David B

Design of P-Chirogenic Aminophosphine–Phosphinite Ligands at Both Phosphorus Centers: Origin of Enantioselectivities in Pd-Catalyzed Allylic Reactions

feedproxy.google.com/~r/acs/joceah/~3/qSqlxXyZzPg/acs.joc.0c00536

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The Journal of Organic Chemistry

Authors: Antonin Jaillet†?, Christophe Darcel‡, Je´ro^me Bayardon†, Adrien Schlachter§, Christine Salomon†?, Yoann Rousselin†, Pierre Harvey§, and Sylvain Juge´*†

Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β‐C(sp3)−H Arylation

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202004485?af=R

Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β‐C(sp3)−H Arylation

Bulk up : A Pd‐catalyzed enantioselective β‐C(sp3)−H functionalization of thioamides has been developed using a chiral phosphoric acid (CPA) as the chiral auxiliary. Mass spectrometry studies and DFT analysis elucidate the role of the bulky CPA and the assistance of the thioamide ligand, which define a robust chiral cavity for achieving a high level of stereocontrol.

Abstract

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp3)−H functionalization of thioamides (up to 99 % yield, 97 % ee ). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp3)−H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.

Authors: Hua‐Jie Jiang, Xiu‐Mei Zhong, Zi‐Ye Liu, Rui‐Long Geng, Yang‐Yang Li, Yun‐Dong Wu, Xinhao Zhang, Liu‐Zhu Gong

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Sustainable Peptide Synthesis Enabled by a Transient Protecting Group

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003676?af=R

Sustainable Peptide Synthesis Enabled by a Transient Protecting Group

Peptide synthesis goes green : A water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group has been developed that enables solid‐phase peptide synthesis under aqueous conditions as well as efficient postsynthetic purification of the peptides. This protecting group is fluorescent both when attached to an Nα atom and when cleaved and so also allows real‐time monitoring of building block coupling

Abstract

The growing interest in synthetic peptides has prompted the development of viable methods for their sustainable production. Currently, large amounts of toxic solvents are required for peptide assembly from protected building blocks, and switching to water as a reaction medium remains a major hurdle in peptide chemistry. We report an aqueous solid‐phase peptide synthesis strategy that is based on a water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group. This approach enables peptide assembly under aqueous conditions, real‐time monitoring of building block coupling, and efficient postsynthetic purification. The procedure for the synthesis of all natural and several non‐natural Smoc‐protected amino acids is described, as well as the assembly of 22 peptide sequences and the fundamental issues of SPPS, including the protecting group strategy, coupling and cleavage efficiency, stability under aqueous conditions, and crucial side reactions.

Authors: Sascha Knauer, Niklas Koch, Christina Uth, Reinhard Meusinger, Olga Avrutina, Harald Kolmar

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Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer

feedproxy.google.com/~r/acs/amclct/~3/nDDqD9J-hlw/acsmedchemlett.0c00224

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ACS Medicinal Chemistry Letters

Authors: Jun Liang*§, Robert Blake§, Jae Chang§, Lori S. Friedman§, Simon Goodacre£, Steven Hartman§, Ellen Rei Ingalla§, James R. Kiefer§, Tracy Kleinheinz§, Sharada Labadie§, Jun Li§, Kwong Wah LaiG, Jiangpeng LiaoG, Vidhi Mody§, Neville McLean£, Ciara Metcalfe§, Michelle Nannini§, Daniel Otwine§, Yingqing Ran§, Nick Ray£, Fabien Roussel£, Amy Sambrone§, Deepak Sampath§, Maia Vinogradova§, John WaiG, Tao WangG, Kuen Yeap£, Amy Young§, Jason Zbieg§, Birong Zhang§, Xiaoping ZhengG, Yu Zhong§, and Xiaojing Wang§

UV Light Generation and Challenging Photoreactions Enabled by Upconversion in Water

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Journal of the American Chemical Society

Journal of the American Chemical Society: Latest Articles (ACS Publications)
feedproxy.google.com/~r/acs/jacsat/~3/dn4zSzmDqUA/jacs.0c02835
Authors: Bjo¨rn Pfund†, Debora M. Steffen†, Mirjam R. Schreier†, Maria-Sophie Bertrams†, Chen Ye‡, Karl Bo¨rjesson‡, Oliver S. Wenger*†, and Christoph Kerzig*†

Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains

feedproxy.google.com/~r/acs/jmcmar/~3/QT458clx_G0/acs.jmedchem.0c00075

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Journal of Medicinal Chemistry

Authors: Michael A. Clegg†‡?, Paul Bamborough†, Chun-wa Chung†, Peter D. Craggs†, Laurie Gordon†, Paola Grandi§, Melanie Leveridge†, Matthew Lindon†?, Gemma M. Liwicki†, Anne-Marie Michon§, Judit Molnar†#, Inmaculada Rioja†, Peter E. Soden†, Natalie H. Theodoulou†‡?, Thilo Werner§, Nicholas C. O. Tomkinson‡, Rab K. Prinjha†, and Philip G. Humphreys*†

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Cross-Coupling of Amide and Amide Derivatives to Umbelliferone Nonaflates: Synthesis of Coumarin Derivatives and Fluorescent Materials

feedproxy.google.com/~r/acs/joceah/~3/Bjy_3q6z9vo/acs.joc.0c00813

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The Journal of Organic Chemistry

Authors: Shane M. Hickey†, Samuel O. Nitschke†, Martin J. Sweetman†, Christopher J. Sumby‡, Douglas A. Brooks†, Sally E. Plush†, and Trent D. Ashton*§?

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N‐Methylated Peptide Synthesis via Generation of an Acyl N‐Methylimidazolium Cation Accelerated by a Brønsted Acid

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002106?af=R

N‐Methylated Peptide Synthesis via Generation of an Acyl N‐Methylimidazolium Cation Accelerated by a Brønsted Acid

A variety of N‐methylated peptides were synthesized in high yield without severe racemization via the generation of acyl N‐methylimidazolium cations. Brønsted acids dramatically accelerated the reaction. The developed amidation reaction enabled the synthesis of a bulky peptide in higher yield and shorter reaction time in comparison with conventional amidation reactions. The first total synthesis of pterulamides I–IV was also achieved.

Abstract

The development of a robust amide‐bond formation remains a critical aspect of N‐methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N‐methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N‐methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate‐limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

Authors: Yuma Otake, Yusuke Shibata, Yoshihiro Hayashi, Susumu Kawauchi, Hiroyuki Nakamura, Shinichiro Fuse

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Electroreductive Cobalt‐Catalyzed Carboxylation: Cross‐Electrophile Electrocoupling with Atmospheric CO2

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003218?af=R

Electroreductive Cobalt‐Catalyzed Carboxylation: Cross‐Electrophile Electrocoupling with Atmospheric CO2

Co‐Operation : An allied cooperation between cobalt catalysis and electrochemical synthesis enabled the mild catalytic carboxylation of allylic chlorides with atmospheric CO2. The resulting products are useful as versatile synthons of γ‐arylbutyrolactones.

Abstract

The chemical use of CO2 as an inexpensive, nontoxic C1 synthon is of utmost topical interest in the context of carbon capture and utilization (CCU). We present the merger of cobalt catalysis and electrochemical synthesis for mild catalytic carboxylations of allylic chlorides with CO2. Styrylacetic acid derivatives were obtained with moderate to good yields and good functional group tolerance. The thus‐obtained products are useful as versatile synthons of γ‐arylbutyrolactones. Cyclic voltammetry and in operando kinetic analysis were performed to provide mechanistic insights into the electrocatalytic carboxylation with CO2.

Authors: Nate W. J. Ang, João C. A. Oliveira, Lutz Ackermann

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Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202005563?af=R

Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

The first enantioselective S−H insertion reaction of α‐carbonyl sulfoxonium ylides was developed under thiourea catalysis. Up to 95 % ee and 97 % isolated yields were obtained in 31 examples.

Abstract

The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee ) and yields (up to 97 %) are achieved for 31 examples in S−H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.

Authors: Patrícia B. Momo, Alexandria N. Leveille, Elliot H. E. Farrar, Matthew N. Grayson, Anita E. Mattson, Antonio C. B. Burtoloso

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Cycloisomerization of Olefins in Water

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003948?af=R

Cycloisomerization of Olefins in Water

Virtues we write in water : Cobalt‐catalyzed cycloisomerization occurs with efficiency in aqueous buffer at high dilution. A variety of putative metal hydride atom‐transfer (MHAT) reactions, including deallylation, proceed under these stringent conditions, even on DNA.

Abstract

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel–Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.

Authors: Jeishla L. M. Matos, Samantha A. Green, Yuge Chun, Vuong Q. Dang, Russell G. Dushin, Paul Richardson, Jason S. Chen, David W. Piotrowski, Brian M. Paegel, Ryan A. Shenvi

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Optimized Conditions for the Palladium‐Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000401?af=R

Optimized Conditions for the Palladium‐Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

Tuning of a palladium catalyst reactivity allows the chemoselective removal of benzyl and naphthyl protecting groups under batch or continuous flow conditions. Hydrogenation of the aromatic groups does not occur under these conditions thus allowing access to pure synthetic glycans.

While carrying out palladium‐catalyzed hydrogenolysis to deprotect synthetic oligosaccharides, saturation of the benzyl and naphthylmethyl ether groups to their corresponding ether was observed. In order to suppress this unwanted hydrogenation, we report a scalable practical approach using a catalyst pre‐treatment strategy, which is effective under batch or continuous flow conditions. This suppressed the unwanted hydrogenation side‐products and created a selective catalyst for hydrogenolysis of benzyl and naphthylmethyl ethers. We demonstrate the efficient deprotection of a set of structurally diverse oligosaccharides (5 examples, > 73 %).

Authors: Conor Crawford, Stefan Oscarson

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Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000329?af=R

Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

An analytical method based on 1H–15N, 1H–13C HMBC and 13C{1H} NMR spectroscopy has been developed that allows unambiguous diagnosis of the occurrence of N‐ or O‐alkylation of aromatic N‐heterocycles and N ‐oxides. A systematic large upfield shift inthe 15N NMR chemical shift is shown to be characteristic of N‐alkylation of aromatic N‐heterocycles (Δ(δN) ≈ –100 ppm). A much smaller systematic change in δN is indicative of N ‐oxide O‐alkylation (ca. –40 ppm).

A series of representative diazines and pyridine N ‐oxides were subjected to alkylation using several different alkylating agents. The 15N NMR chemical shifts (δN values) of the diazines, pyridine N ‐oxides and derived alkylation products were determined using 1H‐15N HMBC NMR spectroscopy at natural 15N abundance. The changes in the 15N NMR chemical shifts (Δ(δN) values) that occurred on going from starting materials to products in these reactions were analyzed. N‐alkylation of diazines resulted in large upfield shifts of the δN values of the alkylated nitrogen (of the order of 100 ppm or greater). While O‐alkylation of pyridine N ‐oxides resulted in upfield shifts of the δN values of the N ‐(alkoxy)pyridinium nitrogen, the Δ(δN) values were of a much smaller magnitude (ca . –42 ppm) than those observed for N‐alkylations of diazines. Nitrogen NMR spectroscopic data from the literature of relevance to alkylation of azines, diazines, azine N ‐oxides and diazine N ‐oxides was gathered together, and using this in tandem with our 15N NMR spectroscopic data, we have been able to corroborate our observations on the trends observed in the Δ(δN) values associated with N‐ and O‐alkylation reactions of aromatic N‐heterocycles and N ‐oxides. An analysis protocol that relies on synergistic evaluation of 1H‐15N HMBC and 1H‐13C HMBC NMR spectra has been developed that enables unambiguous diagnosis of the occurrence of N‐alkylation of aromatic N‐heterocycles and O‐alkylation of aromatic N ‐oxides.

Authors: Kevin J. Sheehy, Lorraine M. Bateman, Niko T. Flosbach, Martin Breugst, Peter A. Byrne

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Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002341?af=R

Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

Just Labeled : Transition‐metal‐free carbon isotope exchange on phenyl acetic acids is described. Utilizing the universal precursor CO2, the carbon isotope can be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with [14C] and [13C]. A proof of concept with [11C] was also obtained with low molar activity valuable for distribution studies.

Abstract

A transition‐metal‐free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2, this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [14C] and [13C]. A proof of concept with [11C] was also obtained with low molar activity valuable for distribution studies.

Authors: Gianluca Destro, Kaisa Horkka, Olivier Loreau, David‐Alexandre Buisson, Lee Kingston, Antonio Del Vecchio, Magnus Schou, Charles S. Elmore, Frédéric Taran, Thibault Cantat, Davide Audisio

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