New Grant Program Funds Exploratory Research for Greener Pharma

[ACSGCI]

Green chemistry principles have provided inspiration to many research chemists looking for a new way to think about a challenging technical problem. Unfortunately, the funding to do this kind of exploratory research isn’t readily available. That’s why the ACS GCI Pharmaceutical Roundtable (GCIPR) has launched a new grant program specifically aimed at funding promising green chemistry research ideas that have yet to be tested—enabling researchers to gather preliminary results with which they can seek funding from traditional sources. The first four awardees of this ‘Ignition’ grant program have now been selected.

“We created the ignition grant program to kick-start research for sustainable solutions to chemistry and engineering problems relevant to our industry,” says Stefan Koenig, co-chair of the Roundtable and senior scientist at Genentech, Inc. “Considering the number of high-caliber applications we received, it’s clear this program is addressing a real funding need.”

Professor Zacharias Amara, Pharm. D., Ph.D., from the Conservatoire National Des Arts Et Métiers in Paris, France in support of his work, “Smart Synthesis with Magnetically Recoverable Visible Light Photocatalysts.”

“The Ignition Grant is a great support to start my research project in Green Chemistry,” says Amara. “The ACS GCIPR provides an ideal mentorship which, I am convinced, will help me produce high-impact research with a real industrial mindset.”

Amara explains his project like this:

“Photocatalysis is an incredibly powerful activation mode that will soon become useful to chemical pharmaceutical production. Our objective is to make photocatalysis more efficient and greener by developing a robust chemical reaction system. Our approach is a fully integrated continuous flow process where both the photoreaction and the purification steps are combined in a single operation. As a result we will deliver a smart recycling technology with simplified access to complex pharmaceutical intermediates and minimized amounts of wastes.

"Our idea is to combine flow photochemistry with magnetic nanoparticles (NPs). As a result heterogeneous and magnetic nano-photo-catalysts will be created to convert the energy of visible light into electron flows that can be harvested to catalyze clean organic reactions. We hope these “smart nano-reactors” will have the potential to demonstrate superior efficiencies compared to conventional photocatalysts.”

Professor Jeffery A. Byers, Ph.D., from Boston College for his work, “Development of an Iron-Based Catalyst for Suzuki-Miyaura Cross Coupling Reactions.”

“Large-scale implementation of palladium-catalyzed cross coupling reactions is often hindered by extensive purification required to remove trace amounts of the toxic palladium catalyst. Replacing palladium catalysts with iron-based catalysts is an alternative that can lead to similar reactivity without the environmental drawbacks. Moreover, because many iron-based cross coupling reactions are mechanistically distinct compared to palladium-catalyzed reactions, the development of iron-based catalysts has great potential to demonstrate complementary reactivity compared to the well-established palladium-based catalysts.

“Despite these advantages, the most well developed iron-based cross coupling reactions have been for Kumada-type cross coupling reactions. This type of cross coupling reaction faces its own environmental and substrate scope limitations because they involve using highly reactive and basic Grignard reagents.

“Unlike Kumada-type cross coupling reactions, the organoboronic acids or esters commonly employed in Suzuki-Miyaura reactions are easily prepared, stored, and handled. However, iron-catalyzed Suzuki-Miyaura reactions are uncommon, and those that do not require preactivation of the transmetalating agent with organolithium reagent are unprecedented. Since the environmental concerns associated with handling organolithium reagents are similar to those for Grignard reagents, these reactions face similar practical limitations as iron-catalyzed Kumada-type cross coupling reactions.

“In this proposal, fundamental studies in organometallic chemistry will be undertaken that are aimed towards understanding the factors that have limited the development of an iron-based catalyst for the Suzuki-Miyaura type cross coupling reaction.

“Through a combination of computational studies and stoichiometric reactions designed to mimic proposed reactive intermediates, the thermodynamic and kinetic feasibility of a boron to iron transmetalation reaction will be investigated. To complement these studies, new analytical tools will be developed to probe the speciation of paramagnetic iron complexes that exist in solution during catalytic reactions. From these studies, it is expected that the factors that currently limit application of iron-based complexes for their use in the Suzuki-Miyaura reaction will be revealed.

“Ultimately this information will be used for the logical design of a Suzuki-Miyaura reaction catalyzed by iron, which is expected to be tremendously useful for addressing the environmental issues that currently face palladium-catalyzed cross coupling reactions. These studies are also expected to lead to mechanistic insight that will open the door for the development of novel cross coupling reactions catalyzed by iron."

Professor Dennis Hall, Ph.D., from the University of Alberta in Edmonton, Canada for his work, “Borate-based catalytic directing groups for alkene and C-H functionalization reactions using readily available alcohol substrates.”

“Transition-metal catalyzed transformations such as CH and alkene functionalization (e.g., catalytic hydroboration) often require large ligating directing-groups that need to be installed and later removed after the desired transformation. The atom- and step-economy of these processes, even the CH functionalization reactions, tends to be suboptimal. This research proposal attempts to address the reliance of current CH and alkene functionalization methodologies on large and wasteful stoichiometric directing groups.

“Despite their synthetic utility, free alcohols – especially phenols – are generally not efficient as ligating directing groups with transition metals. The ability to transform alcohols directly without resorting to any sort of stoichiometric protecting or directing group could lead to substantial economies in chemical processes of great relevance to the pharmaceutical industry, and was deemed a priority research area in the 2007 Roundtable report by Constable, et al.

“To this end, the concept of boron-based catalytic directing group (CDG) is proposed. Alcohols and phenols possess the ability to form reversible borates in the presence of B–OH containing compounds like boric acid and boronic acids. Thus, we will design borate-based reversible CDGs for alcohol substrates, including phenols, that can provide turnover in transition metal-catalyzed reactions leading to significant improvements of atom- and step-economy in useful transformations. A suitable borate directing group must be designed to embed a Lewis basic atom, preferably nitrogen or phosphorous, and be able to bring in the substrate and the transition metal in close proximity for effective reaction. A number of prototype borate CDGs will be evaluated, initially on simple stoichiometric transformations, and promising candidates will be optimized for catalytic turnover.”

Professor Oana R. Luca, Ph.D., from the University of Colorado, Boulder for her work, “Catalyst and electrolyte-free direct electrochemical cross coupling.”

“This type of grant allows us to kick start our research program into a direction focused on sustainable, scalable chemical transformations,” says Luca. “We chose to apply for this grant because it provided us with a unique opportunity to propose a high-risk, high-reward conceptual idea, that if demonstrated, could trigger a wave of new synthetic opportunities in mostly uncharted radical chemical space.”

Luca  further explains:  “In the long term, we hope to gain a deep understanding of reactivity of electrochemically-generated radicals. We look forward to learning how to harness this knowledge towards constructing chemical architectures that were previously inaccessible synthetically. Instead of looking to perfect a catalyst, we take a simpler approach: electrochemistry as a controllable method of direct radical generation and utilize it to form sought-after C-C bonds.”

Each awardee will receive $25K for six months. Since 2005, the Roundtable has given over $1.9 million dollars in research grants to advance the sustainability profile of pharmaceutical processes using green chemistry techniques. To date, these grants have resulted in 64 journal publications and over 2272 citations.

The ACS GCI Pharmaceutical Roundtable brings global industry leaders together to catalyze the implementation of green chemistry and engineering. Current members include Amgen, AstraZeneca, Asymchem, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Codexis, Eli Lilly and Company, F. Hoffman-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer Inc., Roche, Sanofi, WuXi AppTec, Co., Ltd. and ACS GCI.

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