The Dolastatins. 17. Synthesis of Dolaproine and Related Diastereoisomers

George Pettit, Sheo Bux Singh, Delbert L. Herald, Paul Lloyd-Williams, Darko Kantoci, Douglas D. Burkett, József Barkóczy, Fiona Hogan, Terah R. Wardlaw

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Abstract

A special challenge in accomplishing the total synthesis of dolastatin 10 (1) entailed deducing the absolute configuration of the new β-methoxy-γ-amino acid component dolaproine (2) as 2S,2′R,3′R and devising a stereoselective synthesis. Synthesis of this unusual (S)-proline-derived unit as its N-tert-butoxycarbonyl derivative (9b) and three stereoisomers (9a, 9c, 9d) has been summarized. The diastereoisomers were assembled by an aldol condensation between aldehyde 5, derived from (S)-proline, with chiral propionate 6, followed by methylation and cleavage of the chiral directing ester group by hydrogenolysis to afford methyl ethers 9a‒d. The absolute stereochemistry of the diastereoisomers was determined by a combination of X-ray crystallographic analyses (of 9a and lactam 11b formed from isomer 7a) and high-field (400 MHz) NMR studies. By using each of these isomers in a series of dolastatin 10 syntheses the stereochemistry of the dolaproine (2) unit of natural (‒)-dolastatin 10 (1) was shown to be 2S,2′R,3′R.

Original languageEnglish (US)
Pages (from-to)6287-6295
Number of pages9
JournalJournal of Organic Chemistry
Volume59
Issue number21
DOIs
StatePublished - Oct 1 1994

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pettit, G., Singh, S. B., Herald, D. L., Lloyd-Williams, P., Kantoci, D., Burkett, D. D., Barkóczy, J., Hogan, F., & Wardlaw, T. R. (1994). The Dolastatins. 17. Synthesis of Dolaproine and Related Diastereoisomers. Journal of Organic Chemistry, 59(21), 6287-6295. https://doi.org/10.1021/jo00100a034