Asymmetric syntheses and structure elucidation of cystothiazole A metabolites of the myxobacterium Cystobacter fuscus

Abstract

Convergent syntheses of (14 R,15)- and (14 S,15)-dihydroxycystothiazole A 4 were achieved based on a Julia-Kocienski coupling between the functionalized aldehyde (2 E)- 6 or (2 Z)- 6, corresponding to the left-side, and chiral sulfones (14 R)- 16 and (14 S)- 16, bearing a bithiazole moiety corresponding to the right-side, respectively. The absolute configuration of natural (14,15)-dihydroxycystothiazoles A 4 was determined to be (4 R,5 S,14 S) by comparison of the physical data, including the sign of specific rotation, between synthetic (2 E,4 R,5 S,6 E,14 S)- 4 and natural 4. Deprotections of the silyl group and cyclopentane moiety of the coupled product (2 E,4 R,5 S,6 E,14 R)- 17 gave (14 R,15)-dihydroxycystothiazole C 5, which was consistent with natural 5 corresponding to the minor isomer, including the sign of specific rotation. Likewise, deprotection of the silyl group and cyclopentane moiety of the coupled product (2 E,4 R,5 S,6 E,14 S)- 17 afforded (14 S,15)-dihydroxycystothiazole C 5, which was consistent with natural 5 corresponding to the major isomer, including the sign of specific rotation. Finally, convergent synthesis of 14-hydroxycystothiazole C 3 was achieved based on the modified (one-pot) Julia olefination between the aldehyde (2 Z)- 6 and bithiazole sulfone 22. The absolute configurations of natural 14-hydroxycystothiazole C 3 were confirmed to be (4 R) and (5 S). Methylation of synthetic 3 gave cystothiazole B 2.