Dolastatin synthesis

Miyazaki, K. Kobayashi, M. Natsume, T. Gondo, M. Mikami, T. et al. (1995) Synthesis and antitumor activity of novel dolastatin 10 analogs. Chem. Pharm. Bull., 43,1706-18. 

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... 

The pentapeptide dolastatin 10 (198) was isolated from D. auricularia and the structure was proposed on the basis of spectral studies [195], Dolastatin 10 (198) is a very potent antineoplastic agent. The absolute configuration proposed from spectral analysis was confirmed by synthesis [196] and dolastatin 10 (198) has subsequently been synthesised by several other research groups [197-199],... 

D. auricularia from Japan contained dolabellin (199), a cytotoxic bis-thiazole. The structure was elucidated by spectral data examination and chemical degradation [200], D. auricularia also contained the cyclic hexapeptide dolastatin E (200) [201], the stereochemistry of which was determined by chemical degradation and total synthesis [202], A further cytotoxic hexapeptide, dolastatin I (201) was isolated from D. auricularia from Japan [203] and the stereostructure was confirmed by enantioselective synthesis [204], Dolastatin 18 (202) was isolated as a very minor cytotoxic component of D. auricularia from Papua New Guinea [205]. 

The sea hare Dolabella auricularia has been the source of the powerful cytotastic and antineoplastic constituents designated as dolastatins [311]. Some of these compounds are thiazole-containing cyclic peptides. They were found in very small quantities in the animal (ca. 1 mg each from 100 Kg), making the isolation and structural elucidation of these peptides exceptionally challenging. A review on the dolastatins, written by G. R. Pettit in 1997, covers the reported literature regarding their isolation, characterization, biological activity, and synthesis [312]. Pettit and coworkers reported the thiazole-containing dolastatins dolastatin 3 (404) [313], 10 (2) [314], and 18 (407) [315]. The most important dolastatin and the most potent antineoplastic and tubulin-inhibitory substance known to date is the unique linear pentapeptide dolastatin 10 (2). 

During this time, the total synthesis of several marine sulfur-containing natural products cited in this review has been reported and they confirmed the suggested structures. This is the case of the synthesis of some sulfonoceramides (e.g. flavocristamide A (318) discussed in the sulfonic acid and their derivatives section [366], and the synthesis of the thiazole-containing compounds bistratamide D (381) [367], trunkamide (388) [368], mollamide (393) [369], dolastatin I (409) [370], and virenamide B (414) [371]. 

Paterson I, Findlay AD, Florence GJ (2006) Total Synthesis and Stereochemical Reassignment of (+)-Dolastatin 19. Org Lett 8 2131... 

The sea hare Dolabella auricularia was recorded to exhibit exceptionally potent biological properties, which were known to certain ancient Greeks and Romans. The most important antineoplastic constituent of D. auricularia was dolastatin 10 (362) (283), a linear pentapeptide that was reported to be the most potent antineoplastic substance known to date. The absolute configuration of362 was ascertained by total synthesis (284). Synthetic studies revealed that the initial structure (285) proposed for dolastatin 3 was incorrect (286-291). The structure of dolastatin 3 was reassigned as 363, and its absolute chirality was established by synthesis (292). The minimum energy conformation of 363 in solution was estab-... 

Although these compounds are all anticancer agents, they act through different mechanisms. Bryostatin 1, a cyclic macrolide, inhibits protein kinase C tumor promotion while aplidine is a protein synthesis inhibitor. Dolastatin 10, a linear peptide, and ET743, a tetrahydroisoquinoline... 

Sone, H., Nemoto, T., Ishiwata, H., et al. 1993. Isolation, structure, and synthesis of dolastatin D, a cytotoxic cyclic depsipeptide from the sea gare Dolabella auricularia. Tetrahedron Letters, 34 8449-52. 

Pettit GR, Singh SB, Hogan F, Lloyd-Williams P, Herald DL, Burkett DD, Clewlow PJ. Antineoplastic agents. Part 189. The absolute configuration and synthesis of namral -dolastatin 10. J. Am. Chem. Soc. 1989 111 5463-5465. 

G.R. Pettit and co-workers used a novel fefraA/s(triphenylphosphine)cobalt(0)-promoted Reformatsky reaction for the synthesis of a dolastatin 10 unit, dolaproine in a Boc-protected form. ... 

Pettit, G. R., Grealish, M. P. A Cobalt-Phosphine Complex Directed Reformatskii Approach to a Stereospecific Synthesis of the Dolastatin 10 Unit Dolaproine (Dap). J. Org. Chem. 2001,66, 8640-8642. 

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). ... 

The Hantzsch synthesis has been employed by several groups in the syntheses of the thiazole rings of dolastatins 3 and 9. The dolastatin family... 

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