Enantioselective Organocatalytic Conjugate Addition Research Articles

Recent Advances in Organocatalytic Enantioselective Reactions of α‐Functionalized Propargylic Alcohols

AbstractOwing to their unique properties, propargylic alcohols have been recognized as one of the most attractive synthons in the field of organic synthesis. Particularly, with the aid of auxiliary group, the α‐functionalized propargylic alcohols have been frequently involved in the organocatalytic enantioselective substitutions, conjugate additions, annulations and related reactions in recent years. Accordingly, the present review highlights recent advancements in the application of α‐functionalized propargylic alcohols in the field of asymmetric organocatalysis, which is organized according to the type of auxiliary group.

Enantioselective Organocatalytic Conjugate Addition in a Tandem Synthesis of δ-Substituted Cyclohexenones and Four-Step Total Synthesis of Penienone.

A bisperfluorotoluyl-BINOL catalyzed conjugate addition of trifluoroborate salts to doubly vinylogous esters and aldol condensation synthesized chiral δ-substituted cyclohexenones with high yields and enantioselectivities (10 examples, up to 89% yield, 89-98% ee). Stepwise and single-pot sequences were developed, with the former also providing β-substituted masked ketoaldehydes containing a vinyl ether. The transformation was used in a four-step total synthesis of penienone (24% overall yield), ≤ half the steps as in previous syntheses.

Organocatalytic enantioselective conjugate addition of nitroalkanes to trifluoromethylated 3-methyleneoxindoles

A bifunctional squaramide catalyzed asymmetric conjugate addition of nitroalkanes to trifluoromethylated 3-methyleneoxindoles was developed, and a range of trifluoromethyl containing oxindole derivatives were obtained with generally high yields and enantioselectivities. The nitro functionality and oxindole scaffold in the corresponding products are versatile building blocks that readily enable many further valuable transformations.

Organocatalytic Enantioselective Conjugate Addition of Nitromethane to Benzylidene-2-Benzoyl Acetate: Asymmetric Synthesis of ABT - 627, an Endothelin Receptor Antagonist.

First catalytic and enantioselective conjugate addition of nitromethane to benzylidene-2-benzoyl acetate has been developed using dihydroquinine derived squaramide catalyst with moderate to high selectivities. Asymmetric total synthesis of ABT-627, a potent ETA receptor antagonist is accomplished utilizing the developed method in overall 15.7% yield.

Organocatalytic enantioselective conjugate addition of 2-naphthols to ortho-hydroxyphenyl substituted para-quinone methides: access to unsymmetrical triarylmethanes.

The enantioselective conjugate addition of 2-naphthols to ortho-hydroxyphenyl substituted para-quinone methides has been achieved with the aid of a chiral phosphoric acid. Importantly, the reaction took place with excellent chemo- and regioselectivities. In addition, the protocol features a low catalyst loading, mild reaction conditions, and enables the formation of unsymmetrical triarylmethanes in good to high yields with generally high enantioselectivities.

Organocatalytic enantioselective conjugate addition of pyrazolin-5-ones to arylomethylidene malonates.

An efficient asymmetric organocatalytic conjugate addition reaction of pyrazolin-5-ones with arylomethylidene malonates has been successfully developed by employing bifunctional Cinchona derived thiourea organocatalysts. The protocol provides straightforward access to pyrazole substituted scaffolds in good yields with high stereocontrol.

Organocatalytic enantioselective conjugate addition of aldehydes to maleimides in deep eutectic solvents

The conjugate enantioselective addition of aldehydes, mainly α,α-disubstituted, to maleimides leading to enantioenriched succinimides, has been achieved in recyclable deep eutectic solvents at room temperature. Enantiomerically pure carbamate-monoprotected trans-cyclohexane-1,2-diamines are used as organocatalysts, affording high yields and up to 94% ee of the final succinimides. The product can be extracted from the deep eutectic solvent, which retains the chiral organocatalyst, allowing both the solvent and catalyst to be reused.

Organocatalytic Enantioselective Conjugate Addition of Azlactones to Enolizable Linear and Cyclic Enones.

Highly diastereo- and enantioselective conjugate additions of azlactones to enolizable cyclic and linear enones were conducted by employing proline aryl sulfonamide as the organocatalyst in trifluorotoluene. The conjugate adducts bearing contiguous quaternary and tertiary stereocenters were obtained in moderate to good yields with excellent diastereoselectivities and moderate to good enantioselectivities. This developed protocol filled in the substrate gap for the organocatalytic conjugate addition of azlactone to enones.

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Addition of Malonic Acid Half Thioesters to Coumarin‐3‐carboxylic Acids Using N‐Heteroarenesulfonyl Cinchona Alkaloid Amides.

AbstractThe highly enantioselective double‐decarboxylative title reaction is applicable to 3‐oxo‐3‐phenylpropanoic acid, but fails using α‐cyanoacetic acid or α,α‐dimethyl malonic acid half thioesters.

Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Addition of 3‐Fluorooxindoles to Vinyl Sulfone.

AbstractHighly efficient catalytic enantioselective conjugate addition reactions of 3‐fluorooxindoles to activated vinyl sulfone (II) is achieved using a binaphthyl‐modified bifunctional urea catalyst bearing both central and axial chiral elements.

Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates: a Synthetic Strategy for Discoipyrrole D

AbstractBis‐heteroaryl or bis‐aryl stereocenters were formed by an organocatalytic enantioselective conjugate addition using the respective trifluoroborate salts as nucleophiles. Control studies suggested that fluoride dissociation is necessary in the anhydrous conditions. This strategy is applicable to the synthesis of discoipyrrole D, an inhibitor of BR5 fibroblast migration.

Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates: a Synthetic Strategy for Discoipyrrole D.

Bis-heteroaryl or bis-aryl stereocenters were formed by an organocatalytic enantioselective conjugate addition using the respective trifluoroborate salts as nucleophiles. Control studies suggested that fluoride dissociation is necessary in the anhydrous conditions. This strategy is applicable to the synthesis of discoipyrrole D, an inhibitor of BR5 fibroblast migration.

ChemInform Abstract: Origin of the Enantioselectivity in Organocatalytic Michael Additions of β‐Ketoamides to α,β‐Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study.

The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto’s thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

Organocatalytic Enantioselective Conjugate Addition of 3‐Fluorooxindoles to Vinyl Sulfone

Highly efficient catalytic enantioselective conjugate addition reactions of 3-fluorooxindoles to activated vinyl sulfone (II) is achieved using a binaphthyl-modified bifunctional urea catalyst bearing both central and axial chiral elements.

ChemInform Abstract: Enantioselective Organocatalytic Conjugate Addition of Alkenes to α,β‐Enones.

AbstractThe first example of the enantioselective conjugate addition of alkenes to enones, catalyzed by chiral primary amines are reported.The reaction is enabled by chiral primary amines through a typical iminium ion cycle.

Origin of the enantioselectivity in organocatalytic Michael additions of β-ketoamides to α,β-unsaturated carbonyls: a combined experimental, spectroscopic and theoretical study.

The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

ChemInform Abstract: Asymmetric Construction of Benzindoloquinolizidine: Application of an Organocatalytic Enantioselective Conjugate Addition—Cyclization Cascade Reaction.

Many new types of chemicalreactions have been developed to facilitate easier synthesisof complex compounds. Among the strategies, domino reac-tions, which have been utilized for the efficient and stereo-selective construction of complex molecules from simpleprecursors in a single process, are widely used due to theirhigh synthetic efficiency by reducing both the number ofsynthetic operation required and the quantities of chemicalsand solvents used.

Enantioselective Organocatalytic Conjugate Addition of Alkenes to α,β‐Enones

AbstractWe report the first example of the enantioselective conjugate addition of alkenes (aromatic enamines) to enones catalyzed by chiral primary amines. The reactions encompass a plethora of α,β‐enones including difficult α‐substituted vinyl ketones to give vinylation adducts in high yields with good enantioselectivity. The methodology is of synthetic potential in accessing chiral functional materials.

ChemInform Abstract: Organocatalytic Enantioselective Conjugate Addition—Cyclization Domino Reactions of o‐N‐Protected Aminophenyl α,β‐Unsaturated Aldehydes.

AbstractA novel organocatalytic conjugate addition‐cyclization sequence followed by reductive deoxygenation is developed to synthesize chiral 4‐substitued tetrahydroquinolines from α,β‐unsaturated aromatic aldehydes and CH‐acidic compounds.