A General and Stereocontrolled Strategy for the Iterative Assembly of Enantiopure Polypropionate Subunits: Synthesis of the C19−C28 Segment of Rifamycin S from a Single Chiron

Abstract

An operationally simple method has been developed for the stereocontrolled construction of polypropionate stereotriads in high enantio- and diastereomeric purities. The method consists of the stereocontrolled addition of lithium dimethylcuprate to an enantiopure γ-alkoxy-α,β-unsaturated ester, followed by hydroxylation of the corresponding enolate. This leads to an anti/syn orientation of the γ-alkoxy-β-methyl-α-hydroxy ester unit. Chain extension and reiteration of the process, after appropriate functionalization, lead ultimately to an 11-carbon acyclic chain harboring three contiguous polypropionate triads with the correct anticipated absolute configuration. The method relies on two basic bond-forming reactions that involve consecutive 1,2-induction. It is admirably stereocontrolled through four iterative cycles of cuprate additions and hydroxylations. Inversion of the α-alkoxy group after each α-hydroxylation allows passage to stereotriads of different configurations. Thus three of the four possible stereotriad combinations are accessible directly using this simple and general method. The C19−C28 acyclic chain of rifamycin S, harboring eight stereogenic carbon atoms (three triads), was constructed starting with an enantiopure precursor that contains a single stereogenic center. A common precursor serves as the starting chiron for a variety of other propionate derived macrolides and ionophores.