15 research outputs found

    Practical High-Throughput Experimentation for Chemists

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    Large arrays of hypothesis-driven, rationally designed experiments are powerful tools for solving complex chemical problems. Conceptual and practical aspects of chemical high-throughput experimentation are discussed. A case study in the application of high-throughput experimentation to a key synthetic step in a drug discovery program and subsequent optimization for the first large scale synthesis of a drug candidate is exemplified

    Unlocking the Potential of N-O Bonds in Organic Synthesis

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    This thesis examines various aspects of harnessing the reactivity of N-O bond-containing molecules toward useful synthetic organic chemistry. In each chapter, the key to this challenge lies in the careful formation of energetic molecules containing N-O bonds and the controlled release of that energy toward driving the transformation of interest. To achieve this goal, high-throughput experimentation has been employed throughout the course of this research in order to maximize productivity and learning while simultaneously minimizing time and material requirements. Enabled by these tools, this thesis is the result of almost 14,000 experiments. Chapter 1 describes the iron-catalyzed synthesis of indoles from ortho-nitrostyrenes. Mechanistic studies revealed that the iron-phenanthroline catalyst serves to shuttle oxygen atoms from nitro groups to silanes in order to generate reactive ortho-nitrosostyrenes, which then undergo spontaneous 6Ï€-electrocyclization and subsequent reduction to give indoles. Chapter 2 describes the synthesis of furo[2,3-b]indolines from N-hydroxyindoles in a reaction cascade sequence. Key reactive N-alkenyloxyindole intermediates are formed from conjugate addition of N-hydroxyindoles to activated alkynes with catalytic base, and then spontaneously undergo [3,3]-sigmatropic rearrangement and cyclization to form the product heterocycles. Chapter 3 describes the mechanistic study of solvent effects on the [1,4]-4Ï€-electrocyclizations of N-alkenylnitrones and the development of the first example of a catalytic asymmetric [1,4]-4Ï€-electrocyclization. Eyring analysis of activation parameters for the thermal electrocyclization of N-alkenylnitrones was conducted in order to identify solvents with minimal background reactivity that can also solubilize the cationic (MeCN)4Pd(BF4)2 / phosphine catalysts needed to promote enantioselective [1,4]-4Ï€-electrocyclization to form 2,3-dihydroazete-N-oxide products

    Iron-Catalyzed Reductive Cyclization of <i>o</i>‑Nitrostyrenes Using Phenylsilane as the Terminal Reductant

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    Using microscale high-throughput experimentation, an efficient, earth-abundant iron phenanthroline complex was discovered to catalyze the reductive cyclization of <i>ortho</i>-nitrostyrenes into indoles via nitrosoarene reactive intermediates. This method requires only 1 mol % of Fe­(OAc)<sub>2</sub> and 1 mol % of 4,7-(MeO)<sub>2</sub>phen and uses phenylsilane as a convenient terminal reductant. The scope and limitations of the method were illustrated with 21 examples, and an investigation into the kinetics of the reaction revealed first-order behavior in catalyst and silane and zero-order behavior with respect to nitrostyrene

    Asymmetric Synthesis of <i>N</i>‑Boc‑(<i>R</i>)‑Silaproline via Rh-Catalyzed Intramolecular Hydrosilylation of Dehydroalanine and Continuous Flow <i>N</i>‑Alkylation

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    An asymmetric synthesis of a silicon-containing proline surrogate, <i>N</i>-Boc-(<i>R</i>)-silaproline (<b>1</b>), is described. Starting from <i>N</i>-Boc-dehydroalanine ester, deprotonation, followed by <i>N</i>-alkylation with chloromethyldimethylsilane under flow conditions, afforded the <i>N</i>-alkylated product <b>8</b> in 91% yield. An unprecedented enantioselective (NBD)<sub>2</sub>RhBF<sub>4</sub>/Josiphos 404-1 catalyzed 5<i>-endo-trig</i> hydrosilylation afforded the silaproline ester in 85–90% yield and >95% ee. Subsequent saponification and salt formation upgraded <b>1</b> to >99% ee

    Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C–H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design

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    This manuscript describes a mild, functional group tolerant, and metal-free C–H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. This demonstrates a significant expansion of the accessible chemical space of azole-2-amides, compared to previously known methodologies. Key to the described reactivity is the use of silyl triflate reagents, which serve as reaction mediators in C–H deprotonation and stabilizers of (otherwise unstable) azole carboxylic acid intermediates. A diverse azole substrate scope designed via machine-learning-guided analysis demonstrates the broad utility of the sequence. Density functional theory calculations provide detailed insights into the role of silyl triflates in the reaction mechanism. Transferrable applications of the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; (iii) isocyanates as alternative electrophiles for direct C–H amidation; (iv) and the use of the developed chemistry in a 24 × 12 parallel synthesis workflow with a 90% library success rate. Fundamentally, the reported protocol expands the use of heterocycle C–H functionalization from late-stage functionalization applications toward its use in library synthesis. It provides general access to densely functionalized azole-2-carboxylic acid building blocks and demonstrates their one-pot diversification

    Double-Asymmetric Hydrogenation Strategy for the Reduction of 1,1-Diaryl Olefins Applied to an Improved Synthesis of CuIPhEt, a <i>C</i><sub>2</sub>‑Symmetric N‑Heterocyclic Carbenoid

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    A library of iridium and rhodium phosphine catalysts have been screened for the double-asymmetric hydrogenation of 2,6-di-(1-phenylethenyl)-4-methylaniline to produce the <i>C</i><sub>2</sub>-symmetric aniline precursor of the N-heterocyclic carbenoid CuIPhEt. The best catalyst produced the desired enantiomer in 98.6% selectivity. This rare example of a highly selective hydrogenation of a 1,1-diaryl olefin enables a four-step asymmetric synthesis of the <i>C</i><sub>2</sub>-symmetric phenylethyl imidazolium ion (IPhEt) from <i>p-</i>toluidine and phenylacetylene and its conversion to the hydrosilylation catalyst CuIPhEt

    Cobalt-Catalyzed Enantioselective Hydrogenation of Minimally Functionalized Alkenes: Isotopic Labeling Provides Insight into the Origin of Stereoselectivity and Alkene Insertion Preferences

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    The asymmetric hydrogenation of cyclic alkenes lacking coordinating functionality with a <i>C</i><sub>1</sub>-symmetric bis­(imino)­pyridine cobalt catalyst is described and has been applied to the synthesis of important substructures found in natural products and biologically active compounds. High activities and enantioselectivities were observed with substituted benzo-fused five-, six-, and seven-membered alkenes. The stereochemical outcome was dependent on both the ring size and exo/endo disposition. Deuterium labeling experiments support rapid and reversible 2,1-insertion that is unproductive for generating alkane product but accounts for the unusual isotopic distribution in deuterated alkanes. Analysis of the stereochemical outcome of the hydrogenated products coupled with isotopic labeling, stoichiometric, and kinetic studies established 1,2-alkene insertion as both turnover limiting and enantiodetermining with no evidence for erosion of cobalt alkyl stereochemistry by competing β-hydrogen elimination processes. A stereochemical model accounting for the preferred antipodes of the alkanes is proposed and relies on the subtle influence of the achiral aryl imine substituent on the cobalt catalyst

    Enantioselective Synthesis of β‑Aryloxycarboxylic Esters via Asymmetric Hydrogenation of β‑Aryloxy-α,β-Unsaturated Esters

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    A novel synthesis of β-aryloxycarboxylic esters via asymmetric hydrogenation of the corresponding β-aryloxy-α,β-unsaturated esters has been demonstrated. Bis(norbornadiene)rhodium(I) tetrafluoroborate (1 mol %) and Walphos W008-1 were used to generate the saturated products with high enantioselectivity and in high yield. The tolerability of the reaction to a diverse range of substituents on the aromatic ring was also explored

    General Principles and Strategies for Salting-Out Informed by the Hofmeister Series

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    Overarching principles for salting-out extraction are long-established but poorly disseminated. We highlight the opportunity for more widespread application of this technique using the Hofmeister series as a foundational basis for choosing the right salt. The power of this approach is exemplified by the aqueous workup of a highly water-soluble nucleoside in which the use of sodium sulfate allowed for high recoveries without relying on back extraction

    Synthesis and Hydrogenation Activity of Iron Dialkyl Complexes with Chiral Bidentate Phosphines

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    The activity of bis­(phosphine) iron dialkyl complexes for the asymmetric hydrogenation of alkenes has been evaluated. High-throughput experimentation was used to identify suitable iron–phosphine combinations using the displacement of pyridine from py<sub>2</sub>Fe­(CH<sub>2</sub>SiMe<sub>3</sub>)<sub>2</sub> for precatalyst formation. Preparative-scale synthesis of a family of bis­(phosphine) iron dialkyl complexes was also achieved using both ligand substitution and salt metathesis methods. Each of the isolated organometallic iron complexes was established as a tetrahedral and hence high-spin ferrous compound, as determined by Mössbauer spectroscopy, magnetic measurements, and, in many cases, X-ray diffraction. One example containing a Josiphos-type ligand, (SL-J212-1)­Fe­(CH<sub>2</sub>SiMe<sub>3</sub>)<sub>2</sub>, proved more active than other isolated iron dialkyl precatalysts. Filtration experiments and the lack of observed enantioselectivity support dissociation of the phosphine ligand upon activation with dihydrogen and formation of catalytically active heterogeneous iron. The larger six-membered chelate is believed to reduce the coordination affinity of the phosphine for the iron center, enabling metal particle formation
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