Total Synthesis of (−)- and <i>ent</i>-(+)-Vindoline and Related Alkaloids

A concise 11-step total synthesis of (−)- and <i>ent</i>-(+)-vindoline (<b>3</b>) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C−C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (<b>4</b>), 4-desacetoxy-6,7-dihydrovindorosine (<b>5</b>), 4-desacetoxyvindorosine (<b>6</b>), and vindorosine (<b>7</b>) as well as <i>N</i>-methylaspidospermidine (<b>11</b>). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (<b>8</b>), 4-desacetoxyvindoline (<b>9</b>), and 4-desacetoxy-6,7-dihydrovindoline (<b>10</b>).