Total Synthesis of (+)-Aloperine. Use of a Nitrogen-Bound Silicon Tether in an Intramolecular Diels−Alder Reaction

Enantioselective total syntheses of aloperine (1), N-methylaloperine (2), and N-allylaloperine (3) are reported. The central element of the synthetic strategy is an intramolecular Diels−Alder reaction in which the cycloaddends are tethered by a N-silylamine linkage. The total synthesis of 1 proceeds from commercially available 3-hydroxypiperidine hydrochloride (54) and (R)-pipecolinic acid (35) by way of nine isolated and purified intermediates. The synthesis is sufficiently efficient that gram quantities of (+)-aloperine (1) can be readily prepared. Early exploratory studies also introduced a convenient method for tethering cycloaddition partners with a sulfonamide unit to realize the intramolecular Diels−Alder cycloaddition of a vinylsulfonamide:  45 → 46.