Research Focus
Honors
Selected Publications
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Contact
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MacMillan Group Website
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CarolinePhillips
cp@princeton.edu
Frick Laboratory, 191
609-258-2254
Research Focus
Research in the MacMillan Group is centered on the field of organic synthesis and catalysis. We are inspired by the pursuit of new concepts in synthetic organic chemistry that allow access to structural and stereochemical motifs not readily available using conventional methods. In this endeavor, we target the development of general strategies that can be implemented in a wide spectrum of chemical processes. We place particular emphasis on the synthesis of moieties prevalent in medicinal agents, agrochemicalsand natural products, with the goal of streamlining existing synthetic routes and facilitating the discovery of new bioactive scaffolds.
Toward the goal of developing broadly useful strategies for organic synthesis, our research program is focused on platforms for reaction development involving organocatalysis, photoredox catalysis and metal-mediated catalysis. In particular, our group has made contributions to the field of organocatalysis through the development and wide application of chiral imidazolidinone catalysts. These robust amine catalysts are capable of generating diverse activated intermediates such as enamines, iminium ions and 3p-electron (SOMO) species, each of which may be coupled with numerous differentclasses of reaction partners. Additionally, over the past several years, we have become interested in the application of photoredox catalysis to organic synthesis, wherein a transition-metal complex may be triggered by low-energy, visible light to perform single-electron transfers without requiring harsh conditions or stoichiometric oxidants or reductants.
The unique reactivity of these complexes has attracted significant attention, in part due to their ability to functionalize non-traditional sites of reactivity.Photoredox catalysis is now a burgeoning area of research across the synthetic community.
Each of the aforementioned areas of catalysis has proven to be a powerful strategy in its own right, and their implementation has led to the discovery of myriad individual reactions. Exploring combinations of multiple catalysts in a single flask, with two or more catalytic cycles working in concert, has become a key area of research in our laboratory. Through these efforts, we have discovered a number of powerful methodologies by combining organocatalysis with photoredox catalysis or more traditional transition-metal catalysis. Most recently, in a collaborative effort with the Doyle group, we reported the productive merger of nickel and photoredox catalysis to enable the activation of usually “benign” functionality (carboxylic acids) in a decarboxylative cross-coupling with aryl halides. As exemplified by this transformation, interfacing multiple modes of catalysis provides access to novel reactivity and challenging bond disconnections that cannot be accomplished by either catalyst in isolation.
In the field of total synthesis, our group draws inspiration from nature’s ability to rapidly construct enantiopure complex molecules through catalytic cascade reactions within enzyme active sites. As a general strategy, cascade catalysis mimics nature’s approach to molecular construction. Beginning from simple, achiral starting materials, an enantiopure organocatalyst or transition metal complex mediates a multi-step cascade sequence that generates both structural and stereochemical complexity in a single synthetic operation. A representative example in the area of enantioselective organocascade catalysis is our laboratory’s amine-catalyzed Diels–Alder/beta-elimination/conjugate addition cascade. This powerful sequence was used to prepare a common tetracyclic core that was rapidly diversified, leading to expedient asymmetric syntheses of six different natural products. Additionally, we have recently reported a copper-catalyzed arylation/cyclization cascade, which proceeds with exceptional levels of enantioselectivity and efficiency to furnish aryl pyrroloindoline motifs. This scaffold is of particular interest as it represents the basic building block of many polypyrroloindoline natural products.
As part of our group’s efforts to rapidly discover and optimize new reaction methodologies, we have capitalized on the capabilities of the Merck Center for Catalysis at Princeton University, which is a unique state-of-the-art facility that enables the high-throughput execution and analysis of catalytic reactions. The center houses a Chemspeed Accelerator robotic platform, an automated system used to apply the center’s resources to accelerate challenging, high-value projects for both methodology development and optimization of key steps in total synthesis. Recent advancements in the realms of photoredox, SOMO, enamine, and iminium catalysis have emerged from studies in this facility.
Research Areas
Catalysis / Synthesis
Honors
Nobel Prize in Chemistry (2021)
Centenary Prize, Royal Society of Chemistry, UK (2020)
Nagoya Medal, Nagoya University (2019)
Elected to the National Academy of Sciences, USA (2019)
ACS Gabor Somorjai Award in Catalysis (2018)
Noyori Prize, Japanese Society of Synthetic Chemistry (2018)
Henry J. Albert Award from BASF and IMPI (2017)
Janssen Pharmaceutical Prize, Belgium (2016)
Ohio State Edward Mack Jr. Award (2016)
Tischler Award, Harvard University, MA 2016 ACS Kosolapoff Award (2016)
Hamilton Award in Molecular Sciences, University of Nebraska (2015)
Schering Foundation Prize (Berlin) for Outstanding Research in Medicine, Biology or Chemistry (2015)
NJ ACS Award for Creativity in Molecular Design and Synthesis (2014)
Harrison Howe ACS Award in Chemistry (2013)
Elected to the Fellowship of the Royal Society (FRS, 2012)
Elected to the American Academy of Arts and Sciences (2012)
ACS Prize for Creative Work in Organic Synthesis (2011)
MitsuiAward in Catalysis (2011)
MukaiyamaPrize (Japanese Society of Organic Chemists, 2007)
Arthur C. Cope Scholar ACS Award (2007)
Thieme-IUPACPrize in Synthetic Organic Chemistry (2006)
Elias J. Corey ACS Award (2005)
Selected Recent Publications
Qvortrup, K.;Rankic, D. A.; MacMillan, D. W. C., "A General Strategy forOrganocatalyticActivation of C-H Bonds viaPhotoredoxCatalysis: DirectArylationof Benzylic Ethers."Journal of the American Chemical Society2014,136(2), 626-629.
Peifer, M.; Berger, R.;Shurtleff, V. W.; Conrad, J. C.; MacMillan, D. W. C., "A General andEnantioselectiveApproach toPentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir."Journal of the American Chemical Society2014,136(16), 5900-5903.
Zuo, Z.; MacMillan, D. W. C., "DecarboxylativeArylationof alpha-Amino Acids viaPhotoredoxCatalysis: A One-Step Conversion of Biomass to Drug Pharmacophore."Journal of the American Chemical Society2014,136(14), 5257-5260.
Terrett, J. A.; Clift, M. D.; MacMillan, D. W. C., "Direct beta-Alkylation ofAldehydesviaPhotoredoxOrganocatalysis."Journal of the American Chemical Society2014,136(19), 6858-6861.
Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C., "Mergingphotoredoxwith nickel catalysis: Coupling of alpha-carboxyl sp(3)-carbons with aryl halides."Science2014,345(6195), 437-440.
Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C., "Development of a generic activation mode: nucleophilic alpha-substitution of ketones via oxy-allyl cations."Chemical Science2013,4(8), 3075-3079
Laforteza, B. N.;Pickworth, M.; MacMillan, D. W. C., "EnantioselectiveTotal Synthesis of (-)-Minovincine in Nine Chemical Steps: An Approach toKetoneActivation in Cascade Catalysis."AngewandteChemie-InternationalEdition2013,52(43), 11269-11272.
Horning, B. D.; MacMillan, D. W. C., "Nine-StepEnantioselectiveTotal Synthesis of (-)-Vincorine."Journal of the American Chemical Society2013,135(17), 6442-6445.
Comito, R. J.;Finelli, F.G.; MacMillan, D. W. C., "EnantioselectiveIntramolecularAldehydealpha-Alkylationwith Simple Olefins: Direct Access toHomo-EneProducts."Journal of the American Chemical Society2013,135(25), 9358-9361.
Cecere, G.; Koenig, C. M.;Alleva, J. L.; MacMillan, D. W. C., "EnantioselectiveDirectalpha-AnninationofAldehydesvia aPhotoredoxMechanism: A Strategy for Asymmetric Amine Fragment Coupling."Journal of the American Chemical Society2013,135(31), 11521-11524.
Stevens, J. M.; MacMillan, D. W. C., "Enantioselectivealpha-Alkenylation ofAldehydeswith Boronic Acids via the Synergistic Combination of Copper(II) and Amine Catalysis."Journal of the American Chemical Society2013,135(32), 11756-11759.
Evans, R. W.;Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W. C., "Simple Catalytic Mechanism for the Direct Coupling of alpha-Carbonyls withFunctionalizedAmines: A One-Step Synthesis of Plavix."Journal of the American Chemical Society2013,135(43), 16074-16077.
Petronijevic, F. R.;Nappi, M.; MacMillan, D. W. C., "Directbeta-Functionalizationof CyclicKetoneswith ArylKetonesvia the Merger ofPhotoredoxand Organocatalysis."Journal of the American Chemical Society2013,135(49), 18323-18326.
Pirnot, M. T.;Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C., "PhotoredoxActivation for the Directbeta-ArylationofKetonesand Aldehydes."Science2013,339(6127), 1593-1596.
Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C., "A general approach to the enantioselective alpha-oxidation of aldehydes via synergistic catalysis."Chemical Science2012,3(1), 58-61.
Allen, A. E.; MacMillan, D. W. C., "Synergistic catalysis: A powerful synthetic strategy for new reaction development."Chemical Science2012,3(3), 633-658.
Skucas, E.; MacMillan, D. W. C., "Enantioselectivealpha-Vinylation ofAldehydesvia the Synergistic Combination of Copper and Amine Catalysis."Journal of the American Chemical Society2012,134(22), 9090-9093.
Zhu, S.; MacMillan, D. W. C., "EnantioselectiveCopper-Catalyzed Construction of Aryl Pyrroloindolines via an Arylation-Cyclization Cascade."Journal of the American Chemical Society2012,134(26), 10815-10818.
Jui, N. T.; Garber, J. A. O.;Finelli, F. G.; MacMillan, D. W. C., "EnantioselectiveOrgano-SOMOCycloadditions: A Catalytic Approach to ComplexPyrrolidinesfrom Olefins and Aldehydes."Journal of the American Chemical Society2012,134(28), 11400-11403.
Kwiatkowski, P.;Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., "EnantioselectiveOrganocatalyticalpha-Fluorination of Cyclic Ketones."Journal of the American Chemical Society2011,133(6), 1738-1741.
Allen, A. E.; MacMillan, D. W. C., "Enantioselectivealpha-ArylationofAldehydesvia the Productive Merger oflodoniumSalts and Organocatalysis."Journal of the American Chemical Society2011,133(12), 4260-4263.
Harvey, J. S.;Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C., "Enantioselectivealpha-Arylationof Carbonyls via Cu(I)-Bisoxazoline Catalysis."Journal of the American Chemical Society2011,133(35), 13782-13785.
McNally, A.; Prier, C. K.; MacMillan, D. W. C., "Discovery of an alpha-Amino C-HArylationReaction Using the Strategy of Accelerated Serendipity."Science2011,334(6059), 1114-1117.
Jones, S. B.; Simmons, B.;Mastracchio, A.; MacMillan, D. W. C., "Collective synthesis of natural products by means oforganocascadecatalysis."Nature2011,475(7355), 183-188.
Nagib, D. A.; MacMillan, D. W. C., "Trifluoromethylationofarenesandheteroarenesby means ofphotoredoxcatalysis."Nature2011,480(7376), 224-228.
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