A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

H-Bonded Counterion-Directed Catalysis: Enantioselective Gold(I)-Catalyzed Addition to 2-Alkynyl Enones as a Case Study.

H-bonded counterion-directed catalysis (HCDC) is a strategy wherein a chiral anion that is hydrogen-bonded to the achiral ligand of a metal complex is responsible for enantioinduction. In this article we present the application of H-bonded counterion-directed catalysis to the Au(I)-catalyzed enantioselective tandem cycloisomerization-addition reaction of 2-alkynyl enones. Following the addition of C-, N- or O-centered nucleophiles, bicyclic furans were obtained in moderate to excellent yield and enantioselectivity (28 examples, 59-96 % yield, 62 : 38 to 95 : 5 er). The optimal catalytic system, comprising a phosphinosquaramide Au(I) chloride complex and a BINOL-derived phosphoramidate Ag(I) salt, was selected in a combinatorial fashion from a larger library with the help of high-throughput screening. An enantioselectivity switch of ca. 120 Δee% was observed upon addition of the achiral Au(I) component to the Ag(I) salt.

Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by Decarbenation of Alkynylcycloheptatrienes.

Alkynylcyclopropanes have found promising applications in both organic synthesis and medicinal chemistry but remain rather underexplored due to the challenges associated with their preparation. We describe a convenient two-step methodology for the alkynylcyclopropanation of alkenes, based on the rhodium(II)-catalyzed decarbenation of 7-alkynyl cycloheptatrienes. The catalytic system employed circumvents a fundamental problem associated with these substrates, which usually evolve via 6-endo-dig cyclization or ring-contraction pathways under metal catalysis. This unique performance unlocks a rapid access to a diverse library of alkynylcyclopropanes (including derivatives of complex drug-like molecules), versatile intermediates that previously required much lengthier synthetic approaches. Combining experiments and DFT calculations, the complete mechanistic picture for the divergent reactivity of alkynylcycloheptatrienes under metal catalysis has been unveiled, rationalizing the unique selectivity displayed by rhodium(II) complexes.

Enantioselective Friedel-Crafts reaction of hydroxyarenes with nitroenynes to access chiral heterocycles via sequential catalysis.

Naphthols, hydroxyindoles and an activated phenol are reacted with differently substituted (E)-nitrobut-1-en-3-ynes using the commercially available Rawal's chiral squaramide. The corresponding ß-nitroalkynes were obtained with good yields and excellent enantioselectivities. Moreover, dihydronaphthofurans can be accessed via silver catalysed cyclization in a tandem one-pot procedure, with high preservation of the optical purity.

General Cyclopropane Assembly by Enantioselective Transfer of a Redox-Active Carbene to Aliphatic Olefins.

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. The redox-active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect allowed the asymmetric cyclopropanation of various olefins, including unfunctionalized aliphatic alkenes, that enables the three-step total synthesis of (-)-dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally differentiated diazocompounds are viable and advantageous equivalents of single-carbon chirons.

Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes.

Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first-row transition-metal catalysts inspired a new method to access complex poly-heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron-rich olefins in intermolecular [3+2] cycloadditions.

Organocatalytic asymmetric addition of naphthols and electron-rich phenols to isatin-derived ketimines: highly enantioselective construction of tetrasubstituted stereocenters.

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

Enantioselective Catalysis with Pyrrolidinyl Gold(I) Complexes: DFT and NEST Analysis of the Chiral Binding Pocket.

A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC) to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine. The new chiral gold(I) catalysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine led to the formation of opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calculations. As revealed by non-covalent interaction plots, attractive non-covalent interactions between substrates and catalysts direct specific enantioselective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.

Combined Experimental and Computational Study of Ruthenium N-Hydroxyphthalimidoyl Carbenes in Alkene Cyclopropanation Reactions.

A combined experimental-computational approach has been used to study the cyclopropanation reaction of N-hydroxyphthalimide diazoacetate (NHPI-DA) with various olefins, catalyzed by a ruthenium-phenyloxazoline (Ru-Pheox) complex. Kinetic studies show that the better selectivity of the employed redox-active NHPI diazoacetate is a result of a much slower dimerization reaction compared to aliphatic diazoacetates. Density functional theory calculations reveal that several reactions can take place with similar energy barriers, namely, dimerization of the NHPI diazoacetate, cyclopropanation (inner-sphere and outer-sphere), and a previously unrecognized migratory insertion of the carbene into the phenyloxazoline ligand. The calculations show that the migratory insertion reaction yields an unconsidered ruthenium complex that is catalytically competent for both the dimerization and cyclopropanation, and its relevance is assessed experimentally. The stereoselectivity of the reaction is argued to stem from an intricate balance between the various mechanistic scenarios.

Rhodium-catalysed ortho-alkynylation of nitroarenes.

The ortho-alkynylation of nitro-(hetero)arenes takes place in the presence of a Rh(iii) catalyst to deliver a wide variety of alkynylated nitroarenes regioselectively. These interesting products could be further derivatized by selective reduction of the nitro group or palladium-catalysed couplings. Experimental and computational mechanistic studies demonstrate that the reaction proceeds via a turnover-limiting electrophilic C-H metalation ortho to the strongly electron-withdrawing nitro group.

Three-Component Synthesis of α-Aminoperoxides Using Primary and Secondary Dialkylzinc Reagents with O2 and α-Amido Sulfones.

A straightforward strategy for the synthesis of unprecedented α-aminoperoxides bearing primary and secondary alkylperoxide substituents is described. Commercially available dialkylzinc reagents are oxidized with molecular oxygen and the consequent peroxide species react with stable (hetero)aromatic and aliphatic α-amido sulfones in excellent yields (>90%). The now available α-aminoperoxides are of potential interest in medicinal chemistry, specifically for the synthesis of antimalarial compounds. Moreover, modification of the reaction conditions selectively leads to N,O-acetals in good yields.

Hydroxy-Directed Enantioselective Hydroxyalkylation in the Carbocyclic Ring of Indoles.

A Cinchona-derived squaramide catalyzes the reaction between hydroxyindoles and isatins leading to enantioenriched indoles substituted in the carbocyclic ring. The reaction proceeds efficiently with differently substituted isatins, yielding the desired products with excellent regioselectivity, good yields, and high enantiocontrol. Moreover, every position of the carbocyclic ring of the indole can be functionalized by using the appropriate starting hydroxyindole. The OH group was removed smoothly upon hydrogenolysis of the corresponding triflate.