Dienamine Catalysis Research Articles

β,γ-Regioselective inverse-electron-demand aza-Diels-Alder reactions with α,β-unsaturated aldehydes via dienamine catalysis.

A stereoselective inverse-electron-demand aza-Diels-Alder cycloaddition process of cyclic 1-aza-1,3-butadienes and α,β-unsaturated aldehydes has been developed via dienamine catalysis. This reaction exhibits excellent β,γ-regioselectivity for enal substrates with substantial structural diversity and broad functionalities, readily producing highly enantioenriched fused piperidine derivatives and enabling efficient sequential construction of complex polycyclic frameworks.

Formal [5+3] Cycloaddition via Cascade Dienamine–Dienamine Catalysis

Formal [5+3] Cycloaddition via Cascade Dienamine–Dienamine Catalysis

Asymmetric synthesis of tetrahydroquinolines through a [3+2] cycloaddition controlled by dienamine catalysis.

A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.

Asymmetric [5+3] Formal Cycloadditions with Cyclic Enones through Cascade Dienamine–Dienamine Catalysis

AbstractA few aminocatalytic modes, such as iminium ions and different dienamines, have provided versatile tools for the functionalization of cyclic enones at various sites. Described here is a previously unreported cascade dienamine/dienamine catalytic pathway for β‐substituted 2‐cyclopentenones, and even 2‐cyclohexenone. It involves domino α′‐regioselective Michael addition and a γ‐regioselective Mannich reaction with 3‐vinyl‐1,2‐benzoisothiazole‐1,1‐dioxides to give fused or bridged architectures, which incorporate a spirocyclic skeleton, in excellent stereocontrol, thus furnishing unusual [5+3] formal cycloaddition reactions. Moreover, preliminary biological assays showed that some of the chiral products exhibited promising activity against some cancer cell lines, thus indicating that such skeletons might serve as leads in drug discovery.

Organocatalytic γ-oxidation of α,β-unsaturated aldehydes

Direct, organocatalytic γ-oxidation of α,β-unsaturated aldehydes via dienamine catalysis has been developed. The reaction of 2-hexenal with dibenzoyl peroxide (BPO) catalyzed by the MacMillan catalyst gave desired γ-benzoyloxy aldehyde in a moderate yield, notably the formation of α-substituted product was greatly suppressed. γ-Benzoyloxy-α,β-unsaturated aldehyde turned out to be a useful building block in the synthesis of highly functionalized molecules.

Copper–dienamine catalysis: γ-oxyamination of α,β-unsaturated aldehydes

A multicatalytic system composed of copper complexes andsec-amine compounds is proposed for γ-oxyamination of α,β-unsaturated aldehydes.

Catalytic Asymmetric Remote Aziridination

Key words aziridines - dienamine catalysis - 1,6-addition - cascade reaction

Correction for Bencivenni et al., Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

Correction for Bencivenni et al., Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

Asymmetric Vinylogous Aldol Reaction via H-Bond-Directing Dienamine Catalysis

The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with α-keto esters has been developed. The key to success was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.

Stereodivergence in Amine-Catalyzed Regioselective [4 + 2] Cycloadditions of β-Substituted Cyclic Enones and Polyconjugated Malononitriles

Switchable reaction patterns of β-substituted cyclic enones via amine-based dienamine activation are reported. While γ-regioselective vinylogous Michael addition was observed with alkylidenemalononitriles, a completely different [4 + 2] cycloaddition was obtained with allylidene- or alkynylidenemalononitrile substrates, affording densely substituted bicyclo[2.2.2]octanes or analogous architectures with moderate to excellent diastereo- and enantioselectivity by the catalysis of primary amines from natural quinidine or quinine. Importantly, high diastereodivergence was achieved through unusual hydrogen-bonding interactions of multifunctional primary-amine catalytic systems. Endo cycloadducts were efficiently produced using a combination of 9-amino-9-deoxyepiquinidine and salicylic acid, while exo variants were obtained using 6'-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, we successfully isolated the Michael addition intermediates in some cases, indicating that the above [4 + 2] reaction via dienamine catalysis may proceed by a stepwise Michael-Michael cascade rather than by a concerted Diels-Alder cycloaddition pathway.

ChemInform Abstract: Enantio‐ and Diastereoselective Synthesis of Substituted Tetrahydro‐1H‐isochromans Through a Dynamic Kinetic Resolution Proceeding under Dienamine Catalysis.

AbstractStarting from racemic material, a single diastereomer with high enantiomeric purity is formed via a dieneamine intermediate formed by the chiral secondary amine catalyst.

Secondary Amine‐Catalyzed Asymmetric γ‐Alkylation of α‐Branched Enals via Dienamine Activation

AbstractThe direct and enantioselective γ‐alkylation of α‐substituted α,β‐unsaturated aldehydes proceeding under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl‐prolinol silyl ether catalyst in combination with saccharin as an acidic additive promotes an SN1 alkylation pathway, while ensuring complete γ‐site selectivity and a high stereocontrol. Theoretical and spectroscopic investigations have provided insights into the conformational behavior of the covalent dienamine intermediate derived from the condensation of 2‐methylpent‐2‐enal and the chiral amine. Implications for the mechanism of stereoinduction are discussed.

ChemInform Abstract: Asymmetric Diels—Alder Reaction of β,β‐Disubstituted Enals and Chromone‐Fused Dienes: Construction of Collections with High Molecular Complexity and Skeletal Diversity.

An asymmetric inverse-electron-demand Diels–Alder reaction of chromone-fused dienes and β,β-disubstituted α,β-unsaturated aldehydes has been developed via dienamine catalysis. Different domino or sequential transformations could be carried out for electron-deficient dienes with variously substituted patterns, allowing for the efficient construction of caged or fused tetrahydroxanthones with high molecular complexity and skeletal diversity in excellent diastereo- and enantioselectivities.

γ-Amino Alcohols via Organocascade Reactions Involving Dienamine Catalysis

Whereas cascade reactions catalyzed by secondary amines combine iminium- and/or enamine-catalyzed reactions, we introduce the feasibility of combining these modes of catalysis with dienamine-catalysis as a new general mechanism for cascade reactions. Enantioenriched β-functionalized-γ-amino alcohols were produced from simple achiral enals in one flask by combining dienamine- and iminium-catalyzed intermolecular reactions. Reaction products are precursors of γ-amino acids, γ-lactams, and pyrrolidines; one was employed in a synthesis of γ-amino acid (S)-vigabatrin, the bioactive enantiomer of Sabril.

Asymmetric Synthesis of Cyclobutanes by a Formal [2+2] Cycloaddition Controlled by Dienamine Catalysis

Trap it: A combination of aminocatalysis with H-bonding activation is used in two new approaches to carry out formal enantioselective organocatalyzed [2+2] cycloaddition reactions. This cooperative catalysis solves the inconveniences associated with this transformation. These two new reactions will open opportunities to find reactivities involving other organocatalytic cycloadditions.

Enantio- and Diastereoselective Synthesis of Substituted Tetrahydro-1H-isochromanes through a Dynamic Kinetic Resolution Proceeding under Dienamine Catalysis

Racemic 5-acyloxydihydropyranones react with enolizable α,β-unsaturated aldehydes in the presence of a chiral secondary amine catalyst furnishing a wide range of differently substituted tetrahydro-1H-isochromanes with excellent results. The reaction relies on the activation of the enal by the catalyst through the formation of a dienamine intermediate, which undergoes a Diels-Alder/elimination cascade reaction. Moreover, the overall transformation also results in a highly efficient dynamic kinetic resolution process, furnishing the final adducts in high yields and excellent diastereo- and enantioselectivities.

Organocatalytic asymmetric α-benzoyloxylation of α-branched aldehydes and enals: a useful approach to oxygenated quaternary stereocenters

Direct asymmetric α-benzoyloxylation of α-branched aldehydes and α-branched enals via enamine and dienamine catalysis was used to construct quaternary oxygenated stereocenters with good yields and moderate to good enantioselectivity. This method uses an inexpensive and readily available cinchona alkaloid-derived primary amine as the catalyst, benzoyl peroxide as the oxygen source, and stoichiometric amounts of the aldehyde substrates, providing simple metal-free access to valuable protected 2-hydroxyaldehyde derivatives.

ChemInform Abstract: Dienamine Catalysis: An Emerging Technology in Organic Synthesis

AbstractReview: 114 refs.

2+2] Cycloadditions via H-Bond Directing Dienamine Catalysis

Key words dienamine catalysis - cycloaddition - α,β-unsaturated aldehydes - nitroolefins

Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing Dienamine Catalysis

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,β-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented.