Enantioselective Synthesis of the Polyene Antibiotic Aglycone

Enantioselective Synthesis of the Polyene Antibiotic Aglycone Rimocidinolide Methyl 

The complex polyene macrolide antibiotics are clinically effective as antifungal agents. Scott Rychnovsky of the University of California at Irvine has repotted Angew. Chem. Int. Ed. 2004, 43, 2822) 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. 

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 K CO/lS-crown-b gave the all- tetraene, which was deprotected to give the aglycone 4. 

Enantiomericallly-pure carbacyclic rings are important components both of physiologically-active natural products and of important pharmaceuticals. Often it is most effective to control the absolute configuration of the ring as it is formed. Recent developments in the enantioselective construction of carbacyclic rings will be covered next week and the week after. The focus this week is on the asymmetric transformation of preformed prochiral rings. 

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