Trienamine Catalysis Research Articles

Combining cycloisomerization with trienamine catalysis: a regiochemically flexible enantio- and diastereoselective synthesis of hexahydroindoles.

The synthesis of polysubstituted hexahydroindoles through trienamine-organocatalyzed cycloadditions of pyrrolidinyl dienals, prepared by palladium-catalyzed cycloisomerization, is reported. The cycloadditions of this novel class of dienals proceed with excellent levels of enantio- and diastereoselectivity, with the regioselectivity of cycloaddition with respect to the tethering ring readily tuned through design of the cycloisomerization substrate. This work culminates in the first examples of double-stereodifferentiating trienamine catalysis, where catalyst stereocontrol dominates facial selectivity in the cycloaddition, affording azacyclic products that are specifically functionalized at every position.

Enantioselective Formal [4+2] Cycloadditions to 3-Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles.

The first enantioselective formal [4+2] cycloadditions of 3-nitroindoles are presented. By using 3-nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87%) and enantioselectivities (up to 97% ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3-nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.

Enantioselective Formal [4+2] Cycloadditions to 3‐Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles

AbstractThe first enantioselective formal [4+2] cycloadditions of 3‐nitroindoles are presented. By using 3‐nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87 %) and enantioselectivities (up to 97 % ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3‐nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.

ChemInform Abstract: Enantioselective Direct Bisvinylogous 1,6‐Additions of β‐Allyl‐2‐cyclohexenone to α,α‐Dicyanodienes Through Trienamine Catalysis.

An asymmetric direct ϵ-regioselective bisvinylogous 1,6-addition reaction of β-allyl-2-cyclohexenone to β-substituted α,α-dicyanodienes was developed through trienamine catalysis of a bifunctional primary amine–thiourea compound. Excellent enantioselectivity (up to 97 % ee) was obtained even through such a remote reaction mode. In addition, more complex cyclic frameworks could be efficiently constructed with high stereoselectivity.

Trienamine catalysis for asymmetric Diels-Alder reactions of 2,4-dienones: a theoretical investigation.

The mechanism and origin of the selectivity of asymmetric Diels-Alder reactions of 2,4-dienones (R1) by trienamine catalysis is investigated at the M06-2X/6-311++G**(SMD, toluene)//B3LYP/6-311G** level. The acidic additive (salicylic acid or trifluoroacetic acid) promotes the isomerization of the ketoiminium ion into the key reactive cis-trienamine catalytic species with a preferred conformation by constructing a suitable hydrogen-bond bridge for a H shift. One-step cycloaddition was adopted for N-phenylmaleimide (R2), while a stepwise process was used for benzylidenecyanoacetate (R3) dienophile. The -CN and -CO2Et substituents in R3 may play an important role in forming a zwitterionic intermediate by participating in charge transfer by trienamine catalysis. The combination of a hydrogen bond from the protonated N atom of the tertiary amine and steric repulsion from the α-aryl group of trienamine makes the dienophile substrates approach the trienamine from one preferred face. The orbital factors define the most favored alignment of the trienamine and dienophile to realize the endo-selectivity of the product.

Exploring the activation modes of a rotaxane-based switchable organocatalyst.

The reactivity of a rotaxane that acts as an aminocatalyst for the functionalization of carbonyl compounds through HOMO and LUMO activation pathways has been studied. Its catalytic activity is explored for C-C and C-S bond forming reactions through iminium catalysis, in nucleophilic substitutions and additions through enamine intermediates, in Diels-Alder reactions via trienamine catalysis, and in a tandem iminium-ion/enamine reaction. The catalyst can be switched "on" or "off", effectively controlling the rate of all of these chemical transformations, by the in situ change of the position of the macrocycle between two different binding sites on the rotaxane thread.

Enantioselective Direct Bisvinylogous 1,6‐Additions of β‐Allyl‐2‐cyclohexenone to α,α‐Dicyanodienes through Trienamine Catalysis

AbstractAn asymmetric direct ϵ‐regioselective bisvinylogous 1,6‐addition reaction of β‐allyl‐2‐cyclohexenone to β‐substituted α,α‐dicyanodienes was developed through trienamine catalysis of a bifunctional primary amine–thiourea compound. Excellent enantioselectivity (up to 97 % ee) was obtained even through such a remote reaction mode. In addition, more complex cyclic frameworks could be efficiently constructed with high stereoselectivity.

ChemInform Abstract: Aminocatalytic Asymmetric Diels—Alder Reaction of Phosphorus Dienophiles and 2,4‐Dienals.

Abstract Chiral compounds bearing a phosphorus functional group are valuable because of their wide application in biological studies and asymmetric catalysis. Here we present an asymmetric Diels–Alder cycloaddition between phosphor-containing dienophiles and 2,4-dienals under the catalysis of chiral amine 1 via the intermediacy of trienamine species (trienamine catalysis). A spectrum of densely functionalized phosphonocyclohexene derivatives was efficiently constructed in excellent enantioselectivity (up to 99% ee) and with good to high diastereoselectivity (up to >19:1).

ChemInform Abstract: An Asymmetric Normal‐Electron‐Demand Aza‐Diels—Alder Reaction via Trienamine Catalysis.

AbstractThe cycloaddition of indol‐3‐ones (I) and 2,4‐dienals (II) via trienamine catalysis of a chiral secondary amine yields multifunctional tricyclic pyrido[1,2‐a]indoles (III) bearing a quaternary chiral center in good stereoselectivities.

Trienamine catalysis with linear deconjugated 3,5-dienones

Deconjugated linear 3,5-dienones with substantial substitutions were used in β,ε-regioselective Diels–Alder cycloadditions with 3-olefinic oxindoles via trienamine catalysis of cinchona-based primary amines.

Trienamines derived from 5-substituted furfurals: remote ε-functionalization of 2,4-dienals.

The selective ε-functionalization of 5-substituted furfurals via trienamine intermediates is reported herein. This methodology was successfully applied to several 5-substituted furfurals with different amines via formation of a trienamine through the furan ring. The rationalized reaction mechanism involves the addition of the trienamine intermediate to its corresponding iminium-ion producing new furan-containing scaffolds.

Asymmetric Organocatalytic Thio-Diels–Alder Reactions via Trienamine Catalysis

Asymmetric Organocatalytic Thio-Diels–Alder Reactions via Trienamine Catalysis

Aminocatalytic asymmetric Diels–Alder reaction of phosphorus dienophiles and 2,4-dienals

Chiral compounds bearing a phosphorus functional group are valuable because of their wide application in biological studies and asymmetric catalysis. Here we present an asymmetric Diels–Alder cycloaddition between phosphor-containing dienophiles and 2,4-dienals under the catalysis of chiral amine 1 via the intermediacy of trienamine species (trienamine catalysis). A spectrum of densely functionalized phosphonocyclohexene derivatives was efficiently constructed in excellent enantioselectivity (up to 99% ee) and with good to high diastereoselectivity (up to >19:1).

ChemInform Abstract: Asymmetric Organocatalytic Thio‐Diels—Alder Reactions via Trienamine Catalysis.

ChemInform Abstract: Asymmetric Organocatalytic Thio‐Diels—Alder Reactions via Trienamine Catalysis.

ChemInform Abstract: Asymmetric Trienamine Catalysis: New Opportunities in Amine Catalysis

AbstractReview: 19 refs.

Asymmetric Organocatalytic Thio-Diels–Alder Reactions via Trienamine Catalysis

We report a new process to access highly enantioenriched sulfur-based heterocycles by an asymmetric catalytic thio-Diels-Alder reaction. Thiocarbonyls are challenging heterodienophiles in enantioselective Diels-Alder reactions, due to their inherent high reactivity and their poor ability to coordinate to chiral catalysts. We successfully circumvented these problems by employing a different strategy, which explores the use of in situ generated catalyst-bound dienes. Synthetically useful dihydrothiopyrans as well as other bi- and tricyclic sulfur-containing heterocycles are formed in high yields and high to excellent selectivities. DFT calculations were performed to examine the mechanism of the developed reaction. Furthermore, a series of synthetic transformations of the optically active sulfur-based heterocycles are presented.

Asymmetric trienamine catalysis: new opportunities in amine catalysis

Amine catalysis, through HOMO-activating enamine and LUMO-activating iminium-ion formation, is receiving increasing attention among other organocatalytic strategies, for the activation of unmodified carbonyl compounds. Particularly, the HOMO-raising activation concept has been applied to the greatest number of asymmetric transformations through enamine, dienamine, and SOMO-activation strategies. Recently, trienamine catalysis, an extension of amine catalysis, has emerged as a powerful tool for synthetic chemists with a novel activation strategy for polyenals/polyenones. In this review article, we discuss the initial developments of trienamine catalysis for highly asymmetric Diels-Alder reactions with different dienophiles and emerging opportunities for other types of cycloadditions and cascade reactions.

An asymmetric normal-electron-demand aza-Diels–Alder reaction via trienamine catalysis

An asymmetric normal-electron-demand aza-Diels-Alder cycloaddition of 2-aryl-3H-indol-3-ones and 2,4-dienals was explored via trienamine catalysis of a chiral secondary amine. Multifunctional tricyclic polyhydropyrido[1,2-a]indoles were efficiently constructed in good stereoselectivity (up to 92% ee, >19 : 1 dr).

H-Bond-Directed Trienamine Catalysis

H-Bond-Directed Trienamine Catalysis

ChemInform Abstract: Trienamine Catalysis with 2,4‐Dienones: Development and Application in Asymmetric Diels—Alder Reactions.

AbstractThe δ,δ‐substitution pattern of the 2,4‐dienones is necessary for the reaction.