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Synfacts 2021; 17(04): 0365
DOI: 10.1055/s-0040-1720320
Synthesis of Natural Products and Potential Drugs

Synthesis of PF-07059013

Contributor(s):
Philip Kocienski
Piotrowski DW. * et al. Pfizer Worldwide Research & Development, Groton, USA
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.

J. Med. Chem. 2021;
64: 326-342
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Key words

PF-07059013 - sickle cell anemia - biocatalysis - ketoreductase - Pfitzinger quinoline synthesis - Mitsunobu reaction

Significance

Sickle cell disease is a common genetic disorder that affects 15 million people worldwide. It is caused by a single point mutation on the β-chain of adult hemoglobin. PF-07059013 is a noncovalent modulator of hemoglobin that has entered phase I clinical trials for the treatment of sickle cell disease.


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Comment

Key steps in the synthesis depicted are (1) the asymmetric reduction of ketone E using the ketoreductase KRED101 from Codexis to afford ­enantiopure F in 94% yield (>99% ee), (2) the construction of quinoline I using a Pfitzinger reaction, and (3) a Mitsunobu reaction that links fragments F and K.


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Publication History

Article published online:
18 March 2021

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