohol followed by acid-mediated removal of the t-butyl ester led to the acid 14, that was converted to the corresponding acyl fluoride and coupled with serine Me ester (15). After cyclization to the oxazole 17, cross metathesis with five equivalents of 4-bromo-1-butene gave the homoallylic bromide, that was readily eliminated with DBU to give, after saponification, the acid 18.

The cross metathesis of the coupled ester 1, a polyene, with 9 proceeded with remarkable selectivity to give 2, again as the Z geometric isomer. On exposure to the Heck catalyst Pd [(o-tolyl)3P]2, 2 dimerized efficiently. The deprotection was not straightforward, but conditions (H2SiF6, CH3OH, 4C, 72 h) were found that delivered 3 in 68% yield.

D. F. Taber, Org. Chem. Highlights 2015, August 3.