Didemnins synthesis

Cyclosporin (Section 16.1.3) is an undecapeptide that acts as a potent immunosuppressant. Seven of its eleven residues are N-methylated. Its synthesis in solution was carried out by a series of segment condensations)32,33 The didemnins (Section 16.1.4) are isolated from marine organisms known as tunicates. Their therapeutic potential lies in applications as antitumor, antiviral, and immunosuppressant agents. The didemnin family of natural products contains peptidomimetic residues including A,0-dimethyltyrosine-proline and leucine—2-(hydroxyisovaleryl)propionic acid and (4-hydroxy)-2,5-dimethyl-3-oxo-... 

The synthesis of didemnin A (60) consists of four main elements (1) construction of the Hyvpa-isostatine unit 52 (Scheme 9), (2) synthesis of the tetrapeptide unit, Z-Leu-Pro-(Me)Tyr(Me)-0-Boc-Thr-OH (57, Scheme 10), (3) synthesis of the macrocycle, and (4) addition of the A-methyl-D-leucine unit to form didemnin A (60, Scheme 11). 

Deprotection of a robust MOM ether amidst a welter of polar and hydrolytically sensitive groups was a challenge confronted by the Joulli group in their synthesis of the antitumour Didemnins.464 Treatment of 249,1 [Scheme 4 249 with bromodimethylborane in dichloromethane at low temperature liberated the desired hydroxyl in 249,2 in 93% yield ... 

The utility of the phenacyl group is exemplified in the C-terminal deprotection [Scheme 6.70] taken from Schmidt s synthesis of the immunosuppressive and antiviral cyclodepsipeptide Didemnin.113 Here, the phenacyl ester was reduc-tively cleaved with zinc in acetic acid. A similar transformation was used in a synthesis of the potent protein serine/threonine phosphatase inhibitor Motupor-in.lM Zinc-copper couple is an attractive alternative that can be used on a large scale [Scheme 6.71 ]J70... 

Me2BBr, CH2CI2, -78°C, then NaHCOj/HjO, 87-95% yield. This reagent also cleaves the MEM, MTM, and acetal groups. An ester, a BOC, and a TIPS group were unaffected by this reagent in a synthesis of the Didemnins. ... 

Didemnins were isolated from a Caribbean tunicate Trididemnum solidum. These structurally unique cyclic depsipeptides have quite interesting cytotoxic, antiviral, and immunosuppressive activities. The synthesis of the didemnins A, B, and C (173-175) involves the key component 178, which is prepared from acid 176 and amine 177 using the coupling agent DEPC.69... 

Dtdemnins, Biologically active depsipeptides extracted from a Caribbean tunicate (sea squirt) family Didem-nidae. genus Trididemnum. The three components, didem-nins A, B and C are weakly basic compds with antiviral, antitumor activity. Didemnin A is the most abundant, whereas didemnin B is generally the most active. Extraction and purification K., L. Rinehart. Jr., Eur. pat. Appl. 48,149 and U.S. pat. 4,493,796 (1982, 1985 both to Univ. Illinois). Structure determn K, L. Rinehart. Jr. et ah, J. Am. Chem. Soc. 103, 1857 (1981). Revised structure and total synthesis K. L. Rinehart, Jr- et ah. ibid. 109, 6846 (1987). See also U. Sebmidt et ah. Tetrahedron Letters 29, 3057 (1988) eidem, ibid. 4407. Crystal structure of B M. B. Hossain el ah. Proc. Nat. Acad. Sci. USA 85, 4118 (1988). Efficient total synthesis of A and B Y. Hamada et ah. J. 

Portonovo, R Ding, X. Leonard, M. S. Joullie, M. M. Eirst total synthesis of a fluorescent didemnin. 

Li. W.-R. and Joullie, M.M. (1992) The didemnins biological properties, chemistry and total synthesis, in Studies in Natural Products Chemistry, vol. 10 (ed. Atta-ur-Rahman), Elsevier Sdence, Amsterdam, Oxford, New York, pp. 241-302. 

Schmidt, U., Kroner, M., and Griesser, H. (1988) Total synthesis of the didemnins - 1. Synthesis of the peptolide ring. Tetrahedron Lett., 29, 3057-3060. 

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