Organocatalytic Enantio Research Articles

Organocatalytic enantio- and diastereoselective synthesis of trifluoro-ethylamine allenoate derivatives containing axial and central chiralities.

Herein, we report an example of a stereoselective γ-addition reaction of trifluoromethyl ketimines to 1-alkynyl ketones mediated by an isothiourea, BTM, under mild conditions, which afforded tetrasubstituted allenes with central chiralities in high yields (up to 94% yield), good enantioselectivities (up to 91% ee), and excellent diastereoselectivities (all >20 : 1 dr). In addition, the BTM-catalyzed γ-addition reaction was successfully applied to the gram-scale reaction, and an unexpected benzopyrrolothiazine derivative was successfully converted, albeit racemic.

Asymmetric Cascade Dearomatization-Cyclization Reaction of Tryptamines with β,γ-Alkynyl-α-imino Esters: Access to Hexahydropyrrolo[2,3-b]indole-Containing Tetrasubstituted α-Amino Allenoates.

An organocatalytic enantio- and diastereoselective synthesis of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted α-amino allenoates, exhibiting both axial and central chirality, has been accomplished via cascade dearomatization-cyclization reaction. The γ-addition to β,γ-alkynyl-α-imino esters provides a library of densely substituted highly enantioenriched allenes in high yields and excellent stereoselectivities. In addition, the scope of this methodology has been extended to tryptophol as well. A scale-up reaction and synthetic transformations of the products were performed to demonstrate the practical usefulness of this approach.

Organocatalytic enantio- and diastereoselective assembly of cyclopropane-incorporated polycyclic molecules via isobenzopyrylium ions.

A highly enantio- and diastereoselective organocatalytic formation of cyclopropanes embedded in a complex bridged polycyclic architecture is disclosed. In the presence of a chiral phosphoric acid catalyst, this reaction generates four new stereogenic centers and three new C-C bonds efficiently from isochromene acetals and vinylboronic acids under mild conditions. Different from conventional asymmetric cyclopropanation strategies, this process does not involve carbenes or carbenoids. The complex products can serve as precursors to useful homoenolate equivalents. Mechanistically, DFT studies provided insights into the key transition states of the enantiodetermining [4 + 2] cycloaddition, in which the enantioselectivity is induced by the chiral phosphate counter anion of the isobenzopyrylium intermediate.

Cover Picture: Organocatalytic Enantio‐ and Diastereoselective Diels‐Alder Reaction between 2,4‐Dienals and α,β‐Unsaturated Esters (Adv. Synth. Catal. 22/2023)

Cover Picture: Organocatalytic Enantio‐ and Diastereoselective Diels‐Alder Reaction between 2,4‐Dienals and α,β‐Unsaturated Esters (Adv. Synth. Catal. 22/2023)

Organocatalytic Enantio‐ and Diastereoselective Diels‐Alder Reaction between 2,4‐Dienals and α,β‐Unsaturated Esters

AbstractDespite advances in the development of catalytic asymmetric Diels‐Alder reactions, introducing α,β‐unsaturated esters as dienophiles remains challenging owing to their low reactivity. Herein, we report that a chiral aminocatalyst in conjunction with a chiral isothiourea catalyst or a Brønsted acid can promote enantio‐ and diastereoselective Diels‐Alder reactions between 2,4‐dienals and α,β‐unsaturated esters. This method proceeds through the formation of chiral trienamine intermediates for the exo‐cycloaddition with activated dienophiles, α,β‐unsaturated acylammonium species or protonated N‐heteroaryl‐substituted alkenes. Through synergistic activation of both dienes and ester dienophiles, densely functionalized cyclohexenes bearing multiple stereocenters can be afforded with up to >25:1 dr and >99% ee. Moreover, we show that variation of the configurations of the chiral catalysts and the olefin geometry allows the stereodivergent preparation of four stereoisomers of the enantiopure exo‐products.

Enantio- and Diastereoselective Construction of Contiguous Tetrasubstituted Chiral Carbons in Organocatalytic Oxadecalin Synthesis.

The organocatalytic enantio- and diastereoselective cycloetherification of 1,3-cyclohexanedione-bearing enones involving the in situ generation of chiral cyanohydrins was developed. This transformation offers the first catalytic asymmetric approach to oxadecalin derivatives containing contiguous tetrasubstituted chiral carbons at the bridge heads of the fused ring systems. Depending on substituents, both cis- and trans-decalin-type scaffolds were synthesized with good to excellent stereoselectivities, and a range of functional groups accumulated on the chiral quaternary carbon moieties of the trans-oxadecalin derivatives.

Desymmetrization of gem-diols via water-assisted organocatalytic enantio- and diastereoselective cycloetherification.

The first desymmetrization of gem-diols forming chiral hemiketal carbons was accomplished via organocatalytic enantio- and diastereoselective cycloetherification, which afforded optically active tetrahydropyrans containing a chiral hemiketal carbon and tetrasubstituted stereocenters bearing synthetically versatile fluorinated groups. The desymmetrization of silanediols was also demonstrated as an asymmetric route to chiral silicon centers.

Asymmetric Cycloetherification of in Situ Generated Cyanohydrins through the Concomitant Construction of Three Chiral Carbon Centers

The organocatalytic enantio- and diastereoselective cycloetherification of in situ generated cyanohydrins through the concomitant construction of three chiral carbon centers is reported. This protocol facilitates the concise synthesis of optically active tetrahydropyran derivatives, which are ubiquitous scaffolds found in various bioactive compounds, through the simultaneous construction of multiple bonds and stereogenic centers, including tetrasubstituted chiral carbons. The resulting products also contain multiple synthetically important functional groups, which expand their possible usefulness as chiral building blocks.

Organocatalytic enantio- and diastereoselective synthesis of 3,5-disubstituted prolines.

The asymmetric synthesis of substituted pyrrolidines has been accomplished using a novel organocatalytic cyclization reaction promoted by a Cinchona alkaloid based primary amine. The reaction proceeds smoothly yielding pyrrolidine-2,2-dicarboxylates after in situ diastereoselective reduction with high levels of enantioselection. Furthermore, these adducts could be easily transformed into N-protected disubstituted prolines through the base-promoted diastereoselective C → N alkoxycarbonyl transfer reaction.

ChemInform Abstract: Organocatalytic Enantio‐ and Diastereoselective Synthesis of Highly Substituted δ‐Lactones via a Michael‐Cyclization Cascade.

An organocatalyzed Michael-cyclization cascade approach of readily available α,β-unsaturated aldehydes and pyrazoleamides has been developed to get highly substituted δ-lactones in excellent enantioselectivities (up to 97%) and diastereoselectivities. The δ-lactones so obtained could easily be transformed into benzazepine derivatives with excellent enantio- and diastereoselectivities. Furthermore, the pyrazole moiety from the δ-lactones can be simply cleaved without disturbing the stereoselectivity.

ChemInform Abstract: Organocatalytic Enantio‐ and Diastereoselective Synthesis of 1,2‐Dihydronaphthalenes from Isobenzopyrylium Ions.

AbstractThe title reaction is a new catalytic asymmetric synthesis of important dihydronaphthalenes, and also a new example of asymmetric reactions of the versatile isobenzopyrylium species.

Organocatalytic enantio- and diastereoselective synthesis of 1,2-dihydronaphthalenes from isobenzopyrylium ions.

A highly efficient asymmetric synthesis of dihydronaphthalenes is disclosed. The process represents a new addition to the limited asymmetric reactions of isobenzopyryliums, a family of versatile 10π-electron aromatic species. Excellent asymmetric induction is achieved for the first time without an anchoring group in the 4-position or a metal catalyst, both of which were required previously in these reactions. The success is attributed to the unusual chiral counteranion (meanwhile also the nucleophile) generated in situ from the chiral phosphate and the boronic acid as well as the leaving group. Preliminary control experiments provided important insight into the reaction mechanism.

Organocatalytic enantio- and diastereoselective synthesis of highly substituted δ-lactones via a Michael-cyclization cascade.

An organocatalyzed Michael-cyclization cascade approach of readily available α,β-unsaturated aldehydes and pyrazoleamides has been developed to get highly substituted δ-lactones in excellent enantioselectivities (up to 97%) and diastereoselectivities. The δ-lactones so obtained could easily be transformed into benzazepine derivatives with excellent enantio- and diastereoselectivities. Furthermore, the pyrazole moiety from the δ-lactones can be simply cleaved without disturbing the stereoselectivity.

ChemInform Abstract: Organocatalytic Enantio‐ and Diastereoselective Assembly of Thiazolidine Scaffolds by Formal [3 + 2] Annulation.

An organocatalytic enantio- and diastereoselective formal [3+2] annulation between imines and 1,4-dithiane-2,5-diol is disclosed. The reaction provides rapid access to chiral thiazolidine-based molecules starting from a readily available catalyst and achiral starting materials.

Organocatalytic Enantio‐ and Diastereoselective Assembly of Thiazolidine Scaffolds by Formal [3+2] Annulation

AbstractAn organocatalytic enantio‐ and diastereoselective formal [3+2] annulation between imines and 1,4‐dithiane‐2,5‐diol is disclosed. The reaction provides rapid access to chiral thiazolidine‐based molecules starting from a readily available catalyst and achiral starting materials.

Organocatalytic enantio- and diastereoselective 1,3-dipolar cycloaddition between alanine-derived ketonitrones and E-crotonaldehyde: efficiency and full stereochemical studies

Highly enantio- and exo-selective 1,3-dipolar cycloadditions of alanine-derived ketonitrones to E-crotonaldehyde could be realized in a good yield by the use of a chiral imidazolidinone salt without the addition of water. The origin of the stereoselectivity in the reaction was discussed and the absolute configuration of the cycloadduct determined unambiguously.

Highly Diastereo- and Enantioselective Organocatalytic Michael Addition of α-Ketoamides to Nitroalkenes

The first organocatalytic enantio- and diastereoselective conjugate addition of α-ketoamides to nitroalkenes has been achieved using a bifunctional amino thiourea catalyst. In this new approach, the substrate amide proton plays a critical role in the formation of the Michael anti-adducts in high yields and high stereoselectivities. To illustrate the high synthetic potential of this methodology, the diastereo- and enantioselective synthesis of a hexasubstituted cyclohexane via a Michael-Michael-Henry cascade reaction is described.

ChemInform Abstract: The First Organocatalytic Enantio‐ and Diastereoselective 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Nitroalkenes.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The First Organocatalytic Enantio- and Diastereoselective 1,3-Dipolar Cycloaddition of Azomethine Ylides with Nitroalkenes

The first chiral thiourea-catalyzed stereoselective 1,3- dipolar cycloaddition of azomethine ylides with nitroalkenes afforded highly substituted pyrrolidines with high diastereoselectivities of up to <99:1 dr and moderate enantioselectivities.