Frick Laboratory, 191
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, agrochemicals and 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 different classes 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.
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)
Mitsui Award in Catalysis (2011)
Mukaiyama Prize (Japanese Society of Organic Chemists, 2007)
Arthur C. Cope Scholar ACS Award (2007)
Thieme-IUPAC Prize in Synthetic Organic Chemistry (2006)
Elias J. Corey ACS Award (2005)
Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. C., "A General Strategy for Organocatalytic Activation of C-H Bonds via Photoredox Catalysis: Direct Arylation of Benzylic Ethers." Journal of the American Chemical Society 2014, 136 (2), 626-629.
Peifer, M.; Berger, R.; Shurtleff, V. W.; Conrad, J. C.; MacMillan, D. W. C., "A General and Enantioselective Approach to Pentoses: A Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir." Journal of the American Chemical Society 2014, 136 (16), 5900-5903.
Zuo, Z.; MacMillan, D. W. C., "Decarboxylative Arylation of alpha-Amino Acids via Photoredox Catalysis: A One-Step Conversion of Biomass to Drug Pharmacophore." Journal of the American Chemical Society 2014, 136 (14), 5257-5260.
Terrett, J. A.; Clift, M. D.; MacMillan, D. W. C., "Direct beta-Alkylation of Aldehydes via Photoredox Organocatalysis." Journal of the American Chemical Society 2014, 136 (19), 6858-6861.
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.
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 Science 2013, 4 (8), 3075-3079
Laforteza, B. N.; Pickworth, M.; MacMillan, D. W. C., "Enantioselective Total Synthesis of (-)-Minovincine in Nine Chemical Steps: An Approach to Ketone Activation in Cascade Catalysis." Angewandte Chemie-International Edition 2013, 52 (43), 11269-11272.
Horning, B. D.; MacMillan, D. W. C., "Nine-Step Enantioselective Total Synthesis of (-)-Vincorine." Journal of the American Chemical Society 2013, 135 (17), 6442-6445.
Comito, R. J.; Finelli, F. G.; MacMillan, D. W. C., "Enantioselective Intramolecular Aldehyde alpha-Alkylation with Simple Olefins: Direct Access to Homo-Ene Products." Journal of the American Chemical Society 2013, 135 (25), 9358-9361.
Cecere, G.; Koenig, C. M.; Alleva, J. L.; MacMillan, D. W. C., "Enantioselective Direct alpha-Annination of Aldehydes via a Photoredox Mechanism: A Strategy for Asymmetric Amine Fragment Coupling." Journal of the American Chemical Society 2013, 135 (31), 11521-11524.
Stevens, J. M.; MacMillan, D. W. C., "Enantioselective alpha-Alkenylation of Aldehydes with Boronic Acids via the Synergistic Combination of Copper(II) and Amine Catalysis." Journal of the American Chemical Society 2013, 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 with Functionalized Amines: A One-Step Synthesis of Plavix." Journal of the American Chemical Society 2013, 135 (43), 16074-16077.
Petronijevic, F. R.; Nappi, M.; MacMillan, D. W. C., "Direct beta-Functionalization of Cyclic Ketones with Aryl Ketones via the Merger of Photoredox and Organocatalysis." Journal of the American Chemical Society 2013, 135 (49), 18323-18326.
Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C., "Photoredox Activation for the Direct beta-Arylation of Ketones and Aldehydes." Science 2013, 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 Science 2012, 3 (1), 58-61.
Allen, A. E.; MacMillan, D. W. C., "Synergistic catalysis: A powerful synthetic strategy for new reaction development." Chemical Science 2012, 3 (3), 633-658.
Skucas, E.; MacMillan, D. W. C., "Enantioselective alpha-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis." Journal of the American Chemical Society 2012, 134 (22), 9090-9093.
Zhu, S.; MacMillan, D. W. C., "Enantioselective Copper-Catalyzed Construction of Aryl Pyrroloindolines via an Arylation-Cyclization Cascade." Journal of the American Chemical Society 2012, 134 (26), 10815-10818.
Jui, N. T.; Garber, J. A. O.; Finelli, F. G.; MacMillan, D. W. C., "Enantioselective Organo-SOMO Cycloadditions: A Catalytic Approach to Complex Pyrrolidines from Olefins and Aldehydes." Journal of the American Chemical Society 2012, 134 (28), 11400-11403.
Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., "Enantioselective Organocatalytic alpha-Fluorination of Cyclic Ketones." Journal of the American Chemical Society 2011, 133 (6), 1738-1741.
Allen, A. E.; MacMillan, D. W. C., "Enantioselective alpha-Arylation of Aldehydes via the Productive Merger of lodonium Salts and Organocatalysis." Journal of the American Chemical Society 2011, 133 (12), 4260-4263.
Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C., "Enantioselective alpha-Arylation of Carbonyls via Cu(I)-Bisoxazoline Catalysis." Journal of the American Chemical Society 2011, 133 (35), 13782-13785.
McNally, A.; Prier, C. K.; MacMillan, D. W. C., "Discovery of an alpha-Amino C-H Arylation Reaction Using the Strategy of Accelerated Serendipity." Science 2011, 334 (6059), 1114-1117.
Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C., "Collective synthesis of natural products by means of organocascade catalysis." Nature 2011, 475 (7355), 183-188.
Nagib, D. A.; MacMillan, D. W. C., "Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis." Nature 2011, 480 (7376), 224-228.