A5029665191- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Catalytic C–H Functionalization Methods
- Multicomponent Synthesis of Heterocycles
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Advanced Synthetic Organic Chemistry
- Asymmetric Hydrogenation and Catalysis
- Synthetic Organic Chemistry Methods
- Organoboron and organosilicon chemistry
- Synthesis and biological activity
- Synthesis and Catalytic Reactions
- Synthesis of heterocyclic compounds
- Analytical Chemistry and Chromatography
- Innovative Microfluidic and Catalytic Techniques Innovation
- Radical Photochemical Reactions
- Computational Drug Discovery Methods
- Chemical Synthesis and Reactions
- Fluorine in Organic Chemistry
- Sulfur-Based Synthesis Techniques
- Synthesis and Characterization of Pyrroles
- Cyclopropane Reaction Mechanisms
- Oxidative Organic Chemistry Reactions
- Alkaloids: synthesis and pharmacology
- Catalytic Cross-Coupling Reactions
Pfizer (United States)
2015-2025
Scripps (United States)
2011-2017
Scripps Research Institute
2013-2016
Aix-Marseille Université
2008-2015
Centre National de la Recherche Scientifique
2008-2014
Scripps Institution of Oceanography
2011-2014
Centrale Marseille
2014
Institut des Sciences Moléculaires de Marseille
2008-2010
Institut Fresnel
2009
Centre d'Études Scientifiques et Techniques d'Aquitaine
2002
A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from iodides has been developed. This is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness this demonstrated on the late-stage functionalization complex nitrogen-containing drugs. Photophysical...
Nirmatrelvir (PF-07321332, 1) is a selective, orally bioavailable inhibitor of SARS-CoV-2 2 Mpro. Development an efficient synthesis this molecule was critical for the rapid advancement compound from first to successful emergency use authorization in just 17 months. This paper provides overview development commercial synthesis, with focus on supply chains three starting materials, which leveraged key synthetic studies earlier protease research programs and/or products.
The development of an enantioselective catalytic Suzuki-Miyaura reaction that applies to
A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation olefins using visible light is reported. This method characterized by low catalyst loading, thereby enabling a mild selective for radical in thiol-ene reactions between wide scope thiols.
A simple metal-free, step-economic and selective access to pyridines from readily available substrates is reported, involving a flexible 4 Å molecular sieves promoted Michael addition initiated domino three-component reaction between 1,3-dicarbonyl, acceptor synthetic equivalent of ammonia.
Abstract A metal‐free and completely regioselective three‐component synthesis of highly functionalized pyridines from 1,3‐dicarbonyl derivatives Michael acceptors has been achieved. Activated acceptors, that is, β,γ‐unsaturated α‐oxo carbonyl derivatives, were utilized, allowing substitution at the 4‐position remarkable functional diversity 2‐position pyridine ring. The scope limitations this environmentally friendly domino reaction are disclosed, with full experimental data, results...
On all fours: The title reaction with (Ipc)2BH provides tetrasubstituted enolborinates which undergo aldol reactions aldehydes to form products all-carbon quaternary centers exceptional diastereo- and enantioselectivity. A change the substitution pattern of starting amide leads either diastereomer α-methyl-α-ethyl-β-hydroxy carboxamide (1 or 2). As a service our authors readers, this journal supporting information supplied by authors. Such materials are peer reviewed may be re-organized for...
In the presence of a chiral palladium-based catalyst, 1,4-diboryl-2-alkenes undergo enantioselective cross-coupling that results in desymmetrization substrate structure. Depending on reaction conditions and choice ligand, can occur with cis or trans selectivity, allowing construction an array different substituted carbocycles enantiomerically enriched fashion.
In early 2020, severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infections leading to COVID-19 disease reached a global level the World Health Organization (WHO) declaration of pandemic. Scientists around globe rapidly responded try and discover novel therapeutics repurpose extant drugs treat disease. This work describes preclinical discovery efforts that led invention PF-07321332 (nirmatrelvir, 14), potent orally active inhibitor SARS CoV-2 main protease (Mpro) enzyme. At outset...
Versatile partners: α-Ketocarbonyls have been shown for the first time to be versatile partners in a Michael addition promoted oxidative domino three-component reaction under heterogeneous conditions. This multicomponent sequence led development of general synthesis highly functionalized pyridines (see scheme), allowing selective and simultaneous incorporation substituent at 4-position synthetically useful functionality strategic 2-position.
Nirmatrelvir is a potent, selective, and orally bioavailable inhibitor of SARS-CoV-2 Mpro. Herein, we report scalable cyclopropanation to produce the bicyclic [3.1.0]proline derivative, which one key starting materials for synthesis nirmatrelvir. To ensure robust supply chain this building block meet significant API demand, needed develop synthetic process that was complementary existing strategies. achieve goal, used widely available inexpensive raw material...
Development of a scalable route for the synthesis nirmatrelvir, novel SARS-CoV-2 3C-like protease inhibitor discovered in 2020 by Pfizer scientists, was initiated shortly thereafter to supply material first clinical studies. This optimized commercial manufacture nirmatrelvir high yield and acceptable quality with consideration efficiency sustainability. Herein, we report evolution final steps (3–5) used synthesize (steps 3–5), from initial regulatory lot design implementation process.
Nirmatrelvir is a potent, selective, and orally bioavailable inhibitor of SARS-CoV-2 Mpro. In this paper, we report the development magnesium sulfate (MgSO4)-mediated aminolysis for synthesis (S)-2-amino-3-[(S)-2-oxopyrrolidin-3-yl]propenamide hydrogen chloride, eastern fragment nirmatrelvir. Previous building block required protecting group, high equivalents ammonia, long reaction time generated materials with moderate potency levels residual solvents. We determined that MgSO4, widely...
Nirmatrelvir (1), a novel and specific inhibitor of the SARS-CoV-2 3C-like protease, was developed by Pfizer scientists in mid 2020. Efforts to develop scalable process manufacture nirmatrelvir were undertaken with great sense urgency, as there no effective treatments available for worldwide patient population at that time. We used convergent approach generate this molecule. The first two steps western fragment from l-tert-leucine, ethyl trifluoroacetate, [3.1.0] bicyclic proline derivative...
Abstract We have designed a new, user‐friendly oxidative dual heterogeneous catalytic system capable of promoting polysubstituted pyridines as unique products from simple activated Michael acceptors, 1,3‐dicarbonyls and ammonium acetate. This metal‐free environmentally‐respectful totally regioselective domino reaction proved to be great strategy access bi‐ triaryl‐type well challenging triheteroaryl‐type in single operation.
Abstract A visible‐light‐driven Minisci protocol that employs an inexpensive earth‐abundant metal catalyst, decacarbonyldimanganese Mn 2 (CO) 10 , to generate alkyl radicals from iodides has been developed. This is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert ‐butyl carbamates (Boc‐group), cyclobutanes, and spirocycles. The robustness this demonstrated on the late‐stage functionalization complex nitrogen‐containing drugs....
In this paper is described an easily synthesized chiral diazaborolidine that inexpensive, stable, and provides excellent stereoselection across a number of reaction classes. These versatile compounds possess utility in four different classes cycloaddition reactions, offering good yield stereoselectivity. X-ray structure analysis insight about the origin stereocontrol.
Cutting costs, cutting corners: In an inexpensive and straightforward synthesis of syn-propionamide aldols, formation the Z enolborinate by hydroboration 4-acryloylmorpholine with diisopinocampheylborane ((Ipc)2BH) was followed aldol reactions achiral chiral aldehydes to provide syn-α-methyl-β-hydroxymorpholinecarboxamides excellent enantio- diastereoselectivity (see scheme; R=alkyl, alkenyl, aryl, heteroaryl).
Intramolecular amination of organoboronates occurs with a 1,2-metalate shift an aminoboron "ate" complex to form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective boronate-containing azacycles. Enantiomerically enriched azacycles are formed high stereospecificity.
This report describes the synthesis, development, and scale-up (up to 10 kg) of di- trifluoromethoxy prolines, key fragments evaluated in development potential antiviral SARS-CoV2 Mpro inhibitors. We first demonstrate a scalable route 1-tert-butyl 2-methyl (2S,4R)-4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate employing Cu-catalyzed difluoromethylation alcohols using 2,2-difluoro-2-(fluorosulfonyl)acetic acid. then optimization challenging...
The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters 4 is described. Isomerization the kinetically formed Z(O)-enolborinate 5Z to thermodynamic E(O)-enolborinate 5E via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads anti-α-methyl-β-hydroxy 9 or 10 excellent diastereo- (up ≥20:1 dr) and enantioselectivity 87% ee). results double asymmetric reactions several chiral aldehydes are also presented.