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 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).
Vedejs
E
E
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. edved@umich.edu
Kongkittingam
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003460:Crystallization; D009842:Oligopeptides / Q000138:chemical synthesis*; D011161:Porifera / Q000737:chemistry; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D009842:Oligopeptides; C103465:hemiasterlin A; C103466:hemiasterlin B; C121900:hemiasterlin C