Iron has a wealth of untapped potential in chemical synthesis, including use as a cheaper and safer alternative to palladium as a catalyst in forming the carbon-carbon bonds that are essential to pharmaceutical manufacturing.
As a recognized expert in the finer points of modeling and manipulating this complex metal, Texas A&M University chemist Osvaldo Gutierrez is now one step closer to using it to expand medicinal chemistry’s toolbox and help establish his research group as the go-to source for achieving a novel type of iron-catalyzed multicomponent cross-coupling capable of revolutionizing drug and materials synthesis.
In collaboration with chemists at the University of Rochester as an assistant professor of chemistry at the University of Maryland, Gutierrez succeeded in using iron to combine three commercially available building blocks, thereby providing a blueprint for rapid synthesis of highly complex fluorous-based compounds including five-membered tetrafluorinated rings that have broad application across industry, healthcare and environmental sectors.
The team’s research, jointly funded by the National Science Foundation (NSF) and the National Institutes of Health (NIH), is published today (October 22) in the current issue of Science. and also featured in a related Perspective article.
“Prior to this work, making ring systems containing tetrafluorinated groups was extremely challenging, often times requiring several steps and the use of toxic and hazardous reagents,” Gutierrez said. “We have now provided a new route that uses a cheap and non-toxic catalyst and is completed in a matter of minutes, rather than hours or days. In addition, we show that the method is very robust and versatile. This will open the door to synthesis of new pharmaceuticals, novel materials and pesticides that, before this work, were difficult to make and only possible using more expensive and more toxic catalysts.”
Gutierrez says the work originated from detailed mechanistic studies using both computational and experimental techniques — two of his unique expertise areas. In particular, the mechanistic studies gave the team insights into how to rationally design a new system that could permit control of reaction outcomes.
“We were able to use a key phosphine ligand-iron combination that allowed for the first time the union of alpha-boryl radicals generated from selective radical addition to vinyl boronates, and organometallic reagents to form the desired multicomponent products,” Gutierrez said. “From there, we were able to utilize a new technique that facilitates the practical synthesis of previously difficult-to-make tetrafluoroethylene-containing carbocycles and derivatives.”
Gutierrez notes the products can have broad implications to the synthesis of new materials and pharmaceuticals, given that fluorine substituents often enhance the pharmacological activity of a given compound and that carbon-boron groups are extremely versatile in drug and materials synthesis.
“The use of iron as a catalyst is quite advantageous in the making of pharmaceuticals, thanks to its cheapness and its low toxicity,” Gutierrez added. “Given the complexity of the resulting products and the number of newly formed bonds, most of the achieved yields are quite high. Moreover, the reactions are fast and proceed under extremely mild conditions — all very attractive features. Alternative ways of introducing these motifs would be difficult.”
In addition to Gutierrez, the team includes Michael L. Neidig, Marshall D. Gates Jr. Professor of Chemistry at Rochester, along with his Ph.D. student Camila Aguilera, who carried out additional mechanistic studies using sophisticated spectroscopic techniques that advanced the group’s research, for which Gutierrez says the sky is the limit.
“This work will open new areas of research in our lab in which we are able to develop multicomponent reactions with reactivity and selectivity that can complement existing methods,” Gutierrez added.
The team’s paper, “General method for iron-catalyzed multicomponent radical cascades/cross-couplings,” can be viewed online along with related figures and captions.
Gutierrez joined the Texas A&M Department of Chemistry in August after a five-year stint as an assistant professor of chemistry at Maryland. A native of Mexico, he honed his burgeoning skills in computational and experimental transition-metal catalysis as a postdoctoral fellow at the University of Pennsylvania after earning his bachelor’s and master’s degrees in chemistry at UCLA and his Ph.D. in chemistry at the University of California, Davis, in 2012. His major awards to date include an NSF Faculty Early Career Development (CAREER) Award (2018) and an NIH National Institute of General Medical Sciences Maximizing Investigator’s Research Award (2020). Most recently, he was included in the C&EN Talented 12 for 2020 and selected by the Camille and Henry Dreyfus Foundation as a Camille Dreyfus Teacher Scholar for 2021. Aside from his research interests, he is passionate about increasing diversity in the sciences.
To learn more about the Gutierrez group and related research, visit https://www.gutierrezlabs.com/.
See a related feature story from the University of Rochester.
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