Editorial Cite This: J. Org. Chem. 2019, 84, 4577−4579
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Excellence in Industrial Organic Synthesis 2019: The Past, Present, and Future • Richard Schrock (Nobel 2005) for his work on olefin metathesis, including early studies of tantalum alkylidenes performed at DuPont.7 • Richard Heck (Nobel 2010) for palladium-catalyzed cross couplings in organic synthesis, initial studies performed at Hercules.8,9 • William Campbell (Nobel 2015), awarded in Physiology or Medicine, for the discovery of the avermectins (e.g., ivermectin), work done at Merck & Co., Inc., Kenilworth, NJ, USA.10 Antibiotic resistance is a significant health challenge,11−13 and industrial scientists have played a key role in the discovery and development of novel antibiotics. A noteworthy example is the antibiotic vancomycin, discovered by scientists at Eli Lilly and Company.14 Beyond its significant clinical benefits, this structurally novel glycopeptide has inspired important research advances in analytical chemistry,15 biosynthesis,16 and atropisomer stereocontrol in total synthesis.17,18 A particularly compelling example of high-impact research arising from industry is found in the area of steroid synthesis, in which several pharmaceutical companies played key roles,19−21 particularly Syntex22,23 and the Upjohn Company.24 Research in semisynthetic steroids led directly to one of the most impactful contributions of organic synthesis to humankind, the discovery of synthetic steroids to control human reproduction (e.g., the combination of mestranol and norethynodrel, marketed as Enovid by G. D. Searle, approved for oral contraception in 1960). A recent perspective article presents a compelling case for steroid research as a lynchpin for advances in the field of organic chemistry throughout the mid to late 20th century.25 Examples include synthetic methods (e.g., the Robinson annulation), organocatalysis, conformational analysis, stereoelectronic effects, biomimetic synthesis, C−H bond activation, and biocatalysis.26 The development of anti-HIV protease inhibitors is another area where important advances in process chemistry were realized. Several areas of science had to be leveraged to meet the extremely large demand for clinical supplies within very aggressive timelines.27 These challenges tested the limits of synthetic methods, catalysis, and control of chirality. Perhaps just as important, this endeavor led to new paradigms for process development based on “quality by design”. These included the increased use of in situ reaction monitoring and process analytical tools (PAT) for the rapid progression of a laboratory-scale synthesis to a robust commercial process. It may be argued that pharmaceutical process research laboratories led the way in a data-rich revolution that has since reached academic organic chemistry laboratories.
It is our pleasure and honor to serve as guest editors of this Special Issue, “Excellence in Industrial Organic Synthesis, 2019”. We are delighted with the variety and high quality of contributions to this volume, and we hope it will represent the first in a series of many such updates from the industrial organic chemistry community. While the pharmaceutical industry is an important member of this community, as reflected by the affiliations of the two guest editors, we recognize the impact and importance of organic chemistry in a much wider range of industrial applications and are pleased that this issue contains several such contributions. We are particularly pleased that Kai Rossen, the editor-inchief of the ACS journal Organic Process Research & Development, provided an invited Perspective for this issue. Kai describes the role of Green Chemistry in industrial chemistry, and the importance of assessing the entire, holistic “greenness” of a process, rather than just a select few steps in the route. While this special issue of The Journal of Organic Chemistry has been successful in collecting several important contributions, and it will hopefully be the first in a series of such compilations, Kai also makes the very important point that a continuously published journal for publications in this area is necessary. This role has been well served since 1997 by Organic Process Research & Development. For this introduction, we begin with a review of past accomplishments. We then move to a review of the current state of the art, as reflected in the contributions in the current issue. Finally, a perspective on possible future directions and advancements is provided.
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THE PAST Perhaps the most straightforward exemplification of excellence in industrial organic chemistry can be found by reviewing Nobel Prizes in Chemistry, which in several cases have been awarded to scientists who performed a significant portion of the recognized research in industry (in this context, it is also worth noting that Alfred Nobel was himself a highly productive industrial chemist). Eight examples are listed below: • Carl Bosch (Nobel 1931), for high pressure methods in the production of ammonia and ammonium nitrate (Haber− Bosch process), work done at I. G. Farbenindustrie.1 • Irving Langmuir (Nobel 1932) for studies in surface chemistry and electronic theory of organic chemistry, work done at General Electric.2 • Charles Pedersen (Nobel 1987) for the development and use of molecules with structure-specific interactions of high selectivity, work done at DuPont.3 • William Knowles (Nobel 2001) for the development of asymmetric catalytic hydrogenation reactions, work done at Monsanto.4,5 • Koichi Tanaka (Nobel 2002) for development of soft laser desorption methods for mass spectrometry of biomolecules, work done at Shimadzu.6 © 2019 American Chemical Society
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THE PRESENT This Special Issue of The Journal of Organic Chemistry contains 40 publications from 14 different countries and over 40 different Special Issue: Excellence in Industrial Organic Synthesis 2019 Published: April 19, 2019 4577
DOI: 10.1021/acs.joc.9b00847 J. Org. Chem. 2019, 84, 4577−4579
The Journal of Organic Chemistry
Editorial
It is a bright time to be a synthetic chemist, with tremendous room to learn and to innovate and many important unsolved problems waiting for creative synthetic efforts. Applied industrial synthesis will continue to grow and evolve, and The Journal of Organic Chemistry looks forward to celebrating the progress!
organizations. Collaborative research features prominently, with 16 publications; the majority of these are academic−industrial collaborations (10). Research focused on the discovery and development of small molecule drugs is represented in 22 of the publications. Synthetic methods relevant to these types of projects are featured prominently, including metal-catalyzed cross couplings (11), C−H activation (4), and chiral catalysis, including biocatalysis (5). Application of newer technologies such as flow chemistry/continuous manufacturing (5) and computational modeling and machine learning (4) are also well represented. We are particularly pleased to have perspectives from several leading figures at research-based industrial organizations, as summarized below. • “Greening Organic Chemistry with Process Chemistry” (Rossen, K. J. Org. Chem. 2019, 84, DOI: 10.1021/ acs.joc.9b00344). • “Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry” (Caille, S.; Cui, S.; Faul, M. M.; Mennen, S.; Tedrow, J. S.; Walker, S. D. J. Org. Chem. 2019, 84, DOI: 10.1021/acs.joc.9b00735). • “Tackling Challenges in Industrially Relevant Homogeneous Catalysis: The Catalysis Research Laboratory (CaRLa), an Industrial−Academic Partnership” (Schaub, T.; Hashmi, A.S.; Paciello, R. J. Org. Chem. 2019, 84, DOI: 10.1021/acs.joc.8b02362). • “Sustainability Challenges in Peptide Synthesis and Purification: from R&D to Production” (Isidro-Llobet, A.; Kenworthy, J.; Mukherjee, S.; Kopach, M.; Wegner, K.; Gallou, F.; Smith, A.; Roschangar, F. J. Org. Chem. 2019, 84, DOI: 10.1021/acs.joc.8b03001).
John A. Ragan
Chemical Research & Development, Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
Spencer D. Dreher
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Discovery Chemistry Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. Biographies
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THE FUTURE The demand for excellence in industrial synthesis will only accelerate from this point forward. There is a tremendous amount changing in and around the chemistry eco-system that will present new opportunities and will necessitate new ways of thinking about chemistry. Evolving and concomitant societal pressures, including increased competition, increasingly difficult biological targets, rising standards for safety and efficacy in new medicines, and a “greening” of industrial processes married with a continuous drive to cut R&D costs will push industrial synthetic chemists to invent new ways to work better with less. High-tech revolutions in adjoining scientific fields like genetics, computation/informatics, and biological screening will present continuous new opportunities to generate more information more quickly in the preparation, evaluation, and design of new molecules. Holistic solutions in biology will require evaluation of all types of molecules, both traditional small molecules as well as large biomolecules, and synthetic chemists will need to be comfortable moving back and forth into the synthesis of alternate modalities. New synthesis tools that can miniaturize and parallelize synthetic efforts and increasingly fast reaction analytics will redefine what a chemist can accomplish in a day’s work. Big-data chemistry is on the horizon, and robots and machine-learning algorithms will increasingly help guide synthetic chemists through the toughest synthesis problems. And, of course, chemists will continue to invent new synthetic paradigms that can evolve the types of structures that can be efficiently prepared. Biocatalysis and photoredox catalysis, for example, have positively impacted what we can make today, and innovative new synthetic paradigms will continuously emerge, challenging chemists to incorporate these new approaches into their synthesis planning.
John Ragan is a Research Fellow in Chemical Research & Development at Pfizer in Groton, CT. He studied organic synthesis with Rick Danheiser (undergrad), Stuart Schreiber (Ph.D.), and Clayton Heathcock (postdoc) before joining Pfizer in 1992. In the process group at Pfizer, he has worked on both early- and late-stage development programs in multiple therapeutic areas. He recently led the team that developed and filed the commercial synthesis of the SGLT2 inhibitor ertugliflozin. He currently serves on the Editorial Advisory Board of The Journal of Organic Chemistry.
Spencer Dreher is a Principle Scientist in the Chemistry Capabilities Accelerating Therapeutics group within Discovery Chemistry at Merck 4578
DOI: 10.1021/acs.joc.9b00847 J. Org. Chem. 2019, 84, 4577−4579
The Journal of Organic Chemistry
Editorial
(21) Colton, F. B. Steroids and ″the pill″: early steroid research at Searle. Steroids 1992, 57 (12), 624−30. (22) Zaffaroni, A. From paper chromatography to drug discovery: Zaffaroni. Steroids 1992, 57 (12), 642−8. (23) Djerassi, C. Steroid research at Syntex: ″the pill″ and cortisone. Steroids 1992, 57 (12), 631−41. (24) Hogg, J. A. Steroids, the steroid community, and Upjohn in perspective: a profile of innovation. Steroids 1992, 57 (12), 593−616. (25) Denmark, S. E. Organic Synthesis: Wherefrom and Whither? (Some Very Personal Reflections). Isr. J. Chem. 2018, 58 (1−2), 61−72. (26) We acknowledge Professor Scott Denmark for his insights and suggestions regarding the role of industrial chemists in the development of synthetic steroids. (27) Cohen, J. Drug Development: Protease Inhibitors: A Tale of Two Companies. Science 1996, 272 (5270), 1882.
in Kenilworth, NJ. Previously, he spent 15 years in Process Chemistry and was a member of the Catalysis and Automation group, acquiring an expertise in high-throughput experimentation chemistry reaction discovery and development. He studied at Macalester College (B.S.) and Columbia University with Tom Katz (Ph.D) and Jim Leighton (postdoc). He currently serves on the Editorial Advisory Board of The Journal of Organic Chemistry.
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REFERENCES
(1) https://www.nobelprize.org/prizes/chemistry/1931/bosch/ biographical/. (2) Langmuir, I. The Arrangement of Electrons in Atoms and Molecules. J. Am. Chem. Soc. 1919, 41 (6), 868−934. (3) Pedersen, C. J. Cyclic polyethers and their complexes with metal salts. J. Am. Chem. Soc. 1967, 89 (26), 7017−7036. (4) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D.; Weinkauff, D. J. Asymmetric hydrogenation with a complex of rhodium and a chiral bisphosphine. J. Am. Chem. Soc. 1975, 97 (9), 2567−2568. (5) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. Asymmetric hydrogenation. Rhodium chiral bisphosphine catalyst. J. Am. Chem. Soc. 1977, 99 (18), 5946−5952. (6) Tanaka, K.; Waki, H.; Ido, Y.; Akita, S.; Yoshida, Y.; Yohida, T. Protein and polymer analyses up to m/z 100,000 by laser ionization time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom. 1988, 2 (8), 151−153. (7) Schrock, R. R. Multiple Metal−Carbon Bonds for Catalytic Metathesis Reactions (Nobel Lecture). Angew. Chem., Int. Ed. 2006, 45 (23), 3748−3759. (8) Heck, R. F. Acylation, methylation, and carboxyalkylation of olefins by Group VIII metal derivatives. J. Am. Chem. Soc. 1968, 90 (20), 5518−5526. (9) Heck, R. F.; Nolley, J. P. Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides. J. Org. Chem. 1972, 37 (14), 2320−2322. (10) Chabala, J. C.; Mrozik, H.; Tolman, R. L.; Eskola, P.; Lusi, A.; Peterson, L. H.; Woods, M. F.; Fisher, M. H.; Campbell, W. C.; et al. Ivermectin, a new broad-spectrum antiparasitic agent. J. Med. Chem. 1980, 23 (10), 1134−1136. (11) Council, N. R. Technological Challenges in Antibiotic Discovery and Development: A Workshop Summary; The National Academies Press: Washington, DC, 2014; p 48. (12) Tatsuta, K. Reconfirmation of “Art” in Organic Synthesis. J. Org. Chem. 2018, 83 (13), 6825−6825. (13) Movassaghi, M.; van der Donk, W. A. Synthesis of Antibiotics and Related Molecules. J. Org. Chem. 2018, 83 (13), 6826−6828. (14) Nagarajan, R. Structure-activity relationships of vancomycin-type glycopeptide antibiotics. J. Antibiot. 1993, 46 (8), 1181−95. (15) Strege, M. A. Hydrophilic Interaction Chromatography-Electrospray Mass Spectrometry Analysis of Polar Compounds for Natural Product Drug Discovery. Anal. Chem. 1998, 70 (13), 2439−2445. (16) Hubbard, B. K.; Walsh, C. T. Vancomycin assembly: nature’s way. Angew. Chem., Int. Ed. 2003, 42 (7), 730−765. (17) Okano, A.; Isley, N. A.; Boger, D. L. Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues. Chem. Rev. 2017, 117 (18), 11952−11993. (18) Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Nonconventional stereochemical issues in the design of the synthesis of the vancomycin antibiotics: challenges imposed by axial and nonplanar chiral elements in the heptapeptide aglycons. Angew. Chem., Int. Ed. 1998, 37 (19), 2704−2708. (19) Hirschmann, R. The cortisone era: aspects of its impact. Some contributions of the Merck Laboratories. Steroids 1992, 57 (12), 579− 92. (20) Herzog, H.; Oliveto, E. P. A history of significant steroid discoveries and developments originating at the Schering Corporation (USA) since 1948. Steroids 1992, 57 (12), 617−23. 4579
DOI: 10.1021/acs.joc.9b00847 J. Org. Chem. 2019, 84, 4577−4579
