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Synfacts 2015; 11(10): 1011
DOI: 10.1055/s-0035-1560258
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Fluorination Approach to an SYK Inhibitor

Contributor(s):
Philip Kocienski
Curtis NR, Davies SH, Gray M, * Leach SG, * McKie RA, Vernon LE, Walkington AJ. GlaxoSmithKline Medicines Research Centre, Stevenage, UK
Asymmetric Fluorination Approach to the Scalable Synthesis of a SYK Inhibitor.

Org. Process Res. Dev. 2015;
19: 865-871
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Further Information

Publication History

Publication Date:
18 September 2015 (online)

 
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Key words

SYK inhibitor - asymmetric fluorination - N-fluorobenzene-sulfonimide - palladium catalysis - Suzuki–Miyaura cross-coupling

Significance

Spleen tyrosine kinase (SYK) is implicated in diverse cellular responses such as proliferation, differentiation, and phagocytosis. The target molecule is a SYK inhibitor that is of interest for the treatment of rheumatoid arthritis, B-cell lymphoma, and asthma. The highly telescoped, large-scale synthesis depicted delivered eight ­kilograms of API.


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Comment

The asymmetric fluorination of β-keto ester A using (S)-BINAP as the chiral ligand gave a modest 44% ee but this improved to 72% ee with the bulkier DTBM-SEGPHOS ligand. The best results were obtained by the combined use of a chiral auxiliary (l-menthol) and an enantio- and dia­stereoselective fluorination (C + D → E) mediated by Pd[(S)-binap](OTf)2.


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