Stereoselective synthesis of ABT-894 via an asymmetric multiple-component Michael Mannich reaction

ORGN 754

Wenke Li1, Timothy B. Towne1, Michael G. Fickes1, Daniel S. Reno2, and Steven J. Wittenberger1. (1) GPRD Process Chemistry, Abbott Laboratories, R450, R8-116, 1401 Sheridan Rd, North Chicago, IL 60064, (2) Endocyte, West Lafayette, IN 47906
An (L)-proline catalyzed three-component Michael Mannich reaction was developed to establish the desired stereo centers and to also provide the required carbon framework of ABT-894, a potent NNR agonist for pain management. High stereo-control of the reaction was revealed after converting the unstable aldehyde 2 to lactone 3 (ee > 300:1). The efforts leading to ABT-894 will be described, which substantially shortens the current synthetic route.