David W C MacMillan

Princeton University, Princeton, New Jersey, United States

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Publications (154)1540.54 Total impact

  • Chi Chip Le · David W C MacMillan
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    ABSTRACT: In this study we demonstrate that molecular fragments, which can be readily coupled via a simple, in situ RO-C=OR bond forming reaction, can subsequently undergo metal insertion-decarboxylation-recombination to generate Csp2-Csp3 bonds when subjected to metallaphotoredox catalysis. In this embodiment the conversion of a wide variety of mixed anhydrides (formed in situ from carboxylic acids and acyl chlorides) to fragment-coupled ketones is accomplished in good to high yield. A three-step synthesis of the medicinal edivoxetine is also described using this new decarboxylation-recombination protocol.
    Journal of the American Chemical Society 09/2015; 137(37). DOI:10.1021/jacs.5b08304 · 12.11 Impact Factor
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    ABSTRACT: Alkyl oxalates are new bench-stable alcohol-activating groups for radical generation under visible light photoredox conditions. Using these precursors, the first net redox-neutral coupling of tertiary and secondary alcohols with electron-deficient alkenes is achieved.
    Journal of the American Chemical Society 08/2015; DOI:10.1021/jacs.5b07678 · 12.11 Impact Factor
  • Jenna L Jeffrey · Jack A Terrett · David W C MacMillan
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    ABSTRACT: The efficiency and selectivity of hydrogen atom transfer from organic molecules is often difficult to control in the presence of multiple potential hydrogen atom donors and acceptors. Herein, we describe the mechanistic evaluation of a mode of catalytic activation that accomplishes the highly selective photoredox α-alkylation/lactonization of alcohols with methyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a unique role of tetra-n-butylammonium phosphate in enhancing the selectivity for α C-H bonds in alcohols in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds. Copyright © 2015, American Association for the Advancement of Science.
    Science 08/2015; DOI:10.1126/science.aac8555 · 33.61 Impact Factor
  • Jian Jin · David W C MacMillan
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    ABSTRACT: Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.
    Nature 08/2015; 525(7567). DOI:10.1038/nature14885 · 41.46 Impact Factor
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    ABSTRACT: Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(iii) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(iii) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.
    Nature 08/2015; 524(7565). DOI:10.1038/nature14875 · 41.46 Impact Factor
  • Eric R Welin · Alexander A Warkentin · Jay C Conrad · David W C MacMillan
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    ABSTRACT: The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (-)-bursehernin. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 06/2015; 54(33). DOI:10.1002/anie.201503789 · 11.26 Impact Factor
  • Jenna L Jeffrey · Filip R Petronijević · David W C MacMillan
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    ABSTRACT: A direct β-coupling of cyclic ketones with imines has been accomplished via the synergistic combination of photoredox catalysis and organocatalysis. Transient β-enaminyl radicals -derived from ketones via enamine and oxidative photoredox catalysis - readily combine with persistent α-amino radicals in a highly selective hetero radical-radical coupling. This novel pathway to γ-aminoketones is predicated upon the use of DABCO as both a base and a critical electron transfer agent. This protocol also formally allows for the direct synthesis of β-Mannich products via a chemoselective three-component coupling of aryl aldehydes, amines, and ketones.
    Journal of the American Chemical Society 06/2015; 137(26). DOI:10.1021/jacs.5b05376 · 12.11 Impact Factor
  • Lingling Chu · Jeffrey M. Lipshultz · David W. C. MacMillan
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    ABSTRACT: The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie 05/2015; 54(27). DOI:10.1002/ange.201501908
  • Sandrine Ventre · Filip R Petronijević · David W C MacMillan
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    ABSTRACT: The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F• transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
    Journal of the American Chemical Society 04/2015; 137(17). DOI:10.1021/jacs.5b02244 · 12.11 Impact Factor
  • Source
    James D Cuthbertson · David W C MacMillan
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    ABSTRACT: The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.
    Nature 03/2015; 519(7541):74-7. DOI:10.1038/nature14255 · 41.46 Impact Factor
  • Adam Noble · David W. C. MacMillan
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    ABSTRACT: The synthetic utility of this new vinylation protocol is demonstrated in the racemic syntheses of natural products like norruspoline (XVII).
    ChemInform 03/2015; 46(11). DOI:10.1002/chin.201511059
  • Lingling Chu · Chisa Ohta · Zhiwei Zuo · David W. C. MacMillan
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    ABSTRACT: A photon-induced addition is developed which can be applied to a broad spectrum of carboxylic acids including natural and unnatural amino acids.
    ChemInform 03/2015; 46(9). DOI:10.1002/chin.201509027
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    ABSTRACT: The new presented combination of photoredox catalysis and nickel catalysis provides an alternative cross coupling procedure.
    ChemInform 01/2015; 46(2). DOI:10.1002/chin.201502039
  • Adam Noble · Stefan J McCarver · David W C MacMillan
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    ABSTRACT: The decarboxylative cross-coupling of alkyl carboxylic acids with vinyl halides has been accomplished through the synergistic merger of photoredox and nickel catalysis. This new methodology has been successfully applied to a variety of α-oxy and α-amino acids, as well as simple hydrocarbon-substituted acids. Structurally diverse vinyl iodides and bromides give rise to vinylation products in high efficiency under mild, operationally simple reaction conditions.
    Journal of the American Chemical Society 12/2014; 46(27). DOI:10.1021/ja511913h · 12.11 Impact Factor
  • Dominik Hager · David W C MacMillan
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    ABSTRACT: The photoredox-mediated coupling of benzylic ethers with Schiff bases has been accomplished. Direct benzylic C-H activation by a combination of a thiol catalyst with an iridium photocatalyst and subsequent radical-radical coupling with secondary aldimines affords a variety of β-amino ether products in good to excellent yields. Mechanistic studies suggest that a reductive quenching pathway of the photocatalyst is operable.
    Journal of the American Chemical Society 12/2014; 136(49). DOI:10.1021/ja5102695 · 12.11 Impact Factor
  • Jian Jin · David W. C. MacMillan
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    ABSTRACT: The direct α-arylation of cyclic and acyclic ethers with heteroarenes has been accomplished through the design of a photoredox-mediated CH functionalization pathway. Transiently generated α-oxyalkyl radicals, produced from a variety of widely available ethers through hydrogen atom transfer (HAT), were coupled with a range of electron-deficient heteroarenes in a Minisci-type mechanism. This mild, visible-light-driven protocol allows direct access to medicinal pharmacophores of broad utility using feedstock substrates and a commercial photocatalyst.
    Angewandte Chemie International Edition 12/2014; 127(5). DOI:10.1002/anie.201410432 · 11.26 Impact Factor
  • Source
    David W. C. MacMillan · Christopher K Prier
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    ABSTRACT: The direct alpha-heteroarylation of tertiary amines has been accomplished via photoredox catalysis to generate valuable benzylic amine pharmacophores. A variety of five- and six-membered chloroheteroarenes are shown to function as viable coupling partners for the alpha-arylation of a diverse range of cyclic and acyclic amines. Evidence is provided for a homolytic aromatic substitution mechanism, in which a catalytically-generated alpha-amino radical undergoes direct addition to an electrophilic chloroarene.
    Chemical Science 08/2014; 46(12). DOI:10.1039/C4SC02155J · 9.21 Impact Factor
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    ABSTRACT: Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp(2)) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp(3)) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp(3)-sp(2) cross-coupling of amino acids, as well as alpha-O- or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of C-sp3-H in dimethylaniline with aryl halides via C-H functionalization.
    Science 07/2014; 345(6195):437-440. DOI:10.1126/science.1255525 · 33.61 Impact Factor
  • Source
    Lingling Chu · Chisa Ohta · Zhiwei Zuo · David W C MacMillan
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    ABSTRACT: The direct application of carboxylic acids as a traceless activation group for radical Michael additions has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidation of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addition strategy. An application of this technology to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.
    Journal of the American Chemical Society 07/2014; 136(31). DOI:10.1021/ja505964r · 12.11 Impact Factor
  • Source
    Adam Noble · David W C MacMillan
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    ABSTRACT: A new coupling protocol has been developed that allows the union of vinyl sulfones with photoredox-generated α-amino radicals to provide allylic amines of broad diversity. Direct C–H vinylations of N-aryl tertiary amines, as well as decarboxylative vinylations of N-Boc α-amino acids, proceed in high yield and with excellent olefin geometry control. The utility of this new allyl amine forming reaction has been demonstrated via the syntheses of several natural products and a number of established pharmacophores.
    Journal of the American Chemical Society 07/2014; 136(33). DOI:10.1021/ja506094d · 12.11 Impact Factor

Publication Stats

13k Citations
1,540.54 Total Impact Points


  • 2007–2015
    • Princeton University
      • Department of Chemistry
      Princeton, New Jersey, United States
  • 1997–2011
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 1999–2010
    • University of California, Berkeley
      • Department of Chemistry
      Berkeley, California, United States
  • 1995–2010
    • University of California, Irvine
      • Department of Chemistry
      Irvine, California, United States
  • 2001–2008
    • California Institute of Technology
      • Division of Chemistry and Chemical Engineering
      Pasadena, California, United States