TOTAL SYNTHESIS OF (+)-DISCODERMOLIDE

The total synthesis of (+)-discodermolide is described. The approach i nvolves assemblage of three key stereotriad subunits through addition of nonracemic allenyltin, -indium, and -zinc reagents to (S)-3-silylox y-2-methylpropanal derivatives, followed by reduction of the resulting anti,syn- or syn,syn-homopropargylic alcohol adducts to the (E)-homoa llylic alcohols and subsequent Sharpless epoxidation. Addition of meth yl cuprate reagents of Red-Al to the resultant epoxy alcohols yielded the key precursors, alkyne 4, aldehyde 9, and alcohol 24. Addition of alkyne 4 (as the lithio species 10) to aldehyde 9 afforded the proparg ylic alcohol 11 as the major stereoisomer. Lindlar hydrogenation and i nstallation of appropriate protecting groups led to aldehyde 17. This was converted to the (Z)-vinylic iodide 18 upon treatment with alpha-i odoethylidene triphenylphosphorane. Suzuki coupling of this vinylic io dide with a boranate derived from iodide 25 led to the coupled product 27 with the complete carbon backbone of (+)-discodermolide and the co rrect stereochemistry. The synthesis was completed by cleavage of the cyclic PMP acetal at C1 with i-Bu2AlH and three-step oxidation-esterif ication to the ester 31. Cleavage of the C19 Et3Si ether and C19 carba mate formation followed by cleavage of the remaining alcohol protectin g groups, first with DDQ and then aqueous HCl, afforded (+)-discodermo lide (36).