ASSEMBLY OF THE ANTIFUNGAL AGENT FR-900848 AND THE CETP INHIBITOR U-106305 - STUDIES ON REMARKABLE MULTICYCLOPROPANE NATURAL-PRODUCTS

The full structural elucidation of FR-900848, an antifungal pentacyclo propane nucleoside natural product from Streptoverticillum fervens, is reported, A series of model compounds are prepared using multiple asy mmetric Simmons-Smith cyclopropanation reactions, Comparisons of spect roscopic data of synthetic 1,2-dicyclopropylethene, quatercyclopropane -2,2'''-dimethanol and 2-methylcyclopropanecarbaldehyde derivatives of defined absolute stereochemistry with FR-900848 and its degradation p roducts are used to unequivocally establish the absolute stereochemist ry of the natural product. A C-2-symmetric quatercyclopropane-2,2'''-d imethanol is converted by a sequence of desymmetrisation, selective mo nocyclopropanation of a 5-(quatercyclopropyl)penta-2,4-dien-1-ol deriv ative, deoxygenation and Horner-Emmons homologation into the fatty aci d side chain of FR-90084. Coupling of this carboxylic acid with 5'-ami no-5'-deoxy-5,6-dihydrouridine gives synthetic FR-900848, The unusual helical structure of FR-900848 is discussed and compared with U-106305 , a cholesteryl ester transfer protein inhibitor from the fermentation broth of Streptomyces sp. UC 11136. The full structure and stereochem istry of U-106305 is established by total synthesis using a bidirectio nal strategy closely following the route to FR-900848.