Bifunctional Organocatalysis Research Articles

Enamine Acylation Enabled Desymmetrization of Malonic Esters.

Asymmetric enamine alkylation represents a powerful tool for stereoselective C-C bond formation; in contrast, the development of enantioselective enamine acylation remains elusive. Here, we report that a chiral phosphoric acid can render an in-situ-formed enamine to undergo a stereoselective intramolecular α-carbon acylation, providing an alternative approach for the synthesis of useful pyrrolinones and indolinones bearing tetrasubstituted stereocenters. Utilizing an effective integration of the desymmetrization strategy and bifunctional organocatalysis, the first example of enantioselective enamine acylation is achieved by employing readily available aminomalonic esters and cyclic ketones. Instead of reactive and moisture-sensitive acyl chlorides, common esters with low electrophilicity were successfully used as efficient acylating reagents via hydrogen bonding interactions. The utility is demonstrated in the concise and enantioselective synthesis of (+)-LipidGreen I and II. Experimental studies and DFT calculations establish the reaction pathway and the origin of stereocontrol.

New chiral N-heterocyclic olefin bifunctional organocatalysis in α-functionalization of β-ketoesters

New chiral N-heterocyclic olefin bifunctional organocatalysis in α-functionalization of β-ketoesters

Enantioselective Hydroalkylation of Alkenylpyridines Enabled by Merging Photoactive Electron Donor–Acceptor Complexes with Chiral Bifunctional Organocatalysis

Enantioselective Hydroalkylation of Alkenylpyridines Enabled by Merging Photoactive Electron Donor–Acceptor Complexes with Chiral Bifunctional Organocatalysis

Asymmetric Dearomative (3+2)-Cycloaddition Involving Nitro-Substituted Benzoheteroarenes under H-Bonding Catalysis.

In our studies, the organocatalytic 1,3-dipolar cycloaddition between 2-nitrobenzofurans or 2-nitrobenzothiophene and N-2,2,2-trifluoroethyl-substituted isatin imines has been developed. The reaction has been realized by employing bifunctional organocatalysis, with the use of squaramide derivative being crucial for the stereochemical efficiency of the process. The usefulness of the cycloadducts obtained has been confirmed in selected transformations, including aromative and non-aromative removal of the nitro group.

Direct, Asymmetric Synthesis of Carbocycle‐Fused Uracils via [4+2] Cycloadditions: a Noncovalent Organocatalysis Approach

AbstractThe peculiar versatility of remotely enolizable 6‐methyluracil‐5‐carbaldehydes as useful vinylogous pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated. Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization strategy was implemented, to generate oQDM‐type dienolate intermediates that were efficiently and stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral carbocycle‐fused uracils embedding three contiguous stereocenters were thus collected in one step in good yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability to provide enantiopure products via simple one‐cycle recrystallizations and the possibility to further functionalize these scaffolds without losing their chiral integrity were demonstrated.magnified image

Organocatalytic asymmetric synthesis of pyrrolo[3,2-c]quinolines via a formal [3+2] cycloaddition-lactamization cascade reaction using a bifunctional squaramide catalyst

A simple organocatalytic strategy for the asymmetric synthesis of pyrrolo[3,2-c]quinolines has been developed using N -protected o -amino aromatic aldimines and α , β -unsaturated azlactones in the presence of a cinchona-based H-bonding bifunctional squaramide catalyst via a formal [3 + 2] cycloaddition-lactamization cascade reaction. The chiral pyrrolo[3,2-c]quinoline derivatives are obtained in good yields, moderate enantioselectivities and excellent diastereoselectivities. An asymmetric synthesis of pyrrolo[3,2-c]quinolones employing H-bonding bifunctional organocatalysis is reported for the first time.

Enantioselective vinylogous Mukaiyama aldol reaction of α-ketoesters under bifunctional organocatalysis.

A highly enantioselective vinylogous Mukaiyama aldol reaction to ketoesters catalysed by a hydrogen-bond-donor-based bifunctional organocatalyst is presented. The addition of silyloxy dienol ether gives rise to multifunctional chiral tertiary alcohols bearing a versatile α,β-unsaturated aldehyde with excellent enantiocontrol.

Hybrid Peptide-Thiourea Catalyst for Asymmetric Michael Additions of Aldehydes to Heterocyclic Nitroalkenes.

Bifunctional organocatalysis combining covalent and noncovalent activation is presented. The hybrid peptide-thiourea catalyst features a N-terminal proline moiety for aldehyde activation and a thiourea unit for electrophile activation. This catalyst effectively promotes asymmetric Michael additions of aldehydes to challenging but biologically relevant heterocycle-containing nitroalkenes. The catalyst can be used under solvent-free conditions. Spectroscopic and density functional theory studies elucidate the catalyst structure and mode of action.

Multipoint Recognition of Molecular Conformations with Organocatalysts for Asymmetric Synthetic Reactions

Abstract Organocatalysts activate substrates through mild noncovalent and covalent interactions, and their cooperative actions at multiple catalytic sites are essential even in intrinsically rapid organic reactions such as intramolecular cyclizations. The enzyme-like catalytic system is effective for recognizing specific molecular conformations of substrates, which continually change under reaction conditions, through multipoint interactions, thereby leading to high stereoselectivity. On the basis of this concept, we developed a range of organocatalytic asymmetric synthetic reactions, which are challenging using other categories of catalysts. The proposed catalysis was applied to various manners of asymmetric induction including those accompanied by not only facial selectivity but also by kinetic resolution (KR), dynamic kinetic resolution (DKR), desymmetrization, and dynamic kinetic asymmetric transformation (DYKAT). They enabled various asymmetric transformations through intramolecular hetero-Michael addition, construction of axial chirality, and α,β-unsaturated acylammonium catalysis, which advanced the methods for asymmetric heterocycle synthesis, construction of tetrasubstituted chiral carbons, enantioselective synthesis of axially chiral compounds, and asymmetric library synthesis of pharmaceutically potential compounds. This study also expanded the chemistry of bifunctional organocatalysis. This review provides a comprehensive account of our achievements regarding multipoint recognition of molecular conformations with organocatalysts for asymmetric synthetic reactions.

Complementary double-stranded helical oligomers bearing achiral bifunctional groups that catalyze asymmetric aldol reaction.

Two novel chiral dimer and trimer strands composed of m-terphenyl groups linked through p-diethynylbenzene units with the chiral amidine group and achiral piperazine group introduced at the terminus or center of the strands, respectively, and its complementary achiral carboxylic acid dimer and trimer were synthesized. The complementary chiral/achiral strands form an excess-handed double-helical structure as supported by intense split-type Cotton effects in the absorption regions of the conjugated backbones biased by the chiral amidinium-carboxylate salt bridges. The double-helical trimer was found to catalyze the direct aldol reaction of cyclohexanone with 4-nitrobenzaldehyde and produce the products with a moderate enantioselectivity despite the fact that the catalytically active bifunctional piperazine/carboxylic acid pair introduced in the middle is achiral, indicating the key role of the one-handed double-helical framework for supramolecular bifunctional organocatalysis.

Enantioselective Conjugate Azidation of α,β‐Unsaturated Ketones under Bifunctional Organocatalysis by Direct Activation of TMSN3

AbstractAn enantioselective organocatalytic conjugate azidation of α,β‐unsaturated ketones is presented. A bifunctional organocatalyst activates TMSN3, triggering the nucleophilic addition of the azido group to enones in absence of external promoters and avoiding the direct use or the pre‐formation of highly toxic and explosive hydrazoic acid. This protocol proceeds with excellent enantiocontrol under mild conditions. DFT calculations and mechanistic trials have been performed in order to demonstrate the direct activation performed by the bifunctional organocatalyst.magnified image

Incremental Introduction of Organocatalytic Activity into Conformationally Engineered Porphyrins

To study the correlation of macrocycle nonplanarity and catalytic activity of free base porphyrins in detail, a series of six tetraphenylporphyrins with graded degree of β‐ethyl substitution (“H2EtxTPPs” 1–6; x = 0, 2, 4, 6, 8) was applied in organocatalyzed reactions. The macrocycles display incrementally increasing nonplanarity due to repulsive peri‐interactions. This creates an out‐of‐plane vector and better accessibility of the core amine and imine groups as the number of alkyl substituents increases. Following such a molecular engineering approach, the inner core system could be used to activate small molecules as a result of significant saddle distortion. The potential organocatalyst “H2EtxTPPs” were used in benchmark sulfa‐Michael reactions and we found a distinct relationship between nonplanarity and conversion. These observations were attributed to the combined effect of enhanced basicity and increased H‐bonding potential that could facilitate bifunctional organocatalysis. Ultimately, density functional theory (DFT) calculations were performed on 1–6 to monitor some electronic properties of the title compounds.

Highly efficient construction of chiral dispirocyclic oxindole/thiobutyrolactam/chromanone complexes through Michael/cyclization cascade reactions with a rosin-based squaramide catalyst

An efficient asymmetric Michael/cyclization cascade reaction of 4-chromanones with isothiocyanato oxindoles has been revealed. Under bifunctional organocatalysis by rosin-based squaramide catalyst, a series of spiro[oxindole/thiobutyrolactam/chromanone] complexes were conveniently constructed in a highly stereoselective manner (up to 99% yields, > 20:1 dr and >99% ee). The reaction leads to the formation of three contiguous stereogenic centers and two spiro quaternary stereocenters.

Asymmetric vinylogous Mukaiyama aldol reaction of isatins under bifunctional organocatalysis: enantioselective synthesis of substituted 3-hydroxy-2-oxindoles.

A highly enantioselective organocatalytic vinylogous Mukaiyama aldol reaction of silyloxy dienes and isatins under bifunctional organocatalysis is presented. Substituted 3-hydroxy-2-oxindoles are synthesised in good yields and enantioselectivities. These synthetic intermediates are used for the construction of more complex molecules with biological properties such as the formal synthesis of a CB2 agonist presented.

Asymmetric synthesis of Rauhut-Currier-type esters via Mukaiyama-Michael reaction to acylphosphonates under bifunctional catalysis.

A highly enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy dienes and α,β-unsaturated acyl phosphonates under bifunctional organocatalysis is presented. The new reactivity triggered by the catalyst conducted to Rauhut-Currier type esters, via a formal conjugate addition to α,β-unsaturated esters. This protocol proceeds under mild conditions with complete regioselectivity and excellent enantiocontrol.

Bifunctional organocatalysis with squaramide-containing Dawson organo-polyoxotungstates

Abstract Two squaramide-containing organo-polyoxometalates (POMs) have been prepared, which efficiently catalyze the addition of dicarbonyl derivatives onto nitroolefins. The POM surface enhances the reactivity of the squaramide, and the hybrid acts as a bifunctional catalyst, where the highly charged POM surface in the organic medium is a base, which deprotonates the nucleophile and the squaramide activates the nitroalkenes via H-bonds. This opens new perspectives to POM-based catalysis.

Organocatalytic Diels–Alder Reaction of 2‐Vinylindoles with Methyleneindolinones: An Efficient Approach to Functionalized Carbazolespirooxindoles

AbstractAn unprecedented asymmetric Diels–Alder reaction of 2‐vinylindoles with methyleneindolinones has been disclosed. Under bifunctional organocatalysis by cinchona‐derived squaramide catalyst, a series of diversely functionalized carbazolespirooxindole derivatives bearing three contiguous stereocenters are rapidly constructed under mild conditions (48–90% yields, up to >20:1 dr and 99% ee).magnified image

ChemInform Abstract: Recent Advances in Organocatalytic Asymmetric Synthesis of Polysubstituted Pyrrolidines

AbstractReview: [44 refs.

Enantioselective Synthesis of Amaryllidaceae Alkaloids (+)‐Vittatine, (+)‐epi‐Vittatine, and (+)‐Buphanisine

Cat. on a hot tin roof: Enantioselective catalytic Michael addition of α-cyanoketones to acrylates under bifunctional organocatalysis was used to construct the unique arylic all-carbon quaternary stereocenter, which is synthetically crucial in the chemical synthesis of optically pure cis-aryl hydroindole alkaloids. The protocol offers an asymmetric route to (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine.

ChemInform Abstract: Cooperative Assistance in Bifunctional Organocatalysis: Enantioselective Mannich Reactions with Aliphatic and Aromatic Imines.

both of which contain a thiourea moiety (Scheme 1).The catalysts are capable of deprotonating suitable nucleo-philes, such as activated carbonyl compounds. This proton-transfer reaction generates an ion pair, which is composed ofthe protonated catalyst and the anionic nucleophile interact-ing through hydrogen bonds. At least one of the NH moietiesin the protonated catalyst is involved in activating theelectrophilic reaction partner.