Enantioselective Protonation Research Articles

Copper(I)-Catalyzed Asymmetric 1,4-Hydroarsination of α,β-Unsaturated Compounds.

Herein, a copper(I)-catalyzed asymmetric 1,4-hydroarsination of β-substituted α,β-unsaturated esters is achieved in moderate to excellent yields with high to excellent enantioselectivity, based on the proposed nucleophilic [Cu]-AsPh2 species. As for α-substituted α,β-unsaturated esters, a 1,4-hydroarsination/enantioselective protonation event occurs smoothly in satisfying results. Furthermore, β-substituted α,β-unsaturated ketone, α,β-unsaturated amide, and α,β-unsaturated phosphine sulfide are well applied in the present catalytic system. Finally, some control experiments show that HAsPh2 is activated through coordination with the copper(I) catalyst and HAsPh2 exhibits inferior soft Lewis basicity to HPPh2 in the presence of a copper(I)-bisphosphine complex.

Copper(I)‐Catalyzed Asymmetric 1,4‐Hydroarsination of α,β‐Unsaturated Compounds

Herein, a copper(I)‐catalyzed asymmetric 1,4‐hydroarsination of β‐substituted α,β‐unsaturated esters is achieved in moderate to excellent yields with high to excellent enantioselectivity, based on the proposed nucleophilic [Cu]‐AsPh2 species. As for α‐substituted α,β‐unsaturated esters, a 1,4‐hydroarsination/enantioselective protonation event occurs smoothly in satisfying results. Furthermore, β‐substituted α,β‐unsaturated ketone, α,β‐unsaturated amide, and α,β‐unsaturated phosphine sulfide are well applied in the present catalytic system. Finally, some control experiments show that HAsPh2 is activated through coordination with the copper(I) catalyst and HAsPh2 exhibits inferior soft Lewis basicity to HPPh2 in the presence of a copper(I)‐bisphosphine complex.

Photoredox Catalytic Deracemization Enabled Enantioselective and Modular Access to Axially Chiral N-Arylquinazolinones.

Visible light-driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging-to-access axially chiral 2-azaarene-functionalized quinazolinones. The substrate scope is extensive, allowing for both 3-axis and unmet 1-axis assembly through facile oxidation of diverse central chiral 2,3-dihydroquinazolin-4(1H)-ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization.

Photoredox Catalytic Deracemization Enabled Enantioselective and Modular Access to Axially Chiral N‐Arylquinazolinones

AbstractVisible light‐driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging‐to‐access axially chiral 2‐azaarene‐functionalized quinazolinones. The substrate scope is extensive, allowing for both 3‐axis and unmet 1‐axis assembly through facile oxidation of diverse central chiral 2,3‐dihydroquinazolin‐4(1H)‐ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization.

Catalytic Enantioselective Protonation of Gold Enolates Enabled by Cooperative Gold(I) Catalysis.

Enantioselective protonation is a versatile approach to the construction of tertiary α-stereocenters, which are common structural motifs in various natural products and biologically relevant compounds. Herein we report a mild access to these chiral centers using cooperative gold(I) catalysis. From cyclic ketone enol carbonates, this asymmetric catalysis provides highly enantioselective access to cyclic ketones featuring an α tertiary chiral center, including challenging 2-methylsuberone. In combination with the gold-catalyzed formation of cyclopentadienyl carbonates in a one-pot, two-step process, this chemistry enables expedient access to synthetically versatile α'-chiral cyclopentenones with excellent enantiomeric excesses from easily accessible enynyl carbonate substrates.

Radical Cross Coupling and Enantioselective Protonation through Asymmetric Photoredox Catalysis.

An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine-derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α-substituted enones and cyanoazaarenes or 2-(chloromethyl)azaaren-1-iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone-substituted tertiary carbon stereocenter at the β- or γ-position of the azaarenes, are synthesized with high yields and ees.

Enantioselective enolate protonations: Evaluation of achiral templates with fluxional brønsted basic substituents in conjugate addition of malononitriles

Enoates derived from α−substituted acrylates containing 3-pyrazolidinone achiral template with Brønsted basic fluxional substituents were evaluated in chiral Lewis acid catalyzed enantioselective protonation reactions. The tandem 1,4-conjuagte addition/enantioselective protonation reaction catalyzed by chiral Lewis acids was found to depend on the fluxional group present on the achiral template. The enantioselectivity of the protonation step is highly dependent on the position of the Brønsted basic atom with respect to the pyrazolidinone nitrogen. A comparison of fluxional substituents without a Brønsted basic site and their impact on selectivity is also reported here. The results we detail here are in sharp contrast to our previous studies on enantioselective conjugate addition of malononitriles. The reaction showed reasonable substrate scope for varying α−substitution. The reactions gave conjugate adducts in good yields and good enantioselectivities up to 83 %.

Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Rhodium-Catalyzed Asymmetric Arylation-Induced Glycolate Aldol Additions of Silyl Glyoxylates.

(Diene)Rh(I) complexes catalyze the stereoselective three-component coupling of silyl glyoxylates, arylboronic acids, and aldehydes to give glycolate aldol products. The participation of Rh-alkoxides in the requisite Brook rearrangement was established through two component Rh-catalyzed couplings of silyl glyoxylates with ArB(OH)2 to give silyl-protected mandelate derivatives. The intermediacy of a chiral Rh-enolate was inferred through enantioselective protonation using a chiral Rh-catalyst. Diastereoselective three-component couplings with aldehydes as terminating electrophiles to give racemic products were best achieved with a bulky aryl ester on the silyl glyoxylate reagent. Optimal enantioselective couplings were carried out with the tert-butyl ester variant using an anisole-derived enantiopure tricyclo[3.2.2.02,4 ]nonadiene ligand.

Chiral recognition mechanism studies of Tyr-Arg-Phe-Lys-NH2 tetrapeptide on crown ether-based chiral stationary phase.

Even though chiral recognition for crown-ether CSPs is generally understood, on a molecular level, exact mechanisms for the resolution are still unclear. Furthermore, short peptide analytes often contain multiple amino moieties capable of binding to the crown ether selector. In order to extend the understanding in chiral recognition mechanisms, polar organic mode separation of Tyr-Arg-Phe-Lys-NH2 tetrapeptide llll/dddd enantiomers on S- and R-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 stationary phases was studied with 50-mM perchloric acid in methanol as mobile phase. Deviation from the generally acceptable 1:1 stoichiometry was supported by mass spectroscopy analysis of the formed complexes between tetrapeptide enantiomer and crown ether selectors, which revealed adducts possessing 1:1, 1:2, and 1:3 stoichiometry. Further investigation of complexation induced shifts by NMR indicated on different binding mechanisms between llll/dddd enantiomers of Tyr-Arg-Phe-Lys-NH2 and crown ether selectors. Enantioselective proton shifts were observed in studied tetrapeptide tyrosine and phenylalanine residues exclusively for llll enantiomer upon binding with S-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 selector (and dddd enantiomer with R-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 selector), indicating that these two amino acid residues contribute to chiral recognition. The obtained results were in agreement with the LC data.

Rhodium‐Catalyzed Asymmetric Arylation‐Induced Glycolate Aldol Additions of Silyl Glyoxylates

Abstract(Diene)Rh(I) complexes catalyze the stereoselective three‐component coupling of silyl glyoxylates, arylboronic acids, and aldehydes to give glycolate aldol products. The participation of Rh‐alkoxides in the requisite Brook rearrangement was established through two component Rh‐catalyzed couplings of silyl glyoxylates with ArB(OH)2 to give silyl‐protected mandelate derivatives. The intermediacy of a chiral Rh‐enolate was inferred through enantioselective protonation using a chiral Rh‐catalyst. Diastereoselective three‐component couplings with aldehydes as terminating electrophiles to give racemic products were best achieved with a bulky aryl ester on the silyl glyoxylate reagent. Optimal enantioselective couplings were carried out with the tert‐butyl ester variant using an anisole‐derived enantiopure tricyclo[3.2.2.02,4]nonadiene ligand.

Catalytic Asymmetric P-H Insertion Reactions.

Albeit notable endeavors in enantioselective carbene insertion into X-H bonds (X = C, O, N, S, Si, B), the catalytic asymmetric P-H insertion reactions still stand for a long-lasting challenge. By merging transition-metal catalysis with organocatalysis, we achieve a scalable enantioselective P-H insertion transformation between diazo pyrazoleamides and H-phosphine oxides that upon subsequent reduction delivers a wide variety of optically active β-hydroxyl phosphine oxides in good yields with high enantioselectivity. The achiral copper catalyst fosters the carbenoid insertion into the P-H bond, while the chiral cinchona alkaloid-derived organocatalyst controls the subsequent enantioselective outcome. Density functional theory (DFT) calculations further reveal that the copper catalyst chelates to the organocatalyst, enhances its acidity, and accordingly promotes the enantioselective proton transfer. Our work showcases the potential of combining transition-metal catalysis with organocatalysis to realize elusive asymmetric reactions.

NHC-catalyzed enantioselective access to β-cyano carboxylic esters via in situ substrate alternation and release

A carbene-catalyzed asymmetric access to chiral β-cyano carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of enal β-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

Asymmetric Olefin Isomerization via Photoredox Catalytic Hydrogen Atom Transfer and Enantioselective Protonation.

Asymmetric olefin isomerization can be appreciated as an ideal synthetic approach to access valuable enantioenriched C═C-containing molecules due to the excellent atom economy. Nonetheless, its occurrence usually requires a thermodynamic advantage, namely, a higher stability of the product to the substrate. It has thus led to rather limited examples of success. Herein, we report a photoredox catalytic hydrogen atom transfer (HAT) and enantioselective protonation strategy for the challenging asymmetric olefin isomerization. As a paradigm, by establishing a dual catalyst system involving a visible light photosensitizer DPZ and a chiral phosphoric acid, with the assistance of N-hydroxyimide to perform HAT, a wide array of allylic azaarene derivatives, featuring α-tertiary carbon stereocenters and β-C═C bonds, was synthesized with high yields, ees, and E/Z ratios starting from the conjugated α-substituted alkenylazaarene E/Z-mixtures. The good compatibility of assembling deuterium on stereocenters by using inexpensive D2O as a deuterium source further underscores the broad applicability and promising utility of this strategy. Moreover, mechanistic studies have provided clear insights into its challenges in terms of reactivity and enantioselectivity. The exploration will robustly inspire the development of thermodynamically unfavorable asymmetric olefin isomerizations.

Visible-light-mediated catalytic asymmetric synthesis of α-amino esters via free carbene insertion into N[sbnd]H bond

A method that facilitates the construction of valuable chiral products exploiting simple high energy intermediates in an atom- and sustainable fashion could prove highly enabling for asymmetric synthesis. Free carbenes are one kind of such high energy intermediates and their utilization in catalytic asymmetric reactions is still elusive, due to the existence of severe racemic background reaction. In our pursuit to develop catalytic asymmetric NH insertion reaction of free carbene, a general chiral Brønsted acid-catalyzed enantioselective protonation of the in situ generated ammonium ylide was discovered under visible-light irradiation of diazo compound in the presence of arylamine, furnishing the desired α -amino esters with moderate to high enantioselectivity and yield. More importantly, it was found there is a remarkable correlation between the enantioselectivity of product and substituent electronic parameter (σpara) of substrates. This work not only demonstrates chiral phosphoric acid catalysis is compatible with free carbene insertion reactions without disturbing deactivation OH insertion side reactions, but also indicates the pKa of arylamine is also a significant parameter for turning the enantioselectivity of the reaction. The method disclosed herein is expected to bring new insights into the use of free carbene in the catalytic asymmetric reactions under metal free conditions.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline–Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones

An asymmetric retro-Claisen reaction of α-monosubstituted β-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N−H Bonds

AbstractFree carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high‐pKa Brønsted acid catalysts that enable free carbene insertion into N−H bonds of amines to prepare chiral α‐amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high‐energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high‐pKa Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton‐transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N-H Bonds.

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pKa Brønsted acid catalysts that enable free carbene insertion into N-H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pKa Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.

Enantioselective protonation of monofluorinated silyl enol ethers by cooperative cation‐binding catalysis

AbstractHerein, we report on the successful enantioselective protonation of a range of silyl enol ethers of cyclic ketones with labile chiral secondary CF bonds by using Song's chiral oligoethylene glycols (oligoEGs) as cation‐binding catalysts in the presence of CsF and a proton source. Highly enantioselective protonations of an array of silyl enol ethers of α‐fluoro tetralones and α‐fluoro benzosuberones were achieved, producing corresponding chiral α‐secondary α‐fluoro cyclic ketones in full conversion, with up to 96% ee. Furthermore, this protocol has successfully been extended to access chiral α‐choro and α‐bromo cyclic ketones. This successful in situ generated fluoride ion‐based stereoselective catalysis was driven by creating a densely confined chiral cage from the chiral catalyst, substrate, and CsF.

Recent Advances on Catalytic Enantioselective Protonation for Construction of α-Tertiary Carbonyl Compounds

Recent Advances on Catalytic Enantioselective Protonation for Construction of <i>α</i>-Tertiary Carbonyl Compounds