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 I 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.