Abstract
The hydroarylation of 2-azabicyclo[2.2.1]hept-5-en-3-one followed by nucleophilic ring opening was employed as an operationally simple route to stereodefined trisubstituted cyclopentane analogs. This synthetic sequence was successfully executed using a variety of nucleophiles including hydroxide, alkoxide, hydride, Grignard reagents, and amines. This methodology facilitated the preparation of a constrained version of dipeptidyl peptidase 4 inhibitor sitagliptin.
Notes
a Isolated yield after two steps of chromatographically pure, individual regioisomers derived from racemic starting material.
a Reaction conditions: A˭LiOH, THF, H2O; B˭NaH, MeOH; C˭NaBH4, MeOH; D = excess MeMgBr, THF; E˭PhMgBr, THF; F˭NH3(g), Me2AlCl, Yb(OTf)3, THF.
b Separated mixture of ketone (11%) and alcohol (48%).
Note. Reaction conditions: LiOH, THF, H2O.