scholarly journals Benzylic C−H acylation by cooperative NHC and photoredox catalysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Yuan Meng ◽  
Lena Lezius ◽  
Armido Studer
Keyword(s):  
Organic Molecules ◽  
Functional Group ◽  
Photoredox Catalysis ◽  
Diverse Range ◽  
Site Selectivity ◽  
Aryl Ketones ◽  
Direct Acylation ◽  
Selective Acylation ◽  
Site Selective ◽  
Complex Organic

AbstractMethods that enable site selective acylation of sp3 C-H bonds in complex organic molecules are not well explored, particularly if compared with analogous transformations of aromatic and vinylic sp2 C-H bonds. We report herein a direct acylation of benzylic C-H bonds by merging N-heterocyclic carbene (NHC) and photoredox catalysis. The method allows the preparation of a diverse range of benzylic ketones with good functional group tolerance under mild conditions. The reaction can be used to install acyl groups on highly functionalized natural product derived compounds and the C-H functionalization works with excellent site selectivity. The combination of NHC and photoredox catalysis offers options in preparing benzyl aryl ketones.

Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

2020 ◽  
Author(s):  
Sukdev Bag ◽  
Sadhan Jana ◽  
Sukumar Pradhan ◽  
Suman Bhowmick ◽  
Nupur Goswami ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Bond Activation ◽  
Bond Formation ◽  
Ancillary Ligand ◽  
Significant Challenge ◽  
Site Selectivity ◽  
Directing Group ◽  
Covalently Linked ◽  
Complex Organic ◽  
Post Functionalization

<p>Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing group (DG) served as an ancillary ligand to ensure proximal <i>ortho</i>-, distal <i>meta</i>- and <i>para</i>-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. We introduce here a transient directing group for distal C(<i>sp<sup>2</sup></i>)-H functionalization <i>via</i> reversible imine formation. By overruling facile proximal C-H bond activation by imine-<i>N</i> atom, a suitably designed pyrimidine-based transient directing group (TDG) successfully delivered selective distal C-C bond formation. Application of this transient directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the distal position has been explored.</p>

Palladium-catalyzed site-selective arylation of aliphatic ketones enabled by a transient ligand

2018 ◽  
Vol 54 (22) ◽  
pp. 2759-2762 ◽  
Author(s):  
Lei Pan ◽  
Ke Yang ◽  
Guigen Li ◽  
Haibo Ge
Keyword(s):  
Functional Group ◽  
Direct Arylation ◽  
Aliphatic Ketones ◽  
Site Selectivity ◽  
Palladium Catalyzed ◽  
High Site ◽  
Site Selective

A direct arylation of C–H bonds of ketones enabled by a cheap and commercially available transient ligand with high site-selectivity and functional group compatibility is reported.

Enhanced site-selectivity in acylation reactions with substrate-optimized catalysts on solid supports

2017 ◽  
Vol 53 (21) ◽  
pp. 3086-3089 ◽  
Author(s):  
My Linh Tong ◽  
Florian Huber ◽  
Estelle S. Taghuo Kaptouom ◽  
Torsten Cellnik ◽  
Stefan F. Kirsch
Keyword(s):  
Solid Support ◽  
Solid Supports ◽  
Peptide Conjugates ◽  
Site Selectivity ◽  
Selective Acylation ◽  
Site Selective ◽  
Acylation Reactions

A concept for site-selective acylation is presented, using substrate-optimized DMAP–peptide conjugates on a solid support.

scholarly journals Site-Selective Alkoxylation of Benzylic C–H Bonds via Photoredox Catalysis

2019 ◽  
Author(s):  
Byung Joo Lee ◽  
kimberly deglopper ◽  
Tehshik Yoon
Keyword(s):  
Late Stage ◽  
Functional Group ◽  
Bond Formation ◽  
Bioactive Molecules ◽  
Site Selectivity ◽  
Wide Range ◽  
High Site ◽  
Alkoxy Groups ◽  
Site Selective ◽  
Mediated Oxidation

<div> <div> <div> <p>There are relatively few methods that accom- plish the selective alkoxylation of sp3-hybridized C–H bonds, particularly in comparison to the numerous analogous strate- gies for C–N and C–C bond formation. We report a photo- catalytic protocol for the functionalization of benzylic C–H bonds with a wide range of readily available oxygen nucleo- philes. Our strategy merges the photoredox activation of arenes with copper(II)-mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C–O bonds with high site selectivity, chemoselectivity, and functional group tolerance. This method enables the late- stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential appli- cations in synthesis and medicinal chemistry. </p> </div> </div> </div>

Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

2020 ◽  
Author(s):  
Sukdev Bag ◽  
Sadhan Jana ◽  
Sukumar Pradhan ◽  
Suman Bhowmick ◽  
Nupur Goswami ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Bond Activation ◽  
Bond Formation ◽  
Ancillary Ligand ◽  
Significant Challenge ◽  
Site Selectivity ◽  
Directing Group ◽  
Covalently Linked ◽  
Complex Organic ◽  
Post Functionalization

<p>Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing group (DG) served as an ancillary ligand to ensure proximal <i>ortho</i>-, distal <i>meta</i>- and <i>para</i>-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. We introduce here a transient directing group for distal C(<i>sp<sup>2</sup></i>)-H functionalization <i>via</i> reversible imine formation. By overruling facile proximal C-H bond activation by imine-<i>N</i> atom, a suitably designed pyrimidine-based transient directing group (TDG) successfully delivered selective distal C-C bond formation. Application of this transient directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the distal position has been explored.</p>

Visible Light Promoted Functionalisation of Carbon-Carbon Sigma Bonds

2019 ◽  
Author(s):  
Jeremy Nugent ◽  
Carlos Arroniz ◽  
Bethany Shire ◽  
Alistair J. Sterling ◽  
Helena D. Pickford ◽  
...  
Keyword(s):  
Visible Light ◽  
Organic Molecules ◽  
Functional Group ◽  
Single Step ◽  
Transition Metal Catalysts ◽  
Organic Radicals ◽  
Photoredox Catalysis ◽  
Halogen Bonds ◽  
Organic Halides ◽  
Pi Bonds

<p>The use of visible light to activate transition metal catalysts towards redox processes has transformed the way organic molecules can be constructed. Promotion of an electron to an excited state enables the generation of organic radicals through electron transfer to or from the metal complex, with the resulting radicals primed for reactions such as addition to carbon–carbon pi bonds. Despite advances in photoredox catalysis which have led to the discovery of numerous such methods for bond construction, this mild approach to the generation of free radicals has not been applied to the functionalisation of carbon–carbon sigma<i></i>bonds. Here we report the first such use of photoredox catalysis to promote the addition of organic halides to the caged carbocycle [1.1.1]propellane; the products of this process are bicyclo[1.1.1]pentanes (BCPs), motifs that are of high importance as bioisosteres in the pharmaceutical industry, and in materials applications. The methodology shows broad substrate scope and functional group tolerance, and is applicable to both <i>sp</i><sup>2</sup>and <i>sp</i><sup>3</sup>carbon–halogen bonds, while the use of substrates containing alkene acceptors enables the single-step construction of polycyclic bicyclopentane products through cyclisation cascades. Finally, the potential to accelerate drug discovery is demonstrated through examples of late-stage bicyclopentylation to access natural product- and drug-like molecules.</p>

scholarly journals Late-stage trifluoromethylthiolation of benzylic C-H bonds

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Wentao Xu ◽  
Wenliang Wang ◽  
Tao Liu ◽  
Jin Xie ◽  
Chengjian Zhu
Keyword(s):  
Continuous Flow ◽  
Large Scale ◽  
Organic Molecules ◽  
Initiation Mechanism ◽  
Radical Initiation ◽  
Simple Protocol ◽  
Synthetic Methodologies ◽  
Site Selective ◽  
Complex Organic ◽  
Fluoroalkyl Group

Abstract The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.

scholarly journals Imine as a linchpin approach for meta-C–H functionalization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sukdev Bag ◽  
Sadhan Jana ◽  
Sukumar Pradhan ◽  
Suman Bhowmick ◽  
Nupur Goswami ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Bond Activation ◽  
Bond Formation ◽  
Ancillary Ligands ◽  
Significant Challenge ◽  
Site Selectivity ◽  
Directing Group ◽  
Covalently Linked ◽  
Complex Organic ◽  
Post Functionalization

AbstractDespite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C–H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C–H functionalization via reversible imine formation. By overruling facile ortho-C–H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C–C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored.

scholarly journals Selenomethionine as an expressible handle for bioconjugations

2021 ◽  
Vol 118 (8) ◽  
pp. e2005164118
Author(s):  
Dillon T. Flood ◽  
Jordi C. J. Hintzen ◽  
Kyle W. Knouse ◽  
David E. Hill ◽  
Chenxi Lu ◽  
...  
Keyword(s):  
Organic Molecules ◽  
Careful Study ◽  
Selective Chemical ◽  
Site Selective ◽  
Complex Organic

Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins.

scholarly journals Design principles for site-selective hydroxylation by a Rieske oxygenase

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jianxin Liu ◽  
Jiayi Tian ◽  
Christopher Perry ◽  
April L. Lukowski ◽  
Tzanko I. Doukov ◽  
...  
Keyword(s):  
Structural Information ◽  
Diverse Range ◽  
Bond Functionalization ◽  
Site Selectivity ◽  
Site Selective ◽  
Common Architecture ◽  
Rieske Oxygenase ◽  
Rieske Oxygenases ◽  
Native Site ◽  
Selective Hydroxylation

AbstractRieske oxygenases exploit the reactivity of iron to perform chemically challenging C–H bond functionalization reactions. Thus far, only a handful of Rieske oxygenases have been structurally characterized and remarkably little information exists regarding how these enzymes use a common architecture and set of metallocenters to facilitate a diverse range of reactions. Herein, we detail how two Rieske oxygenases SxtT and GxtA use different protein regions to influence the site-selectivity of their catalyzed monohydroxylation reactions. We present high resolution crystal structures of SxtT and GxtA with the native β-saxitoxinol and saxitoxin substrates bound in addition to a Xenon-pressurized structure of GxtA that reveals the location of a substrate access tunnel to the active site. Ultimately, this structural information allowed for the identification of six residues distributed between three regions of SxtT that together control the selectivity of the C–H hydroxylation event. Substitution of these residues produces a SxtT variant that is fully adapted to exhibit the non-native site-selectivity and substrate scope of GxtA. Importantly, we also found that these selectivity regions are conserved in other structurally characterized Rieske oxygenases, providing a framework for predictively repurposing and manipulating Rieske oxygenases as biocatalysts.

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