The Dolastatins. 17. Synthesis of Dolaproine and Related Diastereoisomers

Article abstract of DOI:10.1021/jo00100a034

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.