"FR-900848"

In 1990 Yoshida et al and coworkers in the Fujisawa laboratories in Tsukuba, Japan, a science city 60 km North East of Tokyo, reported the partial structural elucidation of remarkable natural product from Streptoverticillium fervens.1 That the compound was a 5'-amino-5'-deoxydihydrouridine derivative was unusual but not especially exciting. However, the fact that FR-900848 (1), the unassuming Fujisawa file number for the new natural product, possessed an unusual fatty acid side chain was most noteworthy. This fatty acid residue is endowed with five cyclopropanes, four of which are contiguous. At that time there remained eleven elements of ambiguity in the structure: the geometry of the isolated alkene, the stereochemistry of the isolated cyclopropane and the stereochemistry of the quatercyclopropane unit.

FR-900848 (1) shows potent, selective activity against filamentous fungi such as Aspergillus niger, Mucor rouxianus, Aureobasidium pullulans, and various Trichophyton sp. etc. In contrast it is essentially inactive against non-filamentous fungi such as Candida albicans and Gram -positive and -negative bacteria. It shows activity in-vivo and is not appreciably toxic. Thus FR-900848 (1) represents a significant new lead for the design of nucleoside antifungal agents active against the major human pathogen Aspergillus fumigatus.

The stereochemistry and full structure of FR-900848 (1) has recently been established2 and a total synthesis completed.3 A series of model compounds were prepared using multiple asymmetric Simmons-Smith cyclopropanation reactions. Comparisons of spectroscopic data of synthetic 1,2-dicyclopropylethene, 1,12-quatercyclopropanedimethanol and 2-methylcyclopropanecarboxaldehyde derivatives of defined absolute stereochemistry with FR-900848 (1) and its degradation products were used to unequivocally establish the absolute stereochemistry of the natural product. A C2-symmetric 1,12-quatercyclopropanedimethanol was converted by desymmetrisation, selective monocyclopropanation and homologation into the fatty acid side chain of FR-900848. Coupling of this carboxylic acid with 5'-amino-5'-deoxydihydrouridine gave synthetic FR-900848. The unusual helical structure of FR-900848 is comparable with UC-11136, a cholesteryl ester transfer protein inhibitor from the fermentation broth of Streptomyces sp. UC 11136.4