Yeh, Li-Kuan; (1997) Synthetic studies of natural compounds and their analogues. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A83586C, a novel cyclodepsipeptide isolated from Streptomyces Kamatakensis, exhibits antitumour properties in vitro against a CCRF-CEM human T-cell Leukaemia line (IC50 = 0.0135 μg/mL). The strategy for synthesis of the peptide portion of A83586C can, in principle, be divided into three parts. First, the asymmetric synthesis of 3S- or 3R-piperazic acids via the Evans-Vederas alkylation procedure. Second, the formation of the linear hexapeptide Third, the intramolecular coupling to form the cyclic depsipeptide. The problem of N,O-acyl shifts during the cyclization of depsipeptides occurs when serine or threonine residues are present. It was therefore decided to form the lactone bond between (2S,3S)-3-hydroxyleucine and threonine in the last step. Three types of fragment condensations were employed in an attempt to synthesis the linear hexapeptide. The successful synthesis used a "1+2+3" condensation procedure. Synthesis of the linear hexapeptide was achieved by coupling specific amino acids using DCC or BOP-CI. 4-Methyl-2-E-pentenic acid was used inplace of (2S,3S)-3- hydroxyleucine in the coupling reaction. The Fmoc group was employed to protect the amino function of N-Me-(R)-alanine. The Z and Bn permanent protecting groups were employed to protect the amine of 3S- or 3R-piperazic acids and the hydroxyl group of N-hydroxylalanine. The carboxylic acid of threonine was protected by formation of the methyl ester. The 4-methyl-2-E-pentenic acid derivative could potentially be converted to the (2S,3S)-3-hydroxyleucine derivative by a Sharpless asymmetric epoxidation procedure from the linear pseudo-hexapeptide.

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