Chiral Brønsted Acid from Chiral Phosphoric Acid Boron Complex and Water: Asymmetric Reduction of Indoles

A new chiral Brønsted acid, generated in situ from a chiral phosphoric acid boron (CPAB) complex and water, was successfully applied to asymmetric indole reduction. This “designer acid catalyst”, which is more acidic than TsOH as suggested by DFT calculations, allows the unprecedented direct asymmetric reduction of C2-aryl-substituted N-unprotected indoles and features good to excellent enantioselectivities with broad functional group tolerance. DFT calculations and mechanistic experiments indicates that this reaction undergoes C3-protonation and hydride-transfer processes. Besides, bulky C2-alkyl-substituted N-unprotected indoles are also suitable for this system.     

Regioselective and Enantioselective Synthesis of β‐Indolyl Cyclopentenamides by Chiral Anion Catalysis

The regioselective and enantioselective synthesis of β‐indolyl cyclopentenamides, a versatile chiral building block, by asymmetric addition of indoles to α,β‐unsaturated iminium intermediates has been achieved through chiral anion catalysis. Key to the success of this methodology is the generation of a chiral anion‐paired ketone‐type α,β‐unsaturated iminium intermediate from α‐hydroxy enamides. Preliminary mechanistic studies and DFT calculations are consistent with a mechanism involving multiple, concurrent pathways for isomerization of the initially formed azaallylcation into the key α,β‐unsaturated iminium intermediate, all mediated by the phosphoric acid catalyst.     

A Strategy for Synthesizing Axially Chiral Naphthyl‐Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates

A new strategy for enantioselective synthesis of axially chiral naphthyl‐indoles has been established through catalytic asymmetric addition reactions of racemic naphthyl‐indoles with bulky electrophiles. Under chiral phosphoric acid catalysis, azodicarboxylates and o‐hydroxybenzyl alcohols served as bulky but reactive electrophiles that were attacked by C2‐unsubstituted naphthyl‐indoles, which underwent a dynamic kinetic resolution to afford two series of axially chiral naphthyl‐indoles in good yields (up to 98 %) and high enantioselectivities (up to 98:2 er).     

Catalytic Asymmetric Synthesis of 3‐Indolyl Methanamines Using Unprotected Indoles and N‐Boc Imines under Basic Conditions

A chiral imidazolidine‐containing NCN/Pd‐OTf catalyst ( C4 ) promoted the nucleophilic addition of unprotected indoles to N‐Boc imines. Using sulfinyl amines as the N‐Boc imine precursors, the combined use of C4 with K₂CO₃ activated the NH indoles to give chiral 3‐indolyl methanamines with up to 98 % ee. Compared with conventional acid‐catalyzed Friedel–Crafts reactions, this reaction proceeds under mildly basic conditions and is advantageous for the use of acid‐sensitive substrates.     

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.     

Highly Enantioselective Synthesis of Indolines: Asymmetric Hydrogenation at Ambient Temperature and Pressure with Cationic Ruthenium Diamine Catalysts

A highly enantioselective synthesis of indolines by asymmetric hydrogenation of 1H‐indoles and 3H‐indoles at ambient temperature and pressure, catalyzed by chiral phosphine‐free cationic ruthenium complexes, has been developed. Excellent enantio‐ and diastereoselectivities (up to >99 % ee, >20:1 d.r.) were obtained for a wide range of indole derivatives, including unprotected 2‐substituted and 2,3‐disubstituted 1H‐indoles, as well as 2‐alkyl‐ and 2‐aryl‐substituted 3H‐indoles.     

Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds

Described here is a direct catalytic asymmetric functionalization of unactivated alkyl indoles using organocatalysis. In the presence of an effective chiral urea catalyst and a phosphoric acid additive, the intermolecular C?C bond formation between alkyl indoles and trifluoropyruvates proceeded with high efficiency and enantiocontrol. Unlike previous asymmetric C(sp³?H) functionalizations of α‐azaarenes, this process does not require the use of either a strong base or an electron‐deficient substrate. The excellent enantiocontrol is particularly noteworthy in view of the severe background reaction as well as the complete inability of other types of catalysts evaluated. Control experiments, kinetic studies, and DFT calculations provided important insights into the mechanism.     

Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.     

Access to N‐Substituted 2‐Pyridones by Catalytic Intermolecular Dearomatization and 1,4‐Acyl Transfer

A novel rhodium‐catalyzed dearomatization of O‐substituted pyridines to access N‐substituted 2‐pyridones has been developed. A computational study suggests a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4‐acyl migratory rearrangement from O to C. Furthermore, the chiral dirhodium complexes serve as the catalyst for the asymmetric transformation with excellent enantioselective control. DFT calculations indicate the chirality is transferred from axial chirality to the central stereogenic centre. The stronger π–π interaction and CH–π interaction account for the high enantioselectivity.     

Chiral Primary‐Amine‐Catalyzed Conjugate Addition to α‐Substituted Vinyl Ketones/Aldehydes: Divergent Stereocontrol Modes on Enamine Protonation

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α‐chiral carbonyls. We describe herein chiral primary‐amine‐catalyzed conjugate additions of indoles to both α‐substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary–tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate‐limiting in iminium formation and they all involve a uniform H₂O/acid‐bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α‐branched acroleins, facial selections on H₂O‐bridged protonation determine the enantioselectivity, which is enhanced by an OH???π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin–Hammett principle in the C? C bond‐formation step, which precedes a highly stereospecific enamine protonation.     

Asymmetric Synthesis of 1,3‐Butadienyl‐2‐carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst

Asymmetric C(sp)? C(sp²) bond formation to give enantiomerically enriched 1,3‐butadienyl‐2‐carbinols occurred through a homoallenylboration reaction between a 2,3‐dienylboronic ester and aldehydes under the catalysis of a chiral phosphoric acid (CPA). A diverse range of enantiomerically enriched butadiene‐substituted secondary alcohols with aryl, heterocyclic, and aliphatic substituents were synthesized in very high yield with high enantioselectivity. Preliminary density functional theory (DFT) calculations suggest that the reaction proceeds via a cyclic six‐membered chairlike transition state with essential hydrogen‐bond activation in the allene reagent. The catalytic reaction was amenable to the gram‐scale synthesis of a chiral alkyl butadienyl adduct, which was converted into an interesting optically pure compound bearing a benzo‐fused spirocyclic cyclopentenone framework.     

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO₄)₂ Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.     

Chiral Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Compounds Involving Indole Derivatives

Indoles are one of the most ubiquitous subclass of N-heterocycles and are increasingly incorporated to design new axially chiral scaffolds. The rich profile of reactivity and N−H functionality allow chemical derivatization for enhanced medicinal, material and catalytic properties. Although asymmetric C−C coupling of two arenes gives the most direct access of axially chiral biaryl scaffolds, this chemistry has been the remit of metal catalysis and works efficiently on limited substrates. Our group has devoted special interest in devising novel organocatalytic arylation reactions to fabricate biaryl atropisomers. In this realm, indoles and derivatives have been reliably used as the arylation partners in combination with azoarenes, nitrosonapthalenes and quinone derivatives. Their efficient interaction with chiral phosphoric acid catalyst as well as the tunability of electronics and sterics have enabled excellent control of stereo-, chemo- and regioselectivity to furnish diverse scaffolds. In addition, indoles could act as nucleophiles in desymmetrization of 1,2,4-triazole-3,5-diones. This account provides a succinct illustration of these developments.     

Highly Enantioselective [3+2] Coupling of Indoles with Quinone Monoimines Promoted by a Chiral Phosphoric Acid

Highly enantioselective [3+2] coupling of 3‐substituted indoles with quinone monoimines promoted by a chiral phosphoric acid has been reported. A large variety of benzofuroindolines were prepared in moderate to good yields (up to 98 %) with generally excellent enantioselectivities (up to 99 % ee).     

Chiral N,O‐Ligand/[Cu(OAc)2]‐Catalyzed Asymmetric Construction of 4‐Aminopyrrolidine Derivatives by 1,3‐Dipolar Cycloaddition of Azomethine Ylides with α‐Phthalimidoacrylates

A protocol to access useful 4‐aminopyrrolidine‐2,4‐dicarboxylate derivatives has been developed. A variety of chiral N,O‐ligands derived from 2,3‐dihydroimidazo[1,2‐a]pyridine motifs have been evaluated in the asymmetric 1,3‐dipolar cycloaddition of azomethine ylides to α‐phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7‐Cl‐DHIPOH provided the highest level of stereoselectivity for the 1,3‐dipolar cycloaddition reaction. The reaction tolerates both β‐substituted and β‐unsubstituted α‐phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4‐aminopyrrolidine cycloadducts with excellent diastereo‐ (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH₄ reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.     

Chiral Phosphoric Acids in Metal–Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity

Chiral phosphoric acids are incorporated into indium‐based metal–organic frameworks (In‐MOFs) by sterically preventing them from coordination. This concept leads to the synthesis of three chiral porous 3D In‐MOFs with different network topologies constructed from three enantiopure 1,1′‐biphenol‐phosphoric acid derived tetracarboxylate linkers. More importantly, all the uncoordinated phosphoric acid groups are periodically aligned within the channels and display significantly enhanced acidity compared to the non‐immobilized acids. This facilitates the Brønsted acid catalysis of asymmetric condensation/amine addition and imine reduction. The enantioselectivities can be tuned (up to >99 % ee) by varying the substituents to achieve a nearly linear correlation with the concentrations of steric bulky groups in the MOFs. DFT calculations suggest that the framework provides a chiral confined microenvironment that dictates both selectivity and reactivity of chiral MOFs.     

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium‐labeled substrates, and control experiments revealed that nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C?O bonds at fully substituted carbon centers in the synthesis of chiral 2,2‐disubstituted benzomorpholines.     

Access to Chiral Hydropyrimidines through Palladium‐Catalyzed Asymmetric Allylic C−H Amination

A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N ‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.     

Rhodium‐Catalyzed CH Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3‐Diaryl‐Substituted Indoles

The direct C? H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3‐disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3‐diaryl substituted indoles. Herein, we report the rhodium(III)‐catalyzed C? H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3‐diaryl‐substituted N‐unprotected indoles with two different aryl groups. One of the aryl substituents is derived from N?C‐aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.     

Rhodium‐Catalyzed C?H Annulation of Nitrones with Alkynes: A Regiospecific Route to Unsymmetrical 2,3‐Diaryl‐Substituted Indoles

The direct C H annulation of anilines or related compounds with internal alkynes provides straightforward access to 2,3‐disubstituted indole products. However, this transformation proceeds with poor regioselectivity in the synthesis of unsymmetrically 2,3‐diaryl substituted indoles. Herein, we report the rhodium(III)‐catalyzed C H annulation of nitrones with symmetrical diaryl alkynes as an alternative method to prepare 2,3‐diaryl‐substituted N‐unprotected indoles with two different aryl groups. One of the aryl substituents is derived from NC‐aryl ring of the nitrone and the other from the alkyne substrate, thus providing the indole products with exclusive regioselectivity.