Asymmetric Chemocatalysis: Going for the Lowest Loadings

A high proportion (> 50%) of the active pharmaceutical ingredients (APIs) approved by FDA during the past 10 years were manufactured using chiral technology, according to industry estimates. Asymmetric transformations are thus a critical aspect of drug manufacturing today, and catalysis has become the primary method for the efficient and selective synthesis of single enantiomer products. Development chemists now have a choice between enzyme-based biocatalysts and transition metal-based chemocatalysts (some organocatalysts are attracting interest as well but are not discussed in this article).

Chris Senanayake, vice-president of chemical development in the US for Boehringer Ingelheim Pharmaceuticals, Ian C. Lennon, senior vice-president for global business development with Chiral Quest, Antonio Zanotti-Gerosa, team leader with Johnson Matthey Catalysis and Chiral Technologies, Ephraim Honig, chief operating officer with Strem Chemicals, and Wataru Kuriyama, a chemist with Takasago International, discuss important aspects of chemocatalysis for asymmetric synthesis.

Choosing chemocatalysisPharmaceutical Sciences, Manufacturing and Marketplace Report: Considering the state-of-the-art catalytic toolbox of today, when are homogeneous chemocatalysts advantageous over other types of catalysts for chiral transformations?

Senanayake (Boehringer Ingelheim): In preparing the initial batches of API for preclinical studies and early clinical trials, the simplest, not necessarily the best and most economical, method is used due to time constraints. That may be a well-known stoichiometric method using a chiral auxiliary or a resolution-based approach. In parallel, we investigate chemocatalytic routes to determine if there are any cost-effective, scalable alternatives, considering all aspects, such as the metal (availability, cost), ligand (intellectual-property issues, cost), yields, selectivities, and catalyst loadings. Enzymatic routes generally take much longer to develop and often require the use of outside expertise for the engineering of the desired reactivity, so they tend to be used more often in second-generation processes in late-stage drug development.

Kuriyama (Takasago): Chemocatalysts can be classified into two major types, homogeneous catalysts and heterogeneous catalysts. Heterogeneous catalysts have advantages in recovery and reusability; however, generally, homogeneous catalysts show better reactivity and selectivity. In addition, the flexibility of ligand design can improve selectivity, and in asymmetric reactions, high selectivity is required. Therefore, homogeneous catalysts are predominantly used.

Zanotti-Gerosa (Johnson Matthey Catalysis and Chiral Technologies): The use of biocatalysis is growing, but the choice of catalyst technology must be made on a case-by-case basis. Chemical catalysts offer some real advantages. Many are available off-the-shelf and do not need to be engineered for a specific reaction. They have high activity, often require only a simple workup, and most importantly, have high-volume efficiency. What we see is that the speed of development that is possible with chemocatalysis is also very attractive because it enables more rapid development of production solutions. All of these factors have to be considered in order to find the most cost-effective catalytic solution.

Lennon (Chiral Quest): Choice of method—such as between chemocatalysis and biocatalysis—will also depend on the technology that is possessed by the CMO. Chiral Quest, for example, specializes in asymmetric hydrogenation. There are also areas where biocatalysis is not yet effective, such as the asymmetric synthesis of α-amino acids. Asymmetric hydrogenation, on the other hand, is exceptionally good for the commercial-scale manufacture of both aliphatic and aromatic α-amino acids.

Ligand, substrate, recovery and cost challenges Pharmaceutical Sciences, Manufacturing and Marketplace Report: What are the major shortcomings/limitations of current homogeneous chemocatalysts for chiral transformations? What major issues would you like to see addressed in next-generation catalyst technologies?

Lennon (Chiral Quest): The synthesis of chiral ligands is often very difficult and can require the use of cryogenic conditions and resolution steps. On the positive side, in many cases, both enantiomers can be used, and the catalyst loadings are very low, so large quantities of the ligands are not needed. Obviously, having much cheaper and easier to make ligands while still maintaining excellent enantiomeric excess and high activity is a good goal.

On the substrate side, there are also still a number of compound classes that are challenging. For asymmetric hydrogenation, imines, oximes, tetra-substituted double bonds, and aromatic systems fall into this category. Some advances are being made in the asymmetric hydrogenation of heterocycles, and this area holds much promise as it will lead to the manufacture of complex chiral molecules in very few steps and is a reaction that cannot be achieved using enzymes.

Kuriyama (Takasago): Removal of the metal and reuse are issues that must be addressed, but there are processes where homogeneous catalysts are recycled. Rh-BINAP in our l-menthol process, for example, is recycled from the distillation residue. However, there still is much room to improve metal and catalyst removal. Next-generation catalysts should have the advantage of both homogeneous and heterogeneous catalysis as well as high selectivity and recyclability.

Zanotti-Gerosa (Johnson Matthey Catalysis and Chiral Technologies): The catalyst cost is the biggest issue. Most chiral catalysts for asymmetric synthesis contain precious metals and very complex ligands, both of which are very expensive. Therefore, a cost-effective process requires very low catalyst loadings (ideally 100,000:1). Going to such low levels also eliminates the need to recover the catalyst.

Senanayake (Boehringer Ingelheim): Scalability is the biggest issue. Often with catalytic reactions, the catalyst does not seem to behave the same way on a very large scale as it does on the bench scale, and this issue can be more pronounced with asymmetric catalysis. This change in behavior can be due to catalyst stability issues or problems with the purity of the starting materials. Boehringer Ingelheim has established an in-house Catalysis Group to design new ligands and to develop new catalytic reactions that can address both the cost and scalability issues encountered in API development.

OptimizationPharmaceutical Sciences, Manufacturing and Marketplace Report: What is being done to overcome these problems?

Zanotti-Gerosa (Johnson Matthey Catalysis and Chiral Technologies): Existing catalysts are being applied to other transformations, or being modified so that they can be effective for related reactions. For example, some hydrogenation catalysts have been shown to be effective for the reverse dehyrogenation reaction. Other catalysts have been introduced that can do both hydrogenation and transfer hydrogenation reactions. This flexibility has a cost impact. Development work is also proceeding with many important chiral catalysts and ligands whose patents have recently or will soon expire.

Kuriyama (Takasago): Immobilization is one solution for avoiding recovery issues. In general, immobilization can be achieved through binding of the ligands or the metal to a solid support. From the perspective of industry, immobilization of the metal is advantageous because ligands developed for homogeneous catalysts can be used as is, which reduces the cost and time of catalyst development. Rhodium (Rh) with the well-known Duphos ligand on PTA (phosphotungstic acid) for asymmetric hydrogenation is one example of this type of catalyst. Microencapsulation is another important method. Toxic OsO₄ immobilized by this method is used for Sharpless asymmetric dihydroxylation and recovered without any leaching.

Lennon (Chiral Quest): In our experience, it is better to optimize the homogeneous reaction to get the lowest possible catalyst loading and the best selectivity, so that each production run takes the same time, gives the same enantiomeric excess (ee), uses the same catalyst loading, and provides the same purity of product. Consistency is especially important for GMP manufacture. Generally, making the ligand heterogeneous leads to poorer catalyst loadings (often 10 x higher or more), lower and less reproducible ee’s, and sometimes incomplete reactions.

Senanayake (Boehringer Ingelheim): The key to developing a catalytic reaction into commercial scale is to gain an understanding of the mechanism of the reaction and identify the active catalytic species. It is imperative that the interactions between the catalyst and the substrate be identified. The use of high-throughput screening, combinatorial ligand discovery, computational tools, and modern analytical techniques in an integrated manner will make it possible to obtain the necessary level of understanding of catalytic behavior needed for the development of robust systems that will be effective at any scale.

Latest developmentsPharmaceutical Sciences, Manufacturing and Marketplace Report: Of recently introduced chiral chemocatalysts and/or ligands, what do you believe are the most novel and why? Which ones will have the most impact on fine chemical/pharmaceutical synthesis and why?

Kuriyama (Takasago): We believe that our asymmetric hydrogenation catalysts RUCY and DENEB are the most novel catalysts and will have the most impact on fine chemicals. RUCY and DENEB show unprecedentedly high catalyst activity; the productivity per hour or per weight of catalyst is high enough that the cost for production can be reduced and the removal of the metal is relatively easy. In addition, RUCY and DENEB have a wide substrate scope and reduce substrates that can’t be hydrogenated by conventional catalysts. Therefore, we believe that they will have the most impact on the pharmaceutical industry, where efficient chemical transformation of compounds with a variety of functional groups is required and product quality must be tightly controlled.

Honig (Strem): There is a lot of interest in iridium complexes developed by the Kerr group at the University of Strathclyde for the direct, flexible, and selective introduction of hydrogen isotopes to organic molecular frameworks under extremely mild reaction conditions, and these catalysts have successfully been used for the isotopic labeling of several known drug molecules. We also believe that the RUCY-XylBINAP catalyst developed by Takasago, which is effective at catalyst loadings as low as 0.001 mol%, is very promising as an industrially practical catalyst for asymmetric hydrogenation.

Zanotti-Gerosa (Johnson Matthey Catalysis and Chiral Technologies): The Noyori ketone hydrogen technology, for which the Nobel Prize was awarded in 2001, is a very important asymmetric transformation today. In fact, second-generation catalysts that are more robust (more resistant to deactivation) and more active that are being developed by Walter Baratta at the University of Udine and others will be valuable new catalysts for pharmaceutical manufacturing. New catalysts for asymmetric transfer hydrogenation of ketones and imines being developed by Martin Wills at Warwick University are also noteworthy.

Senanayake (Boehringer Ingelheim): Asymmetric hydrogenations are widely used in industrial pharmaceutical synthesis and are least affected by scale up issues. Jacobsen epoxidation chemistry, the Buchwald–Hartwig aminations, Suzuki and other cross-coupling reactions as well as transfer-hydrogenation processes are also important transformations that are being developed on larger scales.

Lennon (Chiral Quest): The ligands that will have the greatest impact on fine chemical/pharmaceutical synthesis are those that are being used today. For example, Chiral Quest manufactures many tons of products using our asymmetric hydrogenation catalysts, such as Rh-DuanPhos and Ru-C3-TunePhos. There are so many useful ligands and catalysts available that any new system will find it hard to compete. A new ligand would need to be very easy to make, very active, and highly enantioselective or carry out a reaction that none of the existing technology can achieve.