Total Synthesis of the Diterpene Alkaloid Thelepogine through Enyne Hydroamination

The total synthesis of the atypical diterpene alkaloid thelepogine is reported. Our pathway features the asymmetric construction of a carbotricyclic intermediate that undergoes a 2,3-Wittig-Still rearrangement of a tetrasubstituted allylic alcohol, installing two adjacent quaternary stereocenters. The α-tertiary amine of thelepogine was delineated from a quaternary carbon through a Beckmann-type rearrangement, while the unusual pyrrolizidine moiety was assembled through a copper(I)-catalyzed (4 + 1) cycloaddition of an amino enyne, amounting to a 2-fold hydroamination. Our synthesis enables the full spectroscopic characterization of thelepogine, which had previously been characterized only by single-crystal X-ray diffraction of a derivative, and opens the door to comprehensive biological evaluation.