This Week in TB R&D – 17 August 2010

16 Aug 2010
by Working Group

Review of JACS Communication, “Catalytic Asymmetric Synthesis of R207910″

By Christopher Cooper, Director of Chemistry, TB Alliance

Catalytic Enantioselective Proton Migration
Retrosynthetic Approach to TMC207 (click to view larger)

The novel antitubercular agent TMC207 (Tibotec, a Johnson & Johnson company) represents an impressive and important new chemical agent for addressing both drug sensitive and drug resistant TB. This compound – which is continuing to advance through clinical trials conducted by both J&J and the TB Alliance – selectively inhibits M.tb ATP synthase leading to disruption in the energy metabolism of both replicating and non-replicating organisms.

As attractive as the biological profile is for this compound, the current synthetic route1 relies on an achiral final coupling reaction to generate all four possible stereoisomers of the diarylquinoline adduct which must then be separated to isolate the single diastereomer of interest.

Recently, researchers at the University of Tokyo published a short paper describing the first asymmetric synthesis of TMC207. This publication presents an elegant approach to synthesizing the target molecule which takes advantage of a catalytic enantioselective proton migration reaction to install the phenyl sidechain with the correct absolute stereochemistry. Having set this center, a second diastereoselective allylation reaction is employed to fix the adjacent quaternary center with an appendage suitable for late-stage conversion to the requisite N,N-dimethylaminoethyl group.

In all, the Shibasaki route requires 12 steps from commercial starting materials to generate TMC207 enantioselectively and in an overall yield of 5%. The chemical yields for both the enantioselective proton migration step, and the allylation reaction were >99% and 95%, and the relative stereoinduction in both instances was equally high (88% ee, and 5.6/1 d.r., respectively).

Important synthetic insights may be derived from this publication including the authors’ ability to introduce the quinoline C6-bromine late in the synthesis. This finding suggests that other metal-mediated coupling reactions or approaches which might normally interfere with such a halogenated precursor could be considered as well. While it will take more time to fully appreciate the overall value of this work for preparing TMC207 in large scale, the demonstrated ability to construct this molecule in an asymmetric fashion suggests that additional research in this area is well-warranted.


1 Andries, K.J.L.M; Koul, A.; Guillemont, J.E.G.; Pasquier, E.T.J. U.S. Patent 7,709498 B2 (May 4, 2010).

1 Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.; Shibasaki, M. “Catalytic Asymmetric Synthesis of R207910,” J. Am. Chem. Soc., 2010, 132 (23), pp.7905-7907.

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