Asymmetric Total Synthesis of (+)-(3E)-Pinnatifidenyne and Studies Toward the Syntheses of trans-Rhodophytin and (-)-(3Z)-Venustinene

Abstract

The marine genus Laurencia of red alga have produced a diverse subset of medium-sized cyclic haloethers containing one or more halogen atoms, diverse stereogenic centers and different lengths of side chains. Since the (+)-Laurencin was reported by T. Irie and co-workers in 1965, which was first isolated medium oxacycle natural product from Laurencia species, numerous medium-ring ethers marine natural products have been reported in recent years. Although these secondary metabolites have received significant attention from the synthetic community due to their unique structural features and the biological activities, the construction of the oxacycle skeleton, particularly the eight-membered cyclic ether with side chains, is still formidable task because of their enthalpic and entropic penalties. Herein, we report the asymmetric total synthesis of (+)-(3E)-Pinnatifidenyne (6) based our unified synthetic strategy. The key features of our synthesis involve the efficient construction of the cis-α,α'-disubstituted oxocene skeleton by highly regioselective intramolecular Tsuji-Trost allylic alkylation, the sequential in situ deconjugative isomerization and the elaboration of the crucial chloride functionality mediated by the substrate-controlled diastereoselective reduction. In the present study, we efficiently synthesized the precursor for Pd(0)-catalyzed cyclization via Lewis acid-mediated epoxide opening reaction as the convergent synthetic strategy and we envision our unified synthetic strategy can widely apply to more complicated and unique oxocene natural products from Laurencia species.