Enantioselective Intramolecular Research Articles

Iridium/Acid-Dual Catalyzed Enantioselective Intramolecular Allylic Dearomatization Reaction of Allylic Alcohol Tethered α- and β-Naphthols.

The first catalytic enantioselective intramolecular allylic dearomatization of allylic alcohol tethered α- and β-naphthols has been developed with iridium/acid-dual catalysis. A wide range of polycyclic spiroketones containing vicinal tertiary and quaternary carbon stereocenters were readily prepared in good to high yields with high diastereo- and moderate to excellent enantioselectivities. An unusual anti-Markovnikov Wacker oxidation has also been shown in synthetic transformations.

Organocatalytic Enantioselective Intramolecular Michael Addition by In Situ Generated Aminoisobenzofulvenes: Construction of Spiro Quaternary Carbon Stereocenters.

An unprecedented enantioselective organocatalytic spirocyclization strategy is presented by in situ generation of aminoisobezofulvenes. The reaction sequence involves a reductive Michael/aldol-condensation/Michael addition cascade by iminium-enamine catalysis. The key success of this spirocyclization was the formation of intermediatory nucleophilic aminoisobenzofuvenes accountable for intramolecular Michael addition. Benzospirononanes featuring an all carbon qauternary spirocenter were obtained using proline-derived amino-organocatalyst in moderate to good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr, and 99 % ee). Post-methodological manipulation of benzospirononanes was also demonstrated.

Organocatalytic Enantioselective Intramolecular (Hetero)Michael Additions in Desymmetrization Processes

AbstractThe organocatalytic enantioselective desymmetrization reaction by means of an intramolecular (hetero)Michael addition is a useful strategy for the creation of complex carbo‐ and heterocycles with the generation of multiple stereocenters in a very simple manner. The intramolecular addition of carbon, oxygen and nitrogen nucleophiles to prochiral substrates bearing electronically deficient olefins takes place in the presence of organocatalysts, such as chiral primary and secondary amines, NHCs, ureas, thioureas, and BINOL phosphoric acid derivatives, reaching high levels of diastereo‐ and enantioselectivity. The main bottleneck of this methodology is the design and synthesis of the starting materials, which compromises its application. To date, the majority of examples are related to the use of 1,4‐cyclohexanedione derivatives.

Silver-Catalyzed, Chemo- and Enantioselective Intramolecular Dearomatization of Indoles to Access Sterically Congested Azaspiro Frameworks.

An asymmetric dearomatization of indoles bearing α-diazoacetamide functionalities was developed for synthesizing high-value spiro scaffolds. A silver phosphate chemoselectively catalyzed the sterically challenging dearomatization, whereas more typically used metal catalysts for carbene transfer reactions, such as a rhodium complex, were not effective and instead resulted in a Büchner ring expansion or cyclopropanation. Mechanistic studies indicated that the spirocyclization occurred through a silver-assisted asynchronous concerted process and not via a silver-carbene intermediate. Analyses based on natural bond orbital population and a distortion/interaction model indicated that the degree of C-Ag mutual interaction is crucial for achieving a high level of enantiocontrol. In addition, an oxidative disconnection of a C(sp3)-C(sp2) bond in the product provided unconventional access to the corresponding chiral spirooxindole.

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

AbstractThe 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.

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.

Iron-Catalyzed Enantioselective Intramolecular Inverse Electron-Demand Hetero Diels-Alder Reactions: An Access to Bicyclic Dihydropyran Derivatives.

A highly enantioselective iron-catalyzed Intramolecular Inverse Electron-Demand Hetero Diels-Alder (IIEDHDA) reaction is reported. By using a chiral semicorrin ligand in the presence of 2,6-lutidine, good isolated yields and excellent enantioselectivities were observed (up to 96% ee). Thanks to the versatile postfunctionalization of the acyl-imidazole moiety, this methodology represents a unique example of the straightforward construction of highly valuable enantioenriched bicyclic dihydropyran derivatives.

Enantioselective Intramolecular Dearomative Lactonization of Naphthols Catalyzed by Planar Chiral Iodoarene

A series of planar chiral iodoarenes based on [2.2]paracyclophane was synthesized. An efficient asymmetric intramolecular oxidative lactonization of naphthols enabled by a combination of these chiral iodoarenes and mCPBA as oxidant is reported. This reaction proceeds under mild conditions, allowing the formation of spirolactones bearing a tetrasubstituted stereocenter in moderate yields and good enantioselectivity.

Hydrogen-Bond-Induced Chiral Axis Construction: Theoretical Study of Cinchonine-Thiourea-Catalyzed Enantioselective Intramolecular Cycloaddition.

Theoretical calculations were performed to investigate the mechanism and enantioselectivity of cinchonine-thiourea-catalyzed intramolecular hetero-Diels-Alder cycloaddition of ethynylphenol derivatives to afford axial chirality naphthalenylpyran products via a vinylidene ortho-quinone methide (VQM) intermediate. The results show that this transformation occurs through a reaction pathway involving the deprotonation of the naphthol moiety by the quinuclidine base, intramolecular proton transfer in ammonium naphthalenolate, and [4+2] cycloaddition. It is found that the axial chirality of the VQM intermediate is generated by the protonation step, which affects the enantioselectivity of the reaction. The enantioselectivity for the generation of the VQM intermediate is controlled by steric repulsion with the cinchonine framework, which provides an R-axial chirality VQM as the major intermediate. Moreover, the enantioselectivity for the axial chirality of the naphthopyran product is controlled by the cycloaddition step, in which an extra hydrogen bond between the naphthalenol and cinchonine moieties leads to a favorable configuration for the generation of the S-axial chirality naphthopyran product. The calculated enantioselectivity and enantiomeric excesses coincide with experimental observations.

Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C-H Bonds Using Ru(II)-Pheox Catalyst.

We have established a method for the highly regio- and enantioselective functionalization of tert-butyl groups via intramolecular amide carbene insertion into C-H bonds, yielding γ-lactams with 91% ee in up to 99% yield. This reaction uses a ruthenium(II) phenyl oxazoline (Ru(II)-Pheox) complex. The catalytic intramolecular carbene transfer reaction to the primary C-H bond proceeds rapidly and selectively compared to that with secondary C-H, benzylic secondary C-H, tert-C-H, or sp2C-H bonds in the presence of 1 mol % Ru(II)-Pheox catalyst. This is the first example of a catalytic carbenoid insertion into an unactivated tert-butyl group with enantiocontrol at the carbenoid carbon.

Synthesis of (−)-Verbenone-derived Triazolium Salts and Their Application in Enantioselective Intramolecular Stetter Reaction

Two novel chiral verbenone-derived triazolium salts have been synthesized from readily available (−)-verbenone and found to be efficient for the enantioselective intramolecular Stetter reaction. The approach, based on the intramolecular annulation between acyl anion equivalents and Michael acceptors, benefits from broad substrate scope, high chemical and stereochemical efficiency, and operational simplicity. Mono-, and disubstituded chromanone derivatives have been obtained in excellent yields and in a highly stereochemical manner.

Palladium-Catalyzed Enantioselective Intramolecular Dearomative Heck Reaction.

Enantioselective intramolecular dearomative Heck reactions have been developed by Pd-catalyzed cross-coupling of aryl halides or aryl triflates with the internal C═C bond of indoles, benzofurans, pyrroles, and furans. A variety of structurally unique spiroheterocycles and benzofused heterocycles having N/O-substituted quaternary carbon stereocenters, and exocyclic olefin moieties were afforded in moderate to excellent yields with good to excellent enantioselectivities, showing a broad scope of the present protocol. A series of new BINOL- and H8-BINOL-based phosphoramidite ligands were synthesized and proved to be efficient chiral ligands in the reactions of C2-tethered substrates to form spiroheterocycles. ( S)-SEGPHOS turned out to be a good ligand for the reaction delivering benzofused indolines and pyrrolines. Synthetic applications based on transformations of the exocyclic double bonds were realized without loss of enantiopurities, including hydrogenation, hydroborylation, and stereospecific ring-expanding rearrangement.

Enantioselective Intramolecular Nicholas Reaction Catalyzed by Chiral Phosphoric Acid: Enantioconvergent Synthesis of Seven‐Membered Cyclic Ethers from Racemic Diols

Enantioselective Intramolecular Nicholas Reaction Catalyzed by Chiral Phosphoric Acid: Enantioconvergent Synthesis of Seven‐Membered Cyclic Ethers from Racemic Diols

Enantioselective Intramolecular Nicholas Reaction Catalyzed by Chiral Phosphoric Acid: Enantioconvergent Synthesis of Seven‐Membered Cyclic Ethers from Racemic Diols

An enantioconvergent intramolecular Nicholas reaction of racemic diols was developed using BINOL- and SPINOL-derived phosphoric acids as the chiral Brønsted acid catalyst. The developed reaction features an efficient approach to the synthesis of seven-membered cyclic ethers in a highly enantioselective manner. Further derivatization of the enantioenriched cyclic ethers, initiated by the de-complexation of the dicobalt species, afforded densely functionalized cyclic ethers having an unsaturated diester moiety without loss of enantiomeric excess.

Copper-Mediated, Heterogeneous, Enantioselective Intramolecular Buchner Reactions of α-Diazoketones Using Continuous Flow Processing.

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper-bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Organocatalytic Enantioselective Intramolecular Povarov Reaction of Anilines

Key words Povarov reaction - anilines - aza-Diels–Alder reaction - phosphoric acid catalysis - tetrahydroquinolines

Developing NHC-Iridium Catalysts for the Highly Efficient Enantioselective Intramolecular Hydroamination Reaction

Chiral, cationic NHC-iridium complexes are introduced as catalysts for the intramolecular hydroamination reaction of unactivated aminoalkenes. The catalysts show high activity in the construction of pyrrolidines, which are accessed with excellent optical purity. Enantiomerically enriched piperidines and indolines are also produced, and various functional groups are tolerated with this LTM system. A reaction mechanism is proposed, and a major deactivation pathway of these catalysts is presented and discussed.

Enantioselective Intramolecular Reductive Heck Reaction with a Palladium/Monodentate Phosphoramidite Catalyst

AbstractA palladium‐catalyzed enantioselective reductive Heck reaction of enones using monodentate phosphoramidite ligands is described. α,α,α’,α’‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐based phosphoramidites with palladium(II) acetate, and N‐methyl dicyclohexylamine as reducing agent gives the reductive Heck product in high yields and enantioselectivities of up to 90 %. The solvent plays an important role and in diethyl carbonate, the chemo‐ and enantioselectivity appeared to be the highest.

TADDOL‐Promoted Enantioselective Intramolecular Diels–Alder Reactions of 1,7,9‐Decatrien‐3‐ones to Octalin Derivatives

The diastereoselective and enantioselective intramolecular Diels–Alder reactions of 1,7,9‐decatrien‐3‐ones to cis‐ or trans‐octalin derivatives were systematically investigated in the presence of different Lewis acids and chiral ligands. The best cis‐selective promoter, consisting of diethylaluminum chloride and (R)‐1,1′‐bi‐2‐naphthol (BINOL), provided an enantiomeric excess (ee) of only 33 %. For the trans‐selective reactions, dichlorotitanium diisopropoxide was the best Lewis acid, and a 2‐naphthyl‐substituted (R,R)‐α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol ligand (TADDOL) furnished excellent diastereoselectivities and enantioselectivities in the range of 50–68 %. Subsequent reactions of a typical trans‐octalin derivative led to compounds, which enabled the determination of the absolute configuration of the favored enantiomer and a deduction of the involved reaction mechanism. Interpretation of the NMR shifts of the enantio‐enriched Mosher esters and an X‐ray structure analysis were the keys for this structural assignment. We could demonstrate that Mosher analyses do not necessarily rely on enantiopure samples.

ChemInform Abstract: Enantioselective Intramolecular Cyclization of Alkynyl Esters Catalyzed by a Chiral Broensted Base.

AbstractAn enantioselective intramolecular cyclization of alkynyl esters yields dibenzofurans by employing a Broensted base catalyst generated in situ from a chiral Schiff base and tBuOK.