A Catalytic Asymmetric Intramolecular [4 + 1]-Cycloaddition for the Total Synthesis of Terpene Alkaloid Natural
Wen Xiu1, Calvin D Huffman1, William A Swann1
1Department of Chemistry, Purdue University, West Lafayette 47907, Indiana, United States.
Abstract:
Intramolecular Diels-Alder reactions are privileged strategic disconnections in the synthesis of polycyclic natural products containing six-membered rings. The analogous [4 + 1]-cycloaddition may possess comparable utility in addressing [n.3.0]-bicyclic frameworks. However, no viable methods suitable for natural product synthesis have been developed. Here, we report a nickel-catalyzed asymmetric intramolecular [4 + 1]-cycloaddition of a vinylidene and a 1,3-diene to form a [4.3.0]-azabicyclic product. The key vinylidene intermediate is generated reductively from a 1,1-dichloroalkene precursor, and DFT models suggest that addition to the 1,3-diene occurs by a stepwise sequence of [2 + 2]-cycloaddition, 1,3-migration, and reductive elimination. The cycloadduct features sterically differentiated tri- and tetrasubstituted alkenes that can be selectively functionalized to achieve divergent syntheses of 7-epi-incarvilline, hydroxyincarvilline, isoincarvilline, incarvilline, tecomanine, 5-hydroxyskytanthine, and tecostanine.
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