Discovery through total synthesis: A retrospective on the himastatin problem Journal Article
| Authors: | Kamenecka, T. M.; Danishefsky, S. J. |
| Article Title: | Discovery through total synthesis: A retrospective on the himastatin problem |
| Abstract: | 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. |
| Keywords: | antibiotic agent; drug structure; drug synthesis; dimerization; chemical structure; molecular structure; conformation; pyrroles; natural product; antibiotics, antineoplastic; structure analysis; antineoplastic antibiotic; alkaloids; indole derivative; reaction analysis; stereospecificity; molecular conformation; total synthesis; peptides, cyclic; cyclopeptide; stereoisomerism; pyrrole derivative; tryptophan; depsipeptide; actinomycetales; antibiotics; natural products; alkaloid; enantiomer; protecting groups; humans; human; article; himastatin; pyrroline derivative; actinomycetes and related organisms |
| Journal Title: | Chemistry - A European Journal |
| Volume: | 7 |
| Issue: | 1 |
| ISSN: | 0947-6539 |
| Publisher: | Wiley V C H Verlag Gmbh |
| Date Published: | 2001-01-05 |
| Start Page: | 41 |
| End Page: | 63 |
| Language: | English |
| DOI: | 10.1002/1521-3765(20010105)7:1<41::aid-chem41>3.0.co;2-d |
| PUBMED: | 11205026 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
