Advances in catalysis have had a tremendous impact on the pharmaceutical industry, enabling the synthesis of highly complex small-molecule intermediates and APIs in fewer steps, with increased atom economy, and often with high selectivities and yields. There are issues with many of the most widely used catalytic systems, however, including the cost, availability, and toxicity of many of the precious metals used to form the catalysts and the need for expensive and complex ligands to achieve the desired transformations. There has been much interest, therefore, in the development of alternative catalysts derived from abundant, nontoxic metals and simple ligand systems. New base metal catalyst platforms are also of interest because they may enable new chemistry not previously observed with traditional precious metal catalysts. Select examples with potential applications in pharmaceutical synthesis are discussed below.
Availability of supply
There is a finite supply of metals in the Earth’s crust, and humans are consuming many of them at an ever-increasing rate. As a result, the availability of certain transition metals for use in the production of catalysts is becoming increasingly limited due to growing demand for these materials in other applications, including the newer organic light emitting diode displays in smart phones and televisions and renewable energy systems, such as fuel cells, wind energy, and photovoltaics.
In fact, in 2012, the British Geological Survey updated its risk list for the supply of chemical elements or element groups that are of importance to human society (1). The availability of each element was determined by considering its abundance in the Earth’s crust, the location of current production and reserves, the political stability of those locations, and the recycling rate and substitutability of the element. The rankings give an indication of which elements might be subject to supply disruption, most likely from human factors such as geopolitics or resource nationalism, along with events such as strikes and accidents. At the top of the list with the highest risk of supply disruption are the rare earths, platinum group metals, niobium, and tungsten. It should be noted that the demand for the elements (outside of their substitutability) was not considered in this analysis.
The platinum group metals are of particular interest to the pharmaceutical industry, because many important catalysts rely on platinum, palladium, ruthenium, rhodium, iridium, and osmium. These metals are expensive and experience high price volatility. The price of platinum, for example, ranged from $1400-$1500/ounce in March 2014, and has varied more than 5-fold in the last few years, according to Paul Chirik, the Edward S. Sanford Professor of Chemistry at Princeton University. With respect to platinum supply, he notes that the amount of platinum produced each year is only approximately 6% of the quantity of gold mined annually.
Some researchers are raising the question of whether or not a reaction can truly be considered sustainable if such rare (and at times toxic) metals are required. According to Amir Hoveyda, Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College, even if a transformation is otherwise green (i.e. minimal/no solvent, high atom economy, no need for heating/cooling, little downstream processing requirements), it can’t be realistically considered as sustainable if a catalyst based on a rare transition metal is required. Hoveyda also notes that to be industrially practical, reactions must proceed in a reasonable period of time, ideally within six to eight hours, and catalysts must provide high selectivities and high yields.
Alternative to copper
One reaction that Hoveyda has focused on is the copper-catalyzed synthesis of enantiomerically enriched homoallylic amines and alcohols, which are important intermediates for the preparation of many different biologically active molecules. As an alternative, his group has developed a transition metal-free route to enantiomerically pure amines and alcohols with inexpensive, easily prepared derivatives of the amino acid valine as catalysts for the reaction of a wide range of readily available unsaturated organoboron reagents with imines and carbonyls. In addition to not requiring any rare transition metal salts, the reactions are generally complete in six hours, require low catalyst loadings, and provide high yields and enantioselectivities. The effectiveness of this new set of catalytic reactions, according to Hoveyda, is due to the use of a proton and internal hydrogen bonding.
New approach to hydrogenation
Chirik, meanwhile, is developing alternative catalysts based on cobalt and iron, which are far more abundant than the precious metals. In addition, while most precious metal catalysts require two-point substrate binding for inducing high levels of enantioselectivity in asymmetric hydrogenation, because iron and cobalt are a new catalyst type, they have yet to exhibit this limitation, he points out. For example, Chirik’s cobalt asymmetric hydrogenation catalysts formed using simple and inexpensive chiral amine ligands are relevant to the pharmaceutical industry. In fact, Chirik developed the catalysts through a collaboration with Merck & Co. that included high-throughput experiments. Notably, the cobalt catalysts are effective for the hydrogenation of both functionalized and unfunctionalized olefins in high yield and high enantiomeric excess.
In a second example, Chirik’s group has developed iron catalysts that mediate both inter- and intramolecular [2π + 2π] reactions of alkenes and alkynes to form cyclobutenes. What is interesting about this system is that it is effective for unactivated olefins and is also selective for 2+2 cycloaddition even in the presence of a diene that can undergo Diels-Alder (4+2) cycloadditions. According to Chirik, such selectivity is unique to iron and results from its ability to engage in radical chemistry with the supporting ligand.
Learning from bacteria
A third strategy for the development of alternative catalysts involves mimicking the behavior of enzymes. Such research is being performed by Robert Morris, a professor at the University of Toronto, who has developed new iron catalysts that perform what he calls “metal-ligand bifunctional catalysis,” in which the ligand and metal both play an active role in the catalytic cycle. Notably, he has shown that with the right choice of ligands, the electronegativity of the iron center can be adjusted such that it is close to that of carbon and thus able to form covalent bonds, particularly iron-hydrogen bonds. Surprisingly, carbon monoxide, which is often a poison to catalysts, is a required ligand as it is for nature’s hydrogenases.
Such catalysts are effective for the asymmetric transfer hydrogenation (ATH) of ketones and can be simply prepared from relatively inexpensive diamines and phosphine aldehydes, which self-assemble (promoted by the metal through a template effect) to form imines that bind to the metal. Morris notes that the catalyst is effective at low loadings and the iron can be readily oxidized upon exposure to air and then precipitated, allowing for simple purification. A third-generation family of these iron-based catalysts was reported in 2013 and should be available for purchase soon (2). These catalysts are more active than any known catalyst for ATH and as selective as more expensive conventional ruthenium-based systems.
The catalyst may also be applicable for direct hydrogenation under a mild hydrogen pressure, and the reverse of the asymmetric transfer hydrogenation reaction may be useful for the kinetic resolution of racemic alcohols.
Tackling coupling reactions
Carbon-carbon coupling reactions have become widely used in organic synthesis, including the commercial manufacture of numerous pharmaceutical building blocks and key intermediates. Robin Bedford, professor of catalysis at the University of Bristol, has been investigating the potential for using iron catalysts to mediate these important transformations. In the past, coupling reactions involving iron have generally been Grignard reactions of “hard” nucleophiles. Bedford wanted to expand the repertoire to other “softer” nucleophiles (e.g., zinc) that are used in coupling reactions catalyzed by platinum and palladium.
What his group found was that the choice of ligand was crucial for creating iron catalysts that are effective for both the Negishi coupling of benzyl halides and phosphates with diarylzinc reagents and Suzuki couplings of arylboronates with alkyl and allyl halides and 2-halopyridines. Most importantly, the best ligand is the simple, inexpensive, bis(diphenylphosphino)ethane (dppe) ligand. The key, according to Bedford, is to prepare the catalyst in the correct manner. “One of the important lessons we learned in this work was that it is important to understand the identity and role of the active catalytic species and how ligands interact with iron in order to generate the desired species,” Bedford states.
The need for unconventional wisdom
Iron is not generally thought of as a good metal for the preparation of catalysts because of its electronic structure. Platinum group metals, which are heavier metals with no unpaired electrons, have always been thought to form stronger bonds with ligands, according to Patrick L. Holland, a professor of chemistry at the University of Rochester. On the contrary, his group has shown that complexes based on metals with unpaired electrons can follow similar reaction mechanisms, and often do so more rapidly, as long as a balance is maintained between the weakness and activity of the ligand-metal bonds.
Holland has developed special bidentate ligands that are designed to afford the high-spin electronic configuration in complexes with first-row metals. For example, his group has developed an iron(III) imido complex that oxidizes hydrocarbons and transfers a nitrene (NR) group to organic substrates.
“We believe that properly designed complexes of iron and other first-row metals can serve not only as alternatives to transition metal catalysts for the mediation of established reactions; given their unusual reactivity, they may also provide access to novel transformations,” observes Holland.
1. British Geological Survey, “Risk list 2012: An updated supply risk index for chemical elements or element groups which are of economic value,” Accessed Apr. 10, 2014.
2. W. Zuo et al., Science, 342 (6162), 1080-1083 (2013).
About the Author
Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.