A Total Synthesis of (−)-Hemiasterlin Using N-Bts Methodology

A total synthesis of (−)-hemiasterlin has been accomplished in nine steps from 25 8 (>35% yield overall). An improved enantiocontrolled route to the tetramethyltryptophan subunit 32 was developed using an asymmetric Strecker synthesis (five steps, 50% yield from 25), and the dipeptide 22 was prep...

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Bibliographic Details
Published in:Journal of organic chemistry 2001-11, Vol.66 (22), p.7355-7364
Main Authors: Vedejs, Edwin, Kongkittingam, Chutima
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Crystallization
Oligopeptides - chemical synthesis
Porifera - chemistry
Stereoisomerism
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Summary:A total synthesis of (−)-hemiasterlin has been accomplished in nine steps from 25 8 (>35% yield overall). An improved enantiocontrolled route to the tetramethyltryptophan subunit 32 was developed using an asymmetric Strecker synthesis (five steps, 50% yield from 25), and the dipeptide 22 was prepared in seven steps, 37% yield from valinol. The synthesis exploits the high reactivity of a Bts-protected amino acid chloride in the difficult peptide coupling of sterically hindered amino acid residues 18 and 20 to form 21 (70%, recrystallized) and also uses N-Bts intermediates for the high-yielding N-methylations of 14 and 31. In addition, the Bts-protected di-tert-butyl N-acylimidodicarbonate 33 is shown to undergo efficient coupling with 22 to form 34 (97% in the coupling step; 79% over the activation; coupling sequence from 32).
ISSN:0022-3263
1520-6904
DOI:10.1021/jo0104882