We report an asymmetric α-amination of aldehydes using a nonsilyl bicyclic secondary amine organocatalyst at 0.1 mol% in the presence of propanoic acid (100 mol%). Catalyst stability toward dibenzyl azodicarboxylate is investigated by 1H NMR spectroscopy under varying acid loadings. This method exhibits a broad substrate scope, affording products in up to 96% yield and 94% ee. This scalable methodology is applied to the concise asymmetric synthesis of solriamfetol and nateglinide.

The asymmetric Michael addition of nitroalkanes to β,β-disubstituted α,β-unsaturated aldehydes is a useful method for the construction of all-carbon quaternary stereocenters. Nonsilyl bicyclic secondary amine organocatalysts were employed in reactions involving a wide range of β,β-disubstituted α,β-unsaturated aldehydes with nitroalkanes to achieve products with all-carbon quaternary stereocenters in up to 69% yield and 95% ee. The scalability of this methodology was demonstrated at the 5.1 mmol scale. The synthetic utility of this methodology is showcased through the concise asymmetric synthesis of methsuximide, an anticonvulsant drug.

Organocatalysis has gained prominence as a powerful tool in asymmetric synthesis, offering a metal-free and environmentally friendly route to enantioenriched molecules. Chiral secondary amines, particularly those derived from proline, have been especially effective, facilitating diverse carbon-carbon and carbon-heteroatom bond-forming transformations under mild conditions. This type of catalysis typically proceeds through two key mechanisms: enamine catalysis, which temporarily converts carbonyl compounds into nucleophilic enamines, and iminium catalysis, which increases the electrophilicity of alpha,beta-unsaturated carbonyl compounds by forming reactive iminium ions. In particular, iminium catalysis has proven valuable for the enantioselective modification of electron-deficient alkenes, enabling important organic transformations. In this account, we summarize our recent advancements in asymmetric aminocatalysis, including the development of novel catalytic methodologies, innovative catalyst architectures, and their implementation in the enantioselective synthesis of biologically active compounds.

We report an enantiodivergent total synthesis of β-lycorane, accomplished in three steps, achieving an overall yield of 28% and an atom economy of 78% via cycloaddition catalyzed by a chiral cis-2,5-disubstituted pyrrolidine organocatalyst. Following successful reaction optimization, a broad substrate scope was explored, affording the corresponding cycloadducts in up to 80% yield, 15:1 dr, and 94% ee. This scalable methodology is also compatible with the branched 2,4-dienals. Importantly, the 5-substituent on the organocatalyst plays a pivotal role in controlling the regioselectivity, effectively suppressing the undesired α- and γ-reactivity.

A general methodology for the asymmetric synthesis of alpha-arylcyclohexeneones from arylacetones and alpha,beta-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether followed by p-TSA-mediated cyclization is developed. A variety of arylacetones and alpha,beta-unsaturated aldehydes were successfully converted to alpha-arylcyclohexeneones in 34-67% yield, 10:1-100:0 dr, and 81-99% ee. The scalability of this methodology by a gram-scale synthesis and their utility by converting the product to the corresponding epoxide, alcohol, and diol are demonstrated.

The first chiral synthesis of nonsilyl bicyclic secondary amine organocatalysts and their application to the asymmetric transfer hydrogenation of α,β-unsaturated aldehydes are disclosed. A lower catalytic loading (5 mol %) is demonstrated for the reduction of a wide range of α,β-unsaturated aldehydes (up to 97% yield and up to 99% ee). The application of this scalable methodology is showcased for the asymmetric synthesis of bioactive molecules such as phenoxanol, citronellol, ramelteon, and terikalant.

The first synthesis of chiral cis-2,5-disubstituted pyrrolidine organocatalysts is described. Their application for the enantioselective Michael addition of nitromethane to α,β-unsaturated aldehydes with excellent yield (up to 91%) and enantioselectivity (up to >99% ee) is demonstrated. Another catalytic application for the reaction of 2,4-hexadienal with nitrostyrene is also showcased.

The Front Cover illustrates the natural environment that needs to be protected by following the principles of 3Rs (Reduce, Reuse, and Recycle). The background of the picture shows our institute's riverfront, where a reusable polymer-supported aminocatalyst was developed for the sustainable synthesis of chiral amino acid derivatives. Cover design by Ms. Gayathri Chandrakumar. More information can be found in the Research Article by C. Appayee et al.

A new class of polystyrene-supported aminocatalysts with a triazole linker from diphenyl prolinol were developed. Their catalytic activity was tested in the asymmetric a-amination of aldehydes. The substrate scope of this catalysis was studied under the optimized reaction conditions. The reusability of the polystyrene-supported aminocatalyst was demonstrated up to four cycles. Based on the reaction results, a reaction mechanism was proposed for the asymmetric a-amination of aldehydes.

A first catalytic asymmetric reaction of acetone with cinnamaldehyde for the synthesis of disubstituted 4-oxocyclohexanecarbaldehyde is developed. A variety of substituted cinnamaldehydes are successfully tested under the optimized reaction conditions. Both the enantiomers of the same diastereomeric products are achieved in good yield and diastereoselectivity with an excellent enantioselectivity by changing the enantiomer of one of the two chiral catalysts. The practicality of this methodology is demonstrated by the gram-scale synthesis.

A first stereodivergent strategy for the asymmetric synthesis of all stereoisomers of 1-hydroxymethylpyrrolizidine alkaloids is developed using an asymmetric self-Mannich reaction as a key step. An anti-selective self-Mannich reaction of methyl 4-oxobutanoate with the PMP-amine catalyzed by a chiral secondary amine is successfully optimized for the asymmetric synthesis of (+)-isoretronecanol and (-)-isoretronecanol. A syn-selective self-Mannich reaction catalyzed by proline is utilized for the asymmetric synthesis of the diastereomer, (+)-laburnine, and its enantiomer, (-)-trachelanthamidine.

The first regio‐ and enantioselective organocatalytic cascade α,γ‐dialkylation of α,β‐unsaturated aldehydes is achieved. Substrates scope is demonstrated with a variety of α,β‐unsaturated aldehydes and alkylating agents. The absolute configuration of the α,γ‐dialkylated product is confirmed using single‐crystal X‐ray analysis of its carbamate derivative. The practicality of this methodology is showcased by the gram‐scale synthesis. Further application of this methodology for the regio‐ and enantioselective α,γ‐difunctionalization of α,β‐unsaturated aldehydes using other electrophiles are currently underway in our laboratory.

The first total synthesis of potent cannabinoid, 9 beta-11-hydroxyhexahydrocannabinol, is achieved through a proline-catalyzed inverse-electron-demand Diels-Alder reaction. Using this asymmetric catalysis, the cyclohexane ring is constructed with two chiral centers as a single diastereomer with 97% ee. The creation of the third chiral center and benzopyran ring is demonstrated with the elegant synthetic strategies. This mild and efficient synthetic methodology provides a new route for the asymmetric synthesis of the other potent hexahydrocannabinols.

The first regioselective MBH-type α-alkylation of α,β,γ,δ-unsaturated aldehydes is achieved using diarylcarbinols with an excellentE/Zselectivity under mild reaction conditions.

The first vinylogous aldol condensation of α,β-unsaturated aldehydes using aqueous formaldehyde is developed under mild reaction conditions to form the γ-methylenated products with excellent regioselectivity. Using this methodology, a short synthesis of α-triticene, an antifungal compound, is achieved in two steps. The practicality of this methodology is demonstrated by the gram-scale synthesis. Formation of the unusual double γ-functionalized products from crotonaldehyde and a direct asymmetric vinylogous aldol product from phenylglyoxal is also described.

A direct N-heterocyclic carbene (NHC) catalysis of maleimides with alkyl aldehydes is established for the synthesis of 3-acylsuccinimides. The first dynamic kinetic resolution of 3-acylsuccinimides is accomplished through asymmetric transfer hydrogenation. These two catalytic methodologies are utilized for the synthesis of each enantiomer of trans-paraconic acids in three steps and cis-paraconic acids in four steps with good yields and high stereoselectivities. This stereodivergent synthetic methodology is applied for the synthesis of seven bioactive paraconic acid natural products.

( R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregulators. The chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the literature for the asymmetric synthesis of ( R)-paraconyl alcohol. Herein, we report the first organocatalytic approach for the short asymmetric synthesis of ( R)-paraconyl alcohol in four steps and by a single column purification. Asymmetric syntheses of IM-2, SCB2, and A-factor γ-butyrolactone autoregulators were achieved from ( R)-paraconyl alcohol in three steps.

The first catalytic approach for the asymmetric synthesis of 3,4-disubstituted cyclohexadiene carbaldehydes through an inverse-electron-demand Diels-Alder reaction is described. A variety of arylacetaldehydes and α,β,γ,δ-unsaturated aldehydes are tested under the mild reaction conditions catalyzed by l-proline to obtain the trans diastereomeric products with good yields and high enantioselectivities. The scope of this methodology is further extended to the asymmetric synthesis 3,4-disubstituted cyclohexane carbaldehydes and their derivatives. The practicality of this method is demonstrated by the gram-scale synthesis. This methodology is successfully applied for the formal total synthesis of cyclobakuchiol A, an antipyretic and anti-inflammatory agent, and cyclobakuchiol C.

Asymmetric alkylation is one of the most useful carbon–carbon bond‐forming reactions in synthetic organic chemistry. Chiral‐amine‐catalyzed alkylation reactions often lack regioselectivity owing to multiple reactive centers. In particular, the alkylation of linear 2‐enals through dienamine catalysis produces a mixture of regioisomers owing to reactive α‐ and γ‐positions. A few attempts have been made to mask the α‐reactive center to achieve γ‐selectivity. Controlling the enantioselectivity at the remote γ‐position has also been found to be quite challenging. Herein, we achieved the highly regioselective γ‐alkylation of linear α,β‐unsaturated aldehydes by using trifluoroethanol (TFE) as a cosolvent. Further, we demonstrated in situ kinetic resolution for enantioenrichment of the γ‐alkylated products. This method brings together the activation of an electrophile facilitated by TFE and in situ kinetic resolution to achieve excellent selectivity in dienamine catalysis.

The cover picture shows a natural environment where green leaves are growing in the presence of sun light, which is also responsible for the dried leaves falling onto the ground. Similarly, the chiral secondary amine not only catalyzes γ-alkylation reactions to form the R-isomers (major) but also destroys the corresponding S-isomers (minor). This in situ kinetic resolution contributes to the enantioenrichment of the γ-alkylated products along with the actual catalytic alkylation reaction. Details are discussed in the Communication by M. S. Kutwal and C. Appayee on page 4230 ff (https://doi.org/10.1002/ejoc.201700645).