38 results on '"Dreher SD"'
Search Results
2. The Open Reaction Database.
- Author
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Kearnes SM, Maser MR, Wleklinski M, Kast A, Doyle AG, Dreher SD, Hawkins JM, Jensen KF, and Coley CW
- Abstract
Chemical reaction data in journal articles, patents, and even electronic laboratory notebooks are currently stored in various formats, often unstructured, which presents a significant barrier to downstream applications, including the training of machine-learning models. We present the Open Reaction Database (ORD), an open-access schema and infrastructure for structuring and sharing organic reaction data, including a centralized data repository. The ORD schema supports conventional and emerging technologies, from benchtop reactions to automated high-throughput experiments and flow chemistry. The data, schema, supporting code, and web-based user interfaces are all publicly available on GitHub. Our vision is that a consistent data representation and infrastructure to support data sharing will enable downstream applications that will greatly improve the state of the art with respect to computer-aided synthesis planning, reaction prediction, and other predictive chemistry tasks.
- Published
- 2021
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3. Chemistry Informer Libraries: Conception, Early Experience, and Role in the Future of Cheminformatics.
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Dreher SD and Krska SW
- Abstract
The synthetic chemistry literature traditionally reports the scope of new methods using simple, nonstandardized test molecules that have uncertain relevance in applied synthesis. In addition, published examples heavily favor positive reaction outcomes, and failure is rarely documented. In this environment, synthetic practitioners have inadequate information to know whether any given method is suitable for the task at hand. Moreover, the incomplete nature of published data makes it poorly suited for the creation of predictive reactivity models via machine learning approaches. In 2016, we reported the concept of chemistry informer libraries as standardized sets of medium- to high-complexity substrates with relevance to pharmaceutical synthesis as demonstrated using a multidimensional principle component analysis (PCA) comparison to the physicochemical properties of marketed drugs. We showed how informer libraries could be used to evaluate leading synthetic methods with the complete capture of success and failure and how this knowledge could lead to improved reaction conditions with a broader scope with respect to relevant applications. In this Account, we describe the progress made and lessons learned in subsequent studies using informer libraries to profile eight additional reaction classes. Examining broad trends across multiple types of bond disconnections against a standardized chemistry "measuring stick" has enabled comparisons of the relative potential of different methods for applications in complex synthesis and has identified opportunities for further development. Furthermore, the powerful combination of informer libraries and 1536-well-plate nanoscale reaction screening has allowed the parallel evaluation of scores of synthetic methods in the same experiment and as such illuminated an important role for informers as part of a larger data generation workflow for predictive reactivity modeling. Using informer libraries as problem-dense, strong filters has allowed broad sets of reaction conditions to be narrowed down to those that display the highest tolerance to complex substrates. These best conditions can then be used to survey broad swaths of substrate space using nanoscale chemistry approaches. Our experiences and those of our collaborators from several academic laboratories applying informer libraries in these contexts have helped us identify several areas for potential improvements to the approach that would increase their ease of use, utility in generating interpretable results, and resulting uptake by the broader community. As we continue to evolve the informer library concept, we believe it will play an ever-increasing role in the future of the democratization of high-throughput experimentation and data science-driven synthetic method development.
- Published
- 2021
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4. Excellence in Industrial Organic Synthesis 2019: The Past, Present, and Future.
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Ragan JA and Dreher SD
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- 2019
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5. The importance of synthetic chemistry in the pharmaceutical industry.
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Campos KR, Coleman PJ, Alvarez JC, Dreher SD, Garbaccio RM, Terrett NK, Tillyer RD, Truppo MD, and Parmee ER
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- Biocatalysis, Drug Industry, Enzymes chemistry, High-Throughput Screening Assays, Inventions, Machine Learning, Photochemistry, Chemistry, Pharmaceutical trends, Drug Discovery, Pharmaceutical Preparations chemical synthesis
- Abstract
Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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6. Response to Comment on "Predicting reaction performance in C-N cross-coupling using machine learning".
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Estrada JG, Ahneman DT, Sheridan RP, Dreher SD, and Doyle AG
- Subjects
- Machine Learning, Models, Chemical
- Abstract
We demonstrate that the chemical-feature model described in our original paper is distinguishable from the nongeneralizable models introduced by Chuang and Keiser. Furthermore, the chemical-feature model significantly outperforms these models in out-of-sample predictions, justifying the use of chemical featurization from which machine learning models can extract meaningful patterns in the dataset, as originally described., (Copyright © 2018, American Association for the Advancement of Science.)
- Published
- 2018
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7. Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS.
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Lin S, Dikler S, Blincoe WD, Ferguson RD, Sheridan RP, Peng Z, Conway DV, Zawatzky K, Wang H, Cernak T, Davies IW, DiRocco DA, Sheng H, Welch CJ, and Dreher SD
- Abstract
Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)., (Copyright © 2018, American Association for the Advancement of Science.)
- Published
- 2018
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8. Predicting reaction performance in C-N cross-coupling using machine learning.
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Ahneman DT, Estrada JG, Lin S, Dreher SD, and Doyle AG
- Abstract
Machine learning methods are becoming integral to scientific inquiry in numerous disciplines. We demonstrated that machine learning can be used to predict the performance of a synthetic reaction in multidimensional chemical space using data obtained via high-throughput experimentation. We created scripts to compute and extract atomic, molecular, and vibrational descriptors for the components of a palladium-catalyzed Buchwald-Hartwig cross-coupling of aryl halides with 4-methylaniline in the presence of various potentially inhibitory additives. Using these descriptors as inputs and reaction yield as output, we showed that a random forest algorithm provides significantly improved predictive performance over linear regression analysis. The random forest model was also successfully applied to sparse training sets and out-of-sample prediction, suggesting its value in facilitating adoption of synthetic methodology., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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9. The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis.
- Author
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Krska SW, DiRocco DA, Dreher SD, and Shevlin M
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- Catalysis radiation effects, Coordination Complexes chemistry, Drug Discovery, Hydrogenation, Miniaturization, Chemistry Techniques, Synthetic methods, Technology, Pharmaceutical methods
- Abstract
The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.
- Published
- 2017
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10. Palladium-Catalyzed Enantioselective Arylation of Aryl Sulfenate Anions: A Combined Experimental and Computational Study.
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Jia T, Zhang M, McCollom SP, Bellomo A, Montel S, Mao J, Dreher SD, Welch CJ, Regalado EL, Williamson RT, Manor BC, Tomson NC, and Walsh PJ
- Abstract
A novel approach to produce chiral diaryl sulfoxides from aryl benzyl sulfoxides and aryl bromides via an enantioselective arylation of aryl sulfenate anions is reported. A (JosiPhos)Pd-based catalyst successfully promotes the asymmetric arylation reaction with good functional group compatibility. A wide range of enantioenriched diaryl, aryl heteroaryl, and even diheteroaryl sulfoxides were generated. Many of the sulfoxides prepared herein would be difficult to prepare via classic enantioselective oxidation of sulfides, including Ph(Ph-d
5 )SO (90% ee, 95% yield). A DFT-based computational study suggested that chiral induction originates from two primary factors: (i) both a kinetic and a thermodynamic preference for oxidative addition that places the bromide trans to the JosiPhos-diarylphosphine moiety and (ii) Curtin-Hammett-type control over the interconversion between O- and S-bound isomers of palladium sulfenate species following rapid interconversion between re- and si-bound transmetalation products, re/si-Pd-OSPh (re/si-PdO-trans).- Published
- 2017
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11. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.
- Author
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Cernak T, Gesmundo NJ, Dykstra K, Yu Y, Wu Z, Shi ZC, Vachal P, Sperbeck D, He S, Murphy BA, Sonatore L, Williams S, Madeira M, Verras A, Reiter M, Lee CH, Cuff J, Sherer EC, Kuethe J, Goble S, Perrotto N, Pinto S, Shen DM, Nargund R, Balkovec J, DeVita RJ, and Dreher SD
- Subjects
- Chromatography, Liquid, Mass Spectrometry, Proton Magnetic Resonance Spectroscopy, Diacylglycerol O-Acyltransferase antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology
- Abstract
Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging S
N Ar reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.- Published
- 2017
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12. Synthesis of Complex Druglike Molecules by the Use of Highly Functionalized Bench-Stable Organozinc Reagents.
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Greshock TJ, Moore KP, McClain RT, Bellomo A, Chung CK, Dreher SD, Kutchukian PS, Peng Z, Davies IW, Vachal P, Ellwart M, Manolikakes SM, Knochel P, and Nantermet PG
- Subjects
- High-Throughput Screening Assays, Molecular Structure, Principal Component Analysis, Pyridines chemistry, Organometallic Compounds chemistry, Pyridines chemical synthesis, Zinc chemistry
- Abstract
The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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13. Aryl amination using ligand-free Ni(II) salts and photoredox catalysis.
- Author
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Corcoran EB, Pirnot MT, Lin S, Dreher SD, DiRocco DA, Davies IW, Buchwald SL, and MacMillan DW
- Abstract
Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
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14. Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods.
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Kutchukian PS, Dropinski JF, Dykstra KD, Li B, DiRocco DA, Streckfuss EC, Campeau LC, Cernak T, Vachal P, Davies IW, Krska SW, and Dreher SD
- Abstract
Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki-Miyaura, cyanation and Buchwald-Hartwig amination.
- Published
- 2016
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15. Palladium-Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles.
- Author
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Mao J, Zhang J, Jiang H, Bellomo A, Zhang M, Gao Z, Dreher SD, and Walsh PJ
- Subjects
- Alkylation, Catalysis, Palladium chemistry, Toluene chemistry
- Abstract
The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)3 , have been developed. These methods enable the enantioselective synthesis of α-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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16. P2Et Phosphazene: A Mild, Functional Group Tolerant Base for Soluble, Room Temperature Pd-Catalyzed C-N, C-O, and C-C Cross-Coupling Reactions.
- Author
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Buitrago Santanilla A, Christensen M, Campeau LC, Davies IW, and Dreher SD
- Abstract
The non-nucleophilic organic superbase P2Et phosphazene can enable a broad range of palladium-catalyzed cross-coupling reactions, including C-C, C-N, and C-O couplings of aryl chlorides, bromides, and iodides at room temperature. The mildness and substrate compatibility of this chemistry can deliver immediate synthetic utility for the preparation of complex molecules.
- Published
- 2015
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17. Organic chemistry. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules.
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Buitrago Santanilla A, Regalado EL, Pereira T, Shevlin M, Bateman K, Campeau LC, Schneeweis J, Berritt S, Shi ZC, Nantermet P, Liu Y, Helmy R, Welch CJ, Vachal P, Davies IW, Cernak T, and Dreher SD
- Subjects
- Biotechnology, Catalysis, Mass Spectrometry, Palladium chemistry, Robotics methods, High-Throughput Screening Assays methods, Nanoparticles, Nanotechnology methods, Pharmaceutical Preparations chemical synthesis
- Abstract
At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
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18. NiXantphos: a deprotonatable ligand for room-temperature palladium-catalyzed cross-couplings of aryl chlorides.
- Author
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Zhang J, Bellomo A, Trongsiriwat N, Jia T, Carroll PJ, Dreher SD, Tudge MT, Yin H, Robinson JR, Schelter EJ, and Walsh PJ
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- Catalysis, Ligands, Models, Molecular, Oxidation-Reduction, Protons, Temperature, Chlorides chemistry, Hydrocarbons, Aromatic chemistry, Palladium chemistry, Phosphines chemistry
- Abstract
Although the past 15 years have witnessed the development of sterically bulky and electron-rich alkylphosphine ligands for palladium-catalyzed cross-couplings with aryl chlorides, examples of palladium catalysts based on either triarylphosphine or bidentate phosphine ligands for efficient room temperature cross-coupling reactions with unactivated aryl chlorides are rare. Herein we report a palladium catalyst based on NiXantphos, a deprotonatable chelating aryldiphosphine ligand, to oxidatively add unactivated aryl chlorides at room temperature. Surprisingly, comparison of an extensive array of ligands revealed that under the basic reaction conditions the resultant heterobimetallic Pd-NiXantphos catalyst system outperformed all the other mono- and bidentate ligands in a deprotonative cross-coupling process (DCCP) with aryl chlorides. The DCCP with aryl chlorides affords a variety of triarylmethane products, a class of compounds with various applications and interesting biological activity. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of aryl chloride substrates bearing heteroaryl groups and sensitive functional groups that are known to undergo 1,2-addition, aldol reaction, and O-, N-, enolate-α-, and C(sp(2))-H arylations. The advantages and importance of the Pd-NiXantphos catalyst system outlined herein make it a valuable contribution for applications in Pd-catalyzed arylation reactions with aryl chlorides.
- Published
- 2014
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19. Development of a practical, asymmetric synthesis of the hepatitis C virus protease inhibitor MK-5172.
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Kuethe J, Zhong YL, Yasuda N, Beutner G, Linn K, Kim M, Marcune B, Dreher SD, Humphrey G, and Pei T
- Subjects
- Amides, Antiviral Agents chemistry, Carbamates, Cyclopropanes, Macrocyclic Compounds chemistry, Molecular Structure, Protease Inhibitors chemistry, Quinoxalines chemistry, Sulfonamides, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Hepacivirus drug effects, Macrocyclic Compounds chemical synthesis, Macrocyclic Compounds pharmacology, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacology, Quinoxalines chemical synthesis, Quinoxalines pharmacology
- Abstract
The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.
- Published
- 2013
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20. Palladium-catalyzed direct arylation of methyl sulfoxides with aryl halides.
- Author
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Jia T, Bellomo A, Baina KE, Dreher SD, and Walsh PJ
- Subjects
- Catalysis, Molecular Structure, Hydrocarbons, Halogenated chemistry, Organometallic Compounds chemistry, Palladium chemistry, Sulfoxides chemistry
- Abstract
The palladium-catalyzed α-arylation of unactivated sulfoxides has been developed. The weakly acidic α-protons of sulfoxides are reversibly deprotonated by LiOtBu, and a palladium phosphine complex facilitates the arylation. A variety of aryl methyl sulfoxides were coupled with aryl bromides. More challenging coupling partners, such as alkyl methyl sulfoxides (including dimethyl sulfoxide) and aryl chlorides proved to be suitable under the optimized conditions. This method was utilized to synthesize bioactive benzyl sulfoxide intermediates.
- Published
- 2013
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21. Asymmetric cross-coupling of aryl triflates to the benzylic position of benzylamines.
- Author
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McGrew GI, Stanciu C, Zhang J, Carroll PJ, Dreher SD, and Walsh PJ
- Subjects
- Benzylamines chemical synthesis, Catalysis, Mesylates chemical synthesis, Benzylamines chemistry, Chromium chemistry, Mesylates chemistry, Palladium chemistry
- Published
- 2012
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22. Palladium-catalyzed C(sp3)-H arylation of diarylmethanes at room temperature: synthesis of triarylmethanes via deprotonative-cross-coupling processes.
- Author
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Zhang J, Bellomo A, Creamer AD, Dreher SD, and Walsh PJ
- Subjects
- Benzene Derivatives chemical synthesis, Benzhydryl Compounds chemical synthesis, Bromides chemical synthesis, Bromides chemistry, Catalysis, Protons, Benzene Derivatives chemistry, Benzhydryl Compounds chemistry, Palladium chemistry
- Abstract
Although metal-catalyzed direct arylation reactions of non- or weakly acidic C-H bonds have recently received much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date, examples of intermolecular arylation of unactivated C(sp(3))-H bonds in the absence of a directing group remain scarce. We report herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp(3))-H arylation of simple diarylmethane derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically diverse hetero- and nonheteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biological activity. Key to the success of this approach is an in situ metalation of the substrate via C-H deprotonation under catalytic cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification were performed by high-throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe(3))(2)/Pd-NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp(2))-H arylation.
- Published
- 2012
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23. Rapid and efficient access to secondary arylmethylamines.
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Fleury-Brégeot N, Raushel J, Sandrock DL, Dreher SD, and Molander GA
- Subjects
- Borates chemistry, Catalysis, Hydrocarbons, Fluorinated chemistry, Methylamines chemistry, Molecular Structure, Palladium chemistry, Borates chemical synthesis, Hydrocarbons, Fluorinated chemical synthesis, Methylamines chemical synthesis
- Abstract
Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
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24. Scope of the palladium-catalyzed aryl borylation utilizing bis-boronic acid.
- Author
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Molander GA, Trice SL, Kennedy SM, Dreher SD, and Tudge MT
- Subjects
- Catalysis, Boronic Acids chemistry, Palladium chemistry
- Abstract
The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C-B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts.
- Published
- 2012
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25. Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors.
- Author
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Bellomo A, Celebi-Olcum N, Bu X, Rivera N, Ruck RT, Welch CJ, Houk KN, and Dreher SD
- Subjects
- Catalysis, Humans, Molecular Structure, Structure-Activity Relationship, HIV Integrase chemistry, HIV Integrase Inhibitors chemical synthesis, HIV Integrase Inhibitors pharmacology, High-Throughput Screening Assays methods, Pyrimidinones metabolism
- Abstract
A microscale chemistry improvement engine: a pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2012
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26. Efficient palladium-catalyzed cross-coupling of highly acidic substrates, nitroacetates.
- Author
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Metz AE, Berritt S, Dreher SD, and Kozlowski MC
- Subjects
- Catalysis, Hydrogen-Ion Concentration, Molecular Structure, Acetates chemistry, Palladium chemistry
- Abstract
Palladium-catalyzed cross-coupling conditions were developed that efficiently afford 2-aryl-2-nitroacetates from aryl bromides and the very acidic nitroacetates., (© 2012 American Chemical Society)
- Published
- 2012
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27. Palladium-catalyzed allylic substitution with (η6-arene-CH2Z)Cr(CO)(3)-based nucleophiles.
- Author
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Zhang J, Stanciu C, Wang B, Hussain MM, Da CS, Carroll PJ, Dreher SD, and Walsh PJ
- Subjects
- Catalysis, Chromium chemistry, Palladium chemistry
- Abstract
Although the palladium-catalyzed Tsuji-Trost allylic substitution reaction has been intensively studied, there is a lack of general methods to employ simple benzylic nucleophiles. Such a method would facilitate access to "α-2-propenyl benzyl" motifs, which are common structural motifs in bioactive compounds and natural products. We report herein the palladium-catalyzed allylation reaction of toluene-derived pronucleophiles activated by tricarbonylchromium. A variety of cyclic and acyclic allylic electrophiles can be employed with in situ generated (η(6)-C(6)H(5)CHLiR)Cr(CO)(3) nucleophiles. Catalyst identification was performed by high throughput experimentation (HTE) and led to the Xantphos/palladium hit, which proved to be a general catalyst for this class of reactions. In addition to η(6)-toluene complexes, benzyl amine and ether derivatives (η(6)-C(6)H(5)CH(2)Z)Cr(CO)(3) (Z = NR(2), OR) are also viable pronucleophiles, allowing C-C bond-formation α to heteroatoms with excellent yields. Finally, a tandem allylic substitution/demetalation procedure is described that affords the corresponding metal-free allylic substitution products. This method will be a valuable complement to the existing arsenal of nucleophiles with applications in allylic substitution reactions., (© 2011 American Chemical Society)
- Published
- 2011
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28. Palladium-catalyzed, direct boronic acid synthesis from aryl chlorides: a simplified route to diverse boronate ester derivatives.
- Author
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Molander GA, Trice SL, and Dreher SD
- Subjects
- Catalysis, Molecular Structure, Boronic Acids chemical synthesis, Boronic Acids chemistry, Esters chemical synthesis, Esters chemistry, Hydrocarbons, Chlorinated chemistry, Palladium chemistry
- Abstract
Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. A simple and efficient palladium-catalyzed, direct synthesis of arylboronic acids from the corresponding aryl chlorides using an underutilized reagent, tetrahydroxydiboron B(2)(OH)(4), is reported. To ensure preservation of the carbon-boron bond, the boronic acids were efficiently converted to the trifluoroborate derivatives in good to excellent yields without the use of a workup or isolation. Further, the intermediate boronic acids can be easily converted to a wide range of useful boronates. Finally, a two-step, one-pot method was developed to couple two aryl chlorides efficiently in a Suzuki-Miyaura-type reaction.
- Published
- 2010
- Full Text
- View/download PDF
29. Nickel-catalyzed cross-coupling of potassium aryl- and heteroaryltrifluoroborates with unactivated alkyl halides.
- Author
-
Molander GA, Argintaru OA, Aron I, and Dreher SD
- Subjects
- Alkylation, Catalysis, Molecular Structure, Fluorine Compounds chemistry, Halogens chemistry, Nickel chemistry, Potassium chemistry
- Abstract
A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles. Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp(3))-Br bonds in the presence of C(sp(2))-Br bonds was achieved.
- Published
- 2010
- Full Text
- View/download PDF
30. Stereospecific cross-coupling of secondary alkyl β-trifluoroboratoamides.
- Author
-
Sandrock DL, Jean-Gérard L, Chen CY, Dreher SD, and Molander GA
- Subjects
- Stereoisomerism, Substrate Specificity, Amides chemistry, Boron Compounds chemistry
- Abstract
The stereospecific cross-coupling of enantioenriched nonbenzylic secondary alkyl boron compounds has been achieved. The high selectivity toward product formation over an undesired β-H elimination pathway is achieved via an intramolecular coordination of an ancillary carbonyl to the metal center in the diorganopalladium intermediate.
- Published
- 2010
- Full Text
- View/download PDF
31. Suzuki-Miyaura cross-coupling reactions of primary alkyltrifluoroborates with aryl chlorides.
- Author
-
Dreher SD, Lim SE, Sandrock DL, and Molander GA
- Subjects
- Indicators and Reagents chemistry, Ligands, Borates chemistry, Chlorides chemistry
- Abstract
Parallel microscale experimentation was used to develop general conditions for the Suzuki-Miyaura cross-coupling of diversely functionalized primary alkyltrifluoroborates with a variety of aryl chlorides. These conditions were found to be amenable to coupling with aryl bromides, iodides, and triflates as well. The conditions that were previously identified through similar techniques to promote the cross-coupling of secondary alkyltrifluoroborates with aryl chlorides were not optimal for the primary alkyltrifluoroborates, thus demonstrating the value of parallel experimentation to develop novel, substrate specific results.
- Published
- 2009
- Full Text
- View/download PDF
32. Copper-facilitated Suzuki reactions: application to 2-heterocyclic boronates.
- Author
-
Deng JZ, Paone DV, Ginnetti AT, Kurihara H, Dreher SD, Weissman SA, Stauffer SR, and Burgey CS
- Subjects
- Catalysis, Boronic Acids chemistry, Copper chemistry, Heterocyclic Compounds chemistry
- Abstract
The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.
- Published
- 2009
- Full Text
- View/download PDF
33. Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides--reaction discovery using parallel microscale experimentation.
- Author
-
Dreher SD, Dormer PG, Sandrock DL, and Molander GA
- Subjects
- Benzene Derivatives chemistry, Catalysis, Pyridines chemistry, Benzene Derivatives chemical synthesis, Borates chemistry, Hydrocarbons, Brominated chemistry, Hydrocarbons, Chlorinated chemistry, Pyridines chemical synthesis
- Abstract
Microscale parallel experimentation was used to discover three catalyst systems capable of coupling secondary organotrifluoroborates with sterically and electronically demanding aryl chlorides and bromides. The ensuing results represent the first comprehensive study of alkylboron coupling to aryl chlorides and, in particular, using secondary alkylboron partners. A ligand-dependent beta-hydride elimination/reinsertion mechanism was implicated in the cross-coupling of more hindered substrates, leading to isomeric mixtures of coupled products in some cases.
- Published
- 2008
- Full Text
- View/download PDF
34. Asymmetric hydrogenation of N-sulfonylated-alpha-dehydroamino acids: toward the synthesis of an anthrax lethal factor inhibitor.
- Author
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Shultz CS, Dreher SD, Ikemoto N, Williams JM, Grabowski EJ, Krska SW, Sun Y, Dormer PG, and Dimichele L
- Subjects
- Amino Acids chemistry, Amino Acids pharmacology, Antigens, Bacterial, Bacillus anthracis chemistry, Bacillus anthracis pathogenicity, Catalysis, Hydrogenation, Stereoisomerism, Amino Acids chemical synthesis, Bacterial Toxins antagonists & inhibitors, Ruthenium chemistry
- Abstract
A novel and highly enantioselective Ru-catalyzed hydrogenation of N-sulfonylated-alpha-dehydroamino acids has been discovered and demonstrated in the synthesis of an anthrax lethal factor inhibitor (LFI). Herein, this methodology is used to prepare N-sulfonylated amino acids in up to 98% ee. This unprecedented hydrogenation uses a chiral Ru catalyst rather than Rh as typical for acylated dehydroamino acids and esters, and this work reports the first asymmetric hydrogenation of a tetrasubstituted dehydroamino acid derivative using a Ru catalyst. [reaction: see text]
- Published
- 2005
- Full Text
- View/download PDF
35. Highly diastereoselective heterogeneously catalyzed hydrogenation of enamines for the synthesis of chiral beta-amino acid derivatives.
- Author
-
Ikemoto N, Tellers DM, Dreher SD, Liu J, Huang A, Rivera NR, Njolito E, Hsiao Y, McWilliams JC, Williams JM, Armstrong JD 3rd, Sun Y, Mathre DJ, Grabowski EJ, and Tillyer RD
- Subjects
- Amides chemical synthesis, Amides chemistry, Amino Acids chemical synthesis, Catalysis, Crystallography, X-Ray, Deuterium, Esters chemical synthesis, Esters chemistry, Hydrogenation, Stereoisomerism, Amines chemistry, Amino Acids chemistry
- Abstract
Pure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral beta-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO2 catalyst are essential in achieving high selectivity.
- Published
- 2004
- Full Text
- View/download PDF
36. Formal total synthesis of mycoticin A.
- Author
-
Dreher SD and Leighton JL
- Subjects
- Anti-Bacterial Agents chemistry, Molecular Structure, Stereoisomerism, Anti-Bacterial Agents chemical synthesis, Macrolides
- Published
- 2001
- Full Text
- View/download PDF
37. Yb(OTf)(3)-Catalyzed oxymercuration of homoallylic alcohol-derived hemiacetals and hemiketals.
- Author
-
Dreher SD, Hornberger KR, Sarraf ST, and Leighton JL
- Subjects
- Alcohols chemistry, Benzaldehydes chemistry, Catalysis, Magnetic Resonance Spectroscopy, Acetals chemical synthesis, Allyl Compounds chemistry, Organomercury Compounds
- Abstract
1,3-Diol synthons, protected as acetonides or benzylidene acetals, may be synthesized efficiently from homoallylic alcohols and acetone or benzaldehyde by oxymercuration of the derived hemiketals and hemiacetals with HgClOAc. The use of catalytic amounts of Yb(OTf)(3) is crucial to the success of the reaction, which was determined to be reversible.
- Published
- 2000
- Full Text
- View/download PDF
38. Easy Synthesis of Functionalized Hetero[7]helicenes.
- Author
-
Dreher SD, Weix DJ, and Katz TJ
- Abstract
Hetero[7]helicenebisquinones can be synthesized easily on a multigram scale by combining the silyl enol ethers of 3,6-diacetyldibenzofuran, 3,6-diacetyldibenzothiophene, and 3,6-diacetylcarbazole with p-benzoquinone. They can be resolved into their enantiomers by a procedure that had previously been used to resolve carbohelicenebisquinones. Their absolute configurations are assigned.
- Published
- 1999
- Full Text
- View/download PDF
Catalog
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