Total Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy.

An 11-step synthesis of (+)-neopeltolide was developed. The C1-C7 carboxylic acid and the C8-C16 alcohol were prepared, each in six steps, from ( R )- and ( S )-epichlorohydrin, respectively. After esterification, our tandem macrocyclization/transannular pyran cyclization strategy was applied to a stereocontrolled construction of the neopeltolide macrolactone. The side chain was synthesized in six steps from ethyl 4-oxazolecarboxylate through palladium-catalyzed cross-couplings. A Mitsunobu reaction of the neopeltolide macrolactone and the side chain completed the synthesis.