Total synthesis of (+)-kalafungin using a tandem Michael–Dieckmann approach

A stereoselective synthesis of the antibiotic kalafungin 1 is reported. A key step involved the tandem Michael–Dieckmann reaction between methyl 2-methoxy-6-methylbenzoate 11 and the α,β-unsaturated lactone (R)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methoxy-5,6-dihydropyran-2-one 10, which was prepared from (S)-aspartic acid. The C5 alkyl substituent was introduced by the use of methylmagnesium bromide and subsequent stereoselective reduction. A sequence of oxidations followed by acid-catalyzed epimerization delivered (+)-kalafungin 1.