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Contributed by Thomas Bishop, Senior Scientist at AstraZeneca; Paul Richardson, Director at Pfizer; and the members of the Reagent Guides Focus Team*
While many of the reagents currently utilized in organic synthesis have been known for many years, the continuing trend to develop more sustainable approaches to prospective biologically active APIs has led to a paradigm shift in not only incentivizing the discovery of new reagents but also in leveraging innovative platform technologies to enable the assembly of molecules of interest under environmentally benign conditions. In addition to this, the landscape of FDA-approved pharmaceuticals continues to evolve specifically regarding the different modalities employed thus vastly expanding the substrate scope of molecular entities that need to be investigated and efficiently accessed.
Providing new tools for both educational purposes and to assist researchers in making balanced decisions is a fundamental goal within the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR). It is critical that such tools do not exist in a vacuum and, as such, evolve to reflect the transformational changes occurring within the discipline that can have a long-term impact on the sustainable discovery, development, and manufacture of pharmaceuticals. The Reagents Guide was one of the earliest tools conceived by the ACS GCIPR and has been highlighted in The Nexus several times, most recently in 2017, at which time we showcased the 15 guides available covering a broad scope of transformations. Today, there are 28 guides, all freely available to the public. Each of the guides features a “Venn diagram” format, with the various reagents positioned based on their (a) breadth of utility, (b) amenability to scale-up, and (c) greenness.
Over the past several years, the new guides produced have reinforced this ethos that the “evolution of the tool should reflect the latest emerging trends within the scientific discipline and the industry” to remain relevant to the current user group. The new guides highlighted in this article demonstrate GCIPR’s commitment to keeping the Reagent Guides current with emerging trends within the industry.
1. Synthesis of Pyridines
The synthesis of heterocycles represents a key competency for both agrochemicals and pharmaceuticals with this guide providing an overview on transformations that can be utilized to specifically assemble the pyridine nucleus, as opposed to accessing desired pyridine derivatives through manipulations of the various substituents. Highlights of the Pyridine Ring Synthesis Guide include an overview of the range of bond disconnections available for the synthesis of pyridines as well as an evaluation of the availability of pyridine-based feedstocks from biomass.
2. Fluorination
Introduction of fluorine is a common strategy within medicinal chemistry to modulate the physicochemical properties, mitigate metabolic liability, and enhance the binding affinity of a lead molecule. While there is a broad array of fluorinated building blocks available, this often places a restraint on where the fluorine is positioned in the final analogue, thus leading to a desire for the development of new fluorinating reagents that allow the precise, chemo-selective introduction of fluorine into a molecule of interest. The Fluorination Guide showcases new, mild, bench-stable fluorinating reagents such as Pyfluor and Phenofluor while highlighting not only the potential hazards of working with many fluorination reagents but also the need to develop greener methods for this important transformation.
3. Biocatalysis
Over the past decade, the use of biocatalysis to mediate exquisitely selective transformation under mild, aqueous-based conditions has represented one of the success stories in terms of enhancing sustainability in the synthesis of pharmaceuticals. Both the greenness and scalability of these processes are highlighted within the new Biocatalysis Reagent Guide while broad uptake within the discovery community is promoted through the availability of enzyme-screening kits to profile transformations on a small scale, as well as efforts to raise awareness through the biocatalysis team of the ACS GCIPR.
4. Peptide Synthesis
The global peptide therapeutic market is currently ~$40 billion, with estimates suggesting that this will continue to grow at an exponential rate over the next decade. However, solid phase peptide synthesis (SPPS) still represents one of the major routes to access these molecular entities and leads to large volumes of waste being generated, owing specifically to the amounts of solvents used in washing steps. The new Peptide Synthesis Guide shows emerging technologies for this chemistry while highlighting environmental concerns around several solvents that have been classically employed in this field.
Conclusion
In addition to the newer guides showcased here, the GCIPR updates all the guides on a recurring basis to ensure that the content captured is the most current, including references to more recent publications. These examples highlight the continued relevance and value of the ACS GCIPR as an educational tool and a practical resource for synthetic chemists within academia and industry. In addition, the Reagent Guides highlight potential future areas in which research efforts can be directed to develop more sustainable approaches to synthetic transformations that have proven real-world application. If you have any suggestions or questions, we would be happy to hear your feedback at gcipr@acs.org.
*Special thanks to the members of the Reagent Guides Focus Team for their contributions: Shubhangi Aggarwal, Christiana Briddell, Michael Carroll, Lorene Calvano, Michael Curtis, Richard Fox, Fabrice Gallou, Eileen Hoang, Nicole Hough, Daniel Laity, Isamir Martinez, Jeishla Meléndez Matos, Andrew Wells, Qiang Yang, and Jingjun Yin.