Transaminases as suitable catalysts for the synthesis of enantiopure β,β-difluoroamines

Transaminases have demonstrated the ability to catalyze the amination of a series of aliphatic and (hetero)aromatic α,α-difluorinated ketones with high stereoselectivity, thus providing the corresponding β,β-difluoroamines in high isolated yields...

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019

Chiral drugs usually contain chiral centers, which are present as single enantiomers or racemates. Compared with achiral drugs, they have significant advantages in safety and efficacy with high stereoselectivity. Of these drugs, chirality not only exerts influence on the solubility and pharmacokinetic characteristics but also has specific mechanistic characteristics on their targets. We noted that small molecules with unique chiral properties have emerged as novel components of antitumor drugs approved by the FDA in decade. Since approved, these drugs have been continuously explored for new indications, new mechanisms, and novel combinations. In this mini review, recent research progress of twenty-two FDA-approved chiral small molecular-targeted antitumor drugs from 2011 to 2019 is summarized with highlighting the potential and advantages of their applications. We believe that these updated achievements may provide theoretical foundation and stimulate research interests for optimizing drug efficacy, expanding clinical application, overcoming drug resistance, and advancing safety in future clinical administrations of these chiral targeted drugs.

Synthesis and Reactivity of Dihalofuranones

Background: Halogenated furanones have been found to act as potent quorum sensing inhibitors in several bacterial species. It is believed that dihalofuranones covalently bind to the LuxS enzyme, which is necessary for autoinducer-2 synthesis. In addition to their antimicrobial activity, halogenated furanones also possess anti-cancer, antioxidant, and depigmentation properties. However, traditional routes to these compounds are low-yielding and capricious. Objective: This study aimed at investigating higher-yielding preparations of gem-dihalofuranones and comparing their reactivity using Suzuki chemistry. Methods: Ramirez dibromoolefination of maleic anhydride was optimised using a variety of conditions. A similar route was investigated for the preparation of bromofluorofuranones and dichlorofuranones. The conversion of a dichlorofuranone to the corresponding iodofuranone derivatives using microwave-assisted Finkelstein chemistry was also studied. Lastly, the reactivity of the different dihalofuranones was compared by Pd-mediated coupling with phenylboronic acid. Results: A higher-yielding, concise synthesis of dibromofuranones was developed using a modified Ramirez reaction. Additionally, a telescoped preparation of dichlorofuranone proved higher yielding than previous approaches. Bromine- and iodine-substituted dihalofuranones proved more reactive than their chlorine-substituted analogues. Conclusion: Higher yielding routes to bromine-, fluorine-, chlorine- and iodine-containing dihalofuranones were successfully developed. Suzuki couplings of gem-dihalofuranones were found to proceed with high stereoselectivity.

Biomimetic enantioselective synthesis of β,β-difluoro-α-amino acid derivatives

Although utilization of fluorine compounds has a long history, synthesis of chiral fluorinated amino acid derivatives with structural diversity and high stereoselectivity is still very appealing and challenging. Here, we report a biomimetic study of enantioselective [1,3]-proton shift of β,β-difluoro-α-imine amides catalyzed by chiral quinine derivatives. A wide range of corresponding β,β-difluoro-α-amino amides were achieved in good yields with high enantioselectivities. The optically pure β,β-difluoro-α-amino acid derivatives were further obtained, which have high application values in the synthesis of fluoro peptides, fluoro amino alcohols and other valuable fluorine-containing molecules.

Metal-Free Stereoselective Cationic Polymerization of Vinyl Ethers by Employing a Confined Brønsted Acid as the Catalyst

The properties of poly(vinyl ether)s (PVEs) are highly dependent on their tacticity, and the appealing thermoplastics features of isotactic PVEs have drawn considerable efforts to develop stereoselective cationic polymerization methods to access this class of polymers. However, re-ported methods that could achieve a high degree of tacticity control are limited to process employing metal-based Lewis acids, and with various limitations on catalyst loading, monomer scope, etc. Here, we introduce a metal-free stereoselective cationic polymerization of vinyl ethers by employing a class of chiral confined Brønsted acids, imidodiphos-phorimidates (IDPis), as the catalyst. This organocatalytic approach features its metal free conditions, high efficiency, high stereoselectivity, single catalyst system, operation simplicity, etc.

Synthesis and Oxidative Transformations of New Chiral Pinane-Type γ-Ketothiols: Stereochemical Features of Reactions

Chiral γ-ketothiols, thioacetates, thiobenzoate, disulfides, sulfones, thiosulfonates, and sulfonic acids were obtained from β-pinene for the first time. New compounds open up prospects for the synthesis of other polyfunctional compounds combining a biologically active pinane fragment with various pharmacophore groups. It was shown that the syntheses of sulfanyl and sulfonyl derivatives based on 2-norpinanone are characterized by high stereoselectivity in comparison with similar reactions of pinocarvone. The conditions for the preparation of diastereomerically pure thioacetyl and thiobenzoyl derivatives based on pinocarvone, as well as for the chemoselective oxidation of γ-ketothiols with chlorine dioxide to the corresponding thiolsulfonates and sulfonic acids, were selected. The effect of the VO(acac)2 catalyst on the increase in the yields of thiosulfonates was shown. A new direction of the transformation of thiosulfonates with the formation of sulfones was revealed. In the case of pinocarvone-based sulfones, the configuration is inversed at the C2 atom. An epimerization scheme is proposed.

Asymmetric Organocatalytic Syntheses of Bioactive Compounds

Background: The total syntheses of complex natural products have evolved to include new methodologies to save time, simplifying the form to achieve these natural compounds. Objective: In this review, we have described the asymmetric synthesis of different natural products and biologically active compounds of the last ten years until the current day. Results: An asymmetric organocatalytic reaction is the key to generate stereoselectively the main structure with the required stereochemistry. Conclusion: Even more remarkable, the organocatalytic cascade reactions, which are carried out with high stereoselectivity, as well as a possible approximation of the organocatalysts activation with substrates are also described.

Multi-Catalytic Approach to One-Pot Stereoselective Synthesis of Secondary Benzylic Alcohols

One-pot multi-step procedures bear the potential to rapidly build up molecular complexity while avoiding the wasteful and costly isolations and purifications of consecutive intermediates. Here we report multi-catalytic protocols that convert alkenes, unsaturated aliphatic alcohols, and aryl boronic acids into secondary benzylic alcohols with high stereoselectivities under sequential catalysis that integrates alkene cross-metathesis, isomerization, and nucleophilic addition. Because each transformation of the sequence is executed by an independent catalyst, without any catalytic cross-reactivity, allylic alcohols bearing a prochiral double bond can be converted to any stereoisomer of the product with high stereoselectivity (>98:2 er and >20:1 dr). Overall, with the aid of up to four catalysts operating in a single vessel, the protocols directly convert simple starting materials into a range of value-added products with high stereocontrol and excellent material efficiency, demonstrating both the efficacy and the advantages of the one-pot synthesis employing multiple transition-metal catalysts.

Multi-Catalytic Approach to One-Pot Stereoselective Synthesis of Secondary Benzylic Alcohols

One-pot multi-step procedures bear the potential to rapidly build up molecular complexity while avoiding the wasteful and costly isolations and purifications of consecutive intermediates. Here we report multi-catalytic protocols that convert alkenes, unsaturated aliphatic alcohols, and aryl boronic acids into secondary benzylic alcohols with high stereoselectivities under sequential catalysis that integrates alkene cross-metathesis, isomerization, and nucleophilic addition. Because each transformation of the sequence is executed by an independent catalyst, without any catalytic cross-reactivity, allylic alcohols bearing a prochiral double bond can be converted to any stereoisomer of the product with high stereoselectivity (>98:2 er and >20:1 dr). Overall, with the aid of up to four catalysts operating in a single vessel, the protocols directly convert simple starting materials into a range of value-added products with high stereocontrol and excellent material efficiency, demonstrating both the efficacy and the advantages of the one-pot synthesis employing multiple transition-metal catalysts.