Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, August 1, 2005
Douglass Taber
University of Delaware

Enantioselective Synthesis of the Polyene Antiobiotic Aglycone Rimocidinolide Methyl Ester

The complex polyene macrolide antibiotics are clinically effective as antifungal agents. Scott Rychnovsky of the University of California at Irvine has reported (Angew. Chem. Int. Ed. 2004, 43, 2822. DOI: 10.1002/anie.200453697) the first synthesis of rimocidinolide methyl ester (4), the aglycone of rimocidin (1). The key step in the synthesis is the condensation of the aldehyde 2 with the phosphonate 3, leading to 4.

Preparation of the Aldehyde 2: The absolute configuration of the triene aldehyde 2 was set by Noyori hydrogenation of ethyl butyrylacetate 5. Silylation and Dibal reduction then gave the aldehyde 6. Reduction of the homologated ester gave the alcohol, which was oxidized to the desired aldehyde 7 by the Swern procedure. Condensation of 7 with the Wollenberg stannyl diene followed by deprotection then gave the unstable aldehyde 2.

The power of convergent synthesis is illustrated by the preparation of the acid 3. The three components 9, 12, and 17 were each prepared in enantiomerically-pure form using readily-available chiral reagents, followed by functional group manipulation. One of the more remarkable transformations was the homologation of the Weinreb amide 15 to give the unstable allyl ketone, which was then reduced with high diastereoselectivity to give the diol 16.

Convergent coupling of 17 with 9, followed by functional group manipulation, gave the iodide 18, which was then homologated with 12 to give 19. Although the two monosubstituted alkenes of 19 appear to be similar, dihydroxylation with OsO4 was remarkably selective, leading to the aldehyde 20.

To complete the synthesis of 1, the acid 3 derived from 20 was converted to the mixed anhydride (Yamaguchi coupling), then esterified with 2. Exposure to K2CO3/18-crown-6 gave the all-E tetraene, which was deprotected to give the aglycone 4.

D. F. Taber, Org. Chem. Highlights 2005, August 1.