SmI2-Mediated Intermolecular Coupling of γ-Lactam N-α-Radicals with Activated Alkenes: Asymmetric Synthesis of 11-Hydroxylated Analogues of the Lead Compounds CP-734432 and PF-04475270

Abstract

We report, for the first time, the synthesis of 8-aza-analogues of PGE2. The SmI2-mediated cross coupling reactions of γ-lactam-hemiaminal 9, lactam 2-pyridyl sulfide 17, and lactam 2-pyridyl sulfone 18 with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49-78%, 45-75%, and 75-90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 trans-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam N-α-alkyl radicals of types B, B1, and B2 with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP4 receptor agonist PF-04475270 (30), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (31), compounds 35 and 36 have been achieved on the basis of this method.