BioChem - DOS

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

Organic letters

Hyde, Alan M.; Liu, Zhijian; Kosjek, Birgit; Tan, Lushi; Klapars, Artis; Ashley, Eric R.; Zhong, Yong-Li; Alvizo, Oscar; Agard, Nicholas J.; Liu, Guiquan; Gu, Xiuyan; Yasuda, Nobuyoshi; Limanto, John; Huffman, Mark A.; Tschaen, David M.

<P>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 <I>trans</I> 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&ndash;O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.</P><P><B>Graphic Abstract</B><BR><IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/orlef7/2016/orlef7.2016.18.issue-22/acs.orglett.6b02910/production/images/medium/ol-2016-02910u_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ol6b02910'>ACS Electronic Supporting Info</A></P>

2016

American Chemical Society

1523-7060

18

22

pp.5888-5891

10.1021/acs.orglett.6b02910

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