Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide

In this paper, the organocatalytic asymmetric 1,4-Michael addition reaction of azadienes and α-thiocyanoindanones was investigated. A series of chiral benzofuran compounds containing thiocyano group and quaternary carbon center were synthesized in moderate yields with good enantioselectivities (up to 90:10 er) and high diastereoselectivities (up to >95:5 dr). This is the first case of 1,4-Michael addition reaction using α-thiocyanoindanones to obtain a series of chiral thiocyano compounds and further broaden the scope of application of azadiene substrates. In addition, a possible reaction mechanism is also described in the article.     

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β,α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids

A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78 % isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino β,α-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.     

Sterically Demanding Unsymmetrical Diaryl-λ3-iodanes for Electrophilic Pentafluorophenylation and an Approach to α-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter

A sterically demanding unsymmetrical pentafluorophenyl-triisopropylphenyl-λ³-iodane was developed as an effective reagent for the electrophilic pentafluorophenylation of various β-keto esters and a β-keto amide. 17 examples of α-pentafluorophenylated 1,3-dicarbonyl compounds 3 having a quaternary carbon center are provided. The resulting compounds were nicely transformed into chiral α-pentafluorophenyl ketones with an all-carbon stereogenic center in high yields and high enantioselectivities using asymmetric organocatalysis (up to 98 % ee) or asymmetric metal catalysis (up to 82 % ee).     

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.     

Remote stereoselective deconjugation of α,β-unsaturated esters by simple amidation reactions

The thermodynamically disfavored isomerization of α,β-unsaturated esters to deconjugated β,γ-unsaturated analogues occurs readily when coupled to an amidation. Within the framework of macrocyclic derivatives, it is shown that 15, 16, and 18 membered macrocycles react with tBuOK and anilines to generate, in one-pot, β,γ-unsaturated amides (yields up to 88%). Importantly, single (chiral) diastereomers are isolated (d.r. > 49 : 1, ¹H NMR) irrespective of the size and nature of the rings, showing an effective transmission of remote stereochemistry during the isomerization process. CSP-chromatographic resolution and absolute configuration determination by VCD are achieved.     

A Nanoporous Supramolecular Metal–Organic Framework Based on a Nucleotide: Interplay of the π···π Interactions Directing Assembly and Geometric Matching of Aromatic Tails

Self-assembly is the most powerful force for creating ordered supramolecular architectures from simple components under mild conditions. π···π stacking interactions have been widely explored in modern supramolecular chemistry as an attractive reversible noncovalent tool for the nondestructive fabrication of materials for different applications. Here, we report on the self-assembly of cytidine 5’-monophosphate (CMP) nucleotide and copper metal ions for the preparation of a rare nanoporous supramolecular metal-organic framework in water. π···π stacking interactions involving the aromatic groups of the ancillary 2,2’-bipyridine (bipy) ligands drive the self-assemblies of hexameric pseudo-amphiphilic [Cu6(bipy)6(CMP)2(µ-O)Br4]²⁺ units. Owing to the supramolecular geometric matching between the aromatic tails, a nanoporous crystalline phase with hydrophobic and hydrophilic chiral pores of 1.2 and 0.8 nanometers, respectively, was successfully synthesized. The encoded chiral information, contained on the enantiopure building blocks, is transferred to the final supramolecular structure, assembled in the very unusual topology 8T6. These kinds of materials, owing to chiral channels with chiral active sites from ribose moieties, where the enantioselective recognition can occur, are, in principle, good candidates to carry out efficient separation of enantiomers, better than traditional inorganic and organic porous materials.     

Design and Synthesis of Pyrrolidinyl Ferrocene-Containing Ligands and Their Application in Highly Enantioselective Rhodium-Catalyzed Olefin Hydrogenation

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements.     

Introduction of a 7-aza-6-MeO-indoline auxiliary in Lewis-acid/photoredox cooperative catalysis: highly enantioselective aminomethylation of α,β-unsaturated amides

An efficient cooperative chiral Lewis acid/photoredox catalytic system for engaging highly reactive radicals in highly enantioselective conjugate addition to α,β-unsaturated carbonyls is highly desirable. Direct photoexcitation of unbound substrates typically induces undesired background pathways for racemic products and remains a formidable challenge to be addressed in the area of enantioselective photocatalysis. Herein, we report a cooperative catalytic system comprising a chiral Cu(i) complex and an Ir(iii) photocatalyst fueled by visible-light irradiation that allows for seamless integration of the catalytic formation of α-amino alkyl radicals and subsequent enantioselective addition to α,β-unsaturated amides. A 7-aza-6-MeO-indoline attachment on the amide substrates plays a pivotal role in suppressing the undesired pathways, resulting in excellent enantioselectivity and enabling expedited access to valuable γ-aminobutyramides. The indoline amide was readily diversified with full recovery of the azaindoline attachment, highlighting the synthetic utility of this cooperative catalytic system.

An efficient cooperative chiral Lewis acid and photoredox catalytic system towards the highly enantioselective radical conjugate addition of α-amino radicals to α,β-unsaturated amides is developed with the implementation of unique auxiliaries.     

Access to chiral β-sulfonyl carbonyl compounds via photoinduced organocatalytic asymmetric radical sulfonylation with sulfur dioxide

An organocatalytic enantioselective radical reaction of potassium alkyltrifluoroborates, DABCO·(SO₂)₂ and α,β-unsaturated carbonyl compounds under photoinduced conditions is developed, which provides an efficient pathway for the synthesis of chiral β-sulfonyl carbonyl compounds in good yields with excellent enantioselectivity (up to 96% ee). Aside from α,β-unsaturated carbonyl compounds with auxiliary groups, common chalcone substrates are also well compatible with this organocatalytic system. This method proceeds through an organocatalytic enantioselective radical sulfonylation under photoinduced conditions, and represents a rare example of asymmetric transformation involving sulfur dioxide insertion.

A photoinduced organocatalytic enantioselective radical reaction is developed, affording chiral β-sulfonyl carbonyl compounds in good yields with excellent enantioselectivity (up to 96% ee).     

Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

Due to their structural similarity with natural α-amino acids, α-aminophosphonic acid derivatives are known biologically active molecules. In view of the relevance of tetrasubstituted carbons in nature and medicine and the strong dependence of the biological activity of chiral molecules into their absolute configuration, the synthesis of α-aminophosphonates bearing tetrasubstituted carbons in an asymmetric fashion has grown in interest in the past few decades. In the following lines, the existing literatures for the synthesis of optically active tetrasubstituted α-aminophosphonates are summarized, comprising diastereoselective and enantioselective approaches.     

An umpolung-enabled copper-catalysed regioselective hydroamination approach to α-amino acids

A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding α-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent. Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of remote steric hindrance enables the otherwise challenging C–N bond formation at the α position to the carbonyl. The point chirality at the β-position is successfully controlled by the Xyl-BINAP or DTBM-SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary, (−)-8-phenylmenthol, also induces stereoselectivity at the α-position to form the optically active unnatural α-amino acids with two adjacent stereocentres.

A copper-catalysed regio- and enantioselective hydroamination of acrylates has been developed to afford the corresponding optically active unnatural α-amino acids.     

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.     

Study on the Influence of Chirality in the Threading of Calix[6]arene Hosts with Dialkylammonium Axles

The influence of chirality in calixarene threading has been studied by exploiting the “superweak anion approach”. In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the “endo-chiral” and “exo-chiral” ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called “endo-alkyl rule” and a newly defined “endo-α-methyl-benzyl rule” (threading of a hexaalkoxycalix[6]arene with a directional (α-methyl-benzyl)benzylammonium axle occurs with an endo-α-methyl-benzyl preference). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers.     

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.

A rhodium-catalyzed asymmetric hydroformylation reaction was reported to construct chiral α-quaternary amino acid derivatives. High chemo-, regio- and enantioselectivity were realized in one step.     

Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Solvent directed chemically divergent synthesis of β-lactams and α-amino acid derivatives with chiral isothiourea

A protocol for the chemically divergent synthesis of β-lactams and α-amino acid derivatives with isothiourea (ITU) catalysis by switching solvents was developed. The stereospecific Mannich reaction occurring between imine and C(1)-ammonium enolate generated zwitterionic intermediates, which underwent intramolecular lactamization and afforded β-lactam derivatives when DCM and CH₃CN were used as solvents. However, when EtOH was used as the solvent, the intermediates underwent an intermolecular esterification reaction, and α-amino acid derivatives were produced. Detailed mechanistic experiments were conducted to prove that these two kinds of products came from the same intermediates. Furthermore, chemically diversified transformations of β-lactam and α-amino acid derivatives were achieved.

A protocol for the solvent directed chemically divergent synthesis of β-lactam and α-amino acid derivatives with chiral isothiourea was reported.     

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis.     

Dynamic parallel kinetic resolution of α-ferrocenyl cation initiated by chiral Brønsted acid catalyst

The dynamic parallel kinetic resolution (DPKR) of an α-ferrocenyl cation intermediate under the influence of a chiral conjugate base of a chiral phosphoric acid catalyst has been demonstrated in an S_N1 type substitution reaction of a racemic ferrocenyl derivative with a nitrogen nucleophile. The present method provides efficient access to a ferrocenylethylamine derivative in a highly enantioselective manner, which is potentially useful as a key precursor of chiral ligands for metal catalysis. The mechanism of the present intriguing resolution system was elucidated by control experiments using the enantio-pure precursor of relevant α-ferrocenyl cation intermediates and the hydroamination of vinylferrocene. Further theoretical studies enabled the elucidation of the origin of the stereochemical outcome as well as the efficient DPKR. The present DPKR, which opens a new frontier for kinetic resolution, involves the racemization process through the formation of vinylferrocene and the chemo-divergent parallel kinetic resolution of the enantiomeric α-ferrocenyl cations generated by the protonation/deprotonation sequence of vinylferrocene.

The dynamic parallel kinetic resolution (DPKR) of an enantiomeric α-ferrocenyl cation using a chiral phosphate anion of an acid catalyst was accomplished by the combination of the PKR and the racemization through the formation of vinylferrocene.