Discovery through total synthesis: a retrospective on the himastatin problem.
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.
Kamenecka
T M
TM
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, New York, NY 10021, USA.
Danishefsky
S J
SJ
D000192:Actinomycetales / Q000737:chemistry* / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D013237:Stereoisomerism; D014364:Tryptophan / Q000737:chemistry
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D010456:Peptides, Cyclic; D011758:Pyrroles; C066106:himastatin; D014364:Tryptophan