Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction
| Autor: | Birgit Kosjek, Oscar Alvizo, Nobuyoshi Yasuda, Mark A. Huffman, John Limanto, Eric R. Ashley, Zhijian Liu, Artis Klapars, Alan M. Hyde, Xiuyan Gu, Guiquan Liu, Yong-Li Zhong, Nicholas J. Agard, Lushi Tan, David M. Tschaen |
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| Rok vydání: | 2016 |
| Předmět: |
chemistry.chemical_classification
Ketone 010405 organic chemistry Stereochemistry Chemistry Organic Chemistry Diastereomer 010402 general chemistry Ring (chemistry) 01 natural sciences Biochemistry 0104 chemical sciences Cyclopropane chemistry.chemical_compound Yield (chemistry) Intramolecular force Pyridine Physical and Theoretical Chemistry Selectivity |
| Zdroj: | Organic Letters. 18:5888-5891 |
| ISSN: | 1523-7052 1523-7060 |
| DOI: | 10.1021/acs.orglett.6b02910 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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