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Synfacts 2015; 11(4): 0345
DOI: 10.1055/s-0034-1380330
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of PLK4 Inhibitor CFI-400945

Contributor(s):
Philip Kocienski
Pauls HW * et al. University Health Network, Toronto, Canada and Celtic Catalysts, Dublin, Ireland
The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1R,2S)-2-(3-((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a Potent, Orally Active Antitumor Agent.

J. Med. Chem. 2015;
58: 147-169
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Further Information

Publication History

Publication Date:
18 March 2015 (online)

 
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Key words

CFI-400946 - Polo-like kinase 4 inhibitors - cyclopropanation - Sharpless asymmetric dihydroxylation - Suzuki–Miyaura coupling

Significance

CFI-400945 is an inhibitor of Polo-like kinase 4 (PLK4) that is a lead for the treatment of various cancers. The synthesis depicted features a diastereoselective one-pot double SN2 displacement reaction (E → H) for the creation of the cyclopropane ring. The authors propose that the stereoselectivity of the cyclopropanation is a consequence of π–π interactions that stabilize conformer G.


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Comment

Attempted hydrogenolysis of the benzyl protecting groups from a close relative of H was accompanied by partial ring opening of the cyclopropane. However, the benzyl groups were removed cleanly using potassium tert-butoxide in an oxygen-saturated solution in THF and DMSO (R. M. Williams, E. Kwast Tetrahedron Lett. 1989, 30, 451).


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