Synthesis of the CETP Inhibitor Torcetrapib: The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization

A practical, efficient synthesis of (−)-(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1), a cholesteryl ester transfer protein (CETP) inhibitor, is described. The key reaction in the synthesis, addition of an N-vinylcarbamate to an iminium ion rapidly followed by an iminium ion cyclization onto the aryl ring, sets up the cis relationship of the two subsituents of the tetrahydoquinoline ring of 6. The origin of the high cis stereoselectivity in the cyclization was explored using high-level quantum chemistry calculations.