2. Academic Validation
  3. Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

  • Org Lett. 2016 Nov 18;18(22):5888-5891. doi: 10.1021/acs.orglett.6b02910.
Alan M Hyde 1,  Zhijian Liu 1,  Birgit Kosjek 1,  Lushi Tan 1,  Artis Klapars 1,  Eric R Ashley 1,  Yong-Li Zhong 1,  Oscar Alvizo 2,  Nicholas J Agard 2,  Guiquan Liu 3,  Xiuyan Gu 3,  Nobuyoshi Yasuda 1,  John Limanto 1,  Mark A Huffman 1,  David M Tschaen 1
Affiliations

Affiliations

  • 1 Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 2 Codexis Inc., Redwood City, California 94063, United States.
  • 3 Shanghai SynTheAll Pharmaceutical Co., Ltd., Jinshan District, Shanghai 201507, China.
PMID: 27802043 DOI: 10.1021/acs.orglett.6b02910
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.

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