Total Synthesis of Marformycins A and D.

We report the synthesis of the antimicrobial cyclodepsipeptides marformycin A ( 1 ) and marformycin D ( 2 ) using a solid-phase approach. A scalable solution-phase synthesis of the γ-hydroxypiperazic acid subunit in 2 , starting from cis -hydroxyproline, is also described. Structural analysis of 1 and its Leu- epi congener demonstrates conformational differences that may underlie their divergent antimicrobial activities. The described approach enables further development of conformation-activity relationships within this class of depsipeptide natural products.