Synthetic studies towards the synthesis of callipeltosides and aurisides.

摘要

Callipeltosides and aurisides are families of natural products isolated from different marine sources. Callipeltosides A, B and C are glycosylated and halogenated macrolides which were isolated from the marine sponge Callipelta sp. They were found to possess cytotoxic activity against different cell lines. Aurisides A and B were isolated from the sea hare Dolabella auricularia and are structurally related to callipeltosides. Aurisides were also found to be halogenated and glycosylated macrolides with cytotoxic activity. These natural products were isolated in small amounts and their mechanism of action was not elucidated. The total synthesis of these important natural products will serve to confirm their structure and provide more material for further biological evaluation to elucidate their mode of action. A highly convergent synthetic approach was designed for the synthesis of both callipeltosides and aurisides. Common synthetic intermediates and starting materials were envisioned for their synthesis. In order to demonstrate how biocatalysis can be successfully blended with modern synthetic organic chemistry, optically active building blocks were obtained using biocatalytic approaches. Thus, the starting material for the synthesis of the C1–C9 fragments of both callipeltoside and auriside aglycons was generated using a lipase desymmetrization approach. In addition, the synthesis of both enantiomeric forms of the C13–C22 fragment of the callipeltoside aglycon also made use of biocatalysis for generation of optically active building blocks.; In the synthesis of the callipeltoside aglycon, the C1–C9 fragment was synthesized in twelve steps and 8% overall yield from a biocatalytically generated bicyclic lactone. The synthesis of this fragment features a stereoselective epoxidation of an unsaturated cis-fused bicyclic lactone, and a chemoselective metal-catalyzed Baeyer-Villiger oxidation. A biocatalytic approach was used to synthesize the C13–C22 fragment of the callipeltoside aglycon. A modified Stille coupling using 1,1-dibromo-1-alkenes proved to be an excellent protocol for the one-step construction of the dienyne side chain of the callipeltoside aglycon.; For the synthesis of the auriside aglycone, the C1–C9 fragment was synthesized from the same starting material employed for the synthesis of the C1–C9 fragment of the callipeltoside aglycon. The synthesis of this fragment required only eight steps and was completed in more than 40% overall yield.