Synthesis of C3-C9 Sulfonyl Derivative of Soraphen A

Abstract

Soraphen A (1) is an 18-membered macrolide isolated from myxobacterium Sorangium Cellulosum. It displays potent antifungal activity against various pathogenic plant fungi because of its highly efficient and specific inhibitory activity on acetyl CoA carboxylase. The structure of soraphen A was well defined by X-ray crystallographic analysis. The presence of an unsubstituted phenyl ring and a hemiketal ring constitutes its structural feature. The first total synthesis of soraphen A was reported by Giese in 1999. We previously reported our synthetic attempt. Toward the synthesis of soraphen A, we deliberated the coupling of two fragments 3 and 4 involving Julia olefination and lactonization (Scheme 1). Julia olefination reaction for trans C9-C10 double bond requires sulfone 4 with a tetrazole ring. As for this sulfonyl compound we envisioned that the stereochemical syn-syn-anti relationship along C5 to C9 could be achieved using the Roush crotylation. The reaction of (R,R)-tartrate ester modified (Z)and (E)-crotylboronates 5 and 7 with aldehydes provides synand anti-homoallyl alcohols 6 and 8, respectively, with required stereochemistry for C5-C9 skeleton (Scheme 2). And the following ozonolysis of the terminal vinyl group of these intermediates would furnish the desired products. The resulting retrosynthetic analysis of the sulfonyl C3-C9 was shown in Scheme 3. Our synthetic pathway to the C3-C9 sulfonyl derivative according to our retrosynthetic analysis is delineated in Scheme 4. At first, we considered acetonide of Lglyceraldehyde as a substrate for the Roush reaction. But the necessity of methylation at C4 suggests the preparation of glyceraldehyde 10, which can be easily prepared from Ltartaric acid rather than L-ascorbic acid. In order to prepare glyceraldehyde 10, (R)-1-(tert-butyldiphenylsilyloxy)but-3en-2-ol was prepared from L-tartaric acid by the modification of the procedure reported in the literature. OMethylation of 11 using methyl iodide and sodium hydride followed by ozonolysis reaction provided aldehyde 10. The