One of the hottest areas of organic synthesis these days is developing more efficient ways of getting fluorine into complex bioactive organic compounds that are being pursued as new products by pharmaceutical and agricultural chemical companies. While fluorine imparts useful properties into the molecules—such as metabolic control and better binding to a target—it is notoriously hard to handle, and chemists’ options for introducing fluorine into compounds have mostly been limited to using harsh fluorinating reagents and modifying simple fluorinated starting materials.
Associate chemistry professor Abigail G. Doyle of Princeton University is among a new wave of organic chemists who are stepping up with their toolbox of easier and gentler synthetic methods to broaden the range of fluorination reactions. Doyle’s research program focuses on catalysis and new reactivity, zeroing in on stereoselective fluorination of complex organic compounds and cross-coupling reactions with cationic intermediates. In addition to the reaction chemistry, Doyle’s group uses physical organic chemistry methods to gain detailed mechanistic and structural information about reaction intermediates, which provides insight on designing new catalysts and further improving the organic transformations.
“These studies illustrate Doyle’s chief characteristic: She is drawn to the most impactful and challenging problems, and then she devises highly workable solutions to them,” says Harvard University chemistry professor Eric N. Jacobsen, whose group Doyle worked in as a student. “Her thoughtful, creative, and persistent approach to science has already made her one of the bright stars of her generation.”
Doyle’s carbon-fluorine bond formation work has involved two approaches. In one, her group discovered the first asymmetric metal-catalyzed methods for nucleophilic fluorination using inexpensive fluorine sources. This approach includes cooperative catalytic systems for asymmetric ring opening of epoxides and aziridines to make chiral alcohols and amines. In the other approach, Doyle’s team invented palladium-catalyzed protocols for enantio- and regioselective nucleophilic fluorination of olefins to produce allylic fluorides. These approaches are giving chemists greater flexibility for introducing fluorine into complex molecules at a late stage in the synthetic process.
In Doyle’s cross-coupling work, she has carried out previously unknown nickel-catalyzed 1,2-addition reactions using iminium and oxocarbenium precursors. This chemistry has made possible access to single-enantiomer heterocyclic α-substituted amines and ethers by asymmetric C–C bond formation with a range of readily accessible, nontoxic reagents that include boronic acids and organozinc compounds. Her team has also created novel alkyl cross-coupling reactions that use epoxides and aziridines rather than traditional organic halides as electrophilic reaction partners.
Doyle, 33, received an undergraduate degree in 2002 and a Ph.D. degree in 2008, both in chemistry from Harvard, working in Jacobsen’s lab. In between those degrees, she was a National Defense Science & Engineering Graduate Predoctoral Fellow at Stanford University, working with chemistry professor Justin Du Bois. Doyle joined the Princeton faculty in 2008.
Among her awards, Doyle recently received a Presidential Early Career Award for Scientists & Engineers from the National Science Foundation and the Bayer Early Excellence in Science Award. Doyle has also received the Amgen Young Investigator Award (2012) and an Alfred P. Sloan Foundation Fellowship (2012). Among her professional activities, she served as coorganizer of the 42nd National Organic Chemistry Symposium (2010–11) and produces chemistry demonstrations for children at the Trenton Science Museum’s Super Science Saturday.