Photosensitization enables Pauson-Khand-type reactions with nitrenes.

The Pauson-Khand reaction has in the past 50 years become one of the most common cycloaddition reactions in chemistry. Coupling two unsaturated bonds with carbon monoxide, the transformation remains limited to CO as a C1 building block. Herein we report analogous cycloaddition reactions with nitrenes as an N1 unit. The reaction of a nonconjugated diene with a nitrene precursor produces bicyclic bioisosteres of common saturated heterocycles such as piperidine, morpholine, and piperazine. Experimental and computational mechanistic studies support relaying of the diradical nature of triplet nitrene into the π-system. We showcase the reaction's utility in late-stage functionalization of drug compounds and discovery of soluble epoxide hydrolase inhibitors.

Atroposelective Chan-Evans-Lam Amination.

The synthetic control of atropoisomerism along C-N bonds is a major challenge, and methods that allow C-N atroposelective bond formation are rare. This is a problem because each atropoisomer can feature starkly differentiated biological properties. Yet, among the three most practical and applicable classical amination methods available: 1) the Cu-catalyzed Ullmann-Goldberg reaction, 2) the Pd-catalyzed Buchwald-Hartwig reaction, and 3) the Cu-catalyzed Chan-Evans-Lam reaction, none has truly been rendered atroposelective at the newly formed C-N bond. The first ever Chan-Evans-Lam atroposelective amination is herein described with a simple copper catalyst and newly designed PyrOx chiral ligand. This method should find important applications in asymmetric synthesis, in particular for medicinal chemistry.

A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues.

Bicyclic amines are important motifs for the preparation of bioactive materials. These species have well-defined exit vectors that enable accurate disposition of substituents toward specific areas of chemical space. Of all possible skeletons, the 2-azabicyclo[3.2.0]heptane framework is virtually absent from MedChem libraries due to a paucity of synthetic methods for its preparation. Here, we report a modular synthetic strategy that utilizes nitroarenes as flat and easy-to-functionalize feedstocks for the assembly of these sp3-rich materials. Mechanistically, this approach exploits two concomitant photochemical processes that sequentially ring-expand the nitroarene into an azepine and then fold it into a rigid bicycle pyrroline by means of singlet nitrene-mediated nitrogen insertion and excited-state-4π electrocyclization. A following hydrogenolysis provides, with full diastereocontrol, the desired bicyclic amine derivatives whereby the aromatic substitution pattern has been translated into the one of the three-dimensional heterocycle. These molecules can be considered rigid pyrrolidine analogues with a well-defined orientation of their substituents. Furthermore, unsupervised clustering of an expansive virtual database of saturated N-heterocycles revealed these derivatives as effective isosteres of rigidified piperidines. Overall, this platform enables the conversion of nitroarene feedstocks into complex sp3-rich heterocycles of potential interest to drug development.

Atroposelective Nenitzescu Indole Synthesis.

Invited for the cover of this issue is the group of Frederic W. Patureau at the RWTH Aachen University. The image depicts atropoisomerism, in particular through the helix-shaped vines in the forefront focus. This metaphorically illustrates the importance of atroposelectivity in biologically active molecules, such as in the 5-hydroxyindoles that were accessed through the first enantioselective Nenitzescu indole synthesis. Read the full text of the article at 10.1002/chem.202300279.

Atroposelective Nenitzescu Indole Synthesis.

In the past decade, compounds bearing a stereogenic C-N axis have gained significant attention in fields ranging from ligand to drug design. Yet, the atroposelective synthesis of these molecules remains a considerable challenge. In contrast to recent methods using more advanced chiral catalysts, a very simply accessed Jacobsen-type chromium(III)-salen complex was used here as a chiral enantiopure Lewis acid catalyst for a highly atroposelective Nenitzescu indole synthesis. Mild reaction conditions afforded various 5-hydroxybenzo[g]indoles in up to 97 % yield. Moreover, through a simple work-up, very high enantiomeric excesses of up to 99 % could be obtained.

TEMPO-mediated late stage photochemical hydroxylation of biaryl sulfonium salts.

The late stage photochemical hydroxylation of biaryl sulfonium salts was enabled with a TEMPO derivative as a simple oxygen source, in metal free conditions. The scope and mechanism of this exceptionally simple synthetic method, which constructs important arylated phenols from aromatic C-H bonds, are herein discussed.

Phosphine-Catalyzed Dearomative [3 + 2] Cycloaddition of Benzoxazoles with a Cyclopropenone.

The triphenylphosphine-catalyzed dearomative [3 + 2] cycloaddition of benzoxazoles with 1,2-diphenylcyclopropenone is herein described. The reaction scope, mechanism, and possible future applications of this rare organocatalyzed cycloaddition are herein discussed.

Dehydrogenative C-H Phenochalcogenazination.

Heavy-atom-modified chalcogen-fused triarylamine organic materials are becoming increasingly important in the photochemical sciences. In this context, the general and direct dehydrogenative C-H phenochalcogenazination of phenols with the heavier chalcogens selenium and tellurium is herein described. The latter dehydrogenative C-N bond-forming processes operate under simple reaction conditions with highly sustainable O2 serving as the terminal oxidant.

Photochemical Cyclopropanation of Cyclooctatetraene and (Poly-)unsaturated Carbocycles.

We report on the use of visible light to conduct carbene-transfer reactions of donor/acceptor diazoalkanes with cyclooctatetraene and polyunsaturated carbocycles to give the corresponding cyclopropanes in excellent yields with excellent stereoselectivities. This photochemical protocol proved to be superior to conventional metal-catalyzed cyclopropanation reactions and now provides platform chemicals containing a cyclic conjugated all-cis triene. The cyclopropane is an important structural feature to prevent 6π electrocyclization. Instead, the triene moiety can now be selectively functionalized in cycloaddition reactions.

Multiple Hydrogen-Bond Activation in Asymmetric Brønsted Acid Catalysis.

An efficient protocol for the asymmetric synthesis of chiral tetrahydroquinolines bearing multiple stereogenic centers by means of asymmetric Brønsted acid catalysis was developed. A chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-based N-triflylphosphoramide (NTPA) proved to be an effective Brønsted acid catalyst for the in situ generation of aza-ortho-quinone methides (aza-o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes to provide the products with excellent diastereo- and enantioselectivities. In addition, DFT calculations provided insight into the activation mode and nature of the interactions between the N-triflylphosphoramide catalyst and the generated aza-o-QMs.

Catalytic Asymmetric Piancatelli Rearrangement: Brønsted Acid Catalyzed 4π†Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones.

The first catalytic asymmetric Piancatelli reaction is reported. Catalyzed by a chiral Brønsted acid, the rearrangement of a wide range of furylcarbinols with a series of aniline derivatives provides valuable aminocyclopentenones in high yields as well as excellent enantioselectivities and diastereoselectivities. The high value of the aza-Piancatelli rearrangement was demonstrated by the synthesis of a cyclopentane-based hNK1 antagonist analogue.

Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers.

An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities.

Asymmetric Brønsted Acid Catalyzed Synthesis of Triarylmethanes-Construction of Communesin and Spiroindoline Scaffolds.

Aza-ortho-quinone methides allow the straightforward asymmetric synthesis of natural-product-inspired indole scaffolds possessing a quaternary stereocenter. Our approach provides access to diverse communesin and spiroindoline derivatives with high enantioselectivity under mild reaction conditions. Predictable substitution patterns are found to be the key to our regiodivergent protocols.

Dual metal and Lewis base catalysis approach for asymmetric synthesis of dihydroquinolines and the α-arylation of aldehydes via N-acyliminium ions.

A dual catalytic system consisting of indium triflate and a chiral imidazolidinone catalyzes the asymmetric addition of aldehydes to N-acyl quinoliniums furnishing optically active dihydroquinolines in good yields and excellent selectivities. The products were further functionalized into optically active tetrahydroquinolines, quinolines and 6-oxa-2-aza-bicyclo[3.3.1]nonanes.

Ortho-quinone methides as reactive intermediates in asymmetric brønsted Acid catalyzed cycloadditions with unactivated alkenes by exclusive activation of the electrophile.

An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL-based N-triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho-quinone methides (o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo- and enantioselectivity.

Asymmetric Synthesis of Functionalized Dihydro- and Tetrahydropyrans via an Organocatalytic Domino Michael-Hemiacetalization Reaction.

Starting from α-hydroxymethyl nitroalkenes and various 1,3-dicarbonyl compounds, a one-pot organocatalyzed diastereo- and enantioselective synthesis of polyfunctionalized dihydro- and tetrahydropyran derivatives via a domino Michael-hemiacetalization sequence is reported. The title compounds bearing a variety of functional groups can be synthesized in this way in good yields (59-91%) and with moderate to excellent diastereoselectivities (26-98% de) and enantioselectivities (71-99% ee).

Fluorine effects in organocatalysis - asymmetric Brønsted acid assisted Lewis base catalysis for the synthesis of trifluoromethylated heterocycles exploiting the negative hyperconjugation of the CF3-group.

An efficient Brønsted acid assisted Lewis base catalysis protocol for the synthesis of enantiomerically pure trifluoromethylated dihydropyridazines starting from readily available hydrazones and α,ß-unsaturated aldehydes has been developed. The reaction exhibits high tolerance towards many functional groups and is applicable to various aliphatic, aromatic and hetero-aromatic α,ß-unsaturated aldehydes, and provides the products in good yields and with excellent enantioselectivities.

N-trifluoromethylthiophthalimide: a stable electrophilic SCF3 -reagent and its application in the catalytic asymmetric trifluoromethylsulfenylation.

Cinchona alkaloid catalysts in combination with air- and moisture-stable N-trifluoromethylthiophthalimide as electrophilic SCF3 source enabled the catalytic enantioselective trifluoromethylsulfenylation. Thus, a series of α-SCF3 esters that bear a quaternary carbon stereogenic center were obtained with excellent yield and enantioselectivity. Moreover, the products can be readily converted into valuable α-SCF3 ß-hydroxyesters.