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DOI: 10.1055/s-0033-1341076
Synthesis of SMO Inhibitor PF-04449913
Development of a Concise, Asymmetric Synthesis of a Smoothened Receptor (SMO) Inhibitor: Enzymatic Transamination of a 4-Piperidone with Dynamic Kinetic Resolution.
Org. Lett. 2014;
16: 860-863
Publication History
Publication Date:
17 April 2014 (online)
Key words
PF-04449913 - smoothened receptor antagonist - enzymatic transamination - dynamic kinetic resolution
Significance
PF-04449913 is an antagonist of the smoothened receptor (SMO), a component of the hedgehog signalling pathway. It is currently undergoing human trials for the treatment of various blood-related cancers. The key steps in the synthesis depicted are (1) the addition of a lithiated benzimidazole to the pyridinium salt B and (2) the asymmetric construction of two stereogenic centers by an enzymatic transamination accompanied by a dynamic kinetic resolution.
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Comment
Complete racemization of the single enantiomer (S)-G occurred in less than eight hours at 40 °C in a mixture of DMSO and aqueous pH 10 buffer, the medium for the enzymatic transamination. A retro-aza-Michael/aza-Michael mechanism for the racemization was proposed though no direct evidence of the ring-opened intermediate H could be adduced. For the discovery synthesis of PF-04449913, see: M. J. Munchhof et al. ACS Med. Chem. Lett. 2012, 3, 106.
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