Synthesis of dolastatin 15

Details Synthesis of dolastatin 15 Synthesis of dolastatin 15

1994-09-14

1996-09-10

Scheiner, Toni R.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

530329, 530333, C07K 500, C07K 700, C07K 1700

Patent

active

055547257

ABSTRACT:
The present invention relates to the synthesis of natural (-)- dolastatin and the elucidation of the absolute configuration of this important sea hare constituent. A segment synthetic strategy was utilized for obtaining the Dolabella auricularia (Indian Ocean sea hare) depsipeptide dolastatin 15. Reaction of protected (S)-Hiva-(S)-Phe (2c) with isopropenyl chloroformate followed by Meldrum's ester, cyclization (2c.fwdarw.3a) of the product in toluene and finally methylation afforded the key (S)-dolapyrrolidine (Dpy) derivative (3b). Condensation of tripeptide (8) with the three unit Dpy segment (5b) followed by deprotection and coupling (diethyl phosphorocyanidate) led to dolastatin 15 in 11% overall yield. The powerful and selective activity of dolastatin 15 against the U.S. National Cancer Institute's panel of human cell lines is reported.

REFERENCES:
Pettit et al. J. Am. Chem. Soc. vol. 113. p. 6692 (1991).

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