Stereospecific Approach to the Synthesis of Ring‑A Oxygenated <i>Sarpagine</i> Indole Alkaloids. Total Synthesis of the Dimeric Indole Alkaloid <i>P</i>‑(+)-Dispegatrine and Six Other Monomeric Indole Alkaloids

Abstract

The first regio- and stereocontrolled total synthesis of the bisphenolic, bisquaternary alkaloid (+)-dispegatrine (<b>1</b>) has been accomplished in an overall yield of 8.3% (12 reaction vessels) from 5-methoxy-d-tryptophan ethyl ester (<b>17</b>). A crucial late-stage thallium­(III) mediated intermolecular oxidative dehydrodimerization was employed in the formation of the C9–C9′ biaryl axis in <b>1</b>. The complete stereocontrol observed in this key biaryl coupling step is due to the asymmetric induction by the natural <i>sarpagine</i> configuration of the monomer lochnerine (<b>6</b>) and was confirmed by both the Suzuki and the oxidative dehydrodimerization model studies on the tetrahydro β-carboline (<b>35</b>). The axial chirality of the lochnerine dimer (<b>40</b>) and in turn dispegatrine (<b>1</b>) was established by X-ray crystallography and was determined to be <i>P</i>(S). Additionally, the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (<b>2</b>), (+)-10-methoxyvellosimine (<b>5</b>), (+)-lochnerine (<b>6</b>), lochvinerine (<b>7</b>), (+)-sarpagine (<b>8</b>), and (+)-lochneram (<b>11</b>) were also achieved via the common pentacyclic intermediate <b>16</b>