Total Synthesis of (+)-Discodermolide

Abstract

The total synthesis of (+)-discodermolide is described. The approach involves assemblage of three key stereotriad subunits through addition of nonracemic allenyltin, -indium, and -zinc reagents to ( S )-3-silyloxy-2-methylpropanal derivatives, followed by reduction of the resulting anti, syn - or syn, syn -homopropargylic alcohol adducts to the ( E )-homoallylic alcohols and subsequent Sharpless epoxidation. Addition of methyl cuprate reagents or 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 propargylic alcohol 11 as the major stereoisomer. Lindlar hydrogenation and installation of appropriate protecting groups led to aldehyde 17 . This was converted to the ( Z )-vinylic iodide 18 upon treatment with α-iodoethylidene triphenylphosphorane. Suzuki coupling of this vinylic iodide with a boranate derived from iodide 25 led to the coupled product 27 with the complete carbon backbone of (+)-discodermolide and the correct stereochemistry. The synthesis was completed by cleavage of the cyclic PMP acetal at C1 with i -Bu 2 AlH and three-step oxidation−esterification to the ester 31 . Cleavage of the C19 Et 3 Si ether and C19 carbamate formation followed by cleavage of the remaining alcohol protecting groups, first with DDQ and then aqueous HCl, afforded (+)-discodermolide ( 36 ).