Stereoselective Construction of Quaternary Carbon Stereocenters via a Semipinacol Rearrangement Strategy

Quaternary carbon stereocenters are found in a broad range of organic compounds, including important bioactive natural products and medicinal agents. Given their ubiquity and the significant synthetic challenges they present, quaternary carbon stereocenters have long attracted great interest from synthetic organic chemists. Numerous efforts have been devoted to their construction, leading to a spectrum of strategies for creating stereogenic quaternary carbon centers. In this context, the semipinacol rearrangement has proven successful. In this extension of the pinacol rearrangement, the 1,2-carbon-to-carbon migration in a 1,2-diol has been expanded to include leaving groups other than the hydroxyl group.Over the past decade, our laboratory has explored the semipinacol rearrangement strategy for the stereoselective construction of quaternary carbon stereocenters. We have investigated various substrates, including 2,3-epoxy alcohols (also termed α-hydroxy epoxides), 2,3-aziridino alcohols, and allylic alcohols. Several promoters that effect the semipinacol rearrangement have been identified, including Lewis acids based on Al, Sm, B, Zn, and Ti for the rearrangement of α-hydroxy epoxides and 2,3-aziridino alcohols; cationic halogen species for the rearrangement of allylic alcohols; and cinchona alkaloids and chiral phosphoric acid for the asymmetric semipinacol rearrangement. Our research efforts have led to a series of valuable synthetic methods, including (1) a tandem semipinacol rearrangement and Meerwein–Ponndorf–Verley reduction, (2) a tandem semipinacol rearrangement and Tishchenko reaction, (3) a tandem semipinacol rearrangement with either an allylation or a propargylation, (4) a tandem semipinacol rearrangement and Schmidt reaction, (5) a semipinacol rearrangement of 2,3-aziridino alcohols, (6) a semipinacol rearrangement of allylic alcohols induced by halogen cation, (7) a tandem aziridination and semipinacol rearrangement of allylic alcohols, and (8) asymmetric semipinacol rearrangements with chiral organic catalysts. One hallmark of these reactions is the creation of stereogenic quaternary carbon centers with high levels of stereocontrol. In this Account, we describe the development of these synthetically useful methodologies and their successful application to the total syntheses of natural products.Our results demonstrate that the semipinacol rearrangement of carefully designed substrates constitutes an efficient approach to the stereoselective construction of quaternary carbon centers. These reactions have produced a broad array of useful compounds that lend themselves to further elaboration. Furthermore, the total synthesis of a series of alkaloids, with significant bioactivity and intriguing molecular architecture, was achieved through these semipinacol rearrangement strategies, highlighting their synthetic value.