title: 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.
authors.affiliation: Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China.
authors.forename: Kong-Zhen
authors.initials: KZ
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Shi
authors.initials: S
authors.lastname: Qiu
authors.forename: Xiao
authors.initials: X
authors.lastname: Zheng
authors.forename: Pei-Qiang
authors.initials: PQ
authors.lastname: Huang
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D006900:Hydroxylation; D007769:Lactams / Q000737:chemistry*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D007769:Lactams; D011725:Pyridines; D011760:Pyrrolidinones