Enantioselective Organocatalytic Research Articles

3-Alkyl-1,2,4-triazines as Heterocyclic Platforms for Organocatalytic Enantioselective Benzylic C-H Functionalization.

The α-3-(1,2,4-triazine)-α-cyanoacetate derivatives exhibit a unique and well-defined dearomatized structure undergoing efficient organocatalytic aromatization-alkylation sequences with Michael acceptors in order to construct an all-carbon tetrasubstituted stereocenter with high ee values. These new players in the field of enantioselective catalytic benzylic C-H functionalization afford versatile molecular platforms toward the construction of valuable 3D-heterocycles.

Organocatalytic Enantioselective Arylation to Access Densely Aryl-Substituted P-Stereogenic Centers.

Although methods for synthesizing chiral phosphorus scaffolds are available, the potential of this molecular chirality remains largely unexplored. Herein, we present a remote desymmetrization of prochiral biaryl phosphine oxides through an organocatalytic asymmetric arylation. This metal-free approach enables the efficient synthesis of a wide range of densely functionalized P(V)-stereogenic compounds with good to excellent yields and satisfactory enantioselectivities. Mechanistic studies reveal that hydrogen bonding and ion-pairing interactions are crucial for achieving precise stereocontrol in this transformation.

Organocatalytic Enantioselective Vinylogous Allylic Alkylation between β,γ‐Unsaturated Pyrazoleamides and MBH Carbonates

AbstractThe direct asymmetric vinylogous allylic alkylation is an efficient method to construct chiral 1,5‐diene compounds. In this work, acyclic unsaturated amides are used as a nucleophile for enantioselective vinylogous allylic alkylation. With 10 mol % of chiral tertiary amine C11, the enantioselective vinylogous allylic alkylation between β,γ‐unsaturated pyrazoleamides and Morita‐Baylis‐Hillman carbonates is achieved, affording optically active multifunctional chiral 1,5‐dienes in moderate‐to‐excellent yields (74–99 %) with good‐to‐excellent enantioselectivities (67–94 % ee).

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.

Cinchona Organocatalyzed Enantioselective Amination for Quaternized Serines as Tertiary Amides.

Herein, we describe a Cinchona-aminocatalyzed enantioselective α-hydrazination of an α-formyl amide for the production of protected quaternized serines as tertiary amides with ee's of generally >98% and ≤99% yields. The proposed TS model supported by density functional theory calculations involves a quinuclidinium ion Brønsted acid-assisted delivery of DtBAD, which occurs from the Re face of an H-bonded enaminone when using a 9S-cinchonamine catalyst, resulting in a hydrazide with the R-configuration as determined by X-ray analysis.

Enantioselective Organocatalyzed Cascade Dearomatizing Spirocycloaddition Reactions of Indole-Ynones.

An intramolecular organocatalytic cascade dearomatizing spirocycloaddition reaction of indole-ynone compounds containing O-silyl-naphthol substituents has been developed with the use of a chiral bifunctional thiourea. This process was able to provide various structurally diverse polycyclic spiroindolines in high yields (up to 98%) with excellent stereoselectivities (>20:1 dr, up to 98% ee) involving the formation of carbonylvinylidene ortho-quinone methide intermediates.

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.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

Asymmetric Synthesis of (-)-Cannabidiol (CBD), (-)-Δ9-Tetrahydrocannabinol (Δ9-THC) and Their cis Analogs Using an Enantioselective Organocatalyzed Diels-Alder Reaction.

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)-trans-CBD and psychoactive (-)-trans-Δ9-THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Organocatalytic Enantioselective Chloroiminocyclization for the Synthesis of Imidazoline.

Imidazoline is an important scaffold in organic synthesis and a pharmacophore in medicinal chemistry. We apply basic imines as nucleophiles for the catalytic asymmetric chloroiminocyclization to furnish tetrasubstituted stereocenter-containing imidazolines in excellent yields and enantioselectivities. The reaction can be conducted in the polar solvent acetonitrile under concentrated reaction conditions.

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles.

Herein, we describe an asymmetric assembly of ortho-aromatic diamines and formyl tethered Michael acceptors forming chiral fused benzimidazoles. A cinchona-alkaloid-derived bifunctional squaramide catalyst enables the methodology through on-site dihydrobenzimidazole formation followed by an aza-Michael addition/oxidation cascade. This protocol stands out for its excellent catalytic efficiency over the background reaction and its mild conditions, making it more practical. Various Michael acceptors, including enones, ester, and thioester, were successful substrates in this study. Additionally, this methodology has demonstrated scalability and successfully showcased postsynthetic transformations.

Front Cover Picture: Organocatalytic Enantioselective Syntheses of Flavonoids and Cannabinoids (Adv. Synth. Catal. 5/2024)

Front Cover Picture: Organocatalytic Enantioselective Syntheses of Flavonoids and Cannabinoids (Adv. Synth. Catal. 5/2024)

Organocatalytic Enantioselective (4+2) Annulation of Cyclopropane Carbaldehydes with 2‐Mercapto‐1‐Arylethanones

AbstractHere, we report the organocatalytic enantioselective synthesis of dihydrothiopyran derivatives from trans racemic donor–acceptor cyclopropane carbaldehydes (DACCs) and 2‐mercapto‐1‐arylethanone via formal thio (4+2) cycloaddition involving thia‐Michael aldol condensation and annulation. Mechanistic studies indicate a typical kinetic resolution (KR) is involved in this transformation, which results in moderate yields and enantiomeric ratios. Remarkably, this method is characterized by its one‐pot simplicity, mild reaction conditions, and resilience towards air and moisture interference.

Organocatalytic Enantioselective Nucleophilic Addition of Indole Imine 5-Methides.

Despite the enormous developments in the asymmetric transformations of indole imine methides (IIMs), the remote asymmetric induction involving IIMs remains challenging due to the spatial interaction requirement between the substrate and catalyst. Herein we report the first catalytic asymmetric nucleophilic addition to indole imine 5-methide (5-IIM), the only topological isomer of IIMs whose asymmetric addition remains unknown. Despite the challenging remote stereocontrol, high efficiency and respectable enantioselectivity were achieved to provide access to a range of enantioenriched indole-containing triaryl alkanes.

Organocatalytic Enantioselective Syntheses of Flavonoids and Cannabinoids

AbstractFlavonoids and cannabinoids comprise two large families of natural products that contain a chromane moiety in their structure. Their therapeutic potential has been extensively investigated as potential treatments to several diseases, ranging from cancer to infectious and neurodegenerative diseases. Despite their relative structural simplicity, in recent years creative synthetic methodologies were designed to overcome limitations from the previous synthetic strategies applied to these compounds. The aim of this review is to provide a comprehensive overview of all the enantioselective organocatalytic strategies that have been applied to the synthesis of flavonoids and cannabinoids to date.

Recent Developments on the Synthesis of Sulfoxides via Sulfenate Anions

AbstractSince the early 2000s, novel synthetic methods for the preparation of sulfoxides have emerged that involve sulfenate anions as sulfur nucleophiles. This short review showcases key advances in these sulfenate protocols, including catalytic enantioselective alkylation and arylation, and provides future directions for this research field.1 Introduction2 Precursors of Sulfenate Anions3 Organocatalytic Enantioselective Alkylation of Sulfenate Anions4 Palladium-Catalyzed Arylation of Sulfenate Anions5 Coupling of Sulfenate Anions with Hypervalent Iodine Reagents6 Conclusions and Outlook

Organocatalytic Enantioselective Intramolecular Michael Addition by In Situ Generated Aminoisobenzofulvenes: Construction of Spiro Quaternary Carbon Stereocenters.

An unprecedented enantioselective organocatalytic spirocyclization strategy is presented by in situ generation of aminoisobezofulvenes. The reaction sequence involves a reductive Michael/aldol-condensation/Michael addition cascade by iminium-enamine catalysis. The key success of this spirocyclization was the formation of intermediatory nucleophilic aminoisobenzofuvenes accountable for intramolecular Michael addition. Benzospirononanes featuring an all carbon qauternary spirocenter were obtained using proline-derived amino-organocatalyst in moderate to good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr, and 99 % ee). Post-methodological manipulation of benzospirononanes was also demonstrated.

Sustainable Organocatalyzed Enantioselective Catalytic Michael Additions in Betaine-Derived Deep Eutectic Solvents

AbstractThe organocatalyst cinchonidine-squaramide was immobilized within three different deep eutectic solvents (DESs): betaine:d-sorbitol:water, betaine: d-xylitol:water, and betaine:d-mannitol:water and evaluated in a well-known asymmetric Michael addition. These reactions provided excellent yields (up to 99%) and enantioselectivities (up to 98%) using only 1 mol% of organocatalyst. It was also possible to achieve 9 cycles in reactions with DES (betaine:d-sorbitol:water), proving the high recyclability of this system. In the reactions realized with only 0.5 mol% of organocatalyst, it was possible to achieve 5 cycles, and the products were obtained with high yields (up to 95%) and excellent enantioselectivities (up to 94%), using DES (betaine:d-sorbitol:water).

Diastereo‐ and Enantioselective Organocatalytic Synthesis of Spirocyclopropyl Pyrazolones

AbstractA diastereo‐ and enantioselective synthesis of spirocyclopropylpyrazolones has been described through a Michael/alkylation cascade reaction of 4‐arylidenepyrazol‐5‐ones with diethyl 2‐bromomalonate catalyzed by (DHQ)2AQN. The reaction afforded selectively the corresponding spirocyclic compounds with 30–83% yield, diastereoselectivities ranging from 60:40 to >95:5 and 26–93% enantiomeric excess under mild reaction conditions. Moreover, we performed two selective transformations with the corresponding chiral compounds.

Organocatalytic Enantioselective Reductive Radical Coupling of Ketimines with Dihydropyridines

Key words photoredox catalysis - chiral Brønsted acid catalysis - α-amino acids