Chiral Hydrogenation of Alkenes Reagent Guide

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General Overview

Asymmetric hydrogenation has become a widely used technique for the synthesis of chiral molecules via the reduction of alkenes, introducing one or two chiral centers depending on the structure of the alkene substrate. Typically based on homogeneous metal-based hydrogenation catalysts in the presence of chiral ligands, asymmetric hydrogenation accounts for a large percent of catalyzed asymmetric transformations carried out in the synthesis of pharmaceuticals, agrochemicals and fine chemicals. The reaction is scalable, and when optimized, can display high turn over number (TON), turn over frequency (TOF) and substrate–catalyst ratios (S/C), which make an attractive industrial catalytic process. Another desirable feature is that many chiral complexes, metal sources/pre-catalysts and ligands can be purchased commercially. Over 3,000 chiral mono and bidentate phosphine ligands have been published for asymmetric hydrogenation. Mixed P,N P,O and non-phosphine ligands have also been developed for asymmetric hydrogenation. Many of the newer catalysts overcome the strict geometric and coordination requirements for substrates that somewhat restricted the field in its early days.

Green Criteria for Asymmetric Hydrogenation

  1. Preferential use of base metals: If possible, base metals like Co should be considered as catalysts in preference to Ru/Ir/Rh or other precious metal catalysts.
  2. The order of preference for precious metals is Ru >Ir >Rh.
  3. For ligands, low Mol. Wt. materials are preferable.
  4. Metal and ligand loadings should be optimized-maximized TON/TOF/S/C ratios.
  5. The use of additives should be explored to maximize catalytic activity and reduce catalyst loadings.
  6. Hydrogen pressure should be minimized – but this is often a trade-off with substrate-catalyst loading.
  7. High impact solvents should be avoided if possible.
  8. Work-up/DSP should ensure that metal levels are reduced to relevant specifications in the product and any waste streams, and if precious metal is used, that its recovery and recycle is optimized.

 

General Reviews

Etayo, P.; Vidal-Ferran, A. Rhodium-CatalysedAsymmetric Hydrogenation as a Valuable Synthetic Tool for the Preparation of Chiral Drugs. Chem. Soc. Rev. 2013, 42, 728-754.

Roseblade, S. J.; Pfaltz, A. Iridium-Catalyzed Asymmetric Hydrogenation of Olefins. Acc. Chem. Res. 2007, 40 (12), 1402–1411.

Zhang, W.; Chi, Y.; Zhang, X. Developing Chiral Ligands for Asymmetric Hydrogenation. Acc. Chem. Res. 2007, 40 (12), 1278–1290.

Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. Asymmetric Hydrogenation. Rhodium Chiral Bisphosphine Catalyst. J. Am. Chem. Soc. 1977, 99 (18), 5946–5952.

Jäkel, C.; Paciello, R. High-Throughput and Parallel Screening Methods in Asymmetric Hydrogenation. Chem. Rev. 2006, 106 (7),  2912–2942.

Ager, D. J.; de Vries, A. H. M.; de Vries, J. G. Asymmetric Homogeneous Hydrogenations at Scale. Chem. Soc. Rev. 2012, 41, 3340-3380.

Knowles, W. S.; Nyori, R. Pioneering Perspectives on Asymmetric Hydrogenation. Acc. Chem. Res. 2007, 40 (12), 1238–1239.

Shultz, C. S.; Krska, S. W. Unlocking the Potential of Asymmetric Hydrogenation at Merck. Acc. Chem. Res. 2007, 40 (12), 1320–1326.

Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Industrial-Scale Synthesis and Applications of Asymmetric Hydrogenation Catalysts. Acc. Chem. Res. 2007, 40 (12), 1291–1299.

Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Developments in Asymmetric Hydrogenation from an Industrial Perspective. Acc. Chem. Res. 2007, 40 (12), 1385–1393.

Gridnev, I. D.; Imamoto, T. On the Mechanism of Stereoselection in Rh-Catalyzed Asymmetric Hydrogenation:  A General Approach for Predicting the Sense of Enantioselectivity. Acc. Chem. Res. 2004, 37 (9), 633–644.

Zhang, X.; Chi, Y.; Tang, W. C-H Bond Formation by Asymmetric and Stereoselective Hydrogenation. Comprehensive Organometallic Chemistry III. 2007, 10, 1-70.

Imamoto, T. Asymmetric Hydrogenation. In Hydrogenation; Karamé, I., Eds. InTech: 2012; 3-30.

Asymmetric Hydrogenation. Wikipedia [Online]; Posted December 10, 2012. https://en.wikipedia.org/wiki/Asymmetric_hydrogenation (Accessed September 2017).

Cadu, A.; Andersson, P. G. Development of Iridium-CatalyzedAsymmetric Hydrogenation: New Catalysts, New Substrate Scope. J. Organomet. Chem. 2012, 714, 3-11.

Woodmansee, D. H.; Pfaltz, A. Asymmetric Hydrogenation of Alkenes Lacking Coordinating Groups. Chem. Commun. 2011, 47, 7912-7916.

© 2015 Green Chemistry Institute Pharmaceutical Roundtable. All rights reserved.