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.

Total synthesis of (+)-neopeltolide, a potent antiproliferative marine macrolide natural product, was accomplished in 11 steps from a commercially available inexpensive material. The 14-membered macrolactone skeleton embedded with a 2,6-cis-substituted tetrahydropyran ring was synthesized in an expedient fashion by our newly developed macrocyclization/transannular pyran cyclization strategy. A concise synthetic entry to the oxazole-containing side chain was developed by exploiting palladium-catalyzed cross-coupling reactions. Total synthesis of (+)-9-epi-neopeltolide was also achieved in 12 steps by late-stage stereochemical diversification at the C9 position.