Mois : juin 2020

Conformational Design Principles in Total Synthesis

Conformational Design Principles in Total Synthesis

Conformational design through purposeful control of the conformation population of molecules significantly facilitates the construction of both stereochemistry and rings in the total synthesis of complex natural products. This Minireview summarizes the progress of this field in the last two decades and especially emphasizes the critical role of implementing a C−H functionalization strategy in natural‐product synthesis.

Abstract

Conformation is one of the most fundamental concepts in organic chemistry for chemists to visualize a molecule as a three‐dimensional object in addition to its constitution and configuration. Conformational factors significantly affect the physical properties, chemical reactivities, and biological activities of a molecule. The significance of conformational design has been generally recognized since its successful application in the total synthesis of complex natural products, such as vitamin B12 and erythronolide. Conformational analysis, especially intentional control of conformational preferences by conformational design, could play a critical role in the synthesis of complex organic molecules by guiding the formation of bonds, stereocenters, or rings. This Minireview highlights selected examples of conformational design in natural‐product synthesis, with particular emphasis on the applications and new insights advanced in the last 20 years. The examples discussed herein are divided into three categories by structural features of the substrates: open‐chain type, cyclohexane type, and medium‐ and large‐ring type.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Renzhi Chen, Yang Shen, Sihan Yang, Yandong Zhang
doi.org/10.1002/anie.202003735

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Enantioselective Preparation of Arenes with β‐Stereogenic Centers: Confronting the 1,1‐Disubstituted Olefin Problem Using CuH/Pd Cooperative Catalysis

Enantioselective Preparation of Arenes with β‐Stereogenic Centers: Confronting the 1,1‐Disubstituted Olefin Problem Using CuH/Pd Cooperative Catalysis

It takes two : CuH/Pd‐catalyzed enantioselective hydroarylation of 1,1‐disubstituted alkenes proceeds with anti‐Markovnikov regioselectivity under mild conditions to access β‐stereogenic arenes. A wide range of aryl bromides, including several heterocycle‐containing substrates, can be used with good efficiency and enantioselectivity. Various 1,1‐disubstituted alkenes were also examined.

Abstract

Arenes with β‐stereogenic centers are important substructures in pharmaceuticals and natural products. We have developed an asymmetric anti‐Markovnikov hydroarylation of 1,1‐disubstituted olefins by dual palladium and copper hydride catalysis as a convenient and general approach to access these substructures. This efficient one‐step process addresses several limitations of the traditional stepwise approaches. The use of cesium benzoate as a base and a common phosphine ligand for both the Cu‐ and Pd‐catalyzed processes were important discoveries that allow these challenging olefin substrates to be efficiently transformed. A variety of aryl bromide coupling partners, including numerous heterocycles, were coupled with 1,1‐disubstituted alkenes to generate arenes with β‐stereogenic centers.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Zhaohong Lu, Stephen L. Buchwald
doi.org/10.1002/anie.202004414

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Intramolecular Nickel‐Catalyzed Ring‐Opening Reactions of Oxabenzonorbornadienes with C1‐Tethered Aryl Halides: An Improvement of Method

Intramolecular Nickel‐Catalyzed Ring‐Opening Reactions of Oxabenzonorbornadienes with C1‐Tethered Aryl Halides: An Improvement of Method

Oxabenzonorbornadienes with C1‐tethered aryl halides were found to rapidly undergo a ring‐opening reaction in the presence of NiCl2(PPh3)2, Zn, and MeCN to selectively form 1,2‐dihydronaphthalen‐1‐ol cores. 17 examples are shown with varying oxabenzonorbornadiene and iodoarene substitution, tether length, and halides, with yields up to 99 %.

An improved method of the recently reported novel transition metal‐catalyzed intramolecular ring‐opening reaction of oxabenzonorbornadienes with C1‐tethered aryl halides is described. Using a nickel catalyst, fused tetracycles containing a 1,2‐dihydronaphthalen‐1‐ol framework were generated with good to excellent yields and selectivities in most cases: a result seldom obtained using the previous palladium‐catalyzed conditions. Electron‐withdrawing, electron‐donating, and bulky substituents were generally found to be well tolerated in the reaction while extension of the tether led to decreased yields.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Samuel Koh, Austin Pounder, Elizabeth Brown, William Tam
doi.org/10.1002/ejoc.202000672

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Enantioselective Synthesis of cis and trans 4‐Aminopipecolic Acids as γ‐Amino Acids for the Construction of Cyclic RGD‐Containing Peptidomimetics Antagonists of αVβ3 Integrin

Enantioselective Synthesis of cis and trans 4‐Aminopipecolic Acids as γ‐Amino Acids for the Construction of Cyclic RGD‐Containing Peptidomimetics Antagonists of αVβ3 Integrin

A stereodivergent preparation of cis and trans 4‐aminopipecolic acids (4‐APAs) was developed from a common precursor to obtain suitably protected, constrained γ‐amino acids useful in peptidomimetic synthesis. Two antagonists of αVβ3 integrin were synthesized.

A stereodivergent strategy to obtain enantiopure cis and trans 4‐aminopipecolic acids (4‐APAs) in a suitably protected form for peptide synthesis has been devised starting from a common, known precursor in turn easily prepared from commercial (R )‐4‐cyano‐3‐hydroxybutyric acid ethyl ester. The two isomers were efficiently obtained in 40 % and 23 % overall yields, respectively, in seven and ten steps. To demonstrate their usefulness in peptidomimetic synthesis, both 4‐APA isomers were incorporated as γ‐amino acids in a cyclic RGD‐containing sequence, although for the trans 4‐APA isomer a further amino acid in the sequence (L‐Phe) was needed to allow ring closure. The two cyclopeptides were tested as αVβ3 integrin antagonists in comparison with cilengitide.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Francesca Dordoni, Dina Scarpi, Francesca Bianchini, Alessandro Contini, Ernesto G. Occhiato
doi.org/10.1002/ejoc.202000634

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Discovery of Novel Selective and Orally Bioavailable Phosphodiesterase-1 Inhibitors for the Efficient Treatment of Idiopathic Pulmonary Fibrosis

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Journal of Medicinal Chemistry

Journal of Medicinal Chemistry: Latest Articles (ACS Publications)
Authors: Yinuo Wu†, Yi-Jing Tian†, Mei-Ling Le†, Si-Rui Zhang, Chen Zhang, Meng-Xing Huang, Mei-Yan Jiang, Bei Zhang, and Hai-Bin Luo*
feedproxy.google.com/~r/acs/jmcmar/~3/qK0-jTXihy8/acs.jmedchem.0c00711

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Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy

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Organic Process Research & Development

Organic Process Research & Development: Latest Articles (ACS Publications)

Authors: Alexander Steiner†‡, Philippe M. C. Roth§, Franz J. Strauss?, Guillaume Gauron§, Gu¨nter Tekautz?, Marc Winter§, Jason D. Williams*†‡, and C. Oliver Kappe*†‡
feedproxy.google.com/~r/acs/oprdfk/~3/kDzpcq8kz2s/acs.oprd.0c00239

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Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst

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Organic Process Research & Development

Organic Process Research & Development: Latest Articles (ACS Publications)

Authors: James R. Gage*, Furong Chen, Changming Dong, Miguel A. Gonzalez, Yong Jiang, Yong Luo, Mark D. McLaws, and Jian Tao
feedproxy.google.com/~r/acs/oprdfk/~3/yV0Z-P7NuTg/acs.oprd.0c00133

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Structure–Permeability Relationship of Semipeptidic Macrocycles—Understanding and Optimizing Passive Permeability and Efflux Ratio

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Journal of Medicinal Chemistry

Journal of Medicinal Chemistry: Latest Articles (ACS Publications)
Authors: Antoine Le Roux†, E´milie Blaise†, Pierre-Luc Boudreault†, Christian Comeau†, Annie Doucet†, Marilena Giarrusso†, Marie-Pierre Collin‡, Thomas Neubauer‡, Florian Ko¨lling‡, Andreas H. Go¨ller‡, Lea Seep‡, Dieudonne´ T. Tshitenge‡, Matthias Wittwer‡, Maximilian Kullmann‡, Alexander Hillisch‡, Joachim Mittendorf‡, and Eric Marsault*†
feedproxy.google.com/~r/acs/jmcmar/~3/d6fSGIb2fLI/acs.jmedchem.0c00013

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C7‐Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

C7‐Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

Lucky seven : The challenging C7−H activation of indoles has been accomplished by ruthenium(II) catalysis. The versatile ruthenium catalysis allowed C−N and C−C bond formation, scalable reactions, and the traceless removal of the directing group. Detailed mechanistic investigations based on diverse analysis tools shed light on a novel mode of action.

Abstract

C7−H‐functionalized indoles are ubiquitous structural units of biological and pharmaceutical compounds for numerous antiviral agents against SARS‐CoV or HIV‐1. Thus, achieving site‐selective functionalizations of the C7−H position of indoles, while discriminating among other bonds, is in high demand. Herein, we disclose site‐selective C7−H activations of indoles by ruthenium(II) biscarboxylate catalysis under mild conditions. Base‐assisted internal electrophilic‐type substitution C−H ruthenation by weak O‐coordination enabled the C7−H functionalization of indoles and offered a broad scope, including C−N and C−C bond formation. The versatile ruthenium‐catalyzed C7−H activations were characterized by gram‐scale syntheses and the traceless removal of the directing group, thus providing easy access to pharmaceutically relevant scaffolds. Detailed mechanistic studies through spectroscopic and spectrometric analyses shed light on the unique nature of the robust ruthenium catalysis for the functionalization of the C7−H position of indoles.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Isaac Choi, Antonis M. Messinis, Lutz Ackermann
doi.org/10.1002/anie.202006164

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Electrochemical C−H Functionalization of (Hetero)Arenes—Optimized by DoE

Electrochemical C−H Functionalization of (Hetero)Arenes—Optimized by DoE

An alternative route for the activation of different arenes including caffeine and theophylline, optimized by design of experiment techniques is presented. We provide a simple electroorganic protocol using BDD electrodes in undivided cells for the synthesis of aryl 1,1,1,3,3,3‐hexafluoroisopropyl ethers. The value of these fluorinated ethers for subsequent functionalization with a variety of nucleophiles has been proved (see scheme).

Abstract

A novel approach towards the activation of different arenes and purines including caffeine and theophylline is presented. The simple, safe and scalable electrochemical synthesis of 1,1,1,3,3,3‐hexafluoroisopropanol (HFIP) aryl ethers was conducted using an easy electrolysis setup with boron‐doped diamond (BDD) electrodes. Good yields up to 59 % were achieved. Triethylamine was used as a base as it forms a highly conductive media with HFIP, making additional supporting electrolytes superfluous. The synthesis was optimized using Design of Experiment (DoE) techniques giving a detailed insight to the significance of the reaction parameters. The mechanism was investigated by cyclic voltammetry (CV). Subsequent transition metal‐catalyzed as well as metal‐free functionalization led to interesting motifs in excellent yields up to 94 %.

Wiley: Chemistry – A European Journal: Table of Contents
Authors: Maurice Dörr, Johannes L. Röckl, Jonas Rein, Dieter Schollmeyer, Siegfried R. Waldvogel
chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.202001171

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Absolute Configuration of Small Molecules by Co‐Crystallization

Absolute Configuration of Small Molecules by Co‐Crystallization

The absolute configuration of difficult‐to‐crystallize small molecules can be obtained by rapid thermal co‐crystallization with TEO, a tetraaryladamantane octaether, and X‐ray crystallography. As little as 3–5 mg of analyte can produce both NMR and diffraction data within 48 hours.

Abstract

The most reliable method to determine the absolute configuration of chiral molecules is X‐ray crystallography, but small molecules can be difficult to crystallize. We report rapid co‐crystallization of tetraaryladamantanes with small molecules as different as n ‐decane to nicotine to produce crystals for X‐ray analysis and the assignment of absolute configuration when the molecules are chiral. A screen of 52 diverse compounds gave inclusion in co‐crystals for 88 % of all cases and a high‐resolution structure in 77 % of cases. Furthermore, starting from three milligrams of analyte, a combination of NMR spectroscopy and X‐ray crystallography produced a full structure in less than three days using an adamantane crystallization chaperone that encapsulates the analyte at room temperature.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Felix Krupp, Wolfgang Frey, Clemens Richert
doi.org/10.1002/anie.202004992

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Profiling and Identification of Biocatalyzed Transformation of Sulfoxaflor In Vivo

Profiling and Identification of Biocatalyzed Transformation of Sulfoxaflor In Vivo

The biotransformation of the neonicotinoid pesticide sulfoxaflor and the metabolic responses in Sprague‐Dawley rats was investigated. Sulfoxaflor transformation was catalyzed by cytochrome P450 while five phase I and four phase II metabolites were identified in vivo. Exposure to sulfoxaflor caused dysregulation of bile acid synthesis and reabsorption by the expression of farnesoid X receptor (FXR).

Abstract

In the present study, we investigated the biotransformation of the neonicotinoid pesticide sulfoxaflor and the metabolic responses in Sprague‐Dawley rats. Sulfoxaflor transformation was catalyzed by cytochrome P450 while five phase I and four phase II metabolites were identified for the first time in vivo. The experimental results demonstrated that sulfoxaflor brought about the metabolic profiling disturbances in liver and bile. Exposure to sulfoxaflor caused dysregulation of bile acid synthesis and reabsorption by the expression of farnesoid X receptor (FXR). Our data provided insights into biotransformation of chemicals while enabling the implementation of a new toolbox for the design of sulfoximine compounds.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Liwei Xu, Lingling Guo, Zhongxing Wang, Xinxin Xu, Shuang Zhang, Xiaoling Wu, Hua Kuang, Chuanlai Xu
doi.org/10.1002/anie.202007079

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Nickel‐Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

Nickel‐Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The direct transformation of readily available phenol derivatives into valuable trifluoromethylarenes was developed. The PMe3‐catalyzed oxidative addition and transmetalation, as well as CCl3CN‐induced reductive elimination play key roles in this successful nickel‐mediated trifluoromethylation.

Abstract

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper‐ and palladium‐mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel‐mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF3). The strategy relies on PMe3‐promoted oxidative addition and transmetalation, and CCl3CN‐induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Wei‐Qiang Hu, Shen Pan, Xiu‐Hua Xu, David A. Vicic, Feng‐Ling Qing
doi.org/10.1002/anie.202004116

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Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ? Inhibitors with Fragment-Merging Strategy

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Journal of Medicinal Chemistry

Journal of Medicinal Chemistry: Latest Articles (ACS Publications)
Authors: Masakazu Atobe*†, Takayuki Serizawa†, Natsumi Yamakawa†#, Kenichiro Takaba†, Yukiko Nagano‡, Toshiaki Yamaura§, Eiichi Tanaka§, Atsutoshi Tazumi??, Shino Bito??, Masashi Ishiguro?, and Masashi Kawanishi†
feedproxy.google.com/~r/acs/jmcmar/~3/fJkqju23Wew/acs.jmedchem.0c00449

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Aromatic Cytokinin Arabinosides Promote PAMP-like Responses and Positively Regulate Leaf Longevity

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ACS Chemical Biology

ACS Chemical Biology: Latest Articles (ACS Publications)
Authors: Magdale´na Bryksova´†?, Siarhei Dabravolski‡?, Zuzana Kuc?erova´§?, Filip Zavadil Koka´s?‡?, Martina S?pundova´§, Lucie Pli´halova´†?, Toma´s? Taka´c?#, Jir?i´ Gru´z?, Martin Hudec?ek?, Veronika Hlous?kova´?, Radoslav Koprna†, Ondr?ej Nova´k?, Miroslav Strnad?, Ondr?ej Pli´hal*‡?, and Karel Dolez?al†?
feedproxy.google.com/~r/acs/acbcct/~3/SW_FCguQgVo/acschembio.0c00306

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Operando Identification of the Dynamic Behavior of Oxygen Vacancy-Rich Co3O4 for Oxygen Evolution Reaction

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Journal of the American Chemical Society

Journal of the American Chemical Society: Latest Articles (ACS Publications)
Authors: Zhaohui Xiao†?, Yu-Cheng Huang‡?, Chung-Li Dong‡?, Chao Xie†, Zhijuan Liu†, Shiqian Du†, Wei Chen†, Dafeng Yan†, Li Tao†, Zhiwen Shu§, Guanhua Zhang§, Huigao Duan§, Yanyong Wang†, Yuqin Zou†, Ru Chen†, and Shuangyin Wang*†
feedproxy.google.com/~r/acs/jacsat/~3/qDKbWfyHWZQ/jacs.0c00257

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Mechanism of Oxygen Evolution Catalyzed by Cobalt Oxyhydroxide: Cobalt Superoxide Species as a Key Intermediate and Dioxygen Release as a Rate-Determining Step

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Journal of the American Chemical Society

Journal of the American Chemical Society: Latest Articles (ACS Publications)
Authors: Aliki Moysiadou†‡, Seunghwa Lee†‡, Chia-Shuo Hsu§, Hao Ming Chen§, and Xile Hu*†
feedproxy.google.com/~r/acs/jacsat/~3/iAZzNLlmU8M/jacs.0c04867

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Discovery of 4,6- and 5,7-Disubstituted Isoquinoline Derivatives as a Novel Class of Protein Kinase C ? Inhibitors with Fragment-Merging Strategy

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Journal of Medicinal Chemistry

Journal of Medicinal Chemistry: Latest Articles (ACS Publications)
Authors: Masakazu Atobe*†, Takayuki Serizawa†, Natsumi Yamakawa†#, Kenichiro Takaba†, Yukiko Nagano‡, Toshiaki Yamaura§, Eiichi Tanaka§, Atsutoshi Tazumi??, Shino Bito??, Masashi Ishiguro?, and Masashi Kawanishi†
feedproxy.google.com/~r/acs/jmcmar/~3/fJkqju23Wew/acs.jmedchem.0c00449

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