Marine natural products method development

Several other novel, structurally and mechanistically diverse marine natural products have entered various preclinical and clinical studies. One of these products is ecteinascidin-743 (89 ET-743), isolated from the tunicate Ecteinscidea turbinata (105, 106) and recently approved for the treatment of sarcoma in the European Union as the first direct-from-the-sea drug. Total synthesis and methods developed during the total synthesis allowed the preparation of a simpler analog phthalascidin (90) with comparable activities (107-109). 

As the usual in marine natural products development, obtaining sufficient amounts of ET743 has been a significant challenge due to its restricted natural availability (1 g from 1 ton of tunicate). Methods to produce ecteinascidins by in-the-sea culture of E. turbinata have been evolved [130] and much synthetic effort has been directed towards the synthesis of ecteinascidins [82]. Currently, ET-743 for clinical application is produced by a semi-synthetic process in 17 chemical steps developed by Pharma Mar starting from cyanosafracin B, an antibiotic produced by the fermentation of Pseudomonas fluorescens [131]. 

The wide-ranging biological activities exhibited by members of the cembranoid family of marine diterpenes, for example, deoxysarcophine, lophotoxin, sinularin, aseperdiol, and sarcophytol A, in combination with their diversity of structure and the lack of flexible synthetic methodology for the elaboration of 14-ring carbo-cycles, have made this family of natural products a particularly challenging area for the synthetic chemist. Methods that have been developed for macrocyclization in the cembranoid field include... 

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