Assembly of the antifungal agent FR-900848 and the CETP inhibitor U-106305: studies on remarkable multicyclopropane natural products

Abstract

The full structural elucidation of FR-900848, an antifungal pentacyclopropane nucleoside natural product from Streptoverticillum fervens, is reported. A series of model compounds are prepared using multiple asymmetric Simmons–Smith cyclopropanation reactions. Comparisons of spectroscopic data of synthetic 1,2-dicyclopropylethene, quatercyclopropane-2,2′′′-dimethanol and 2-methylcyclo-propanecarbaldehyde derivatives of defined absolute stereochemistry with FR-900848 and its degradation products are used to unequivocally establish the absolute stereochemistry of the natural product. A C ₂ -symmetric quatercyclopropane-2,2′′′-dimethanol is converted by a sequence of desymmetrisation, selective monocyclopropanation of a 5-(quatercyclopropyl)penta-2,4-dien-1-ol derivative, deoxygenation and Horner–Emmons homologation into the fatty acid side chain ofFR-900848. Coupling of this carboxylic acid with 5′-amino-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 stereochemistry of U-106305 is established by total synthesis using a bidirectional strategy closely following the route to FR-900848.