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Discovery through Total Synthesis: A Retrospective on the Himastatin Problem
Author(s) -
Kamenecka Theodore M.,
Danishefsky Samuel J.
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20010105)7:1<41::aid-chem41>3.0.co;2-d
Subject(s) - total synthesis , pharmacophore , moiety , stereochemistry , depsipeptide , stille reaction , chemistry , indole test , stereospecificity , combinatorial chemistry , organic chemistry , catalysis
A total synthesis of a structure proposed for himastatin was accomplished. The non‐identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti – cis and syn – cis pyrrolindoline substructures; ii) a practical synthesis to 5‐hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi‐indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D ‐ and L ‐substituents in the 6‐mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.