The ACS Green Chemistry Institute® Pharmaceutical Roundtable has assembled an updated list of key research areas to highlight transformations and reaction media where more sustainable technologies would be most impactful.

A review that highlights water as the logical reaction medium in which organic chemistry can be practiced. The key roles that water can play in directing reaction outcomes, including impacting mechanistic features, are discussed using selected examples.

In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and >200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.

Previous studies have shown that aqueous solutions of designer surfactants enable a wide variety of valuable transformations in synthetic organic chemistry. Since reactions take place within the inner hydrophobic cores of these tailor-made nanoreactors, and products made therein are in dynamic exchange between micelles through the water, opportunities exist to use enzymes to effect secondary processes. Herein we report that ketone-containing products, formed via initial transition metal-catalyzed reactions based on Pd, Cu, Rh, Fe and Au, can be followed in the same pot by enzymatic reductions mediated by alcohol dehydrogenases. Most noteworthy is the finding that nanomicelles present in the water appear to function not only as a medium for both chemo- and bio-catalysis, but as a reservoir for substrates, products, and catalysts, decreasing noncompetitive enzyme inhibition.

During our evaluation of the potential of surfactant technology, we rapidly experienced a straightforward and highly advantageous technology, which we applied on-scale. This resulted into significant benefits across our entire synthetic route, not just from an environmental standpoint but also from an economic and productivity perspective. To name a few: reduction of organic solvent use, reduction of water use, reduction of metric such as PMI, reduction of cost, reduction of cycle time, milder reaction conditions, improved yields, and improved process performances. Quantatively, the differences for some of these virtues approached 50% in favor of surfactant technology, all of which realised in multi-purpose facilities already within the infrastructure of standard pharmaceutical or chemical organizations. All of these benefits were achieved using a catalytic amount of a nonionic designer surfactant (e.g. TPGS-750-M) in water instead of traditional organic solvents.