Abstract
Homogenous transition metal-catalyzed reactions have become a mainstay in organic synthesis and are frequently employed in the discovery and manufacture of modern pharmaceutical compounds. Due to the complex, multi-variant nature of these transformations, the pharmaceutical industry primarily relies on parallel experimentation, such as high-throughput (HTP) screening and design of experiments approaches, to identify and optimize conditions for metal-mediated reactions. Although useful for rapid reaction development, these methods have limitations and may fail to provide critical data for the successful scale-up and implementation of these complex multi-step processes. Due to these limitations, it may be necessary to also evaluate a fundamental mechanism-focused approach towards reaction development. In this article, we review several important lessons from our laboratories at Bristol-Myers Squibb where a combination of HTP screening and mechanistic understanding revealed new insights into known catalytic transformations and facilitated the development of robust, reliable catalytic processes to support the bulk production of pharmaceutical targets.
Similar content being viewed by others
Notes
In the context of a catalytic reaction in which the base stoichiometry is often two orders of magnitude greater than the catalyst amount, the adventitious water present in the base can be sufficient to promote reduction of the catalyst precursor.
References
Li J, Eastgate MD (2015) Org Biomol Chem 13:7164
Beletskaya IP, Cheprakov AV (2000)Chem Rev 100:3009
Suzuki A (2011) Angew Chem Int Ed 50:6722
Negishi E-I (2011) Angew Chem Int Ed 50:6738
Negishi E-I (2007) Bull Chem Soc Jpn 80:233
Negishi E (2002) Handbook of Organopalladium Chemistry for Organic Synthesis. Vol I, II. Wiley, New York
Busacca CA, Fandrick DR, Song JJ, Senanayake CH (2011) Adv Synth Catal 353:1825
Schneider N, Lowe DM, Sayle RA, Tarselli MA, Landrum GA (2016) J Med Chem 59:4385
Torborg C, Beller M (2009) Adv Synth Catal 351:3027
Roughley SD, Jordan AM (2011) J Med Chem 54:3451
Carey JS, Laffan D, Thomson C, Williams MT (2006) Org Biomol Chem 4:2337
Buitrago Santanilla A, Regalado EL, Pereira T, Shevlin M, Bateman K, Campeau L-C, Schneeweis J, Berritt S, Shi Z-C, Nantermet P, Liu Y, Helmy R, Welch CJ, Vachal P, Davies IW, Cernak T, Dreher SD (2015) Science 347:49
Murray PM, Tyler, SNG, Moseley JD (2013) Org Process Res Dev 17:40
Fitzgerald MA, Soltani O, Wei C, Skliar D, Zheng B, Li J, Albrecht J, Schmidt M, Mahoney M, Fox RJ, Tran K, Zhu K, Eastgate MD (2015) J Org Chem 80:6001
Carole WA, Colacot TJ (2016) Chem Eur J 22:7686
Thirupathi N, Amoroso D, Bell A, Protasiewicz JD (2007) Organometallics 26:3157
Wei CS, Davies, GHM, Soltani O, Albrecht J, Gao Q, Pathirana C, Hsiao Y, Tummala S, Eastgate MD (2013) Angew Chem Int Ed 52:5822
Grushin VV, Alper H (1993) Organometallics 12:1890
Grushin VV, Bensimon C, Alper H (1994) Inorg Chem 33:4804
Ioele M, Ortaggi G, Scarsella M, Sleiter G (1991) Polyhedron 10:2475
Rahaim RJ Jr, Maleczka RE Jr (2002) Tetrahedron Lett 43:8823
Ramanathan A, Jimenez LS (2010) Synthesis 2010:217
Ji Y, Plata RE, Regens CS, Hay M, Schmidt M, Razler T, Qiu Y, Geng P, Hsiao Y, Rosner T, Eastgate MD, Blackmond DG (2015) J Am Chem Soc 137:13272
Ozawa F, Kubo A, Hayashi T (1992) Chem Lett 21:2177
Hu J, Hirao H, Li Y, Zhou J (2013) Angew Chem Int Ed 52:8676
Hu J, Lu Y, Li Y, Zhou J (2013) Chem Commun 49:9425
Gorelsky SI, Lapointe D, Fagnou K (2008) J Am Chem Soc 130:10848
Coyle RJ, Slovokhotov YL, Antipin MY, Grushin VV (1998) Polyhedron 17:3059
Marshall WJ, Grushin VV (2003) Organometallics 22:555
Brown RG, Davidson JM (1971) J Chem Soc A 1971:1321
Bäckvall JE, Byström SE, Nordberg RE (1984) J Org Chem 49:4619
Aranyos A, Szabo KJ, Bäckvall JE (1998) J Org Chem 63:2523
Bäckvall JE, Nordberg RE (1981) J Am Chem Soc 103:4959
Eastgate MD, Buono FG (2009) Angew Chem Int Ed 48:5958
Stephenson TA, Morehouse SM, Powell AR, Heffer JP, Wilkinson G (1965) J Chem Soc 1965:3632
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Wei, C.S., Simmons, E.M., Hsaio, Y. et al. Development of Robust, Scaleable Catalytic Processes through Fundamental Understanding of Reaction Mechanisms. Top Catal 60, 620–630 (2017). https://doi.org/10.1007/s11244-017-0736-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11244-017-0736-x