Editor's Page Cite This: Organometallics 2019, 38, 1−2
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The Roles of Organometallic Chemistry in Pharmaceutical Research and Development
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Further challenges highlighted within the context of hydrogenation were “perceived difficulties with air-sensitivity and robustness on scale-up”. While such issues can be found for any complex, air- and water-sensitive reaction with multiple potential failure modes, a core mandate of process chemistry groups is the design and optimization of reactions to mitigate known problems. As catalytic technologies matured and a generation of chemists trained in these methods became practitioners in pharma, such methodologies began to be incorporated more frequently and with greater success. The same holds for other early problems identified in the commercial deployment of asymmetric hydrogenation: “expertise in screening, and efficient access to large numbers of commercially available... ligands and catalysts”. The most recent generations of graduate student and postdoctoral researchers have begun to be trained in the high-throughput experimentation (HTE) mindset, and are positioned to embrace the powerful HTE tools at their disposal in pharma. Reaction robustness and reliability are the most significant of the remaining impediments to translation of new catalytic methods from bench to process scale. New reactions are invariably developed on ideal, model substrates, devoid of the functional groups that enable many of the core properties of pharmaceuticals. Such functionalities include Lewis basic nitrogen atoms and base-sensitive functional groups and heterocyclic moieties, which commonly result in significantly poorer performance compared with published procedures.11 However, increasing pressure on resources and efficiency have provided a powerful impetus for both academic and industrial scientists to innovate. This has resulted in continued development of catalytic methods to address these challenges, in turn resulting in more reliable and robust reactions. It is unsurprising, therefore, that an analysis of methods used in medicinal chemistry today offers a dramatically different perspective than for 1984. Every month in the pharmaceutical industry, thousands of catalytic reactions are performed by chemists across the spectrum from discovery to development. Such industrial laboratories have now fully embraced catalysis, and regularly contribute to fundamental advances in the field.12 Indeed, pharmaceutical winners of the U.S. Environmental Protection Agency’s Green Chemistry Challenge Awards routinely incorporate and highlight effective and optimized catalytic steps. Catalytic cross-coupling technology, in particular, has become a staple of the pharmaceutical chemistry, owing to its efficiency, predictability, and reliability. Going forward, challenges of sustainability will continue to drive innovation and development of new reactions with the imperatives of reduced costs, reduced waste, and responsible sourcing.
he world of pharmaceutical research and development and manufacturing is facing increasing challenges of productivity, cost, and sustainability. Within the realm of smallmolecule therapeutics, synthetic chemistry plays a pivotal role in the discovery and eventual commercialization of novel active pharmaceutical agents. Innovations in chemistry have a direct impact on human health through their application to this goal. Simultaneously, advances in organometallic chemistry, and particularly advances in catalysis, are critical in aligning synthetic objectives with the urgent need to maximize efficiency in energy and materials usage. Not many years ago, however, a Special Issue of Organometallics such as that presented here, dedicated to the impact of organometallic chemistry in pharmaceutical research and development, would have been a contradiction in terms. An analysis of methods used in medicinal chemistry in 1984 reveals little to no use of catalysis in production steps. Traditional, robust condensation reactions dominate the list, while use of organometallics is limited to addition of organolithium/magnesium reagents to electrophiles.1 Highlighting the very different focus of the academic community at the time, the top-cited paper published in Organometallics that year was “Halide, Hydride, and Alkyl Derivatives of (Pentamethylcyclopentadienyl)bis(trimethylphosphine)ruthenium,” by Tilley, Grubbs, and Bercaw.2 On the horizon were changes that would bring these worlds together and create new opportunities in what was beginning to be recognized as sustainable development.3 Pioneering work on carbon−carbon bond-forming catalysis was under way,4,5 and Miyaura and Suzuki’s seminal review “Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds” would appear in 1995.6 The breakthrough technologies of asymmetric hydrogenation were already the focus of intense academic study, and the 2001 Nobel Prize in Chemistry would formalize recognition of the power of asymmetric catalysis in organic synthesis. Also just a decade off were the advances in olefin metathesis that would engender widespread adoption of these methodologies in organic synthesis.7,8 These and other ground-breaking advances in catalysis, including ligand design, rapidly transformed organic synthesis. Their adoption in pharmaceutical chemistry, however, lagged. Even for the vanguard methodology of asymmetric hydrogenation, just 10 processes were in place industry-wide by 2001.9 The barriers to uptake have received attention over the years, including in a Merck review of a decade ago,10 and it is instructive to compare these with challenges still relevant today. For example, early in the commercialization of new catalysts, the uncertainty about costs and freedom to operate can be a deterrent. As the commercial value of new innovations is clarified through real-world applications, especially within the process chemistry space where the value proposition of any given technology can be assessed with a fair degree of accuracy, this uncertainty is resolved, facilitating negotiations. © 2019 American Chemical Society
Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Published: January 14, 2019 1
DOI: 10.1021/acs.organomet.8b00918 Organometallics 2019, 38, 1−2
Organometallics
Editor's Page
Notes
This Special Issue was inspired by the fundamental roles that organometallic chemistry has played in the discovery and development of such methods. The reliable catalytic methods of today were built on a solid foundation of organometallic chemistry, uncovering new reactivity modes and ultimately changing how synthetic organic chemists think about making molecules. The past 40 years have seen a democratization of such methods beyond specialist laboratories, enabling their uptake in real-world applications. While medicinal and process chemists working in pharma and practicing organometallic chemists still do not routinely associate with one another, the papers in this Special Issue show how this is beginning to change. This issue features 18 contributions across academia and the pharmaceutical industry. It offers 4 review articles aimed at connecting innovations in each field, as well as covering the latest developments for reactions of interest to both communities. The topics range from mechanistic investigation of new reactions (DOI: 10.1021/acs.organomet.8b00543, Lehnherr et al.) and organometallic complexes (DOI: 10. 1021/acs.organomet.8b00516, Chirik et al.), to a number of new developments in catalyst design and optimization. This issue highlights the application of both catalytic methodologies and stoichiometric organometallic complexes to new synthetic strategies, with the common goal being construction of molecules of significance to the pharmaceutical sector. It also reflects the desire to expand the toolkit of reactions built on more sustainable base-metal reactions. Finally, given the regulatory landscape, pharmaceutical scientists are also tasked with removal of trace metals from final active pharmaceutical ingredients. A further paper highlights the challenges arising from metal speciation in these efforts, and analytical solutions that can be leveraged (DOI: 10.1021/acs.organomet.8b00638, Jo and Bu et al.). With this Special Issue, we seek to further connect the pharmaceutical and academic communities in catalysis, and to inspire new developments and applications of organometallic chemistry and catalysis in the pharmaceutical industry. We hope to promote cross-fertilization of ideas and practices, and to give researchers in academia−including younger practitioners who represent the leading talent of tomorrow−a window onto a fertile area of industrial innovation, and a perspective on needs and challenges that emerge further down the innovation pipeline. We believe that many will embrace this most inspiring of goals: improving human health while reducing the environmental footprint of pharmaceutical manufacturing.
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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Louis-Charles Campeau*,‡ Deryn E. Fogg*,† ‡
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REFERENCES
(1) Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458. (2) Tilley, T. D.; Grubbs, R. H.; Bercaw, J. E. Halide, Hydride, and Alkyl Derivatives of (Pentamethylcyclopentadienyl) bis(trimethylphosphine)ruthenium. Organometallics 1984, 3, 274−278. (3) Keeble, B. R. The Brundtland report: ‘Our Common Future’. Medicine and War 1988, 4, 17−25. (4) Mizoroki, T.; Mori, K.; Ozaki, A. Arylation of Olefin with Aryl Iodide Catalyzed by Palladium. Bull. Chem. Soc. Jpn. 1971, 44, 581. (5) Heck, R. F.; Nolley, J. P. Palladium-Catalyzed Vinylic Hydrogen Substitution Reactions with Aryl, Benzyl, and Styryl Halides. J. Org. Chem. 1972, 37, 2320−2322. (6) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457− 2483. (7) Fu, G. C.; Grubbs, R. H. The Synthesis of Nitrogen Heterocycles via Catalytic Ring-Closing Metathesis of Dienes. J. Am. Chem. Soc. 1992, 114, 7324−7325. (8) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. A Series of Well-Defined Metathesis Catalysts - Synthesis of RuCl2(CHR′)(PR3)2 and Their Reactions. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039−2041. (9) Blaser, H.-U.; Spindler, F.; Studer, M. Enantioselective Catalysis in Fine Chemicals Production. Appl. Catal., A 2001, 221, 119−143. (10) Shultz, C. S.; Krska, S. W. Unlocking the Potential of Asymmetric Hydrogenation at Merck. Acc. Chem. Res. 2007, 40, 1320−1326. (11) Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.; DiRocco, D. A.; Streckfuss, E. C.; Campeau, L.-C.; Cernak, T.; Vachal, P.; Davies, I. W.; Krska, S. W.; Dreher, S. D. Chemistry Informer Libraries: A Chemoinformatics Enabled Approach to Evaluate and Advance Synthetic Methods. Chem. Sci. 2016, 7, 2604−2613. (12) (a) Li, B. X.; Le, D. N.; Mack, K. A.; McClory, A.; Lim, N.-K.; Cravillion, T.; Savage, S.; Han, C.; Collum, D. B.; Zhang, H.; Gosselin, F. Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki−Miyaura Coupling. J. Am. Chem. Soc. 2017, 139, 10777−10783. (b) Friedfeld, M. R.; Zhong, H.; Ruck, R. T.; Shevlin, M.; Chirik, P. J. CobaltCatalyzed Asymmetric Hydrogenation of Enamides Enabled by Single-Electron Reduction. Science 2018, 360, 888−893. (c) Merchant, R. R.; Edwards, J. T.; Qin, T.; Kruszyk, M. M.; Bi, C.; Che, G.; Bao, D.-H.; Qiao, W.; Sun, L.; Collins, M. R.; et al. Modular Radical CrossCoupling with Sulfones Enables Access to sp3-Rich (Fluoro)alkylated Scaffolds. Science 2018, 360, 75−80. (d) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-L.; et al. Decarboxylative Alkenylation. Nature 2017, 545, 213−218. (e) Buitrago-Santanilla, A.; Regalado, E. L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L.C.; Schneeweis, J.; Berritt, S.; Shi, Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Davies, I. W.; Cernak, T.; Dreher, S. D. Nanomole-Scale High-Throughput Chemistry for the Synthesis of Complex Molecules. Science 2015, 347, 49−53. (f) Perry, I. B.; Brewer, T. F.; Sarver, P. J.; Schultz, D. M.; DiRocco, D. A.; MacMillan, D. W. C. Direct Arylation of Strong Aliphatic C−H Bonds. Nature 2018, 560, 70−75.
Department of Process Research and Development, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, United States † Centre for Catalysis Research & Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N 6N5 Ontario, Canada
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AUTHOR INFORMATION
EDITOR'S NOTE Views expressed in this editorial are those of the authors and not necessarily the views of ACS.
Corresponding Author
*E-mail:
[email protected]. ORCID
Deryn E. Fogg: 0000-0002-4528-1139 2
DOI: 10.1021/acs.organomet.8b00918 Organometallics 2019, 38, 1−2
