Scott J Miller

Yale University, New Haven, Connecticut, United States

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Publications (161)1479.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The selective recruitment of oligosaccharides, or even simple sugars, in water solvent is an unsolved molecular recognition problem. Structure-guided, electrostatic redesign led to a significant increase in the affinity of a β-peptide "borono-bundle" for simple sugars in neutral aqueous solution. The affinity for fructose (663 M(-1)) in water should allow its recruitment to the bundle surface for selective catalysis, and future work will focus in this direction.
    Organic Letters 09/2015; DOI:10.1021/acs.orglett.5b02187 · 6.36 Impact Factor
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    ABSTRACT: We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using DFT calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereo-determining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other, atropisomerically-defined products of interest. For example, (1) a dehalogenation-Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.
    Journal of the American Chemical Society 09/2015; DOI:10.1021/jacs.5b07726 · 12.11 Impact Factor
  • Michael W Giuliano · Scott J Miller
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    ABSTRACT: The problem of catalyst-controlled site-selectivity can potentially require a catalyst to overcome energetic barriers larger than those associated with enantioselective reactions. This challenge is a signature of substrates that present reactive sites that are not of equivalent reactivity. Herein we present a narrative of our laboratory's efforts to overcome this challenge using peptide-based catalysts. We highlight the interplay between understanding the inherent reactivity preferences of a given target molecule and the development of catalysts that can overcome intrinsic preferences embedded within a substrate.
    Topics in current chemistry 08/2015; DOI:10.1007/128_2015_653 · 4.46 Impact Factor
  • Christopher R Shugrue · Scott J Miller
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    ABSTRACT: Phosphothreonine (pThr) was found to constitute a new class of chiral phosphoric acid (CPA) catalyst upon insertion into peptides. To demonstrate the potential of these phosphopeptides as asymmetric catalysts, enantioselective transfer hydrogenations of a previously underexplored substrate class for CPA-catalyzed reductions were carried out. pThr-containing peptides lead to the observation of enantioselectivities of up to 94:6 e.r. with 2-substituted quinolines containing C8-amino functionality. NMR studies indicate that hydrogen-bonding interactions promote strong complexation between substrates and a rigid β-turn catalyst. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 08/2015; 54(38). DOI:10.1002/anie.201505898 · 11.26 Impact Factor
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    ABSTRACT: We report an approach to the asymmetric Baeyer-Villiger oxidation utilizing bioinformatics-inspired combinatorial screening for catalyst discovery. Scaled-up validation of our on-bead efforts with a circular dichroism-based assay of alcohols derived from the products of solution-phase reactions established the absolute configuration of lactone products; this assay proved equivalent to HPLC in its ability to evaluate catalyst performance, but was far superior in its speed of analysis. Further solution-phase screening of a focused library suggested a mode of asymmetric induction that draws distinct parallels with the mechanism of Baeyer-Villiger monooxygenases.
    Advanced Synthesis & Catalysis 07/2015; 357(10). DOI:10.1002/adsc.201500230 · 5.66 Impact Factor
  • David K Romney · Scott J Miller
    Science 02/2015; 347(6224):829. DOI:10.1126/science.aaa5623 · 33.61 Impact Factor
  • Sabesan Yoganathan · Scott J Miller
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    ABSTRACT: Emergence of antibiotic-resistant infections highlights the need for novel antibiotic leads, perhaps with a broader spectrum of activity. Herein, we disclose a semisynthetic, catalytic approach for structure diversification of vancomycin. We have identified three unique peptide catalysts that exhibit site-selectivity for the lipidation of the aliphatic hydroxyls on vancomycin, generating three new derivatives 9a, 9b and 9c. Incorporation of lipid chains into vancomycin scaffold provides promising improvement of its bioactivity against vancomycin-resistant enterococci (Van A and Van B phenotypes of VRE). The MICs for 9a, 9b, and 9c against MRSA and VRE (Van B phenotype) range from 0.12 to 0.25 μg/mL. We have also performed a structure activity relationship (SAR) study to investigate the effect of lipid chain length at the newly accessible G4-OH derivatization site.
    Journal of Medicinal Chemistry 02/2015; 58(5). DOI:10.1021/jm501872s · 5.45 Impact Factor
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    Kimberly T Barrett · Scott J Miller
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    ABSTRACT: The enantioselective synthesis of atropisomeric, tribrominated benzamides and subsequent regioselective transformations to afford derivatized, axially chiral molecules is reported. The enantioenriched tribromides were carried through sequential Pd-catalyzed cross-coupling and lithium-halogen exchange with high regioselectivity and enantioretention. A variety of complexity-generation functional group installations were performed to create a library of homochiral benzamides. The potential utility of these molecules is demonstrated by using a phosphino benzamide derivative as an asymmetric ligand in a Pd-catalyzed allylic alkylation.
    Organic Letters 01/2015; 17(3). DOI:10.1021/ol503593y · 6.36 Impact Factor
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    ABSTRACT: The polystyrene-supported N-alkylimidazole-based dendritic catalysts for the Baylis–Hillman reaction exhibit one of the strongest beneficial effects of multivalent architecture ever reported for an organocatalyst. The yields in the model reaction of methyl vinyl ketone with p-nitrobenzaldehyde are more than tripled when a non-dendritic catalyst is replaced by a second- or third-generation analogue. Moreover, the reaction of the less active substrates will not occur with the non-dendritic catalyst and will proceed to a significant extent only with the analogous catalysts of higher generations. A substantial additional enhancement of the reaction yield could be achieved by increasing the content of water in the reaction solvent. The plausible cause of the dendritic effect is the assistance of the second, nearby imidazole moiety in the presumably rate-determining proton transfer in the intermediate adduct, after the first imidazole unit induced the formation of the new carbon–carbon bond.
    Chemistry - A European Journal 11/2014; 21(3). DOI:10.1002/chem.201404560 · 5.73 Impact Factor
  • Curren T. Mbofana · Scott J. Miller
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    ABSTRACT: We have developed phosphine-catalyzed annulation reactions for the synthesis of highly substituted cyclopentene derivatives from 2-alkynoate and α-keto esters. These transformations involve carbon–carbon bond cleavage of α-keto esters. Preliminary mechanistic studies suggest that, in addition to facilitating carbon–carbon bond formation, the phosphine catalyst plays a role in promoting methanolysis.Keywords: alkynoates; α-keto esters; phosphines; organocatalysis; annulation reactions; fused rings; C−C bond cleavage
    ACS Catalysis 10/2014; 4(10):3671-3674. DOI:10.1021/cs501117h · 9.31 Impact Factor
  • David K Romney · Sean M Colvin · Scott J Miller
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    ABSTRACT: We report a peptide-based catalyst that can strongly influence the regio- and enantioselectivity of the Baeyer–Villiger (BV) oxidation of cyclic ketones bearing amide, urea, or sulfonamide functional groups. Both types of selectivity are thought to arise from a catalyst–substrate hydrogen-bonding interaction. Furthermore, in selected cases, the reactions exhibit the hallmarks of parallel kinetic resolution. The capacity to use catalysis to select between BV products during an asymmetric process may have broad utility for both the synthesis and diversification of complex molecules, including natural products.
    Journal of the American Chemical Society 09/2014; 136(40). DOI:10.1021/ja508757g · 12.11 Impact Factor
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    ABSTRACT: We report X-ray crystal structure of a site-selective peptide catalyst moiety and teicoplanin A2-2 complex. The expressed protein ligation technique was used to couple T4 lysozyme (T4L) and a synthetic peptide catalyst responsible for the selective phosphorylation of the N-acetylglucosamine sugar in teicoplanin A2-2 derivative. The T4L-Pmh-DPro-Aib-DAla-DAla construct was crystallized in the presence of teicoplanin A2-2. The resulting 2.3 Angstrom resolution protein-peptide-teicoplanin complex crystal structure revealed that the nucleophilic nitrogen of N-methylimidazole in the Pmh residue is in closer proximity (7.6 Angstrom) to the N-acetylglucosamine than two other sugar rings present in teicoplanin (9.3 and 20.3 Angstrom, respectively). This molecular arrangement is consistent with the observed selectivity afforded by the peptide-based catalyst when it is applied to a site-selective phosphorylation reaction involving a teicoplanin A2-2 derivative.
    The Journal of Organic Chemistry 08/2014; 79(18). DOI:10.1021/jo501625f · 4.72 Impact Factor
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    ABSTRACT: We detail an investigation of a peptide-based catalyst (6) that is effective for the site- (>100:1:1) and enantioselective epoxidation (86% ee) of farnesol. Studies of the substrate scope exhibited by the catalyst are included, along with an exploration of optimized reaction conditions. Mechanistic studies are reported, including relative rate determinations for the catalyst and propionic acid, a historical perspective, truncation studies, and modeling using NMR data. Our compiled data advances our understanding of the inner workings of a catalyst that was identified through combinatorial means.
    Chemical Science 08/2014; 46(12). DOI:10.1039/C4SC01440E · 9.21 Impact Factor
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    ABSTRACT: Many natural products that contain basic nitrogen atoms--for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.
    Nature 05/2014; 509(7500):318-24. DOI:10.1038/nature13273 · 41.46 Impact Factor
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    ABSTRACT: One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes-one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.
    Nature 04/2014; 509(7498). DOI:10.1038/nature13189 · 41.46 Impact Factor
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    Phillip A Lichtor · Scott J Miller
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    ABSTRACT: We describe mechanistic investigations of a catalyst (1) that leads to selective epoxidation of farnesol at the 6,7-position, remote from the hydroxyl directing group. The experimental lineage of peptide 1 and a number of resin-bound peptide analogues were examined to reveal the importance of four N-terminal residues. We examined the selectivity of truncated analogues to find that a trimer is sufficient to furnish the remote selectivity. Both 1D and 2D (1)H NMR studies were used to determine possible catalyst conformations, culminating in proposed models showing possible interactions of farnesol with a protected Thr side chain and backbone NH. The models were used to rationalize the selectivity of a modified catalyst (17) for the 6,7-position relative to an ether moiety in two related substrates.
    Journal of the American Chemical Society 04/2014; 136(14). DOI:10.1021/ja410567a · 12.11 Impact Factor
  • Curren T Mbofana · Scott J Miller
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    ABSTRACT: A selective peptide-catalyzed addition of allenic esters to N-acylimines is reported. Tetrasubstituted allenes were achieved with up to 42:1 diastereomeric ratio and 94:6 enantiomeric ratio (up to 99:1 er after recrystallization of the major diastereomer). An exploration of the role of individual amino acids within the peptide was undertaken. The scope of the reaction was explored and revealed heightened reactivity with thioester-containing allenes. A mechanistic framework that may account for the observed reactivity is also described.
    Journal of the American Chemical Society 02/2014; 136(8). DOI:10.1021/ja412996f · 12.11 Impact Factor
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    Anthony J Metrano · Scott J Miller
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    ABSTRACT: We report the development and optimization of a tetrapeptide that catalyzes the methanolytic dynamic kinetic resolution of oxazol-5(4H)-ones (azlactones) with high levels of enantioinduction. Oxazolones possessing benzylic-type substituents were found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis.
    The Journal of Organic Chemistry 02/2014; 79(4). DOI:10.1021/jo402828f · 4.72 Impact Factor
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    ABSTRACT: We report the synthesis and biochemical validation of a phosphatidyl inositol-3 phosphate (PI3P) immunogen. The inositol stereochemistry was secured through peptide-catalyzed asymmetric phosphorylation catalysis, and the subsequent incorporation of a cysteine residue was achieved by native chemical ligation (NCL). Conjugation of the PI3P hapten to maleimide-activated keyhole limpet hemocyanin (KLH) provided a PI3P immunogen, which was successfully used to generate selective PI3P antibodies. The incorporation of a sulfhydryl nucleophile into a phosphoinositide hapten demonstrates a general strategy to reliably access phosphoinositide immunogens.
    Journal of the American Chemical Society 12/2013; 136(1). DOI:10.1021/ja410750a · 12.11 Impact Factor
  • C Liana Allen · Scott J Miller
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    ABSTRACT: Catalyst-controlled regioselective functionalization of partially protected saccharide molecules is a highly important yet under-developed area of carbohydrate chemistry. Such reactions allow for the reduction of protecting group manipulation steps required in syntheses involving sugars. Herein, an approach to these processes using enantiopure copper-bis(oxazoline) catalysts to control couplings of electrophiles to various partially protected sugars is reported. In a number of cases, divergent regioselectivity was observed as a function of the enantiomer of catalyst that is used.
    Organic Letters 11/2013; 45(22). DOI:10.1021/ol4033072 · 6.36 Impact Factor

Publication Stats

8k Citations
1,479.91 Total Impact Points


  • 2006–2015
    • Yale University
      • Department of Chemistry
      New Haven, Connecticut, United States
  • 2011
    • Massachusetts Institute of Technology
      • Department of Chemistry
      Cambridge, Massachusetts, United States
  • 1999–2010
    • Boston College, USA
      • Chemistry Department
      Boston, Massachusetts, United States
  • 1992–2010
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 1997–2006
    • Chestnut Hill College
      Boston, Massachusetts, United States
  • 2004
    • Pomona College
      • Department of Chemistry
      Клермонт, California, United States
  • 2003
    • Johns Hopkins University
      • Department of Chemistry
      Baltimore, Maryland, United States
  • 1995–1998
    • California Institute of Technology
      • Division of Chemistry and Chemical Engineering
      Pasadena, California, United States