Bringing Biocatalysis into the Deuteration Toolbox

2019 ◽  
Author(s):  
Jack Rowbotham ◽  
Oliver Lenz ◽  
Holly Reeve ◽  
Kylie Vincent
Keyword(s):  
Late Stage ◽  
Hydrogen Isotope ◽  
Reductive Amination ◽  
Mechanistic Studies ◽  
Ambient Conditions ◽  
Synthetic Pathway ◽  
Drug Candidates ◽  
Isotopic Selectivity ◽  
Reducing Equivalents

<p></p><p>Chemicals labelled with the heavy hydrogen isotope deuterium (<sup>2</sup>H) have long been used in chemical and biochemical mechanistic studies, spectroscopy, and as analytical tracers. More recently, demonstration of selectively deuterated drug candidates that exhibit advantageous pharmacological traits has spurred innovations in metal-catalysed <sup>2</sup>H insertion at targeted sites, but asymmetric deuteration remains a key challenge. Here we demonstrate an easy-to-implement biocatalytic deuteration strategy, achieving high chemo-, enantio- and isotopic selectivity, requiring only <sup>2</sup>H<sub>2</sub>O (D<sub>2</sub>O) and unlabelled dihydrogen under ambient conditions. The vast library of enzymes established for NADH-dependent C=O, C=C, and C=N bond reductions have yet to appear in the toolbox of commonly employed <sup>2</sup>H-labelling techniques due to requirements for suitable deuterated reducing equivalents. By facilitating transfer of deuterium atoms from <sup>2</sup>H<sub>2</sub>O solvent to NAD<sup>+</sup>, with H<sub>2</sub> gas as a clean reductant, we open up biocatalysis for asymmetric reductive deuteration as part of a synthetic pathway or in late stage functionalisation. We demonstrate enantioselective deuteration via ketone and alkene reductions and reductive amination, as well as exquisite chemo-control for deuteration of compounds with multiple unsaturated sites.</p><p></p>

Bringing Biocatalysis into the Deuteration Toolbox

2019 ◽  
Author(s):  
Jack Rowbotham ◽  
Oliver Lenz ◽  
Holly Reeve ◽  
Kylie Vincent
Keyword(s):  
Late Stage ◽  
Hydrogen Isotope ◽  
Reductive Amination ◽  
Mechanistic Studies ◽  
Ambient Conditions ◽  
Synthetic Pathway ◽  
Drug Candidates ◽  
Isotopic Selectivity ◽  
Reducing Equivalents

<p></p><p>Chemicals labelled with the heavy hydrogen isotope deuterium (<sup>2</sup>H) have long been used in chemical and biochemical mechanistic studies, spectroscopy, and as analytical tracers. More recently, demonstration of selectively deuterated drug candidates that exhibit advantageous pharmacological traits has spurred innovations in metal-catalysed <sup>2</sup>H insertion at targeted sites, but asymmetric deuteration remains a key challenge. Here we demonstrate an easy-to-implement biocatalytic deuteration strategy, achieving high chemo-, enantio- and isotopic selectivity, requiring only <sup>2</sup>H<sub>2</sub>O (D<sub>2</sub>O) and unlabelled dihydrogen under ambient conditions. The vast library of enzymes established for NADH-dependent C=O, C=C, and C=N bond reductions have yet to appear in the toolbox of commonly employed <sup>2</sup>H-labelling techniques due to requirements for suitable deuterated reducing equivalents. By facilitating transfer of deuterium atoms from <sup>2</sup>H<sub>2</sub>O solvent to NAD<sup>+</sup>, with H<sub>2</sub> gas as a clean reductant, we open up biocatalysis for asymmetric reductive deuteration as part of a synthetic pathway or in late stage functionalisation. We demonstrate enantioselective deuteration via ketone and alkene reductions and reductive amination, as well as exquisite chemo-control for deuteration of compounds with multiple unsaturated sites.</p><p></p>

scholarly journals Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhan Li ◽  
Ke-Feng Wang ◽  
Xin Zhao ◽  
Huihui Ti ◽  
Xu-Ge Liu ◽  
...  
Keyword(s):  
Carboxylic Acids ◽  
Late Stage ◽  
Materials Science ◽  
Reaction Pathway ◽  
Chemical Conversion ◽  
Primary Amines ◽  
Mechanistic Studies ◽  
Reaction Conditions ◽  
Aliphatic Acids ◽  
Redox Active

Abstract Alkyl carboxylic acids as well as primary amines are ubiquitous in all facets of biological science, pharmaceutical science, chemical science and materials science. By chemical conversion to redox-active esters (RAE) and Katritzky’s N-alkylpyridinium salts, respectively, alkyl carboxylic acids and primary amines serve as ideal starting materials to forge new connections. In this work, a Mn-mediated reductive decarboxylative/deaminative functionalization of activated aliphatic acids and primary amines is disclosed. A series of C-X (X = S, Se, Te, H, P) and C-C bonds are efficiently constructed under simple and mild reaction conditions. The protocol is applicable to the late-stage modification of some structurally complex natural products or drugs. Preliminary mechanistic studies suggest the involvement of radicals in the reaction pathway.

On-Line Reaction Monitoring and Mechanistic Studies by Mass Spectrometry: Negishi Cross-Coupling, Hydrogenolysis, and Reductive Amination

2014 ◽  
Vol 126 (23) ◽  
pp. 6041-6045 ◽  
Author(s):  
Xin Yan ◽  
Ewa Sokol ◽  
Xin Li ◽  
Guangtao Li ◽  
Shiqing Xu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Reductive Amination ◽  
Cross Coupling ◽  
Reaction Monitoring ◽  
Mechanistic Studies ◽  
On Line

scholarly journals Systematically understanding the key roles of microglia in AD development

2019 ◽  
Author(s):  
Zhiwei Ji ◽  
Changan Liu ◽  
Weiling Zhao ◽  
Claudio Soto ◽  
Xiaobo Zhou
Keyword(s):  
Late Stage ◽  
Early Stage ◽  
The United States ◽  
Scale Model ◽  
Drug Candidates ◽  
Multi Scale ◽  
Age Related ◽  
Activation Profile ◽  
Current Therapies ◽  
Optimal Therapeutic Strategy

AbstractAlzheimer’s disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States. Unfortunately, current therapies are largely palliative and several potential drug candidates have failed in late-stage clinical trials. Studies suggest that microglia-mediated neuroinflammation might be responsible for the failures of various therapies. Microglia contribute to Aβ clearance in the early stage of neurodegeneration and may contribute to AD development at the late stage by releasing pro-inflammatory cytokines. However, the activation profile and phenotypic changes of microglia during the development of AD are poorly understood. To systematically understand the key role of microglia in AD progression and predict the optimal therapeutic strategyin silico, we developed a 3D multi-scale model of AD (MSMAD) by integrating multi-level experimental data, to manipulate the neurodegeneration in a simulated system. Based on our analysis, we revealed how TREM2-related signal transduction leads to an imbalance in the activation of different microglia phenotypes, thereby promoting AD development. Our MSMAD model also provides an optimal treatment strategy for improving the outcome of AD treatment.

scholarly journals Co-Catalyzed E-(β)-Selective Hydrogermylation of Terminal Alkynes

2021 ◽  
Author(s):  
Maxim Radzhabov ◽  
Neal Mankad
Keyword(s):  
Natural Products ◽  
Late Stage ◽  
Functional Group ◽  
Terminal Alkynes ◽  
Mechanistic Studies ◽  
Practical Utility ◽  
Π Complex ◽  
Accessible Method ◽  
High Yields

<a></a><a>We demonstrated unprecedentedly that Co complexes can catalyze hydrogermylation of alkynes. Subsequently, a selective, accessible method was developed to synthesize E-(β)-vinyl(trialkyl)germanes from various terminal alkynes with high yields. As shown on multiple examples, the developed method demonstrates broad functional group tolerance and practical utility for late-stage hydrogermylation of drugs and natural products. The method is compatible with alkynes bearing both aryl and alkyl substituents, providing unrivaled selectivity for previously challenging 1° alkyl-substituted alkynes. Moreover, the catalyst used in this method, Co<sub>2</sub>(CO)<sub>8</sub>, is a cheap and commercially available reagent. Conducted mechanistic studies supported syn-addition of Bu<sub>3</sub>GeH to an alkyne</a> π-complex.

scholarly journals Cu(OTf)2-Mediated Ionizing Cross-Coupling of N(sp) and N(sp2) with Arylboronic Acids

2020 ◽  
Author(s):  
Allan Watson ◽  
Nicola Bell ◽  
Chao Xu ◽  
James Fyfe ◽  
Julien Vantourout ◽  
...  
Keyword(s):  
Late Stage ◽  
Cross Coupling ◽  
Reductive Elimination ◽  
Subsequent Generation ◽  
Mechanistic Studies ◽  
Arylboronic Acids ◽  
Bond Forming ◽  
Drug Synthesis ◽  
C And N ◽  
Metal Catalyzed

Metal-catalyzed C–N cross-coupling generally forms C–N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C–N cross-coupling that uses a dative N-ligand in the bond forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu(II) complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative Cu(III) complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp<sup>2</sup>) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

scholarly journals Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Leitao Huan ◽  
Xiaomin Shu ◽  
Weisai Zu ◽  
De Zhong ◽  
Haohua Huo
Keyword(s):  
Carboxylic Acids ◽  
Organic Synthesis ◽  
Late Stage ◽  
Coupling Reaction ◽  
Cross Coupling ◽  
Photoredox Catalysis ◽  
Mechanistic Studies ◽  
Cross Coupling Reaction ◽  
Aryl Ketones ◽  
Alkyl Benzenes

AbstractAsymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C−H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C−H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C−H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.

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