David W C MacMillan

Princeton University, Princeton, NJ, United States

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Publications (121)1077.83 Total impact

  • Zhiwei Zuo, David W C Macmillan
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    ABSTRACT: The direct decarboxylative arylation of α-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapid entry to prevalent benzylic amine architectures from an abundant biomass, specifically α-amino acid precursors. Significant substrate scope is observed with respect to both the amino acid and arene components.
    Journal of the American Chemical Society 04/2014; 136(14):5257-60. · 10.68 Impact Factor
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    ABSTRACT: An efficient route toward biologically relevant pentose derivatives is described. The de novo synthetic strategy features an enantioselective α-oxidation reaction enabled by a chiral amine in conjunction with copper(II) catalysis. A subsequent Mukaiyama aldol coupling allows for the incorporation of a wide array of modular two-carbon fragments. Lactone intermediates accessed via this route provide a useful platform for elaboration, as demonstrated by the preparation of a variety of C-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use.
    Journal of the American Chemical Society 03/2014; · 10.68 Impact Factor
  • Katrine Qvortrup, Danica A Rankic, David W C Macmillan
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    ABSTRACT: The direct C-H functionalization and arylation of benzyl ethers has been accomplished via photoredox organocatalysis. The productive merger of a thiol catalyst and a commercially available iridium photoredox catalyst in the presence of household light directly affords benzylic arylation products in good to excellent yield. The utility of this methodology was further demonstrated in the direct arylation of 2,5-dihydrofuran to form a single regioisomer.
    Journal of the American Chemical Society 12/2013; · 10.68 Impact Factor
  • Source
    Filip R Petronijevic, Manuel Nappi, David W C Macmillan
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    ABSTRACT: The direct β-aldol reaction of cyclic ketones with aryl ketones has been achieved via the synergistic combination of photoredox catalysis and organocatalysis. Diaryl oxymethyl or aryl-alkyl oxymethyl radicals, transiently generated via single-electron reduction of ketone precursors, readily merge with β-enaminyl radical species - generated by photon-induced enamine oxidation - to produce γ-hydroxyketone adducts. Experimental evidence indicates that two discrete reaction pathways can be operable in this process depending upon the nature of the ketyl radical precursor and the photocatalyst.
    Journal of the American Chemical Society 11/2013; · 10.68 Impact Factor
  • Ryan W Evans, Jason R Zbieg, Shaolin Zhu, Wei Li, David W C Macmillan
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    ABSTRACT: The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.
    Journal of the American Chemical Society 10/2013; · 10.68 Impact Factor
  • Brian N Laforteza, Mark Pickworth, David W C Macmillan
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    ABSTRACT: Dressed to the nines: The first enantioselective total synthesis of (-)-minovincine has been accomplished in nine chemical steps and 13 % overall yield. A novel, one-step Diels-Alder/β-elimination/conjugate addition organocascade sequence allowed rapid access to the central tetracyclic core in an asymmetric manner. Boc=tert-butoxycarbonyl, LG=leaving group, PMB=para-methoxybenzyl.
    Angewandte Chemie International Edition 09/2013; · 13.73 Impact Factor
  • Jason M Stevens, David W C Macmillan
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    ABSTRACT: The enantioselective α-alkenylation of aldehydes has been accomplished using boronic acids via the synergistic combination of copper and chiral amine catalysis. The merger of two highly utilized and robust catalytic systems has allowed for the development of a mild and operationally trivial protocol for the direct formation of α-formyl olefins employing common building blocks for organic synthesis.
    Journal of the American Chemical Society 07/2013; · 10.68 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated, nitrogen-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require post-reaction manipulation.
    Journal of the American Chemical Society 07/2013; · 10.68 Impact Factor
  • Mark N. Vander Wal, Andrew K. Dilger, David W. C. MacMillan
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    ABSTRACT: Oxy-allyl cations have been known as transient electrophilic species since they were first proposed as intermediates in the Favorskii rearrangement in 1894. Since that time, they also have been used as a mode of activation for [4 + 3] cycloadditions in a variety of natural product syntheses. In this manuscript, we describe a method for the interception of oxy-allyl cations with a diverse range of common nucleophiles, thereby demonstrating the value of this intermediate as a generic mode of activation. This simple, mild, room temperature protocol allows for the formation of a variety of high value carbon–carbon and carbon–heteroatom bonds that are readily incorporated within a series of cyclic and acyclic ketone systems. Initial efforts into the development of an enantioselective catalytic variant are also described.
    Chemical Science 06/2013; · 8.31 Impact Factor
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    ABSTRACT: A highly selective method for the synthesis of asymmetrically substituted carbocycles and heterocycles from unactivated aldehyde-olefin precursors has been achieved via enantioselective SOMO-catalysis. Addition of a catalytically generated enamine radical cation across a pendent olefin serves to establish a general asymmetric strategy towards the production of a wide range of formyl-substituted rings with alkene transposition. Conceptually, this novel mechanism allows direct access to "homo-ene" type products.
    Journal of the American Chemical Society 06/2013; · 10.68 Impact Factor
  • Benjamin D Horning, David W C Macmillan
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    ABSTRACT: A concise and highly enantioselective total synthesis of the akuammiline alkaloid (-)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels-Alder, iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered, azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (-)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials.
    Journal of the American Chemical Society 04/2013; · 10.68 Impact Factor
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    ABSTRACT: The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.
    Science 03/2013; 339(6127):1593-6. · 31.20 Impact Factor
  • Christopher K Prier, Danica A Rankic, David W C Macmillan
    Chemical Reviews 03/2013; · 41.30 Impact Factor
  • Source
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    ABSTRACT: A new method to rapidly generate pyrrolidines via a SOMO-activated enantioselective (3 + 2) coupling of aldehydes and conjugated olefins has been accomplished. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnish a cationic intermediate which is vulnerable to nucleophilic addition of a tethered amine group. A range of olefins, including styrenes and dienes, are shown to provide stereochemically complex pyrrolidine products with high chemical efficiency and enantiocontrol.
    Journal of the American Chemical Society 07/2012; 134(28):11400-3. · 10.68 Impact Factor
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    Shaolin Zhu, David W C MacMillan
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    ABSTRACT: An enantioselective arylation-cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products.
    Journal of the American Chemical Society 06/2012; 134(26):10815-8. · 10.68 Impact Factor
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    Eduardas Skucas, David W C MacMillan
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    ABSTRACT: The enantioselective α-vinylation of aldehydes using vinyl iodonium triflate salts has been accomplished via the synergistic combination of copper and chiral amine catalysis. These mild catalytic conditions provide a direct route for the enantioselective construction of enolizable α-formyl vinylic stereocenters without racemization or olefin transposition. These high-value coupling adducts are readily converted into a variety of useful olefin synthons.
    Journal of the American Chemical Society 05/2012; 134(22):9090-3. · 10.68 Impact Factor
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    ABSTRACT: A new enantioselective α-oxidation of aldehydes has been accomplished using TEMPO and a synergistic combination of copper and organic catalysis. Expanding upon recently reported mechanistic studies, these mild catalytic conditions provide stable aldehyde products bearing a wide array of electronically and sterically diverse substructures. The utility of these oxidized products is highlighted by subsequent derivatization to a variety of common chiral synthons, without loss in enantiopurity.
    Chemical Science 01/2012; 3(1):58-61. · 8.31 Impact Factor
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    Anna E Allen, David W C Macmillan
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    ABSTRACT: Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature.
    Chemical Science 01/2012; 2012(3):633-658. · 8.31 Impact Factor
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    David A Nagib, David W C MacMillan
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    ABSTRACT: Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF(3)) group, into drug candidates. The CF(3) group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug. Although common pharmacophores often bear CF(3) motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF(3) group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF(3) to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.
    Nature 12/2011; 480(7376):224-8. · 38.60 Impact Factor
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    Andrew McNally, Christopher K Prier, David W C MacMillan
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    ABSTRACT: Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C-H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.
    Science 11/2011; 334(6059):1114-7. · 31.20 Impact Factor

Publication Stats

4k Citations
1,077.83 Total Impact Points

Institutions

  • 2007–2013
    • Princeton University
      • Department of Chemistry
      Princeton, NJ, United States
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • University of California, Los Angeles
      • Department of Chemistry and Biochemistry
      Los Angeles, CA, United States
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, MA, United States
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
  • 2001–2006
    • California Institute of Technology
      • Division of Chemistry and Chemical Engineering
      Pasadena, CA, United States
    • University of California, Irvine
      • Department of Chemistry
      Irvine, CA, United States
  • 1999–2001
    • University of California, Berkeley
      • Department of Chemistry
      Berkeley, MO, United States