Contact
Research Focus

Abby Doyle video interview clipsResearch in the Doyle lab takes place at the interface between the fields of organic synthesis, organometallic catalysis, and physical organic chemistry.  We are involved in designing synthetic strategies that enable efficient and selective preparation of complex molecules and biologically privileged structural motifs. To achieve these goals, we harness the activity of inexpensive and abundant transition metal catalysts to achieve novel bond-forming processes. In the past, we have pursued two areas within this program: (1) the invention of new catalytic reaction methods for the synthesis of fluorinated compounds using nucleophilic fluorine sources; and (2) the development of transition metal-catalyzed Csp3–C bond-forming reactions with electrophiles that possess abundant but unconventional leaving groups.

Projects in the group are designed to provide students with expertise in reaction discovery and development, while exposing them to problems in complex target synthesis and mechanistic analysis.

(1)  Despite the expansive array of fluorine-containing medicines, agrochemicals, and materials, the availability of synthetic methods for carbon–fluorine (C–F) bond formation remains a chief obstacle to the discovery and production of these compounds.  Our laboratory has achieved the first catalytic methods for aliphatic nucleophilic fluorination.  These pursuits have led to the identification of highly enantioselective methods for the synthesis of β-fluoroalcohols, allylic fluorides, β-fluoroamines, a-fluorocarbonyl derivatives, and other versatile fluorinated chiral building blocks for basic and biomedical science. Through our mechanistic studies, we have discovered that well-defined transition metal fluorides and bimetallic mechanisms can overcome the many challenges associated with working with fluoride, including its solubility, chemoselectivity, and reactivity. Building upon this understanding, we have successfully translated one of our methods to a radiofluorination protocol for the synthesis of small-molecule tracers for positron emission tomography (PET). These studies and methods represent exciting platforms for the invention of a wide spectrum of chemical transformations; our continued efforts should yield effective solutions to a broad collection of problems in the area of organofluorine chemistry.

(2)  Transition metal-catalyzed cross coupling has revolutionized the way that chemists assemble carbon–carbon (C–C) bonds.  Our laboratory is interested in advancing this field by developing a class of Csp3 cross-coupling reactions that use electrophiles bearing abundant but unconventional leaving groups. Electrophiles that have captivated our interest over the past five years range from acetals and epoxides to anilines and aziridines. By co-opting the versatility of a cross-coupling reaction, we aim to broaden the scope of C–C bond-forming reactions with these electrophiles, and do so while using catalyst-control to influence aspects of regio-, diastereo- or enantioselectivity in potentially useful and unusual ways.  As examples, we have identified new cross-coupling reactions that are initiated by oxidative insertion of Ni into the C=N or C=O π system of iminium and oxocarbenium ions.  Using N,O-acetals and acetals as substrates, this novel activation mode enables the base- and acid-free synthesis of a-substituted amines and ethers by Csp3–C instead of C–heteroatom bond formation.  With insight gained from our mechanistic studies, we have developed enantioselective methods for the derivatization of pyridinium and quinolinium ions. Our laboratory has also designed a series of new electron-deficient olefin ligands for nickel-catalyzed cross-coupling reactions with aziridines.  These ligands impart unique reactivity and may have broad utility for catalysis.  Finally, we recently discovered that by trapping organic radicals, generated by visible light photoredox catalysis, with nickel, we could effect a variety of Csp3–C bond-forming reactions previously unrealized using transition metal catalysis alone.

Research Areas
Catalysis / Synthesis
Inorganic Chemistry
Honors

NSF CAREER Award (2012-2017)

BMS Unrestricted Grant in Synthetic Organic Chemistry (2016)

Novartis Chemistry Lectureship (2014/2015)

Phi Lambda Upsilon National Fresenius Award (2014)

Presidential Early Career Award for Scientists and Engineers (2014)

Eli Lilly Grantee Award (2012-2014)

Bayer Excellence in Science Award (2013)

Arthur C. Cope Scholar Award (2013)

Camille-Dreyfus Teacher Scholar Award (2013)

Presidential Early Career Award for Scientists and Engineers (2012)

Amgen Young Investigator Award (2012)

Alfred P. Sloan Foundation Fellowship (2012)

Roche Early Excellence in Chemistry Award (2012)

Boehringer Ingelheim New Investigator Award (2012)

Selected Recent Publications

Shields, J. D.; Ahneman, D. T.; Graham, T. J. A.; Doyle, A. G., "Enantioselective, Nickel-Catalyzed Suzuki Cross-Coupling of Quinolinium Ions." Organic Letters 2014, 16 (1), 142-145.

Katcher, M. H.; Norrby, P.-O.; Doyle, A. G., "Mechanistic Investigations of Palladium-Catalyzed Allylic Fluorination." Organometallics 2014, 33 (9), 2121-2133.

Graham, T. J. A.; Lambert, R. F.; Ploessl, K.; Kung, H. F.; Doyle, A. G., "Enantioselective Radiosynthesis of Positron Emission Tomography (PET) Tracers Containing F-18 Fluorohydrins." Journal of the American Chemical Society 2014, 136 (14), 5291-5294.

Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C., "Merging photoredox with nickel catalysis: Coupling of alpha-carboxyl sp(3)-carbons with aryl halides." Science 2014, 345 (6195), 437-440.

Braun, M.-G.; Katcher, M. H.; Doyle, A. G., "Carbofluorination via a palladium-catalyzed cascade reaction." Chemical Science 2013, 4 (3), 1216-1220.

Chau, S. T.; Lutz, J. P.; Wu, K.; Doyle, A. G., "Nickel-Catalyzed Enantioselective Arylation of Pyridinium Ions: Harnessing an Iminium Ion Activation Mode." Angewandte Chemie-International Edition 2013, 52 (35), 9153-9156.

Graham, T. J. A.; Ploessl, K.; Kung, H. F.; Doyle, A. G., "Enantioselective ring opening of epoxides with F-18 fluoride." Journal of Labelled Compounds & Radiopharmaceuticals 2013, 56, S74-S74.

Kalow, J. A.; Doyle, A. G., "Enantioselective fluoride ring opening of aziridines enabled by cooperative Lewis acid catalysis." Tetrahedron 2013, 69 (27-28), 5702-5709.

Braun, M.-G.; Doyle, A. G., "Palladium-Catalyzed Allylic C-H Fluorination." Journal of the American Chemical Society 2013, 135 (35), 12990-12993.

Nielsen, D. K.; Huang, C.-Y.; Doyle, A. G., "Directed Nickel-Catalyzed Negishi Cross Coupling of Alkyl Aziridines." Journal of the American Chemical Society 2013, 135 (36), 13605-13609.

Graham, T. J. A.; Doyle, A. G., "Nickel-Catalyzed Cross-Coupling of Chromene Acetals and Boronic Acids." Organic Letters 2012, 14 (6), 1616-1619.

Kalow, J. A.; Schmitt, D. E.; Doyle, A. G., "Synthesis of beta-Fluoroamines by Lewis Base Catalyzed Hydrofluorination of Aziridines." Journal of Organic Chemistry 2012, 77 (8), 4177-4183.

Huang, C.-Y.; Doyle, A. G., "Nickel-Catalyzed Negishi Alkylations of Styrenyl Aziridines." Journal of the American Chemical Society 2012, 134 (23), 9541-9544.

Sylvester, K. T.; Wu, K.; Doyle, A. G., "Mechanistic Investigation of the Nickel-Catalyzed Suzuki Reaction of N,O-Acetals: Evidence for Boronic Acid Assisted Oxidative Addition and an Iminium Activation Pathway." Journal of the American Chemical Society 2012, 134 (41), 16967-16970

Graham, T. J. A.; Shields, J. D.; Doyle, A. G., "Transition metal-catalyzed cross coupling with N-acyliminium ions derived from quinolines and isoquinolines." Chemical Science 2011, 2 (5), 980-984.

Nielsen, D. K.; Doyle, A. G., "Nickel-Catalyzed Cross-Coupling of Styrenyl Epoxides with Boronic Acids." Angewandte Chemie-International Edition 2011, 50 (27), 6056-6059.

Katcher, M. H.; Sha, A.; Doyle, A. G., "Palladium-Catalyzed Regio- and Enantioselective Fluorination of Acyclic Allylic Halides." Journal of the American Chemical Society 2011, 133 (40), 15902-15905.

Kalow, J. A.; Doyle, A. G., "Mechanistic Investigations of Cooperative Catalysis in the Enantioselective Fluorination of Epoxides." Journal of the American Chemical Society 2011, 133 (40), 16001-16012.

Kalow, J. A.; Doyle, A. G., "Enantioselective Ring Opening of Epoxides by Fluoride Anion Promoted by a Cooperative Dual-Catalyst System." Journal of the American Chemical Society 2010, 132 (10), 3268-+.

Katcher, M. H.; Doyle, A. G., "Palladium-Catalyzed Asymmetric Synthesis of Allylic Fluorides." Journal of the American Chemical Society 2010, 132 (49), 17402-17404.

Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N., "Enantioselective thiourea-catalyzed additions to oxocarbenium ions." Journal of the American Chemical Society 2008, 130 (23), 7198-+.

Doyle, A. G.; Jacobsen, E. N., "Enantioselective alkylation of acyclic alpha,alpha-disubstituted tributyltin enolates catalyzed by a {Cr(salen)) complex." Angewandte Chemie-International Edition 2007, 46 (20), 3701-3705.

Doyle, A. G.; Jacobsen, E. N., "Small-molecule H-bond donors in asymmetric catalysis." Chemical Reviews 2007, 107 (12), 5713-5743.

Doyle, A. G.; Jacobsen, E. N., "Enantioselective alkylations of tributyltin enolates catalyzed by Cr(salen)Cl: Access to enantiomerically enriched all-carbon quaternary centers." Journal of the American Chemical Society 2005, 127 (1), 62-63.

Ellsworth, B. A.; Doyle, A. G.; Patel, M.; Caceres-Cortes, J.; Meng, W.; Deshpande, P. P.; Pullockaran, A.; Washburn, W. N., "C-Arylglucoside synthesis: triisopropylsilane as a selective reagent for the reduction of an anomeric C-phenyl ketal." Tetrahedron-Asymmetry 2003, 14 (20), 3243-3247.