Catalytic Enantioselective Intramolecular Aza‐Diels–Alder Reactions

A readily available chiral Brønsted acid was identified as an efficient catalyst for intramolecular Povarov reactions. Polycyclic amines containing three contiguous stereogenic centers were obtained with excellent stereocontrol in a single step from secondary anilines and aldehydes possessing a pendent dienophile. These transformations constitute the first examples of catalytic enantioselective intramolecular aza‐Diels–Alder reactions.     

Brønsted Acid Catalyzed Addition of Enamides to ortho‐Quinone Methide Imines—An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines

The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho‐quinone methide imines and subsequent elimination. This novel one‐step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N‐heterocycles with a 1,4‐dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N‐deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.     

Catalytic Asymmetric Diels–Alder Reaction of Quinone Imine Ketals: A Site‐Divergent Approach

The catalytic asymmetric Diels–Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl‐substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels–Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3‐alkyl quinone imine ketals from the inherently favored unsubstituted C?C bond to the disfavored alkyl‐substituted C?C bond.     

Catalytic Asymmetric Intramolecular [4+2] Cycloaddition of In Situ Generated ortho‐Quinone Methides

Herein, we describe the first catalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho‐quinone methides. In the presence of a confined chiral imidodiphosphoric acid catalyst, various salicylaldehydes react with dienyl alcohols to give transient ortho ‐quinone methide intermediates, which undergo an intramolecular [4+2] cycloaddition to provide highly functionalized furanochromanes and pyranochromanes in excellent diastereoselectivity and enantioselectivity.     

Catalytic Enantioselective Synthesis of α‐Chiral Azaheteroaryl Ethylamines by Asymmetric Protonation

The direct enantioselective synthesis of chiral azaheteroaryl ethylamines from vinyl‐substituted N‐heterocycles and anilines is reported. A chiral phosphoric acid (CPA) catalyst promotes dearomatizing aza‐Michael addition to give a prochiral exocyclic aryl enamine, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a broad range of N‐heterocycles, nucleophiles, and substituents on the prochiral centre, generating the products in high enantioselectivity. DFT studies support a facile nucleophilic addition based on catalyst‐induced LUMO lowering, with site‐selective, rate‐limiting, intramolecular asymmetric proton transfer from the ion‐paired prochiral intermediate.     

Brønsted Acid‐Catalyzed,Highly Enantioselective Addition of Enamides to In Situ‐Generated ortho‐Quinone Methides: A Domino Approach to Complex Acetamidotetrahydroxanthenes

The highly enantioselective conjugate addition of enamides and enecarbamates to in situ‐generated ortho‐quinone methides, upon subsequent N,O‐acetalization, gives rise to acetamido‐substituted tetrahydroxanthenes with generally excellent enantio‐ and diastereoselectivities. A chiral BINOL‐based phosphoric acid catalyst controls the enantioselectivity of the carbon–carbon bond‐forming event. The products are readily converted into other xanthene‐based heterocycles.     

Asymmetric Vinylogous Diels–Alder Reactions Catalyzed by a Chiral Phosphoric Acid

An unprecedented way to extend the synthetic utility of the Diels–Alder reaction to include a vinylogous reactivity space is described. A commercially available chiral phosphoric acid catalyst effectively activates cyclic 2,4‐dienones towards a vinylogous [4+2] cycloaddition with 2‐vinylindoles, which leads to stereochemically dense tetrahydrocarbazoles. The reaction proceeds with a high level of remote stereocontrol and exclusive chemoselectivity for the more distant double bond of the dienone.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

The first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.     

Recent Advances in Chiral Guanidine‐Catalyzed Enantioselective Reactions

Chiral guanidines have been widely used as Brønsted base catalysts and phase transfer catalysts in enantioselective reactions. Due to their amendable structure and powerful catalytic ability, they have attracted much interest. Several new catalysts containing a guanidinium moiety have been reported over the past decade and many promising outcomes have been achieved. This article illustrates the progress of chiral guanidine catalysis in asymmetric synthesis from 2009 to 2018. It is an update of a review of the same title published in 2009.     

Catalytic Enantioselective Aza‐Benzoin Reactions of Aldehydes with 2H‐Azirines

The unprecedented enantioselective aza‐benzoin reaction of aldehydes with 2H‐azirines was developed by utilizing a chiral N‐heterocyclic carbene as the catalyst. A wide range of corresponding aziridines can be obtained in good yields with high enantioselectivities. The obtained optically active aziridines should be useful in the synthesis of other valuable molecules.     

Catalytic Enantioselective Inverse Electron Demand Hetero‐Diels–Alder Reaction with Allylsilanes

The first diastereo‐ and enantioselective inverse electron demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the β,γ‐unsaturated α‐ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.     

Cooperative Catalysis: Combining an Achiral Metal Catalyst with a Chiral Brønsted Acid Enables Highly Enantioselective Hydrogenation of Imines

Asymmetric hydrogenation of imines leads directly to chiral amines, one of the most important structural units in chemical products, from pharmaceuticals to materials. However, highly effective catalysts are rare. This article reveals that combining an achiral pentamethylcyclopentadienyl (Cp*)–iridium complex with a chiral phosphoric acid affords a catalyst that allows for highly enantioselective hydrogenation of imines derived from aryl ketones, as well as those derived from aliphatic ones, with ee values varying from 81 to 98 %. A range of achiral iridium complexes containing diamine ligands were examined, for which the ligands were shown to have a profound effect on the reaction rate, enantioselectivity and catalyst deactivation. The chiral phosphoric acid is no less important, inducing enantioselection in the hydrogenation. The induction occurs, however, at the expense of the reaction rate.     

Highly Acidic Conjugate‐Base‐Stabilized Carboxylic Acids Catalyze Enantioselective oxa‐Pictet–Spengler Reactions with Ketals

Acyclic ketone‐derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products, however, they have thus far eluded efforts aimed at asymmetric catalysis. We report that a readily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone‐derived trisubstituted oxocarbenium ions, thereby providing access to highly enantioenriched dihydropyran products containing a tetrasubstituted stereogenic center. The high acidity of the carboxylic acid catalyst, which exceeds that of the well‐known chiral phosphoric acid catalyst TRIP, is largely derived from stabilization of the carboxylate conjugate base through intramolecular anion‐binding to a thiourea site.     

Catalytic Enantioselective 1,3‐Alkyl Shift in Alkyl Aryl Ethers: Efficient Synthesis of Optically Active 3,3′‐Diaryloxindoles

Reported is the first organocatalytic asymmetric 1,3‐alkyl shift in alkyl aryl ethers for the synthesis of chiral 3,3′‐diaryloxindoles using a chiral Brønsted acid catalyst. Preliminary results showed that each enantiomer of the 3,3′‐diaryloxindole, and a racemic mixture, showed different antiproliferative activities against HeLa cell lines by using an MTT assay.