Organocatalytic Enantioselective Synthesis of Seven-Membered Ring with Inherent Chirality.

Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)-catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7-membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee).

Organocatalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes.

Inherently chiral calix[4]arenes are an excellent structural scaffold for asymmetric synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic asymmetric synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade asymmetric cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33 examples), high efficiency (up to 90% yield), and excellent enantioselectivity (>95% ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

Racemic Benzenesulfonohydrazide Enantioconvergent Tertiary C(sp3 )-H Amination Catalyzed by Copper and Chiral Phosphoric Acid: Mechanistic Insights and Computational Prediction.

Density functional theory computations reveal mechanistic insights into Cu and chiral phosphoric acid (CPA) catalyzed enantioconvergent amination of racemic benzenesulfonohydrazide. The O-O bond homolysis of tert-butyl 4-phenylbutaneperoxoate was found to be the turnover-limiting step with a total free energy barrier of 19.1 kcal/mol. The enantioconvergent amination is realized to obtain the same intermediate through prochiral carbon atom. The order and mode of hydrogen atom transferred by CPA and tert-butyloxy have a significant influence on the enantioselectivity and energy barriers. The olefinic side product generated by ß-hydride elimination is 9.9 kcal/mol thermodynamically less favourable. A series of phosphoric acids are predicted as promising co-catalysts with lower barriers for O-O bond homolysis.

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.

Asymmetric Hydrophosphinylation of Alkynes: Facile Access to Axially Chiral Styrene-Phosphines.

A Cu/CPA co-catalytic system has been developed for achieving the direct hydrophosphinylation of alkynes with phosphine oxides in delivering novel axially chiral phosphorus-containing alkenes in high yields and excellent enantioselectivities (up to 99 % yield and 99 % ee). DFT calculations were performed to elucidate the reaction pathway and the origin of enantiocontrol. This streamlined and modular methodology establishes a new platform for the design and application of new axially chiral styrene-phosphine ligands.

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N'-Bisindoles.

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N'-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N'-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N'-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N'-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.

Catalytic Asymmetric Synthesis of Axially Chiral Diaryl Ethers through Enantioselective Desymmetrization.

Axially chiral diaryl ethers are a type of unique atropisomers bearing two potential axes, which have potential applications in a variety of research fields. However, the catalytic enantioselective synthesis of these diaryl ether atropisomers is largely underexplored when compared to the catalytic asymmetric synthesis of biaryl or other types of atropisomers. Herein, we report a highly efficient catalytic asymmetric synthesis of diaryl ether atropisomers through an organocatalyzed enantioselective desymmetrization protocol. The chiral phosphoric acid-catalyzed asymmetric electrophilic aromatic aminations of the symmetrical 1,3-benzenediamine type substrates afforded a series of diaryl ether atropisomers in excellent yields and enantioselectivities. The facile construction of heterocycles by the utilizations of the 1,2-benzenediamine moiety in the products provided access to a variety of structurally diverse and novel azaarene-containing diaryl ether atropisomers.

Organocatalytic Enantioselective Diels-Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,ß-Unsaturated Ketones.

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels-Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,ß-unsaturated carbonyl compounds 2. Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1, 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Expedient Access to Enantioenriched 1-Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement.

Leveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well-recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid-catalyzed enantioselective synthesis of 1-azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to >99 % ee, >20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale-up synthesis of spirocyclic products and their facile post-synthetic modifications.

Enantioselective Synthesis of Azahelicenes through Organocatalyzed Multicomponent Reactions.

We have developed an efficient modular asymmetric synthesis of azahelicenes through an organocatalyzed asymmetric multicomponent reaction from readily available polycyclic aromatic amines, aldehydes, and (di)enamides, by employing a central-to-helical chirality conversion strategy. A series of aza[5]- and aza[4]helicenes bearing various substituents were readily afforded through this one-pot sequential enantioselective Povarov reaction/oxidative aromatization process, with good yields and high enantioselectivities. The fruitful and diverse derivatizations of the chiral azahelicene products demonstrated the potential of this method, and a preliminary application of the azahelicene derivative as a chiral organocatalyst was showcased. The photophysical and chiroptical properties of these azahelicenes, particularly the acid/base-triggered switching of these properties, were also well studied, which may find potential applications in the development of novel organic optoelectronic materials.

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes.

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.

Chiral Brønsted acid catalyzed asymmetric oxidation of N-acyl sulfenamide by H2 O2 : An efficient approach to obtaining chiral N-acyl sulfinamide.

Although the power of chiral sulfinamide reagents in synthetic chemistry has long been recognized, methods for their synthesis are still auxiliary-based approaches which possess the disadvantages of poor atom economy and limited substrate universality. Due to the weak nucleophilicity of amides, it is more difficult to prepare chiral N-acylsulfinamides by traditional methods. Herein, we describe an example of catalytic asymmetric synthesis of N-acyl sulfinamides. In this work, N-acyl sulfenamides act as useful substrates, because of the indispensable N-H bond, which could form an efficient hydrogen bond with chiral phosphoric acid. H2 O2 (35%) was used as the terminal oxidant for preparation of sulfinamides in high yields and enantioselectivities, which could be easily derivatized to sulfoxides without loss of the enantioselectivity.

Enantioselective synthesis of indole-based unnatural ß-Alkynyl α-amino acid derivatives via chiral phosphoric acid catalysis.

The synthesis of unnatural α-amino acid derivatives has attracted considerable interest in recent years, as they are ubiquitous in protein synthesis and peptide-based drug discovery. Herein, we reported the chiral phosphoric acid catalyzed asymmetric reaction of indoles with ß,γ-alkynyl-α-imino esters for the enantioselective synthesis of unnatural indole-based α-amino acid derivatives. This asymmetric organocatalysis protocol enables efficient synthesis of unnatural α-amino acid derivatives with a tetrasubstituted stereogenic center and an alkyne moiety with up to 99% yield and 98% ee, resulting in operationally simple conditions, short reaction time, and broad substrate scope.

Enantioselective synthesis and selective functionalization of 4-aminotetrahydroquinolines as novel GLP-1 secretagogues.

Polysubstituted tetrahydroquinolines were obtained in moderate to high yields (28% to 92%) and enantiomeric ratios (er 89:11 to 99:1) by a three-component Povarov reaction using a chiral phosphoric acid catalyst. Significantly, post-Povarov functional group interconversions allowed a rapid access to a library of 36 enantioenriched 4-aminotetrahydroquinoline derivatives featuring five points of diversity. Selected analogs were assayed for their ability to function as glucagon-like peptide-1 (GLP-1) secretagogues.

A Mechanistic Study of Asymmetric Transfer Hydrogenation of Imines on a Chiral Phosphoric Acid Derived Indium Metal-Organic Framework.

A density functional theory (DFT) study is reported to examine the asymmetric transfer hydrogenation (ATH) of imines catalyzed by an indium metal-organic framework (In-MOF) derived from a chiral phosphoric acid (CPA). It is revealed that the imine and reducing agent (i.e., thiazoline) are simultaneously adsorbed on the CPA through H-bonding to form an intermediate, subsequently, a proton is transferred from thiazoline to imine. The transition state TS-R and TS-S are stabilized on the CPA via H-bonding. Compared to the TS-S, the TS-R has shorter H-bonding distances and longer C-H···π distances, it is more stable and experiences less steric hindrance. Consequently, the TS-R exhibits a lower activation barrier affording to the (R)-enantiomer within 68.1% ee in toluene. Imines with substituted groups such as -NO2, -F, and -OCH3 are used to investigate the substitution effects on the ATH. In the presence of an electron-withdrawing group like -NO2, the electrophilicity of imine is enhanced and the activation barrier is decreased. The non-covalent interactions and activation-strain model (ASM) analysis reveal that the structural distortions and the differential noncovalent interactions of TSs in a rigid In-MOF provide the inherent driving force for enantioselectivity. For -OCH3 substituted imine, the TS-S has the strongest steric hindrance, leading to the highest enantioselectivity. When the solvent is changed from toluene to dichloromethane, acetonitrile, and dimethylsulfoxide with increasing polarity, the activation energies of transition state increase whereas their difference decreases. This implies the reaction is slowed down and the enantioselectivity becomes lower in a solvent of smaller polarity. Among the four solvents, toluene turns out to be the best for the ATH. The calculated results in this study are in fairly good agreement with experimental observations. This study provides a mechanistic understanding of the reaction mechanism, as well as substitution and solvent effects on the activity and enantioselectivity of the ATH. The microscopic insights are useful for the development of new chiral MOFs toward important asymmetric reactions.

Synthesis of Chiral Propargylamines, Chiral 1,2-Dihydronaphtho[2,1-b]furans and Naphtho[2,1-b]furans with C-Alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals and ß-Naphthols.

Chiral phosphoric acid-catalyzed couplings of C-alkynyl N,N'-di-(tert-butoxycarbonyl)-aminals with ß-naphthols led to chiral propargylamines in moderate to high yields with high to excellent enantioselectivity, in which the reactions underwent sequential chiral phosphoric acid-catalyzed in situ formation of N-(tert-butoxycarbonyl)-imines (N-Boc-imines) from the aminals, and 1,2-addition of ß-naphthols to the N-Boc-imines. Chiral 1,2-dihydronaphtho[2,1-b]furans and naphtho[2,1-b]furans were prepared with satisfactory results when 10 mol% AgOAc and 20 mol% 2,6-lutidine or 1.2 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the resulting chiral propargylamines solution, respectively.

Asymmetric Allylation Catalyzed by Chiral Phosphoric Acids: Stereoselective Synthesis of Tertiary Alcohols and a Reagent-Based Switch in Stereopreference.

The substrate scope of the asymmetric allylation with zinc organyls catalyzed by 3,3-bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) has been extended to non-cyclic ester organozinc reagents and ketones. Tertiary chiral alcohols are obtained with ee's up to 94% and two stereogenic centers can be created. Compared to the previous lactone reagent the stereopreference switches almost completely, proving the fact that the nature of the organometallic compound is of immense importance for the asymmetry of the product.

Organocatalytic Asymmetric [2 + 4] Cycloadditions of 3-Vinylindoles with ortho-Quinone Methides.

Catalytic asymmetric [2 + 4] cycloadditions of 3-vinylindoles with ortho-quinone methides and their precursors were carried out in the presence of chiral phosphoric acid to afford a series of indole-containing chroman derivatives with structural diversity in overall high yields (up to 98%), good diastereoselectivities (up to 93:7 dr) and moderate to excellent enantioselectivities (up to 98% ee). This approach not only enriches the chemistry of catalytic asymmetric cycloadditions involving 3-vinylindoles but is also useful for synthesizing chiral chroman derivatives.

Stereochemical Control via Chirality Pairing: Stereodivergent Syntheses of Enantioenriched Homoallylic Alcohols.

We report herein the development of stereodivergent syntheses of enantioenriched homoallylic alcohols using chiral nonracemic α-CH2 Bpin-substituted crotylboronate. Chiral phosphoric acid (S)-A-catalyzed asymmetric allyl addition with the reagent gave Z-anti-homoallylic alcohols with excellent enantioselectivities and Z-selectivities. When the enantiomeric acid catalyst (R)-A was utilized, the stereoselectivity was completely reversed and E-anti-homoallylic alcohols were obtained with high E-selectivities and excellent enantioselectivities. By pairing the chirality of the boron reagent with the catalyst, two complementary stereoisomers of chiral homoallylic alcohols can be obtained selectively from the same boron reagent. DFT computational studies were conducted to probe the origins of the observed stereoselectivity. These reactions generate highly enantioenriched homoallylic alcohol products that are valuable for rapid construction of polyketide structural frameworks.

Nitrosobenzene-Enabled Chiral Phosphoric Acid Catalyzed Enantioselective Construction of Atropisomeric N-Arylbenzimidazoles.

Described herein is an imidazole ring formation strategy for the synthesis of axially chiral N-arylbenzimidazoles by means of chiral phosphoric acid catalysis. Two sets of conditions were developed to transform two classes of 2-naphthylamine derivatives into structurally diverse N-arylbenzimidazole atropisomers with excellent chemo- and regioselectivity as well as high levels of enantiocontrol. It is worth reflecting on the unique roles played by the nitroso group in this domino reaction. It functions as a linchpin by first offering an electrophilic site (N) for the initial C-N bond formation while the resulting amine performs the nucleophilic addition to form the second C-N bond. Additionally, it could facilitate the final oxidative aromatization as an oxidant. The atropisomeric products could be conveniently elaborated to a series of axially chiral derivatives, enabling the exploitation of N-arylbenzimidazoles for their potential utilities in asymmetric catalysis.