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Synfacts 2019; 15(03): 0219
DOI: 10.1055/s-0037-1611189
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of a Carbapenem Intermediate

Contributor(s):
Philip Kocienski
Noyori R. * Ikeda T, Ohkuma T, Widhalm M, Kitamura M, Takaya H, Akutagawa S. * Sayo N, Saito T, Taketomi T, Kumobayashi H. Nagoya University, Kyoto University, and Takasago Research Institute, Tokyo, Japan
Stereoselective Hydrogenation via Dynamic Kinetic Resolution.

J. Am. Chem. Soc. 1989;
111: 9134-9135
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Publication History

Publication Date:
15 February 2019 (online)

 
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Key words

carbapenems - asymmetric hydrogenation - dynamic kinetic resolution - β-lactams - ruthenium catalysis

Significance

Azetidinone G is a key intermediate in the commercial synthesis of carbapenem antibiotics such as Meropenem. Many syntheses of G have been reported (see first Review below). One of the simplest and shortest was developed jointly by workers at Takasago and the Noyori group, that is conspicuous for being an early example of the practical application of asymmetric catalytic hydrogenation and dynamic kinetic resolution in the construction of APIs.


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Reviews

A. H. Berks Tetrahedron 1996, 52, 331–375; H. Kumobayashi, T. Miura, N. Sayo, T. Saito, X. Zhang Synlett 2001, 1055–1064.


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Comment

Over 100 tons of G are produced annually by Takasago using a variation of the process depicted. The conditions and yields for C → F are taken from a patent by Takasago International Corporation (N. Sayo, T. Saito, Y. Okeda, H. Nagashima, H. Kumobayashi, US Pat. 4,981,992; January 1, 1991). There have been many improvements and refinements in the asymmetric hydrogenation that have increased the turnover number, reduced the catalyst load, and improved the de and ee of the process (see second Review below). For a multikilogram-scale synthesis of the starting β-keto ester A, see: M. Chao, A. Hao, H. Wang Org. Process Res. Dev. 2009, 13, 645.


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