Organocatalytic Enantioselective Addition Research Articles

Synthesis of Chiral 3H‐Pyrrolo[1,2‐a]indoles Via Organocatalytic Enantioselective Addition of Alkynyl Biphenyl Quinone Methides

AbstractAn organocatalytic enantioselective reaction utilizing α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols and 3‐substituted indoles has been successfully established for the synthesis of chiral 3H‐pyrrolo[1,2‐a]indoles. Through the assistance of an appropriate chiral phosphoric acid, a cascade sequence is facilitated, beginning with the dehydration of α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols to form alkynyl 4,4’‐biphenyl quinone methides (4,4’‐BQMs). Subsequently, 1,12‐addition of 3H‐pyrrolo[1,2‐a]indoles to these alkynyl 4,4’‐BQMs results in the formation of allenes, which are then protonated and regenerate 4,4’‐BQMs. Finally, an enantioselective intramolecular annulation of 4,4’‐BQMs occurs smoothly, leading to the production of a range of 3H‐pyrrolo[1,2‐a]indoles with high efficiency and asymmetric induction.

Enantioselective Construction of Tetrasubstituted Carbon Stereocenters via Chiral Phosphoric Acid-Catalyzed Friedel-Craft Alkylation of Indoles with 5-Substituted Hydroxybutyrolactams.

The first intermolecular organocatalytic enantioselective addition of indoles to prochiral 5-membered cyclic N-acyliminium ions, generated from 5-hydroxy-α,β-unsaturated pyrrolidin-2-ones, is reported hereinafter. The reaction proceeds smoothly with a range of 5-hydroxy-5-substituted-α,β-unsaturated pyrrolidin-2-ones and indoles using BINOL-derived phosphoric acid catalyst to afford α,β-unsaturated lactams embedding a tetrasubstituted stereogenic center in high yields and enantioselectivities.

DoE-Driven Development of an Organocatalytic Enantioselective Addition of Acetaldehyde to Nitrostyrenes in Water.

The development of an enantioselective enamine‐catalysed addition of masked acetaldehyde to nitroalkenes via a rational approach helped to move away from the use of chloroform. The presented research allows the use of water as a reaction medium, therefore improving the industrial relevance of a protocol to access very important pharmaceutical intermediates. Critical to the success is the use of chemometrics‐assisted ‘Design of Experiments’ (DoE) optimisation during the development of the presented new synthetic approach, which allows to investigate the chemical space in a rational way.

Organocatalytic Enantioselective Addition of α-Aminoalkyl Radicals to Isoquinolines.

With a dual organocatalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and under the irradiation with visible light, an enantioselective Minisci-type addition of α-amino acid-derived redox-active esters (RAEs) to isoquinolines has been developed. A variety of prochiral α-aminoalkyl radicals generated from RAEs were successfully introduced on isoquinolines, providing a range of valuable α-isoquinoline-substituted chiral secondary amines in high yields with good to excellent enantioselectivities.

2-Carboxythioester-1,3-dithiane: A Functionalized Masked Carbonyl Nucleophile for the Organocatalytic Enantioselective Michael Addition to Enones

An S-(2,2,2-trifluoroethyl) 1,3-dithiane-2-carbothioate has been successfully employed as acyl anion synthon in the organocatalytic enantioselective addition to enones promoted by quinine- and quinidine-derived tertiary/primary diamines. By proper selection of a co-catalyst and by optimization of the reaction parameters, convenient experimental conditions were found that allowed to obtain the highly functionalized products in up to 90% yield and 98% ee in short reaction times. These compounds, featuring selectively removable functionalities, proved to be versatile synthetic intermediates, which could be transformed into different derivatives without any erosion of the stereochemical integrity of the molecules.

ChemInform Abstract: Organocatalytic Enantioselective Addition of Thiols to Ketimines Derived from Isatins.

AbstractA cinchona alkaloid sulfonamide is used for the title reaction and both enantiomers of the products can be obtained by using pseudoenantiomeric chiral catalyst.

Organocatalytic enantioselective addition of thiols to ketimines derived from isatins.

The first catalytic enantioselective addition of thiols to ketimines derived from isatins has been developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines and thiols using a cinchona alkaloid sulfonamide catalyst. Both enantiomers of products could be obtained by using pseudoenantiomeric chiral catalysts.

Quinine-thiourea catalyzed enantioselective hydrophosphonylation of trifluoromethyl 2(1H)-quinazolinones

An organocatalytic enantioselective addition reaction of cyclic ketoimines with phosphites has been developed for the first time. The process, catalyzed by Soós' quinine thiourea, affords synthetically and medicinally interesting enantioenriched trifluoromethyl dihydroquinazolinones in high yields and with high enantioselectivities.

Enantioselective Asymmetric Michael Addition of Cyclic Diketones to β,γ‐Unsaturated α‐Keto Esters

AbstractAn efficient, organocatalytic enantioselective addition of cyclic diketones with β,γ‐unsaturated α‐keto esters has been developed that affords products in high yields (up to 95 %) and excellent enantioselectivity (up to >99 % ee) under mild conditions with a low catalyst loading (2.5 mol‐%). The unsaturated α‐keto esters are effectively coordinated and activated through hydrogen bonds with the squaramides and proved to be excellent hydrogen‐bond acceptors in this asymmetric organocatalytic reaction. This reaction provides valuable and easy access to chiral Michael adducts, which are important moieties in the skeletons of biological and pharmaceutical molecules.

Asymmetric Aza-Mannich Addition of Oxazolones to N-Tosyl Aldimines: Synthesis of Chiral α-Disubstituted α,β-Diamino Acids

An organocatalytic enantioselective addition of oxazolones to N-tosyl aldimines has been developed. The process is promoted by a readily prepared cinchona alkaloid ligand and affords a series of valuable alpha-disubstituted alpha,beta-diamino acid derivatives with excellent enantioselectivities (up to 97% ee) and diastereoselectivities (up to >30:1 dr). The adducts can be transformed into the corresponding protected chiral alpha-disubstituted alpha,beta-diamino acids by a one-pot hydrolyzed reaction smoothly.