Discodermolide synthetic routes

ABSTRACT Discodermolide and pironetin are two immunosuppressive agents with antitumor activity. The isolation, structure elucidation, biological activity are reported as well as the synthetic routes to these two compounds. Five syntheses of discodermolide and seven syntheses of pironetin are described. 

The discodermolide isolated from the 6 g campaign proved to be a monohydrate. In agreement with our quality assurance department, we could only use the material from the 60 g campaign and eventually the 500 g campaign without repeating the toxicology if the following conditions were met a) the synthetic route was identical, b) the material produced had the same side product profile c) the material was equally pure or better and d) the same crystal modification was produced (8 or 9 modifications are known) and e) the material was sterile. 

Clinical development is hampered due to the extremely scarce supply of discodermolide from the natural source. Thus, total synthesis provides the only viable route to useful quantities of this novel cytotoxic polyketide. Consequently, there have been considerable synthetic efforts toward the total synthesis of discodermolide [16], Up to date, five total synthesis of (+)- and/or (-)-discodermolide have been reported, one by Schreiber [3], one by Smith [17], one by Myles [18], one by Marshall [19] and one by Paterson [20]. All the syntheses are convergent. Schreiber and Myles employed an analogous connection by using a Nozaki-Kishi addition of a C8 acetylenic or (Z)-vinylic chromium to a C7 aldehyde for the major... 

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