218 results on '"Nelu Grinberg"'
Search Results
2. Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)
- Author
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Rogelio Frutos, Thomas G. Tampone, Jason Mulder, Joe Gao, Joshua D. Sieber, Sonia Rodriguez, Nizar Haddad, Katrin Baer, Jack Brown, Bing-Shiou Yang, Riccardo Giovannini, Jinhua J. Song, Nelu Grinberg, Heewon Lee, and Chris H. Senanayake
- Subjects
Organic Chemistry ,Physical and Theoretical Chemistry - Published
- 2023
3. Ewing’s Analytical Instrumentation Handbook, Fourth Edition
- Author
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Nelu, Grinberg, primary and Sonia, Rodriguez, additional
- Published
- 2019
- Full Text
- View/download PDF
4. Advances in Chromatography
- Author
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Nelu Grinberg and Peter W. Carr
- Published
- 2022
5. Sulfone-Mediated SNAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More—Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420
- Author
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Heewon Lee, Nelu Grinberg, Nitinchandra D. Patel, Andrew Ye, Azad Hossain, Carl A. Busacca, Jon C. Lorenz, Chris H. Senanayake, Anjan Saha, Denis Byrne, Nizar Haddad, Suresh R. Kapadia, Xudong Wei, Nathan K. Yee, Philomen DeCroos, Bikshandarkoil A. Narayanan, Max Sarvestani, and Scott Pennino
- Subjects
Protease ,010405 organic chemistry ,Chemistry ,medicine.medical_treatment ,Organic Chemistry ,Convergent synthesis ,Substrate (chemistry) ,Ether ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Protease inhibitor (biology) ,0104 chemical sciences ,Sulfone ,chemistry.chemical_compound ,Nucleophilic aromatic substitution ,Yield (chemistry) ,medicine ,medicine.drug - Abstract
An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.
- Published
- 2020
6. Advances in Chromatography
- Author
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Nelu Grinberg and Peter W. Carr
- Subjects
Chromatography ,Volume (thermodynamics) ,Chemistry - Published
- 2021
7. Advances in Chromatography : Volume 60
- Author
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Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Abstract
For six decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to-date information on a wide range of developments in chromatographic methods and applications. The clear presentation of topics and vivid illustrations for which this series has become known make the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill. Presents an in-depth review of chaotropic chromatography. Reviews recent advances in HPLC and SFC columns packed with hybrid organic/inorganic particles. Explores new advances in nano-liquid chromatography for proteomics analysis. Outlines the heterogeneity of gangliosides and advances in the chromatographic techniques used in their separation.
- Published
- 2024
8. Advances in Chromatography Volume 57
- Author
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Nelu Grinberg and Peter W. Carr
- Subjects
Chromatography ,Volume (thermodynamics) ,Chemistry - Published
- 2020
9. Sulfone-Mediated S
- Author
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Nitinchandra D, Patel, Xudong, Wei, Denis, Byrne, Bikshandarkoil A, Narayanan, Scott, Pennino, Max, Sarvestani, Anjan, Saha, Nizar, Haddad, Suresh, Kapadia, Jon C, Lorenz, Philomen, DeCroos, Andrew, Ye, Heewon, Lee, Nelu, Grinberg, Azad, Hossain, Carl A, Busacca, Nathan K, Yee, and Chris H, Senanayake
- Subjects
Humans ,Protease Inhibitors ,Hepacivirus ,Sulfones ,Viral Nonstructural Proteins ,Antiviral Agents ,Hepatitis C ,Ethers - Abstract
An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive S
- Published
- 2020
10. Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki–Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis
- Author
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Sergei Tcyrulnikov, Joshua D. Sieber, Nitinchandra D. Patel, Kendricks S. Lao, Marisa C. Kozlowski, Soumik Biswas, Chris H. Senanayake, Nelu Grinberg, Krishnaja Duvvuri, Neil K. Garg, B. Frank Gupton, Daniel Rivalti, Jinhua J. Song, Scott Pennino, Bo Qu, Heewon Lee, Donghong A. Gao, Yongda Zhang, Hari P. R. Mangunuru, Nizar Haddad, Bryan J. Simmons, and Keith R. Fandrick
- Subjects
biology ,010405 organic chemistry ,Negishi coupling ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,biology.organism_classification ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,Reductive elimination ,Coupling reaction ,0104 chemical sciences ,Transmetalation ,chemistry ,Catalytic cycle ,Tetra ,Palladium - Abstract
Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.
- Published
- 2018
11. Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF3-Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation
- Author
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Yanchao Xin, Frank Roschangar, Zeena Williams, Denis Byrne, Dmitry Kurouski, Jason A. Mulder, Jinhua J. Song, Alice T. Granger, Laurence J. Nummy, Jon C. Lorenz, Scott Pennino, Frederic G. Buono, Chris H. Senanayake, Yaping Hong, Ajith Premasiri, Nathan K. Yee, Joe Gao, Sonia Rodriguez, Xinzhu Zhang, Bo Qu, Jack D. Brown, Rogelio P. Frutos, Bikshandarkoil A. Narayanan, Zhantong Mao, Azad Hossain, Ning Li, Mariusz Krawiec, Heewon Lee, Yongda Zhang, Zhengxu S. Han, Nizar Haddad, Zhibin Li, Yibo Xu, Nelu Grinberg, Joshua D. Sieber, and Carl A. Busacca
- Subjects
Chiral auxiliary ,Trifluoromethyl ,Chromatography ,010405 organic chemistry ,Ligand ,Organic Chemistry ,Asymmetric hydrogenation ,Enantioselective synthesis ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Yield (chemistry) ,Vinyl acetate ,Enantiomeric excess - Abstract
A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
- Published
- 2018
12. Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones via dynamic kinetic resolution
- Author
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Joshua D. Sieber, Heewon Lee, Yongda Zhang, Sergei Tcyrulnikov, Jean-Nicolas Desrosiers, Joyce C. Leung, Nathan K. Yee, Olga V. Zatolochnaya, Kendricks S. Lao, Sonia Rodriguez, Soumik Biswas, Hari P. R. Mangunuru, Bo Qu, Nelu Grinberg, Daniel Rivalti, Chris H. Senanayake, Xiao-Jun Wang, Guisheng Li, Marisa C. Kozlowski, Nizar Haddad, and Jinhua J. Song
- Subjects
010405 organic chemistry ,Chemistry ,Asymmetric hydrogenation ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Stereocenter ,Kinetic resolution ,chemistry.chemical_compound ,Crystallography ,Copper catalyzed ,Copper hydride ,Single crystal - Abstract
A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones via dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers with up to >99 : 1 dr and 98 : 2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT calculations revealed a novel heteroligated dimeric copper hydride transition state.
- Published
- 2018
13. Advances in Chromatography : Volume 59
- Author
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Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Subjects
- TP248.3
- Abstract
For six decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to-date information on a wide range of developments in chromatographic methods and applications. The clear presentation of topics and vivid illustrations for which this series has become known make the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill. Describes the thermodynamics and kinetics underlying hydrophobic interaction chromatography of proteins. Outlines use of a kinetic model in the predictive modeling of evaporation processes that eliminates the need to know the composition and identity of the chemical constituents in the sample. Explores building and employing QSRR models in cyclodextrin modified high-performance liquid chromatography (HPLC). Reviews chemometric methods commonly paired with comprehensive 2D separations and key instrumental and preprocessing considerations.
- Published
- 2022
14. Advances in Chromatography : Volume 58
- Author
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Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Subjects
- Chromatographic analysis
- Abstract
For six decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to date information on a wide range of developments in chromatographic methods and applications. The clear presentation of topics and vivid illustrations for which this series has become known makes the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill.Key Features: Discusses the basic concepts of affinity chromatography and examines recent developments in this method and related supramolecular separation methods. Outlines the different types of gradient stationary phases and how they have been used in and benefited the field of separation science. Reviews recent trends in detectors for GC, focusing on those that are readily available and seeing wide usage. Addresses peak compression in GELC and offers the reader a plate height equation to work with that incorporates its effects.
- Published
- 2021
15. P-Stereogenic Chiral Phosphine−Palladium Complex Catalyzed Enantioselective Synthesis of Phosphoryl-Substituted Atropisomeric Vinylarenes
- Author
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Zhengxu S. Han, Heewon Lee, Yongda Zhang, Chris H. Senanayake, Hao Wu, Frank Roschangar, Nelu Grinberg, Bo Qu, Dan Wang, Guijun Wang, Jinhua J. Song, and Yibo Xu
- Subjects
inorganic chemicals ,010405 organic chemistry ,Stereochemistry ,Aryl ,Enantioselective synthesis ,Grignard reaction ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,chemistry ,Axial chirality ,Enantiomer ,Phosphine ,Palladium - Abstract
P-Stereogenic chiral phosphine BI-BOP is employed for the first time as ligand to promote catalytic enantioselective synthesis of phosphoryl-substituted atropisomeric vinylarenes through a palladium−carbene pathway. This strategy utilizes 10 mol% palladium(II) acetate, 10 mol% phosphine ligand as well as a variety of N-tosylhydrazones and phosphoryl-substituted aryl bromides as the reaction partners. The desired axially chiral vinylarenes were isolated with up to 80% yield and 96:4 er, and can be further converted effectively and stereoselectively into dialkylphosphoryl-substituted atropisomeric arenes through a Grignard reaction. This protocol offers a general approach to synthesize phosphoryl-substituted atropisomeric vinylarenes with high enantiomeric purities.
- Published
- 2017
16. Early Development Scale-Up of a Structurally-Challenging 5-Lipoxygenase Activating Protein (FLAP) Inhibitor
- Author
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Zhidong Chen, Carl A. Busacca, Shengli Ma, Xingzhong Zeng, Peter Allen Nemoto, Paige E. Mahaney, Jason A. Mulder, Chris H. Senanayake, Jun Wang, Nitinchandra D. Patel, Zhibin Li, Todd Bosanac, Daniel R. Fandrick, Jean-Nicolas Desrosiers, Heewon Lee, Sonia Rodriguez, Jon C. Lorenz, Nathan K. Yee, Joe Gao, Nelu Grinberg, Hidenori Takahashi, Alessandra Bartolozzi, Jinhua J. Song, and Keith R. Fandrick
- Subjects
Chromatography ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Structural component ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Supercritical fluid chromatography ,biology.protein ,Physical and Theoretical Chemistry ,5-lipoxygenase-activating protein - Abstract
A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.
- Published
- 2017
17. Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations
- Author
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Nelu Grinberg, Jon C. Lorenz, Xudong Wei, Philomen DeCroos, Nathan K. Yee, Xiao-Jun Wang, Zhulin Tan, Yongda Zhang, Guisheng Li, and Chris H. Senanayake
- Subjects
Phosphine oxide ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Ligand ,Organic Chemistry ,Resolution (electron density) ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,law.invention ,chemistry.chemical_compound ,law ,Yield (chemistry) ,Core (graph theory) ,Epimer ,Crystallization - Abstract
An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.
- Published
- 2017
18. Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines
- Author
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Chris H. Senanayake, Daniel R. Fandrick, Keith R. Fandrick, Christine A. Hart, James T. Masters, Max Sarvestani, Ifeanyi S. Okafor, Nelu Grinberg, Heewon Lee, Sanjit Sanyal, Jennifer L. Stockdill, Michael A. Mercadante, and Nina C. Gonnella
- Subjects
chemistry.chemical_classification ,Aldimine ,Indolizidines ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Imine ,Trimer ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Asymmetric induction ,0104 chemical sciences ,chemistry.chemical_compound ,Monomer ,chemistry ,Hydroamination ,Physical and Theoretical Chemistry ,Equilibrium constant - Abstract
The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (-)-crispine A and (-)-harmicine.
- Published
- 2016
19. Techniques of Chiroptical Spectroscopy
- Author
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Nelu Grinberg, Harry G. Brittain, and Sonia Rodriguez
- Published
- 2019
20. Enantioselective Synthesis of 4-Methyl-3,4-dihydroisocoumarin via Asymmetric Hydroformylation of Styrene Derivatives
- Author
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Bo Qu, Marisa C. Kozlowski, Nizar Haddad, Madison R. Herling, Renchang Tan, Nelu Grinberg, Xumu Zhang, and Chris H. Senanayake
- Subjects
Aldehydes ,Molecular Structure ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Stereoisomerism ,Ligands ,Article ,Styrene ,chemistry.chemical_compound ,Dihydroisocoumarin ,Coumarins ,Organic chemistry ,Hydroformylation - Abstract
[Image: see text] Enantioenriched aldehydes are produced through asymmetric hydroformylation of styrene derivatives using BIBOP type ligands. The featured example is enantioselective synthesis of 4-methyl-3,4-dihydroisocoumarin, which was prepared in a 95.1:4.9 enantiomeric ratio from asymmetric hydroformylation of ethyl 2-vinylbenzoate, then in situ lactonization during reduction process. The conditions are compatible with both electron-rich and electron-poor substituents.
- Published
- 2019
21. Advances in Chromatography
- Author
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Nelu Grinberg and Peter W. Carr
- Subjects
Materials science ,Chromatography ,Volume (thermodynamics) ,Chemistry - Published
- 2019
22. Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra
- Author
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Nitinchandra Dahyabhai, Patel, Joshua D, Sieber, Sergei, Tcyrulnikov, Bryan J, Simmons, Daniel, Rivalti, Krishnaja, Duvvuri, Yongda, Zhang, Donghong A, Gao, Keith R, Fandrick, Nizar, Haddad, Kendricks So, Lao, Hari Prasad Reddy, Mangunuru, Soumik, Biswas, Bo, Qu, Nelu, Grinberg, Scott, Pennino, Heewon, Lee, Jinhua J, Song, B Frank, Gupton, Neil K, Garg, Marisa C, Kozlowski, and Chris H, Senanayake
- Subjects
Article - Abstract
Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.
- Published
- 2018
23. Advances in Chromatography, Volume 57
- Author
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Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Subjects
- QD79.C4
- Abstract
For more than five decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to date information on a wide range of developments in chromatographic methods and applications. The clear presentation of topics and vivid illustrations for which this series has become known makes the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill. This volume considers the achievements and legacy of Lloyd R. Snider in separation science and analytical chemistry. Key Features:• Provides a historical perspective of the evolution of SMB technology together with a theoretical analysis of the most relevant underlying phenomena • Presents a brief survey of the polar columns suitable for HILIC separations and pays special attention to the role of the mobile phase in RP and HILIC modes • Describes recent strategies of method development in Kosmotropic chromatography• Surveys the many approaches to avert the effects of temperature in reversed-phase liquid chromatographic separations• Reviews separation of isotopic compounds by HPLC in relation to the advances of columns and stationary phases
- Published
- 2020
24. Advances in Chromatography : Volume 56
- Author
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Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Subjects
- Chromatographic analysis
- Abstract
For more than five decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-todate information on a wide range of developments in chromatographic methods and applications. The clear presentation of topics and vivid illustrations for which this series has become known makes the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill.Key Features: Includes a chapter dedicated to Izaak Maurits Kolthoff, offering a unique look at his non-professional life as well as his impact and legacy in Analytical Chemistry. Discusses recent advances in two-dimensional liquid chromatography for the characterization of monoclonal antibodies and other therapeutic proteins. Reviews solvation processes, methodologies of their measurement, and parameters influenced solvation Explores recent advances in TLC analysis of natural colorings, determination of synthetic dyes, and determination of EU-permitted natural colors, in foods. Offers comprehensive and critical insights on the key aspects of CE-MS analysis of intact proteins
- Published
- 2019
25. Ewing's Analytical Instrumentation Handbook, Fourth Edition
- Author
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Nelu Grinberg, Sonia Rodriguez, Nelu Grinberg, and Sonia Rodriguez
- Subjects
- Analytical chemistry--Instruments--Handbooks, manuals, etc, Instrumental analysis--Handbooks, manuals, etc, Analytical chemistry--Technique, Analytical chemistry--Equipment and supplies
- Abstract
This handbook is a guide for workers in analytical chemistry who need a starting place for information about a specific instrumental technique. It gives a basic introduction to the techniques and provides leading references on the theory and methodology for an instrumental technique. This edition thoroughly expands and updates the chapters to include concepts, applications, and key references from recent literature. It also contains a new chapter on process analytical technology.
- Published
- 2019
26. Buscopan labeled with carbon-14 and deuterium
- Author
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Heewon Lee, Zhibin Li, Carl A. Busacca, Nelu Grinberg, Michael Dipl Chem Dr Stiasni, Chris H. Senanayake, Bachir Latli, and Matt Hrapchak
- Subjects
Active ingredient ,010405 organic chemistry ,medicine.drug_class ,Chemistry ,Organic Chemistry ,Radiosynthesis ,Radiochemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Tropic acid ,0104 chemical sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Bromide ,Drug Discovery ,Anticholinergic ,medicine ,Moiety ,Organic chemistry ,Radiology, Nuclear Medicine and imaging ,Carbon-14 ,Butyl bromide ,Spectroscopy - Abstract
Hyosine butyl bromide, the active ingredient in Buscopan, is an anticholinergic and antimuscarinic drug used to treat pain and discomfort caused by abdominal cramps. A straightforward synthesis of carbon-14– and deuterium-labeled Buscopan was developed using scopolamine, n-butyl-1-14C bromide, and n-butyl-2H9 bromide, respectively. In a second carbon-14 synthesis, the radioactive carbon was incorporated in the tropic acid moiety to follow its metabolism. Herein, we describe the detailed preparations of carbon-14– and deuterium-labeled Buscopan.
- Published
- 2016
27. Reengineered BI-DIME Ligand Core Based on Computer Modeling to Increase Selectivity in Asymmetric Suzuki-Miyaura Coupling for the Challenging Axially Chiral HIV Integrase Inhibitor
- Author
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Heewon Lee, Nelu Grinberg, Nizar Haddad, Chris H. Senanayake, Nathan K. Yee, Joshua D. Sieber, Dmitry Kurouski, Nitinchandra D. Patel, Keith R. Fandrick, Jinhua J. Song, Bo Qu, Jean-Nicolas Desrosiers, Sonia Rodriguez, and Hari P. R. Mangunuru
- Subjects
Coupling ,Atropisomer ,biology ,010405 organic chemistry ,Stereochemistry ,Ligand ,Quinoline ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Integrase ,chemistry.chemical_compound ,chemistry ,Suzuki reaction ,biology.protein ,Selectivity - Abstract
Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki–Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3′,5′-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki–Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates.
- Published
- 2016
28. Synthesis of Enantioenriched 2-Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts
- Author
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Joshua D. Sieber, Shengli Ma, Jolaine Savoie, Xudong Wei, Max Sarvestani, Dmitry Kurouski, Jean-Nicolas Desrosiers, Hari P. R. Mangunuru, Bo Qu, Heewon Lee, Nizar Haddad, Nelu Grinberg, Lalith P. Samankumara, Keith R. Fandrick, Jinhua J. Song, Nathan K. Yee, and Chris H. Senanayake
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Ligand ,Organic Chemistry ,Enantioselective synthesis ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,Molecule ,Pyridinium ,Piperidine ,Physical and Theoretical Chemistry ,Alkyl ,Tricyclic - Abstract
An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.
- Published
- 2016
29. Construction of Quaternary Stereocenters by Nickel‐Catalyzed Heck Cyclization Reactions
- Author
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Liana Hie, Nelu Grinberg, Neil K. Garg, Chris H. Senanayake, Soumik Biswas, Olga V. Zatolochnaya, Nathan K. Yee, Sonia Rodriguez, Jean-Nicolas Desrosiers, Heewon Lee, and Nizar Haddad
- Subjects
010405 organic chemistry ,Chemistry ,Stereochemistry ,chemistry.chemical_element ,Homogeneous catalysis ,General Medicine ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Stereocenter ,Nickel ,Heck reaction - Abstract
A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.
- Published
- 2016
30. Rhodium-Catalyzed Asymmetric Allenylation of Sulfonylimines and Application to the Stereospecific Allylic Allenylation
- Author
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Veronica V. Angeles‐Dunham, Dimitry Kurouski, Nelu Grinberg, Joshua D. Sieber, Chris H. Senanayake, Nathan K. Yee, Daniel R. Fandrick, Anita E. Mattson, Heewon Lee, Nizar Haddad, Jinhua J. Song, and Divya Chennamadhavuni
- Subjects
Allylic rearrangement ,010405 organic chemistry ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,Rhodium ,Catalysis ,Tsuji–Trost reaction ,Stereospecificity ,chemistry ,Palladium - Published
- 2016
31. An Enantioselective Synthesis of an 11-β-HSD-1 Inhibitor via an Asymmetric Methallylation Catalyzed by (S)-3,3′-F2-BINOL
- Author
-
Nelu Grinberg, Jun Wang, Guisheng Li, Jon C. Lorenz, Joe Johnson, Xiufeng Sun, Heewon Lee, Yongda Zhang, Wenjie Li, Joe Gao, Sanjit Sanyal, Zhulin Tan, Nathan K. Yee, Bruce Z. Lu, Keith R. Fandrick, Jiang-Ping Wu, Chris H. Senanayake, Jonathan T. Reeves, and Sonia Rodriguez
- Subjects
010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Stereoisomerism ,Naphthols ,Ketones ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Propane ,Yield (chemistry) ,11-beta-Hydroxysteroid Dehydrogenases - Abstract
An efficient asymmetric synthesis of 11-β-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.
- Published
- 2016
32. Nickel-catalyzed C-3 direct arylation of pyridinium ions for the synthesis of 1-azafluorenes
- Author
-
Marisa C. Kozlowski, Xingzhong Zeng, Bo Qu, Nizar Haddad, Jean-Nicolas Desrosiers, Xudong Wei, Nelu Grinberg, Heewon Lee, Osvaldo Gutierrez, Frank Roschangar, Jolaine Savoie, Nathan K. Yee, Jinhua J. Song, and Chris H. Senanayake
- Subjects
inorganic chemicals ,010405 organic chemistry ,Phenanthroline ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Oxidative addition ,Article ,0104 chemical sciences ,Catalysis ,Homolysis ,chemistry.chemical_compound ,Nickel ,Deprotonation ,chemistry ,Pyridine ,Organic chemistry ,Pyridinium - Abstract
The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.
- Published
- 2016
33. Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl) Boronic Acid
- Author
-
Keith R. Fandrick, Nitinchandra D. Patel, Nelu Grinberg, Heewon Lee, Nathan K. Yee, Shengli Ma, Kanwar Sidhu, Yongda Zhang, Carl A. Busacca, Jason A. Mulder, Jinhua J. Song, Zhibin Li, Joe Gao, Jon C. Lorenz, Melissa A. Herbage, and Chris H. Senanayake
- Subjects
010405 organic chemistry ,Pinacol ,Organic Chemistry ,010402 general chemistry ,Key features ,01 natural sciences ,Borylation ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Suzuki reaction ,Yield (chemistry) ,Organic chemistry ,Amine gas treating ,Physical and Theoretical Chemistry ,Boronic acid - Abstract
A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal–halogen exchange using n-BuLi and trapping with B(Oi-Pr)3. The water-soluble boronic acid is isolated by a well-designed acid–base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki–Miyaura borylation to form the pinacol boronic ester is also described.
- Published
- 2015
34. BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation
- Author
-
Joshua D. Sieber, Bo Qu, Heewon Lee, Olga V. Zatolochnaya, Nizar Haddad, Jean-Nicolas Desrosiers, Ling Wu, Soumik Biswas, Chris H. Senanayake, Guisheng Li, Nathan K. Yee, Nelu Grinberg, Xiao-Jun Wang, Daniel R. Fandrick, Daniel Rivalti, Sonia Rodriguez, Hari P. R. Mangunuru, Shuklendu D. Karyakarte, and Jinhua J. Song
- Subjects
Steric effects ,Denticity ,010405 organic chemistry ,Chemistry ,Aryl ,Organic Chemistry ,Asymmetric hydrogenation ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Physical and Theoretical Chemistry ,Selectivity ,Phosphine - Abstract
Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.
- Published
- 2018
35. Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF
- Author
-
Joshua D, Sieber, Sonia, Rodriguez, Rogelio, Frutos, Frederic, Buono, Yongda, Zhang, Ning, Li, Bo, Qu, Ajith, Premasiri, Zhibin, Li, Zhengxu S, Han, Yibo, Xu, Denis, Byrne, Nizar, Haddad, Jon, Lorenz, Nelu, Grinberg, Dmitry, Kurouski, Heewon, Lee, Bikshandarkoil, Narayanan, Laurence, Nummy, Jason, Mulder, Jack D, Brown, Alice, Granger, Joe, Gao, Mariusz, Krawiec, Zeena, Williams, Scott, Pennino, Jinhua J, Song, Azad, Hossain, Nathan K, Yee, Carl, Busacca, Frank, Roschangar, Yanchao, Xin, Zhantong, Mao, Xinzhu, Zhang, Yaping, Hong, and Chris H, Senanayake
- Abstract
A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
- Published
- 2018
36. Three-dimensional structure of cyclic antibiotic teicoplanin aglycone using NMR distance and dihedral angle restraints in a DMSO solvation model
- Author
-
Shengli Ma, Nina C. Gonnella, Om P. Choudhary, Keith R. Fandrick, Nelu Grinberg, and Mark Mcloughlin
- Subjects
Quantitative Biology::Biomolecules ,Crystallography ,Chemistry ,Chemical shift ,Side chain ,Teicoplanin aglycone ,Molecule ,General Materials Science ,Density functional theory ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Dihedral angle ,Root-mean-square deviation - Abstract
The three-dimensional solution conformation of teicoplanin aglycone was determined using NMR spectroscopy. A combination of NOE and dihedral angle restraints in a DMSO solvation model was used to calculate an ensemble of structures having a root mean square deviation of 0.17 A. The structures were generated using systematic searches of conformational space for optimal satisfaction of distance and dihedral angle restraints. Comparison of the NMR-derived structure of teicoplanin aglycone with the X-ray structure of a teicoplanin aglycone analog revealed a common backbone conformation with deviation of two aromatic side chain substituents. Experimentally determined backbone 13C chemical shifts showed good agreement with those computed at the density functional level of theory, providing a cross validation of the backbone conformation. The flexible portion of the molecule was consistent with the region that changes conformation to accommodate protein binding. The results showed that a hydrogen-bonded DMSO molecule in combination with NMR-derived restraints together enabled calculation of structures that satisfied experimental data. Copyright © 2015 John Wiley & Sons, Ltd.
- Published
- 2015
37. Quantitative Analysis of Pectin in Drug Product by Size Exclusion Chromatography with Indirect Photometric Detection
- Author
-
Nelu Grinberg, Jane Li, Shengli Ma, Chris H. Senanayake, Heewon Lee, Keith R. Fandrick, and Frank Roschangar
- Subjects
Chromatography ,food.ingredient ,Pectin ,Clinical Biochemistry ,Size-exclusion chromatography ,Pharmaceutical Science ,Chromophore ,Biochemistry ,Analytical Chemistry ,chemistry.chemical_compound ,food ,chemistry ,Phase (matter) ,Drug product ,Derivatization ,Quantitative analysis (chemistry) ,Boronic acid - Abstract
A method for quantitative analysis of pectin in lozenges is reported. The separation was achieved using size exclusion chromatography. While pectin has no chromophore, to detect the separated pectins, an on-column derivatization with phenylboronic added as an additive in the mobile phase followed by indirect photometric detection was employed. The mobile phase, pH, and concentration of the additive were investigated to develop the optimal method with good linearity (R2 = 0.999). The method was applied to the determination of quantity of pectins in commercial lozenges.
- Published
- 2015
38. Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor
- Author
-
Nelu Grinberg, Marc-André Poupart, Jon C. Lorenz, Bo Qu, Nizar Haddad, Nina C. Gonnella, Shengli Ma, Nathan K. Yee, Wenjun Tang, Jiang-Ping Wu, Youla S. Tsantrizos, Wenjie Li, Joe Gao, Kanwar Sidhu, June Wang, Nitinchandra D. Patel, Sonia Rodriguez, Sanjit Sanyal, Heewon Lee, Yongda Zhang, Carl A. Busacca, Diana C. Reeves, Bruce Z. Lu, Keith R. Fandrick, and Chris H. Senanayake
- Subjects
Atropisomer ,Sulfonamides ,biology ,Stereochemistry ,Chemistry ,Acylation ,Enantioselective synthesis ,HIV ,Stereoisomerism ,General Chemistry ,HIV Integrase ,General Medicine ,Ligands ,Catalysis ,Integrase ,biology.protein ,Molecule ,Humans ,HIV Integrase Inhibitors ,Copper - Abstract
A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.
- Published
- 2015
39. Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic Phosphinamides for Catalyst Design
- Author
-
DiAndra M. Rudzinski, Frank Roschangar, Bo Qu, Jinhua J. Song, Shengli Ma, Anji Chen, Guijun Wang, Jean-Nicolas Desrosiers, Lalith P. Samankumara, Zhengxu S. Han, Nathan K. Yee, Chris H. Senanayake, Yibo Xu, Zhibin Li, Keith R. Fandrick, Nelu Grinberg, Jonathan T. Reeves, Nitinchandra D. Patel, Li Zhang, Maurice A. Marsini, and Joshua D. Sieber
- Subjects
General method ,Molecular Structure ,Phosphines ,Chemistry ,Enantioselective synthesis ,Stereoisomerism ,Chemistry Techniques, Synthetic ,General Chemistry ,General Medicine ,Phosphinate ,Amides ,Phosphinic Acids ,Catalysis ,Stereocenter ,Transfer agent ,Lewis Bases ,Nucleophilic substitution ,Organic chemistry ,Lewis acids and bases - Abstract
The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.
- Published
- 2015
40. Revisiting large volume injection in non-miscible diluents: an on-line reversed phase supported liquid extraction/liquid chromatography scenario
- Author
-
Florentin Tache, Paul Lazar, Florin Albu, Stefan Udrescu, Andrei Medvedovici, and Nelu Grinberg
- Subjects
Chromatography ,Chemistry ,Dodecane ,Elution ,Silica gel ,General Chemical Engineering ,Extraction (chemistry) ,General Engineering ,Reversed-phase chromatography ,Decane ,Analytical Chemistry ,Homologous series ,chemistry.chemical_compound ,Phase (matter) - Abstract
According to some recently published studies, large volume injection (LVI) of diluents immiscible with the eluents used in reversed phase liquid chromatography (RPLC) appears to be feasible, despite the widely accepted rules governing injection related phenomena. The process was previously described and was successfully applied in practice. The present study describes a simple theoretical model explaining LVI of diluents immiscible with the mobile phase in RPLC; the model relies on the on-line coupling of reversed phase supported liquid extraction (RP-SLE) to the chromatographic separation. The compliance of the theoretical model with experimental observations was tested by using data collected for LVI of a homologous series of para-hydroxy alkyl benzoates (methyl, ethyl, propyl, butyl, pentyl, hexyl and octyl congeners) in liquid alkanes (hexane, heptane, iso-octane, decane and dodecane). The SP consisted of an octadecyl chemically modified silica gel eluted with a mixture of acetonitrile:water 4:6 (v/v). Although the model mainly focuses on explaining the linear reduction of the retention time with the injected volume, some aspects relating to zone spreading and thermodynamic aspects are also discussed.
- Published
- 2015
41. A Mild Dihydrobenzooxaphosphole Oxazoline/Iridium Catalytic System for Asymmetric Hydrogenation of Unfunctionalized Dialins
- Author
-
Keith McKellop, Bo Qu, Zhibin Li, Lalith P. Samankumara, Scott Pennino, Keith R. Fandrick, Jinhua J. Song, Zhengxu S. Han, Nizar Haddad, Shengli Ma, Sonia Rodriguez, Jean-Nicolas Desrosiers, Nina C. Gonnella, Nelu Grinberg, and Chris H. Senanayake
- Subjects
Models, Molecular ,Chemistry ,Imine ,Asymmetric hydrogenation ,Enantioselective synthesis ,chemistry.chemical_element ,Stereoisomerism ,General Chemistry ,Oxazoline ,General Medicine ,Iridium ,Catalysis ,chemistry.chemical_compound ,Polymer chemistry ,Organic chemistry ,Hydrogenation ,Imines ,Oxazoles ,Hydrogen - Abstract
Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2 , up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones.
- Published
- 2014
42. Advances in Chromatography : Volume 55
- Author
-
Nelu Grinberg, Peter W. Carr, Nelu Grinberg, and Peter W. Carr
- Subjects
- QD79.C4
- Abstract
For more than five decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to-date information on a wide range of developments in chromatographic methods and applications. For Volume 55, established, well-known chemists offer cutting-edge reviews of chromatographic methods to pay tribute to the late Eli Grushka, beloved series editor, who inspired and mentored many in the field of separation science. The clear presentation of topics and vivid illustrations for which this series has become known makes the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill.
- Published
- 2017
43. Advances in Chromatography, Volume 53
- Author
-
Eli Grushka, Nelu Grinberg, Eli Grushka, and Nelu Grinberg
- Subjects
- QD79.C4
- Abstract
For more than four decades, scientists and researchers have relied on the Advances in Chromatography series for the most up-to-date information on a wide range of developments in chromatographic methods and applications. For Volume 53, the series editors have invited established, well-known chemists to offer cutting-edge reviews of chromatographic methods with applications in the life sciences. The clear presentation of topics and vivid illustrations for which this series has become known makes the material accessible and engaging to analytical, biochemical, organic, polymer, and pharmaceutical chemists at all levels of technical skill.
- Published
- 2017
44. Long-Range Molecular Interactions Involved in the Retention Mechanisms of Liquid Chromatography
- Author
-
Serban C. Moldoveanu, Nelu Grinberg, and Victor David
- Subjects
Range (particle radiation) ,Molecular interactions ,Chromatography ,Chemistry ,Mass spectrometry imaging - Published
- 2017
45. Enantioselective Nickel-Catalyzed Mizoroki-Heck Cyclizations to Generate Quaternary Stereocenters
- Author
-
Carl A. Busacca, Sergei Tcyrulnikov, Bo Qu, Nizar Haddad, Soumik Biswas, Liana Hie, Dmitry Kurouski, Jialin Wen, Marisa C. Kozlowski, Neil K. Garg, Jean-Nicolas Desrosiers, Xumu Zhang, Jinhua J. Song, Nathan K. Yee, Ling Wu, Nelu Grinberg, and Chris H. Senanayake
- Subjects
010405 organic chemistry ,Chemistry ,Organic Chemistry ,Chiral ligand ,Enantioselective synthesis ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Oxidative addition ,Article ,0104 chemical sciences ,Catalysis ,Stereocenter ,Nickel ,Organic chemistry ,Reactivity (chemistry) ,Physical and Theoretical Chemistry ,Selectivity - Abstract
The development of enantioselective carbon-carbon bond couplings catalyzed by non-precious metals is highly desirable in terms of cost-efficiency and sustainability. The first nickel-catalyzed enantioselective Mizoroki-Heck coupling is reported. This transformation is accomplished via mild reaction conditions, leveraging on QuinoxP* as a chiral ligand to afford oxindoles containing quaternary stereocenters. Good reactivity and selectivity are observed in the presence of various functional groups. Computational studies suggest that the oxidative addition assembles an atropisomeric intermediate responsible for the facial selectivity of the insertion step.
- Published
- 2017
46. Remarkable Enhancement of Enantioselectivity in the Asymmetric Conjugate Addition of Dimethylzinc to (Z)-Nitroalkenes with a Catalytic [(MeCN)4Cu]PF6-Hoveyda Ligand Complex
- Author
-
Xingzhong Zeng, Nathan K. Yee, Nizar Haddad, Melissa A. Herbage, Joe J. Gao, Xudong Wei, Sonia Rodriguez, Bo Qu, Chris H. Senanayake, Shengli Ma, Heewon Lee, Jason A. Mulder, Nelu Grinberg, Keith R. Fandrick, Jinhua J. Song, and Jean-Nicolas Desrosiers
- Subjects
Chemistry ,Stereochemistry ,Ligand ,Dimethylzinc ,Enantioselective synthesis ,General Medicine ,General Chemistry ,Nitroalkene ,Catalysis ,Stereocenter ,chemistry.chemical_compound ,Stereoselectivity ,Isomerization ,Conjugate - Abstract
An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.
- Published
- 2014
47. Addressing the Configuration Stability of Lithiated Secondary Benzylic Carbamates for the Development of a Noncryogenic Stereospecific Boronate Rearrangement
- Author
-
Heewon Lee, Rolf Schmid, Nelu Grinberg, Daniel R. Fandrick, Keith R. Fandrick, Jinhua J. Song, Adil Duran, Shengli Ma, Joe Gao, Elizabeth Archer, Nathan K. Yee, Jason A. Mulder, Juergen Daeubler, Carl A. Busacca, Michael Konrad, Nitinchandra D. Patel, Chris H. Senanayake, and Frederic G. Buono
- Subjects
chemistry.chemical_classification ,Molecular Structure ,Aryl ,Organic Chemistry ,Iodide ,Substrate (chemistry) ,Esters ,Stereoisomerism ,Boronic Acids ,Biochemistry ,chemistry.chemical_compound ,Stereospecificity ,chemistry ,Bromide ,Benzyl Compounds ,Organic chemistry ,Carbamates ,Physical and Theoretical Chemistry - Abstract
A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.
- Published
- 2014
48. Facile Entry to an Efficient and Practical Enantioselective Synthesis of a Polycyclic Cholesteryl Ester Transfer Protein Inhibitor
- Author
-
Nina C. Gonnella, Nizar Haddad, Chris H. Senanayake, Zhibin Li, Markus Ostermeier, Jürgen Mack, Lukas Neumann, Nathan K. Yee, Zeno A. Leuter, Jürgen Schnaubelt, Gunter Koch, Emanuel Stehle, Sonja Steigmiller, Daniel R. Fandrick, Rainer Hamm, Sanjit Sanyal, Annette Buba, Yibo Xu, Waldemar Pfrengle, Patrick Tielmann, Dhileep Krishnamurthy, Shengli Ma, Rainer Soyka, Nelu Grinberg, Jürgen Däubler, Juan M. Rodriguez Dehli, Jinhua J. Song, Svenja Renner, Thomas Trieselmann, Jonathan T. Reeves, Christian Stange, Zhengxu S. Han, Sonia Rodriguez, Florian Schmelcher, and Bo Qu
- Subjects
chemistry.chemical_classification ,Steric effects ,Ketone ,Molecular Structure ,biology ,Pyridines ,Lactol ,Drug candidate ,Organic Chemistry ,Molecular Conformation ,Enantioselective synthesis ,Stereoisomerism ,Crystallography, X-Ray ,Ring (chemistry) ,Biochemistry ,Cholesterol Ester Transfer Proteins ,chemistry.chemical_compound ,chemistry ,Pyridine ,Cholesterylester transfer protein ,biology.protein ,Organic chemistry ,Hydrogenation ,Physical and Theoretical Chemistry - Abstract
An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.
- Published
- 2014
49. General and Rapid Pyrimidine Condensation by Addressing the Rate Limiting Aromatization
- Author
-
Jean-Nicolas Desrosiers, Shengli Ma, Delia Reinhardt, Sanjit Sanyal, Heewon Lee, Nelu Grinberg, Keith R. Fandrick, Jinhua J. Song, Daniel R. Fandrick, and Chris H. Senanayake
- Subjects
Molecular Structure ,Pyrimidine ,Spectrum Analysis ,Organic Chemistry ,Condensation ,Amidines ,Aromatization ,Alkenes ,Photochemistry ,Biochemistry ,Combinatorial chemistry ,Adduct ,Amidine ,Solvent ,chemistry.chemical_compound ,Pyrimidines ,chemistry ,Alkoxide ,Solvents ,Physical and Theoretical Chemistry ,Solvent effects - Abstract
The rate limiting aromatization within the condensation approach toward pyrimidines utilizing amidines and activated olefins was addressed to provide for a general and rapid process. A strong solvent effect was elucidated to affect the rate for the initial alkoxide elimination from the intermediate Michael adduct wherein polar aprotic solvents demonstrate an addition controlled aromatization. Spectroscopic studies support a solvent dependent equilibrium between the amidine and alkoxide base wherein the rate for aromatization is optimal when the equilibrium toward the amidine anion was strongly favored.
- Published
- 2014
50. Amine-Tunable Ruthenium Catalysts for Asymmetric Reduction of Ketones
- Author
-
Xingzhong Zeng, Frederic G. Buono, Sonia Rodriguez, Keith R. Fandrick, Shengli Ma, Yibo Xu, Bo Qu, Melissa A. Herbage, Nizar Haddad, Zhengxu S. Han, Nathan K. Yee, Heewon Lee, Chris H. Senanayake, and Nelu Grinberg
- Subjects
Chemistry ,Asymmetric hydrogenation ,Enantioselective synthesis ,Noyori asymmetric hydrogenation ,chemistry.chemical_element ,General Chemistry ,Transfer hydrogenation ,Combinatorial chemistry ,Catalysis ,Ruthenium ,chemistry.chemical_compound ,Organic chemistry ,Chirality (chemistry) ,Phosphine - Abstract
A series of efficient ruthenium catalysts has been developed for the asymmetric hydrogenation and transfer hydrogenation of ketones with high reactivities and selectivities. The new chiral bisdihydrobenzooxaphosphole (BIBOP)/diamine-ruthenium complexes catalyzed the enantioselective hydrogenation of substrates such as aryl and heteroaryl cyclic and alkyl ketones with substrate/catalyst (S/C) ratios of up to 100,000. The opposite sense of enantioselectivity can be obtained by proper selection of a diamine with a given chirality of the phosphine. The usefulness of the new system has been demonstrated in the asymmetric hydrogenation of a complex synthetic intermediate towards cholesteryl ester transfer protein (CETP) inhibitors at S/C 20,000 on large-scale operation.
- Published
- 2014
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