Organocatalytic Strategy Research Articles

Catalytic Asymmetric N-Alkylation of Indoles and Carbazoles through 1,6-Conjugate Addition of Aza-para-quinone Methides.

Catalytic asymmetric N-alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza-para-quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N-protective group, the intermolecular C-N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional-group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.

Light‐Driven Enantioselective Organocatalytic β‐Benzylation of Enals

AbstractA photochemical organocatalytic strategy for the direct enantioselective β‐benzylation of α,β‐unsaturated aldehydes is reported. The chemistry capitalizes upon the light‐triggered enolization of 2‐alkyl‐benzophenones to afford hydroxy‐o‐quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael‐type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring‐opening.

Light-Driven Enantioselective Organocatalytic β-Benzylation of Enals.

A photochemical organocatalytic strategy for the direct enantioselective β‐benzylation of α,β‐unsaturated aldehydes is reported. The chemistry capitalizes upon the light‐triggered enolization of 2‐alkyl‐benzophenones to afford hydroxy‐o‐quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael‐type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring‐opening.

Enantioselective synthesis of cyclopenta[b]benzofurans via an organocatalytic intramolecular double cyclization.

An enantioselective organocatalytic strategy, combining Brønsted base and N-heterocyclic carbene catalysis in a unique manner, is demonstrated for a concise construction of the privileged cyclopenta[b]benzofuran scaffold, present in many bioactive compounds having both academic and commercial interests. The reaction concept relies on an intramolecular one-pot double cyclization involving a cycle-specific enantioselective Michael addition followed by a benzoin condensation of ortho-substituted cinnamaldehydes. Cyclopenta[b]benzofurans were achieved in moderate to good yields, with excellent stereoselectivities. A proof of principle for a diastereodivergent variation is demonstrated through the synthesis of cyclopenta[b]benzofurans containing two contiguous aromatic substituents in a substitution pattern present in commercial and natural compounds. Furthermore, several transformations have been performed, demonstrating the synthetic utility of the products. Finally, insights into the activation mode and stereoindution models are presented for this new synthetic strategy.

Light-Triggered Enantioselective Organocatalytic Mannich-Type Reaction

Disclosed herein is a photochemical organocatalytic strategy for the direct enantioselective Mannich-type reaction of 2-alkylbenzophenones and cyclic imines. The chemistry exploits the light-triggered enolization of 2-alkylbenzophenones to generate transient hydroxy-<i>o</i>-quinodimethanes. These fleeting intermediates can be stereoselectively intercepted by imines upon activation with a chiral organic catalyst, derived from natural cinchona alkaloids. The developed method uses mild conditions, simple sources of illumination, and easily available substrates and catalysts, affording enantioenriched chiral amines that are difficult to synthesize by other approaches.

Enantioselective Organocatalytic Cascade Approach to Different Classes of Benzofused Acetals.

A novel enantioselective organocatalytic strategy is presented for the synthesis of tetrahydrofurobenzofuran and methanobenzodioxepine natural product core structures. The strategy is based on a pair of divergent reaction pathways in which hydroxyarenes react with γ-keto-α,β-unsaturated aldehydes, catalyzed by a chiral secondary amine. One reaction pathway, which leads to chiral 5,5-fused acetals with two stereocenters-the tetrahydrofurobenzofuran scaffolds-proceeds in moderate yields and up to 96 % ee. The other reaction pathway provides 5,6-bridged methanobenzodioxepine scaffolds with three stereocenters in moderate to good yields and up to 95 % ee. The reaction is remarkable as it can proceed with catalyst loadings as low as 0.25 mol %, providing one of the highest known turnover numbers in iminium ion catalysis. Furthermore, the hemiacetal tetrahydrofurobenzofuran can undergo functionalizations including reduction, oxidation, and allylation. Finally, the effects involved in the substrate control for the divergent pathways, based on both experimental and computational studies, have been investigated. A model involving steric, electronic and stereoelectronic interactions is discussed to rationalize the observed selectivities.

ChemInform Abstract: Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene‐Oxetane Scaffolds.

AbstractAn efficient catalytic system is found for the unprecedented enantioselective cycloaddition of dienals such as (I), (IX), and (XI) to α,β,β‐trisubstituted nitroolefins (II).

Studies on Pumiliotoxin A Alkaloids: An Approach to Preparing the Indolizidinic Core by Intramolecular Dia­stereoselective N‐Heterocyclic Carbene Catalyzed Benzoin Reaction

AbstractIn this article, we describe the development of a convergent organocatalytic strategy to prepare the indolizidinic core of the pumiliotoxin A alkaloid family. The key step of the proposed strategy is based on a diastereoselective N‐heterocyclic carbene catalyzed benzoin reaction, in which the Breslow intermediate generated from an enal moiety (umpolung a1 to d1 – acyl anion equivalent) attacks a ketone moiety intramolecularly to provide the indolizidinone core in good yield with good selectivity.

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds.

The first catalytic enantioselective cycloaddition reaction to α,β,β-trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and -azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane.

Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene‐Oxetane Scaffolds

AbstractThe first catalytic enantioselective cycloaddition reaction to α,β,β‐trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4‐dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene‐oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene‐cyclobutanes and ‐azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring‐opening of the oxetane.

An Organocatalytic Asymmetric Diels-Alder Strategy for the Enantioselective Synthesis of Spirocyclic Oxindole-Cyclohexenones

An Organocatalytic Asymmetric Diels-Alder Strategy for the Enantioselective Synthesis of Spirocyclic Oxindole-Cyclohexenones

ChemInform Abstract: Inter‐ and Intramolecular Dienamine Organocatalytic Strategies for the Synthesis of Tetrahydroisoquinolines and Tricyclic Derivatives via [3 + 2] and [4 + 2] Cycloadditions

AbstractReview: [34 refs.

ChemInform Abstract: Highly Stereoselective [4 + 2] and [3 + 2] Spiroannulations of 2‐(2‐Oxoindolin‐3‐ylidene)acetic Esters Catalyzed by Bifunctional Thioureas.

AbstractThe first asymmetric organocatalytic strategy enabling access to both five‐ and six‐membered ‐nitro‐spirocarboxylic oxindoles containing up to six consecutive stereogenic centers is developed.

ChemInform Abstract: Organocatalytic Strategies for the Synthesis of Axially Chiral Compounds

AbstractReview: [26 refs.

Practical synthesis of polysubstituted naphthalene derivatives via HNTf2-catalyzed benzannulation reaction

The synthesis of polysubstituted naphthalenes using the triflimide-catalyzed benzannulation of arylacetaldehydes with alkynes at room temperature is described. This method demonstrates a high functional group tolerance and, in the case of halogen substituted naphthalenes, opens the route for further functionalization by palladium-ca talyzed cross-coupling reactions. With an analogous organocatalytic strategy, arylepoxides or 2-arylacetal derivatives are also suitable partners in the related benzannulation reactions wi th aryl-alkynes.

ChemInform Abstract: Stereoselective Reaction of 2‐Carboxythioesters‐1,3‐dithiane with Nitroalkenes: An Organocatalytic Strategy for the Asymmetric Addition of a Glyoxylate Anion Equivalent.

AbstractThe enantioselective organocatalyzed conjugate addition of a newly activated thioester acting as an acyl anion mimic is presented using a chiral bifunctional catalyst to control the stereochemistry.

Inter- and Intramolecular Dienamine Organocatalytic Strategies for the Synthesis of Tetrahydroisoquinolines and Tricyclic Derivatives via [3+2] and [4+2] Cycloadditions

The use of dienamines represents a new approach for carrying out asymmetric aminocatalytic reactions controlled by a remote chiral catalyst. In this account, we describe our contributions on the use of dienamine methodologies for the synthesis of interesting compounds from a natural product and pharmaceutical point-of-view. Dienamine aminocatalysis is employed for the synthesis of tetrahydroisoquinoline derivatives via intermolecular [3+2] cycloadditions, and for the preparation of tricyclic products by means of intramolecular [4+2] Diels–Alder reactions. 1 Introduction 2 Intermolecular Dienamine versus Iminium Ion Catalysis: Synthesis of Tetrahydroisoquinoline Derivatives 3 Intramolecular Dienamine Catalysis: Synthesis of Tricyclic Derivatives 4 Outlook

Organocatalytic Strategies for the Synthesis of Axially Chiral Compounds

Atropisomers are compounds in which chirality arises from hindered rotation along the carbon–carbon or carbon–heteroatom single bond. Recently, organocatalysis appeared to be a rapid, valuable, and efficient strategy for their preparation in an enantioselective manner. In this report a general overview of the most important organocatalyzed atroposelective transformations will be given pointing out in particular the specific role played by the catalyst. 1 Dynamic Kinetic Resolution 2 Desymmetrization of Biaryls 3 Direct Synthesis of Biaryls 4 Asymmetric Friedel–Crafts Amination of Naphthols 5 N-Alkylation via Phase-Transfer Catalysis 6 Desymmetrization of N-Arylmaleimides

ChemInform Abstract: Organocatalytic Asymmetric Synthesis of 1,1‐Diarylethanes by Transfer Hydrogenation.

AbstractA new organocatalytic transfer hydrogenation strategy for the efficient asymmetric synthesis of 1,1‐diarylethanes is given.

Highly stereoselective [4+2] and [3+2] spiroannulations of 2-(2-oxoindolin-3-ylidene)acetic esters catalyzed by bifunctional thioureas.

A new Michael-Michael cascade reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 1 and nitroenoates 2, catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon-carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double-bond configuration of the donor-acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five- and six-membered β-nitro spirocarbocyclic oxindoles.