Hydrogenation with Metal Complexes and Chiral Ligands

Mechanism + Description

The mechanism of asymmetric reduction can be complex and dependent on the metal, the charge on the active catalytic complex, the substrate, and other factors like hydrogen pressure. The key steps are the generation of the catalytically active complex, the oxidative addition of H2, and the coordination of the alkene. The chiral induction in the product is kinetically determined, and governed by the geometry of the catalyst, installed by the chiral ligands.

General comments

Generally, for each individual substrate, a screening exercise needs to be conducted to locate the best conditions to establish a chemically successful and commercially attractive chiral hydrogenation. Good starting points can be identified from literature precedent with data available on the structural requirements of many of the catalysts/ligand sets in use today.

The key reaction parameters include:

• Choice of pre-formed catalyst or metal source and ligand
• Solvent
• Temperature
• H₂ pressure
• Additives – Lewis/Bronstead acids, metal salts
• Mixing – gas liquid transfer
• Maximizing TOF/TON/S/C numbers

Some other key considerations, especially for scale-up are that:

Most metal precursors/ligands – especially phosphines – and pre-formed catalysts are very highly oxygen sensitive and require O2 levels of less then 10 ppm for reliable operation at scale.

If a mixture of ligand and metal precursor is to be employed instead of a pre-formed metal-ligand complex, these are often pre-mixed in a small amount of solvent to prepare the active catalyst prior to its introduction to the substrate and hydrogen.

With optimized S/C ratios in some processes of 10,000-20,000 and up to 200,000 reported, the quality of input materials needs to be carefully considered and controlled to ensure no catalyst poisons are introduced. Each metal will have its own specific requirements, but chelators, low-valent sulphur, and phosphorus compounds are of particular concern. Metal contamination by redox-active metals, especially Pd either as an impurity in the substrate from previous steps in the synthesis or as a reactor/equipment contaminant, can introduce an achiral hydrogenation catalyst that can erode ee in the product by competing with the chiral hydrogenation pathway.

A large body of data has been published on heterogeneous catalysts for asymmetric alkene reduction – including supported versions of homogeneous chiral catalysts. Despite the attractions of using recoverable, heterogeneous chiral catalysts, these have not yet made great inroads in larger-scale processes. Some detractions include slower reaction rates and ee erosion compared to soluble homogeneous catalysts, and leaching of the metal from the support.

The majority of asymmetric alkene reductions are run with H₂ gas. A number of instances of transfer hydrogenation using reagents like formic acid or isopropanol have been reported, principally with nitroalkenes.

Although not as well developed as with other classes of metal-catalyzed reactions, some reports are coming out on the replacement of Ru/Rh/Ir in asymmetric reductions of alkenes by base metals like cobalt in the presence of chiral ligands.

 

Key references

Burk, M. J. Modular Phospholane Ligands in Asymmetric Catalysis. Acc. Chem. Res. 2000, 33 (6), 363–372.

Verendel, J.; Pàmies, O.; Diéguez, M.; Andersson, P. G. Asymmetric Hydrogenation of Olefins Using Chiral Crabtree-type Catalysts: Scope and Limitations. Chem. Rev. 2014, 114 (4), 2130–2169.

Arena, G.; Barreca, G.; Carcone, L.; Cini, E.; Marras, G.; Nedden, H. G.; Rasparini, M.; Roseblade, S.; Russo, A.; Taddei, M.; et al. Rhodium-CatalyzedEnantioselective Hydrogenation of (E)-Enol Acetate Acids. Adv. Synth. Catal. 2013, 355 (8), 1449–1454.

Barnard, C. F. J.; Rouzaud, J.; Stevenson, S. H. Straightforward Preparation of Highly Enantioselective Anchored Chiral Homogeneous Catalysts. Org. Process Res. Dev. 2005, 9 (2), 164-167.

Genet, J. Asymmetric Catalytic Hydrogenation. Design of New Ru Catalysts and Chiral Ligands: From Laboratory to Industrial Applications. Acc. Chem. Res. 2003, 36 (12), 908-918.

Nair, D.; Wong, H.; Han, S.; Vankelecom, I. F. J.; White, L. S.; Livingston, A. G.; Boam, A. T. Extending Ru-BINAP Catalyst Life and Separating Products from Catalyst Using Membrane Recycling. Org. Process Res. Dev. 2009, 13 (5), 863–869.

Gridnev, I. D.; Higashi, N.; Asakura, K.; Imamoto, T. Mechanism of Asymmetric Hydrogenation Catalyzed by a Rhodium Complex of (S,S)-1,2-Bis(tert-butylmethylphosphino)ethane. Dihydride Mechanism of Asymmetric Hydrogenation. J. Am. Chem. Soc. 2000, 122 (30), 7183–7194.

RajanBabu, T. V.; Radetich, B.; You, K K.; Ayers, T. A.; Casalnuovo, A. L.; Calabrese, J. C. Electronic Effects in Asymmetric Catalysis:  Structural Studies of Precatalysts and Intermediates in Rh-Catalyzed Hydrogenation of Dimethyl Itaconate and Acetamidocinnamic Acid Derivatives Using C2-Symmetric DiarylphosphiniteLigands. J. Org. Chem. 1999, 64 (10), 3429–3447.

Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Asymmetric Hydrogenation Using MonodentatePhosphoramiditeLigands. Acc. Chem. Res. 2007, 40 (12), 1267–1277.

Hansen, K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; et al. Highly Efficient Asymmetric Synthesis of Sitagliptin. J. Am. Chem. Soc. 2009, 131 (25), 8798–8804.

Cui, X.; Burgess, K. Catalytic Homogeneous Asymmetric Hydrogenations of Largely UnfunctionalizedAlkenes. Chem. Rev. 2005, 105 (9), 3272-3296.  

Church, T. L.; Andersson, P. G. Iridium Catalysts for the Asymmetric Hydrogenation of Olefins with Nontraditional Functional Substituents. Coordination Chemistry Reviews. 2008, 252 (5-7), 513-531.

He, Y.; Fan, Q. Phosphine-Free Chiral Metal Catalysts for Highly Effective Asymmetric Catalytic Hydrogenation. Org. Biomol. Chem. 2010, 8, 2497-2504.

Knowles, W. S. Asymmetric Hydrogenations (Nobel Lecture). Angew. Chem. Int. Ed. 2002 , 41, 1998-2007.

Lennon, I. C.; Ramsden, J. A.; Brear, C. J.; Broady, S. D.; Muir, J. C. Asymmetric Enamide Hydrogenation in the Synthesis of N-acetylcolchinol: A Key Intermediate for ZD6126. Tetrahedron Lett. 2007, 48 (26), 4623-4626.

Appleby, I.; Boutlton, L. T.; Cobley, C. J.; Hill, C.; Hughes, M. L.; de Koning, P. D.; Lennon, I. C.; Praquin, C.; Ramsden, J. A.; Samuel, H. J.; et al. Efficient Synthesis of an Imidazole-Substituted δ-Amino Acid by the Integration of Chiral Technologies. Org. Lett. 2005, 7 (10), 1931-1934.

Friedfeld, M. R.; Shevlin, M.; Hoyt, J. M.; Krska, S. W.; Tudge, M. T.; Chirik, P. J. Cobalt Precursors for High-Throughput Discovery of Base Metal Asymmetric Alkene Hydrogenation Catalysts. Science. 2013, 342 (6162), 1076-1080.

Barbaro. P.; Liguori, F. Ion Exchange Resins: Catalyst Recovery and Recycle. Chem. Rev. 2009, 109 (2), 515-529.

Trindade, A. F.; Gois, P. M. P.; Afonso, C. A. M. Recyclable StereoselectiveCatalysts. Chem. Rev. 2009, 109 (2), 418-514.

Bergbreiter, D. E.; Tian, J.; Hongfa, C. Using Soluble Polymer Supports To Facilitate Homogeneous Catalysis. Chem. Rev. 2009, 109 (2), 530-582.

Fraile, J. M.; Garcia, J. I.; Mayoral, J. A. Noncovalent Immobilization of EnantioselectiveCatalysts. Chem. Rev. 2009, 109 (2), 360–417.

 

Relevant Scale-up Examples with Scheme – Ru metal based catalysts

Org. Process Res. Dev. 2001, 5 (4), 438-441.
Experimental
230 kg scale

Org. Process Res. Dev. 2003, 7 (3), 369-378.
Experimental
50 kg scale

Org. Process Res. Dev. 2003, 7 (3), 362-368.
Experimental
1.1 kg scale

Org. Process Res. Dev. 2009, 13 (3), 525–534.
Experimental
4 kg scale

Org. Process Res. Dev. 2004, 8 (5), 738-743.

Experimental
50 kg scale

Org. Process Res. Dev. 2014, 18 (12), 1702-1713.
Experimental
15 g scale

Org. Process Res. Dev. 2008, 12 (6), 1253–1260.
Experimental
600 g scale

Org. Process Res. Dev. 2014, 18 (1), 135−141.
Experimental
15 kg scale

Org. Process Res. Dev. 2005, 9 (4), 472-478.
Experimental
2 kg scale

Org. Process Res. Dev. 2010, 14 (3), 568–573.
Experimental
4 g scale

Org. Process Res. Dev. 2010, 14 (3), 568–573.
Experimental
130 g scale

Org. Process Res. Dev. 2012, 16 (5), 1017−1038.
Experimental
100 kg scale Process run in flow reactor

Org. Process Res. Dev. 2010, 14 (3), 568–573.
Experimental
600 g scale

Org. Process Res. Dev. 2003, 7 (3), 407-411.
Experimental
40 g scale

Org. Process Res. Dev. 2012, 16 (5), 830−835.
Experimental
12 kg scale

Org. Process Res. Dev. 2013, 17 (8), 1061−1065.
Experimental
4 kg scale

Org. Process Res. Dev. 2007, 11 (3), 585-591.
Experimental
50 g scale

Org. Process Res. Dev. 2009, 13 (1), 84–90.
Experimental
150 g scale

Org. Process Res. Dev. 2009, 13 (1), 84–90.
Experimental
150 g scale

Org. Process Res. Dev. 2013, 17 (1), 69−76.
Experimental
120 kg scale

Org. Process Res. Dev. 2011, 15 (5), 1138–1148.
Experimental
6 kg scale

Org. Process Res. Dev. 2011, 15 (6), 1358–1364.
Experimental
100 kg scale

Relevant Scale-up Examples with Scheme – Ir metal based catalyst

Org. Process Res. Dev. 2006, 10 (2), 262-271.
Experimental
20 kg scale

Org. Process Res. Dev. 2010, 14 (4), 787–798.
Experimental
2.2 kg scale

 

Green Review

1. Atom efficiency (by-products Mwt)
   With optimized metal and ligand stoichiometry, catalytic metals and ligands have negligible contribution to the atom/mass intensity. Hydrogen is typically used in large molar excess, but this is non-polluting.
2. Safety Concerns
   No major concerns around scaling asymmetric hydrogenation reactions beyond those for handling hydrogen at pressure. Generally, the lowest pressure for acceptable performance is recommended for safety, but this can be at the expense of the S/C ratio. Many catalysts perform better (TON & TOF) at a higher H₂ pressure, although a few give better ee at lower H₂ pressure.
   
   Exotherms may be experienced when hydrogen is introduced to the reactor.
3. Toxicity and environmental/aquatic impact
   The main concern is around the loss of precious metal/heavy metal catalysts into waste streams. Most precious and heavy metal levels are tightly regulated. The same applies to potential metal carried through into the API. More details later on permitted hydrophobic, high mol wt phosphines and phosphine oxides that can be persistent and bioaccumulative, and should not be discharged into aqueous waste streams.
4. Cost, availability & sustainable feedstocks
   With high catalytic efficiency, this methodology can be an economical way to access chiral molecules. Precious metals like Ru/Ir/Rh are commodities and thus the price and availability can fluctuate widely with demand and general global economic cycles. Since 2010, the price of Rh has dropped from ~US$2,500 to ~ US$800 per ounce. In 2007, Rh approached US$10,000 per ounce.
5. Sustainable implications
   All metals have a high LCI impact from mining and refining operations, so use should be catalytic with efficient recovery and recycle. Ru/Ir/Rh are the most commonly used precious metals for chiral hydrogenation, and these are rated at high risk of depletion. No concern for abundant base metals like Co, Ni, Fe, etc.

Updated ICH Guidelines for Metals in API's

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step2b.pdf