title: Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction.
abstract: A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Alan M
authors: AM
authors: Hyde
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Zhijian
authors: Z
authors: Liu
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Birgit
authors: B
authors: Kosjek
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Lushi
authors: L
authors: Tan
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Artis
authors: A
authors: Klapars
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Eric R
authors: ER
authors: Ashley
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Yong-Li
authors: YL
authors: Zhong
authors: Codexis Inc., Redwood City, California 94063, United States.
authors: Oscar
authors: O
authors: Alvizo
authors: Codexis Inc., Redwood City, California 94063, United States.
authors: Nicholas J
authors: NJ
authors: Agard
authors: Shanghai SynTheAll Pharmaceutical Co., Ltd., Jinshan District, Shanghai 201507, China.
authors: Guiquan
authors: G
authors: Liu
authors: Shanghai SynTheAll Pharmaceutical Co., Ltd., Jinshan District, Shanghai 201507, China.
authors: Xiuyan
authors: X
authors: Gu
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Nobuyoshi
authors: N
authors: Yasuda
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: John
authors: J
authors: Limanto
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: Mark A
authors: MA
authors: Huffman
authors: Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors: David M
authors: DM
authors: Tschaen