Development of an efficient, practical synthesis of a DP receptor antagonist: Highly selective enzymatic resolution of an indole ester derivative

ORGN 523

Michel Journet1, Kevin Campos1, Edward G. Corley1, Edward J. J. Grabowski1, Anthony O. King1, Jason J. Kowal1, Robert D. Larsen1, Jeff Marcoux1, Ali Shafiee1, Rich D. Tillyer1, and Dalian Zhao2. (1) Department of Process Research, Merck & Co., Inc, P.O. Box 2000, Rahway, NJ 07065, (2) Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065
A short and efficient synthesis of the DP receptor antagonist 1 will be presented. The indole core is assembled via an imine/Heck cyclization in a racemic fashion. The key step of the synthesis is a highly selective enzymatic resolution (Lipase) leading to an enantiopure indole acid. It is noteworthy that the wrong enantiomer can be racemized and therefore potentially recycled. Subsequent functionalization of the aromatic ring, and N-benzylation affords 1 in 20% overall yield.

 

Practical Synthesis and Total Synthesis of Complex Molecules
8:00 AM-12:00 PM, Wednesday, August 25, 2004 Pennsylvania Convention Center -- 201B, Oral

Division of Organic Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004