Dolastatin sequence

The antineoplastic, cyclic peptide dolastatin 3 (197) was isolated from the sea hare Dolabella auricularia in small quantities [187]. It bears much structural resemblance to the cyclic peptides of tunicates. Synthetic attempts indicated that the original published structure was incorrect [188]. Three reports of research directed towards synthesis of possible components of dolastatin 3 (197) failed to help with the correct structure [189-191]. Reisolation of 197 allowed the determination of the correct sequence of amino acids in this cyclic pentapeptide and the new structure was confirmed by synthesis [192]. Synthesis of dolastatin 3 (197) and the corresponding 12R diastereoisomer permitted study of the solution... 

One of the most powerful anticancel- agents known is dolastatin, isolated from the sea-hare Dolabella. Dolastatin contains an unusual amino acid, with three stereogenic centres, and chemists in Germany managed to exploit Felkin-Anh control very effectively to make it from the much more widespread amino acid isoleucine. This is the sequence of reactions. 

We consider that all of the dolastatins will prove to be of cyanobacterial or other dietary origin. There are some important biosynthetic signatures, for exanqile, which suggest that dolastatin 15 (2) (Figure 1) is most probably derived from L majuscula. These signatures include the presence of the N,N-dimethylvaline residue, a valine-N-methylvaline-proline sequence also found in the microcolins (27, 28) (Figure 7) and the presence of a pyrrolidone ring presumably derived from condensation of phenylalanine and acetate. A... 

The unusual chiral (3-methoxy-y-amino acid dolaproine (Dap) is the most complex unit of dolastatin 52, which has a remarkable antineoplastic activity and is now in Phase II human cancer clinical trials. Many synthetic strategies such as aldol condensation and a cobalt-catalyzed Reformatsky reaction have been employed in its synthesis. Almeida and Coelho have demonstrated a stereoselective synthetic method for A-Boc-dolaproine (53) through a sequence of MBH reaction, a diastereoselective double bond hydrogenation and hydrolysis of the ester functional group (Scheme 5.8). ... 

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