Development of a Third-Generation Total Synthesis of (+)-Discodermolide:  An Expedient Still−Gennari-Type Fragment Coupling Utilizing an Advanced β-Ketophosphonate

A novel total synthesis of the complex polyketide discodermolide, a promising anticancer agent of marine sponge origin, has been completed in 11.1% overall yield over 21 linear steps. This third-generation approach features an unprecedented Still−Gennari-type HWE olefination reaction between advanced C1−C8 β-ketophosphonate 61 and C9−C24 aldehyde 7, introducing the (8Z)-alkene with 10:1 selectivity. The stereotetrad found in the C1−C8 subunit 61 was established via a highly diastereoselective boron-mediated aldol reaction/in situ reduction between ketone (S)-8 and 3-benzyloxypropanal. The (7S)-configuration was installed by the reduction of enone 73 with K-Selectride.