One-pot Method for Regioselective Bromination in the Total Syntheses of Natural Products

<p> We developed a novel one-pot method for regioselective bromination of allyl alcohol derivatives (Scheme 1), utilizing the HBr-elimination as a key step. The high yield and regioselectivity of the DBU-promoted elimination appear to be controlled by the inductive electron-withdrawing effects of the neighboring O-functional group. Our method requires neither drastic conditions, nor extra-dry conditions, nor expensive reagents, nor complex manipulations. This two-step reaction sequence proceeds smoothly even in the presence of sensitive functional groups, and should have broad utility in the synthesis of complex molecules such as natural products.</p><p> We herein report the efficient, first total syntheses of (+)-heteroplexisolide E ((+)-6), (–)-5,6-seco-germacrane lactone ((–)-12), aplysinoplide B ((+)-19), and (–)-lincomolide A ((–)-25), utilizing this one-pot method for regioselective bromination. At first, the chiral building blocks (+)-1 and (–)-1 were converted into (+)-3 and (–)-2 in one pot, respectively. Especially, for the transformation to (+)-3, it is noteworthy that the third Negishi coupling reaction catalyzed by the transition-metal-based system in this sequence proceeded smoothly with high efficiency. Finally, the compound (+)-3 was converted to (+)-6 as a single product in 6 steps with an overall yield of 71% (Scheme 2), meanwhile (–)-2 was transformed to (–)-12in 7 steps with an overall yield of 15% (Scheme 3). In addition, using our one-pot method to synthesize the requisite trisubstituted bromoalkenes 14 and (–)-23, the total syntheses of (+)-19and (–)-25 were achieved, respectively (Schemes 4 and 5).</p>