Total synthesis of (+)-roxaticin via C-C bond forming transfer hydrogenation: a departure from stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles in polyketide construction

Abstract

A total synthesis of the oxo-polyene macrolide (+)-roxaticin is achieved in 20 steps from 1,3-propanediol. In this approach, 9 of 10 C-C bonds formed in the longest linear sequence are made via metal catalysis, including 7 C-C bonds formed by iridium catalyzed alcohol C-C coupling. Notably, the present synthesis, which represents the most concise preparation of any oxo-polyene macrolide reported to date, is achieved in the absence of chiral reagents and chiral auxiliaries with minimal use of premetalated C-nucleophiles.

Scheme 1

Representative oxo-polyene macrolides and retrosynthetic analysis of the (+) roxaticin.^{a a}See supporting information for a graphical summary of prior syntheses.

Scheme 2

Total synthesis of the oxo-polyene macrolide (+)-roxaticin via C-C bond forming transfer hydrogenation.^{a a}Yields are of material isolated by silica gel chromatography and represent the average of two runs. Enantiomeric excess of 1 was determined by chiral stationary phase HPLC analysis. See Supporting Information for preparation of homoallylic ether A and other experimental details.