Stereodefined Cyclopentanes by Hydroarylation–Ring Opening

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.

GRAPHICAL ABSTRACT

Keywords:

• Cyclopentane
• hydroarylation
• ring opening
• stereodefined

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.