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 stereo-controlled 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.

Automated summary

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