TBADT-Mediated Photocatalytic Stereoselective Radical Alkylation of Chiral N-Sulfinyl Imines: Towards Efficient Synthesis of Diverse Chiral Amines.

Herein we describe a sustainable and efficient photocatalytic method for the stereoselective radical alkylation of chiral sulfinyl imines. By employing readily available non-prefunctionalized radical precursors and the cost-effective TBADT as a direct HAT photocatalyst, we successfully obtain diverse chiral amines with high yields and excellent diastereoselectivity under mild conditions. This method provides an efficient approach for accessing a diverse array of medicinally relevant compounds, including both natural and synthetic α-amino acids, aryl ethyl amines, and other structural motifs commonly found in approved pharmaceuticals and natural product.

Access to N-Fused Quinazolinones by Radical-Promoted Cascade Annulations of Alkenyl N-Cyanamides with Aromatic Aldehydes.

A cascade radical cyclization of alkenyl N-cyanamides with aromatic aldehydes has been achieved for an expeditious synthesis of keto-methylated dihydropyrrolo-quinazolinones. Benzoyl radicals, generated from aryl aldehydes in the presence of di-tert-butyl peroxide (DTBP), promoted the domino annulations leading to distinctive functionalized quinazolinones in good yields. In addition, the robustness of the present protocol is validated by employing heterocyclic and natural product-based aldehydes.

Electrocatalytic dehydrogenative and defluorinative coupling between aldehyde-derived N,N-dialkylhydrazones and fluoromalonates: synthesis of 2-pyrazolines.

An electrocatalytic synthesis of 2-pyrazolines via dehydrogenative and defluorinative cross-coupling reactions between (hetero)arylaldehyde-derived N,N-dialkylhydrazones and fluoromalonates is disclosed. Salient features of this work include (i) readily available starting materials, (ii) practical reaction conditions, and (ii) a formal oxidative (4 + 1)-cycloaddition via triple C-H bond functionalization. Cyclic voltammetry analyses support the electrocatalytic formation of an α-fluoromalonyl radical.

Electrochemically-Driven 1,4-Aryl Migration via Radical Fluoromethylation of N-Allylbenzamides: a Straightforward Access to Functionalized ß-Arylethylamines.

An electrochemical radical Truce Smiles rearrangement of N-allylbenzamides is documented herein. The selective 1,4-aryl migration was triggered by the radical fluoromethylation of the alkene providing a direct route to fluoro derivatives of the highly privileged ß-arylethylamine pharmacophore. This practical transformation utilizes readily available starting materials and employs an electrical current to drive the oxidative process under mild reaction conditions. It accommodates a variety of migratory aryl groups with different electronic properties and substitution patterns. Careful selection of the protecting group on the nitrogen atom of the N-allylbenzamide is crucial to outcompete the undesired 6-endo cyclization and achieve high level of selectivity towards the 1,4-aryl migration. DFT calculations support the reaction mechanism and unveil the origin of selectivity between the two competitive pathways.

Photocatalytic Asymmetric Acyl Radical Truce Smiles Rearrangement for the Synthesis of Enantioenriched α-Aryl Amides.

The radical Truce-Smiles rearrangement is a straightforward strategy for incorporating aryl groups into organic molecules for which asymmetric processes remains rare. By employing a readily available and non-expensive chiral auxiliary, we developed a highly efficient asymmetric photocatalytic acyl and alkyl radical Truce-Smiles rearrangement of α-substituted acrylamides using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom-transfer photocatalyst, along with aldehydes or C-H containing precursors. The rearranged products exhibited excellent diastereoselectivities (7:1 to >98:2 d.r.) and chiral auxiliary was easily removed. Mechanistic studies allowed understanding the transformation in which density functional theory (DFT) calculations provided insights into the stereochemistry-determining step.

Enantioselective and Regiodivergent Synthesis of Dihydro-1,2-oxazines from Triene-Carbamates via Chiral Phosphoric Acid-Catalysis.

Conjugated trienes are fascinating building blocks for the rapid construction of complex polycyclic compounds. However, limited success has been achieved due to the challenging regioselectivity control. Herein, we report an enantio- and diastereoselective process allowing to regioselectively control the functionalization of NH-triene-carbamates. Synthesis of chiral cis-3,6-dihydro-2H-1,2-oxazines is achieved by a chiral phosphoric acid catalyzed Nitroso-Diels-Alder cycloaddition involving [(1E,3E,5E)-hexa-1,3,5-trien-1-yl]carbamates. Moreover, modular access to three different regioisomers with excellent diastereoselectivities and high to excellent enantioselectivities is obtained by a careful choice of the reaction conditions. A computational study reveals that the regioselectivity is influenced by the steric demand of the substituents at the 6-position of the triene, as well as noncovalent interactions between the two cycloaddition partners. Utility of each regioisomeric cycloadduct is highlighted by a variety of synthetic transformations.

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.

This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting. This latest edition was postponed twice for the reasons that we know. This has given us the opportunity to invite additional speakers of great standing. This year, Institut Curie hosted around 300 participants, including 220 on site and over 80 online. The pandemic has had, at least, the virtue of promoting online meetings, which we came to realize is not perfect but has its own merits. In particular, it enables those with restricted time and resources to take part in events and meetings, which can now accommodate unlimited participants. We apologize to all those who could not attend in person this time due to space limitation at Institut Curie.

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,ß-Substituted Amines.

Enamide and enecarbamate derivatives containing a nucleophilic center at the ß-position from their nitrogen atom as well as a latent electrophilic site at their α-position are interesting motifs in organic chemistry. This dual reactivity─analogous that of the enamines─enables difunctionalization and increased structural complexity. Furthermore, an electron-withdrawing group on nitrogen drastically increases their stability. In that respect, enamides and enecarbamates are excellent partners for multicomponent transformations, and our research primarily focuses on these compounds in particular.Difunctionalization generally occurs through the nucleophilic addition of the enecarbamate on an electrophile to form iminium, which can subsequently react with a nucleophilic species. Although potent, such an approach is highly challenging due to the low stability of the intermediate iminium, leading to undesired hydrolysis or oligomerization. Epimerization, competitivity, and compatibility issues between the reaction partners are additional hindrances to developing these methodologies. To overcome these limitations, we described many complementary strategies.To control the enantioselectivity of these transformations, chiral phosphoric acids were found to be particularly well-suited to activate multiple reactants due to the formation of a hydrogen bonds network, allowing for an organized transition state in a chiral pocket. Interestingly, when deprotonated as phosphates, they can also play the role of ligands for Lewis acidic metals.To avoid iminium oligomerization, we successfully used stabilized α-arylated enamides. However, this approach was restricted to a simple nucleophilic addition at the ß-position. To achieve the difunctionalizations of α-unsubstituted derivatives, we explored reversibly linked nucleophile and electrophile to address their compatibility problem. Alternatively, we devised a sequential methodology for resolving the stability issue of the N-acyl iminium based on its intermediate trapping using a temporary nucleophile (alcohol or thiol). Interestingly, the trapping agent could further be displaced by the desired final α-substituent under Lewis acidic or photocatalytic activation. This led us to design new chiral and bifunctional phosphoric acid catalysts bearing chromophores to merge asymmetric organocatalysis and photochemistry.These photocatalysis studies incited us to focus on radical processes to manage original functionalizations that would not be feasible otherwise. ß-Alkylation and ß-trifluoromethylation of enecarbamates via visible-light-promoted atom transfer radical additions were successfully performed. As ß-allylations remained unattainable with the precedent methods, we eventually turned our attention to cerium(IV)-mediated oxidative single electron transfers. It allowed for singly occupied molecular orbital activation of these substrates to elicit their umpolung reactivity.Thus, the functionalization of enecarbamate derivatives appears as a valid synthetic strategy for obtaining important building blocks for agrochemical, pharmaceutical, and cosmetic industries, including diamines, haloamines, aminotryptamines, and less accessible trifluoromethylated or allylic compounds.

Electroreductive Cross-Coupling of Trifluoromethyl Alkenes and Redox Active Esters for the Synthesis of Gem-Difluoroalkenes.

An electroreductive access to gem-difluoroalkenes has been developed through the decarboxylative/defluorinative coupling of N-hydroxyphtalimides esters and α-trifluoromethyl alkenes. The electrolysis is performed under very simple reaction conditions in an undivided cell using cheap carbon graphite electrodes. This metal-free transformation features broad scope with good to excellent yields. Tertiary, secondary as well as primary alkyl radicals could be easily introduced. α-aminoacids L-aspartic and L-glutamic acid-derived redox active esters were good reactive partners furnishing potentially relevant gem-difluoroalkenes. In addition, it has been demonstrated that our electrosynthetic approach toward the synthesis of gem-difluoroalkenes could use an easily prepared Kratitsky salt as alkyl radical precursor via a deaminative/defluorinative carbofunctionalization of trifluoromethylstyrene.

Decatungstate-Photocatalyzed Dearomative Hydroacylation of Indoles: Direct Synthesis of 2-Acylindolines.

We report herein a convenient and scalable dearomative hydroacylation reaction of indoles. Employing readily available aldehydes as the acyl source and TBADT as an inexpensive direct HAT photocatalyst, a variety of indoles derivatives were converted into synthetically interesting 2-acylindolines in good to excellent yields as well as great diastereoselectivity under mild conditions. An asymmetric version of the reaction was successfully developed and an experimental mechanistic investigation was carried out in order to gain further insights on the assumed reaction pathway.

Divergent cyclodimerizations of styrylnaphthols under aerobic visible-light irradiation and Brønsted acid catalysis.

Dimeric cyclization reactions show great potential to rapidly form highly substituted complex cyclic molecules from simple starting materials. However, such an appealing process is often hampered by the lack of selectivity. Herein we report two divergent cyclodimerization reactions of 1-styrylnaphthalen-2-ol derivatives under simple and very mild reaction conditions. A stereoselective visible light-induced oxidative (1 + 1 + 4 + 4) homodimerization gave rise to highly substituted 1,5-dioxocanes in moderate yields. This transformation harnessed singlet oxygen as a safe and mild oxidant under photocatalyst-free reaction conditions. Additionally, we demonstrated that the same substrates undergo a (4 + 2) heterodimerization under Brønsted-acid catalysis to produce chromane derivatives featuring 3 contiguous tertiary stereocenters in good to high yields with excellent diastereoselectivities.

Enantioselective and Diastereodivergent Synthesis of Spiroindolenines via Chiral Phosphoric Acid-Catalyzed Cycloaddition.

A diastereodivergent and enantioselective synthesis of chiral spirocyclohexyl-indolenines with four contiguous stereogenic centers is achieved by a chiral phosphoric acid-catalyzed cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-dienecarbamates. Modular access to two different diastereoisomers with high enantioselectivities was obtained by careful choice of reaction conditions. Their functional group manipulation provides an efficient access to enantioenriched spirocyclohexyl-indolines and -oxindoles. The origins of this stereocontrol have been identified using DFT calculations, which reveal an unexpected mechanism compared to our previous work dealing with enecarbamates.

Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse-Electron-Demand Aza-Diels-Alder Reactions.

A stable asymmetric intramolecular Povarov reaction has been established to provide an efficient method to access structurally diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-b]quinolines in high stereoselectivities of up to >99:1 diastereomeric ratio and 99 % enantiomeric excess, without any purification step. Additionally, to facilitate large-scale application of this method, a low catalyst loading protocol was employed, 0.2 mol % chiral phosphoric acid, which provided the cycloadducts without any loss in yield and enantioselectivity. Theoretical studies revealed that the reaction occurred through a sequential Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as a bifunctional catalyst to activate the para-phenolic dienophile and N-2-hydroxy-2-azadiene simultaneously.

Preparation of Chiral Photosensitive Organocatalysts and Their Application for the Enantioselective Synthesis of 1,2-Diamines.

Chiral phosphoric acid based organocatalysis and visible-light photocatalysis have both emerged as promising technologies for the sustainable production of fine chemicals. In this context, we have envisioned the design and the synthesis of a new class of chimeric catalytic entities that would feature both catalytic capabilities. Given their multitask nature, such catalysts would be particularly attractive for the development of new catalytic transformations, tandem processes in particular. Toward this goal, several BINOL-based chiral phosphoric acid backbones presenting one or two visible-light-sensitive thioxanthone moieties have been prepared and studied. The utility of these new photoactive chiral organocatalysts is then demonstrated in the enantioselective tandem three-component electrophilic amination of enecarbamates. Of note, the C1-symmetric organo/photocatalyst has shown a better catalytic activity than those presenting a C2 symmetry.

Tritylium assisted iodine catalysis for the synthesis of unsymmetrical triarylmethanes.

The combined Lewis acid catalytic system, generated from molecular iodine and tritylium tetrafluoroborate effectively catalyzed the Friedel-Crafts (FC) arylation of diarylmethyl sulfides providing an efficient access to various unsymmetrical triarylmethanes. The addition of tritylium and iodine created a more active catalytic system to promote the cleavage of sulfidic C-S bonds.

Enantioselective Redox-Divergent Chiral Phosphoric Acid Catalyzed Quinone Diels-Alder Reactions.

An efficient enantioselective construction of tetrahydronaphthalene-1,4-diones as well as dihydronaphthalene-1,4-diols by a chiral phosphoric acid catalyzed quinone Diels-Alder reaction with dienecarbamates is reported. The nature of the protecting group on the diene is key to the success of achieving high enantioselectivity. The divergent "redox" selectivity is controlled by using an adequate amount of quinones. Reversible redox switching without erosion of enantioselectivity was possible from individual redox isomers.

2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology.

Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment.

s-Tetrazine Dyes: A Facile Generation of Photoredox Organocatalysts for Routine Oxidations.

A series of organic dyes derived from s-tetrazine have been synthesized, and their photophysical and electrochemical properties are systematically investigated. Testing these compounds as photoredox catalysts in a model oxidative C-S bond cleavage of thioethers has led us to identify new classes of active s-tetrazines. Moreover, some of them can be formed in situ from commercially available 3,6-dichlorotetrazine, making this photocatalyzed C-S bond functionalization simple and highly practical.

Catalyst-free cycloaddition of 1,3-diene-1-carbamates with azodicarboxylates: A rapid click reaction.

Novel click reactions are of continued interest in many scientific research areas and applications. Herein, we report a novel practical, catalyst-free, azo-Diels-Alder reaction between dienecarbamates and azodicarboxylates exhibiting a remarkable functional group tolerance. The availability of starting materials, mild reaction conditions, chemoselectivity and scalability make this cycloaddition a viable supplement to the other reactions in "click" chemistry.

Prenatal Diagnosis, Management, and Outcome of Fetal Subdural Haematoma: A Case Report and Systematic Review.

BACKGROUND: Fetal subdural haematoma (SDH) is associated with poor prognosis. OBJECTIVE: The conflicting evidence from the literature presents a challenge in prenatal counselling. We present a case study and systematic review of the literature for the management and outcome of fetal SDH. METHODS: Systematic search of electronic database. RESULTS: A total 45 cases were extracted from 39 papers. Prenatal ultrasonographic features were intracranial echogenicity (42%), lateral ventriculomegaly (38%), presence of an intracranial mass (31%), macrocephaly (24%), midline deviation of cerebral falx (20%), and intracranial fluid collection (11%). Further secondary features were noted including reversed diastolic flow in the middle cerebral artery (11%), echogenic bowel (4%), hydrops fetalis (2%), and elevated middle cerebral artery peak systolic velocity (2%) (all highly likely to be associated with fetal anaemia). The rates of termination of pregnancy, stillbirth, and neonatal death were 18% (8/45), 16% (7/45), and 11% (5/45), respectively. Overall, therefore, the fetal and perinatal mortality was 32% (12/37). Amongst the 24 survivors with available neurological outcome, 42% (10/24) and 58% (14/24) had abnormal and normal neurological outcome, respectively. Underlying aetiology of fetal SDH was not identified in 47% (21/45). Fetal SDH with an identifiable underlying aetiology was the only factor associated with a higher chance of normal neurological outcome when compared to fetal SDH without a detectable cause (78.5 vs. 21.4%, p = 0.035). CONCLUSIONS: Stillbirth and neonatal death occurred in a significant proportion of fetal SDH. 58% of survivors had normal neurological outcome, and better prognosis was seen in SDH with identifiable underlying aetiology.