A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been c ompleted in 10.3% overall yield (23 steps longest linear sequence). The abs olute stereochemistry of the C-1-C-6 (7), C-9-C-16 (8), and C-17-C-24 (9) s ubunits was established via substrate-controlled, boron-mediated, aldol rea ctions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling re actions were a lithium-mediated, anti-selective, aldol reaction of aryl est er 8 (under Felkin-Anh induction from the aldehyde component 9), followed b y in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheyl boron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7 S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discode rmolide, which should serve as valuable probes for structure-activity studi es.