Chapter 3 – Discodermolide: Total Synthesis of Natural Product and Analogues

Abstract This account describes an efficient and modulable total synthesis of (+)-discodermolide and analogues. Particularly notable is the repeated application of a crotylation reaction of aldehydes, with α-oxygenated crotyltitanium reagent to ensure the stereocontrolled elaboration of syn–anti methyl-hydroxy-methyl triads connected to a Z - O -enecarbamate. This particular group allowed direct and easy access to either a triple bond or terminal Z -diene function. The stereocontrolled generation of the trisubstituted Z -double bond, representing a significant synthetic challenge, is ensured by a 1,2-dyotropic rearrangements on dihydrofuran with organocopper reagents. The synthesis of natural product was achieved in 21 steps with 1.6% overall yield. The same methodologies and synthetic strategy were applied for the preparation of five original analogues. The biological activities of natural product and synthetic analogues have also been studied.