The increasing complexity of small-molecule APIs, combined with the growing cost pressures faced by drug companies, is driving process chemists to develop transformations that achieve in one step what previously took several. Catalysts used today enable the synthesis of highly complex, small-molecule intermediates and APIs not only in fewer steps, but also with increased atom economy, and also with very high selectivities and yields.
Often, however, these catalysts are based on precious (and frequently toxic) metals and expensive, complex chiral ligand systems. Fortunately, they tend to be effective at very low loadings, but many of the key metals are considered to be critical raw materials that are of growing economic importance but also face a high risk of supply shortage. As a result, researchers are turning to alternatives: enzymes, complexes based on abundant metals and organocatalysts.
Precious and critical
Many of the transition metals used in pharmaceutical catalysts are also used in applications experiencing rapid growth – renewable energy and mobile devices, for example. Politics and price speculation have also contributed to the issue. The platinum group metals (PGMs) – ruthenium, rhodium, palladium, osmium, iridium and platinum – are of greatest concern for pharmaceutical synthesis.
The platinum group0 metals, along with the rare earth metals, niobium and tungsten, are at the top of the British Geological Society’s 2012 list of economically important metals that are at risk of supply disruption
The PGMs, along with the rare earth metals, niobium and tungsten, are at the top of the British Geological Society’s 2012 list of economically important metals that are at risk of supply disruption. Factors influencing the determination included their restricted reserve distribution combined with relatively low political stability ratings for some major producing countries, low rates of recycling and limited substitutes. Human factors such as geopolitics and resource nationalism, as well as events such as strikes and accidents are noted as most likely to disrupt supply.
Consequently there is great interest in finding industrially practical alternatives to ‘conventional’ transition-metal catalysts, but the task is not easy. To be sustainable, much more than the metal centre must be considered. A truly ‘green’ catalyst must mediate the desired transformation selectively in high yield with high atom economy, minimal use of solvent, heating/cooling and downstream processing and be complete in a timeframe reasonable for industrial production.
Alternative 1: Synthetic biology
Advances in the development and commercialisation of many different types of enzymes capable of numerous, highly selective organic transformations have opened the possibility of performing multiple biocatalysed reactions in one pot for the synthesis of complex inter-mediates and APIs. The longer-term goal is to achieve the reactions inside cells, rather than in reactors.
Because enzyme-catalysed reactions typically proceed with very high efficiencies and stereo- and regio-selectivities, synthetic biology offers the opportunity to develop synthetic routes with fewer steps that have limited or no requirements for hazardous reagents and proceed under mild conditions with high enantioselectivity and atom economy. In such systems, multiple enzymes work simultaneously and/or sequentially to selectively produce chiral compounds.
Synthetic biology offers the opportunity to develop synthetic routes with fewer steps that have limited or no requirements for hazardous reagents and proceed under mild conditions with high enantioselectivity and atom economy
Synthetic biology is not yet widely practised in industry. Single-step biocatalytic reactions are much more common, and even they are still used to produce only a small fraction of pharma intermediates and APIs. The challenge is to develop more types of enzymes that are robust and produced in quantities suitable for commercial-scale synthesis. Progress is being made, however, as more data on genomic sequences and enzyme structures become available.
One example of an industrial multi-enzyme system was developed by ChiroTech. An engineered N-acetyl amino acid racemase that catalyses the racemisation of many N-acetyl amino acids is combined with an L- or D-acylase enzyme to achieve the dynamic kinetic resolution of non-natural α-amino acids with enantiomeric purities typically near 99%. In a second case, John Ward of University College London has shown that transketolases and transaminases can be used in a cascade to produce chiral amino diols, and by carrying the different enzymes, all four enantiomers of these ketodiols can be made.
Xi Chen at the University of California-Davis has developed one-pot multi-enzyme (OPME) approaches for the synthesis of carbohydrates with post-glycosylational modifications (PGMs) and non-naturally modified carbohydrate derivatives. For instance, her group applied a one-pot, three-enzyme system for the synthesis of structurally defined fucose-containing oligosaccharides, which have been shown to have important biological functions, from free L-fucose.
Down the road, scientists hope to be able to develop engineered, whole-cell biocatalysts that operate via complete and complex biosynthetic pathways
Chen’s group also achieved the synthesis of structurally defined naturally and non-naturally occurring sialosides using a one-pot, three-enzyme method based on bacterial enzymes that tolerate a wide range of substrates. Sialosides are typically found as the terminal carbohydrate units on glycoproteins and glycolipids and directly affect numerous important physiological processes. They are difficult to synthesise on a large scale, however, because the anomeric carbon is sterically hindered and has reduced reactivity towards glycosylation, and there is no close neighbouring group that can efficiently direct the stereochemistry of the reaction. Chen’s method enables the synthesis of a wider variety of sialosides from inexpensive starting materials under mild conditions.
Down the road, scientists hope to be able to develop engineered, whole-cell biocatalysts that operate via complete and complex biosynthetic pathways for the production of desired end products at high concentrations. Permeablised whole cells expressing multiple recombinant enzymes have, in fact, been used as catalysts for organic synthesis. Of course, engineered micro-organisms (yeast, bacteria, fungi) are currently used for the production of protein therapeutics.
Alternative 2: Abundant Metal Catalysts
Rather than use enzymes directly, Robert Morris at the University of Toronto has developed ‘metal-ligand bifunctional catalysts’ that mimic the behaviour of enzymes. In these catalysts, which are based on the very abundant metal iron, the ligand and metal both play an active role in the catalytic cycle, and with the right choice of ligands, the electro-negativity of the Fe centre can be adjusted such that it is close to that of carbon and thus able to form covalent bonds, particularly iron-hydrogen bonds. As a result, carbon monoxide, which usually poisons catalysts due to very tight binding, is a required ligand in these systems, as is the case for hydrogenases.
The catalysts are effective at very low loadings for the asymmetric transfer hydrogenation (ATH) of ketones, and can be simply prepared via the self assembly of relatively inexpensive diamines and phosphine aldehydes, which is promoted by the metal through a template effect. The imines that are formed bind to the metal. Importantly for pharmaceutical applications, the iron can be readily oxidised upon exposure to air and then precipitated, allowing for simple purification. Numerous other applications of the catalyst are being explored, including direct hydrogenation under a mild H2 pressure and the kinetic resolution of racemic alcohols.
Paul Chirik at Princeton University is also developing alternative catalysts based on abundant metals, particularly cobalt and iron. His cobalt asymmetric hydrogenation catalysts, which are formed using very simple and inexpensive chiral amine ligands, do not proceed via two-point substrate binding (required by precious metal catalysts) to achieve high enantioselectivities. The result of a collaboration with Merck that included high-throughput experiments, the cobalt catalysts are effective for the hydrogenation of both functionalised and unfunctionalised olefins in high yield and high enantiomeric excess.
Fe catalysts developed by Chirik’s group mediate both inter- and intra-molecular [2π + 2π] reactions of alkenes and alkynes to form cyclobutenes. Notably, the system is effective for unactivated olefins and is also selective for the 2+2 cycloaddition even in the presence of a diene that can undergo Diels-Alder (4+2) cycloadditions. Such selectivity is unique to iron and results from its ability to engage in radical chemistry with the supporting ligand.
There are many examples of interesting reactions mediated by catalysts based on abundant metals
Researchers in the Baran laboratory at The Scripps Research Institute (TSRI) developed an Fe-mediated reaction for the coupling of heteroatom-substituted olefins with electron-deficient olefins to construct highly substituted and uniquely functionalised C–C bonds. The reaction is run in ethanol open to the atmosphere and tolerates numerous functional groups. To demonstrate its scope, the researchers prepared more than 60 compounds, the vast majority of which are new chemical entities.
There are many other examples of interesting reactions mediated by catalysts based on abundant metals. Robin Bedford at the University of Bristol has developed Negishi and Suzuki coupling reactions catalysed by Fe systems with the simple, inexpensive, bis(diphenylphosphino)ethane (dppe) ligand. Patrick L. Holland at the University of Rochester has developed special bidentate ligands that can be used to form Fe(III) NR complexes that oxidise hydrocarbons and transfer the NR group to organic substrates.
Very recently, students in the Grubbs and Stoltz groups at the California Institute of Technology stumbled on a dehydrogenative heteroaromatic C–H silylation reaction catalysed by the common base potassium tert-butoxide (KOtBu). Not only is the reaction novel; it is also catalysed by an inexpensive, commercially available substance based on potassium, which is an abundant alkali metal. The reaction proceeds under mild conditions, has no complicated byproducts, the product is readily isolated, and in many cases no solvent is required. In addition, many different functional groups are tolerated and the process is scalable. In fact, the researchers silylated different APIs in reasonable yields with high chemo- and regioselectivity, demonstrating that the reaction has potential use for late-stage modification of pharma compounds.
Alternative 3: Organocatalysts
Organocatalysts have been widely investigated for many years, and numerous transformations have been reported. Typical examples include prolines and derivatives, amino acids, cinchona alkaloids, chiral phosphoric acids and chiral diols, among others.
Organocatalysts have been widely investigated for many years, and numerous transformations have been reported
One recent example from the Hoveyda group at Boston College is a metal-free route to enantiomerically pure amines and alcohols. Inexpensive, easily prepared derivatives of the amino acid valine serve as catalysts for the reaction of a wide range of readily available unsaturated organoboron reagents with imines and carbonyl compounds. The reactions are typically complete in six hours, require low catalyst loadings, and provide high yields and enantio-selectivities.
Very recently, Donglin Jiang of the National Institutes of Natural Sciences in Japan developed crystalline porous covalent organic frameworks (COFs) and converted them to chiral catalysts by appending chiral centres and catalytically active sites to the channel walls. These organocatalysts were then used for asymmetric C–C bond formation in water under ambient conditions.
Dr Challener has provided technical writing and editing services to the chemical, pharmaceutical, and allied industries for more than 15 years, supporting corporate clients, trade associations, public relations firms and research organisations, including Nice Insight.
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