99(P-34) Determination of Absolute Structure of Macroviracins by Chemical Synthesis
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Macroviracins are a new class of macrocyclic dilactones, which were isolated from the mycelium extracts of Streptmyces sp. BA-2836, and classified into eight types of congeners by the length (C_<22> or C_<24>) of the constitutive fatty acids. These compounds exhibit a powerful anti-viral activity against HSV-1 and VZV. Degradation studies of macroviracins suggested the corresponding constitutive acids to have the same relative stereochemistry. The relative and absolute configuration of macroviracins, however, remained unsolved. In this symposium, we present determination of the absolute configuration of macroviracins by synthesizing methyl ester 2a of a constitutive C_<22>-fatty acid of macroviracin A (1). Prior to the synthesis of methyl ester 2 of an acid constituted macroviracin A (1), we designed two types of glucosides (6 and 7) as the left- and right-half model of 2, respectively and synthesized them employing regioselective reduction of epoxides and stereoselctive glycosidation as key steps. Direct comparison of the ^1H-NMR data of the model compounds with those of 2 suggested that the acid 2 might have the stereochemistry of 3R, 15S, and 21R if possessing a D-glucose residue. In order to confirm the estimation, 3R,15S,21R-methyl ester 2a was synthesized through a coupling reaction of the epoxide 5a with an organocopper reagent derived from a chiral iodide 7. The spectroscopic data and specific rotation of 2a were identical with those of 2, showing macroviracin A (1) to have the structure 1a as depicted in Scheme 3. In summary, the absolute configuration of macroiviracins was unambiguously established by chemical synthesis of C_<22>-fatty acid methyl ester 2a.
