A Cooperative Hydrogen Bond Donor-Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans

Abstract

<p class="first" id="P1">Carbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Brønsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid <i>oxa</i>-Pictet-Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Brønsted acid. </p><p id="P2">A novel, cooperative catalytic method for the asymmetric <i>oxa</i>-Pictet-Spengler reaction has been developed. This method, demonstrated in the synthesis of substituted tetrahydropyranoindoles, has enabled a six-step asymmetric synthesis of (−)-coixspirolactam C. </p><p id="P3"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/a34b4861-60a3-40c9-9410-bcf92764af90/PubMedCentral/image/nihms-1521654-f0001.jpg"/> </div> </p>