Total Synthesis of L-156,373 and an oxoPiz Analogue via a Submonomer Approach

The first chemical synthesis of L-156,373 (1), a potent oxytocin receptor antagonist isolated from Streptomyces silvensis, is reported. Assembly of the unusual D-Piz-L-Piz dipeptide subunit was achieved through a sequential electrophilic amination-acylation-deprotection strategy followed by late-stage Piz ring formation. Synthesis and incorporation of a novel N-hydroxy-L-isoleucine building block is also described. This submonomer approach was further applied to the expedient synthesis of a di-delta-oxopiperazic acid analogue of 1 starting from Fmoc-Glu(tBu)-OH building blocks.