Asymmetric Synthesis Research Articles

Enantioselective Synthesis of Azatricycles via Post-Ugi Cyclizations.

We report a new method to create enantioenriched azatricycles using chiral α-amino acids in a two-step process after an Ugi reaction. Amino acids are great building blocks for making pure chiral molecules. Using chiral natural molecules in multicomponent reactions (MCRs) helps increase their variety by adding new chiral centers. The Ugi reaction, discovered by Ivar Karl Ugi in 1959, is a versatile MCR that helps create complex molecular structures and natural products through additional transformations called post-Ugi modifications. Designing these modifications requires selecting the right amine, acid, aldehyde/ketone, and isocyanide. Amino acids, with their primary amine and carboxylic acid groups and a pre-existing chiral center, are ideal for making diverse and selective post-Ugi modifications. Our method uses ipso-cyclization and aza-Michael cyclization with hypervalent iodine to create various azaspirotricyclic structures with high stereocontrol. This approach works well with different substrates and shows promise for further development in drug discovery.

Repurposing Naturally Occurring Enzymes Using Visible Light

AbstractEnzymes are natural treasure troves that hold multiple superiority. Enzymatic catalysis has become a powerful tool for asymmetric synthesis, though it is typically limited to a relatively narrow range of reaction types. By integrating the advantages of enzymatic catalysis with photocatalysis, photoenzymatic catalysis not only expands the catalytic capabilities of enzymes but also provides an effective strategy for the stereo‐control of photochemical reactions, thereby emerging as a significant research field. Herein, we focus on new‐to‐nature photoenzymatic catalysis by repurposing naturally occurring enzymes with visible light. We highlight the seminal work in reshaping various classes of enzymes, emphasizing their catalytic mechanism and synthetic potentials. Early Day Record

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt-Catalyzed Enantioselective Intermolecular C-H Annulation.

Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt-catalyzed C-H activation/annulation strategy in high yield with excellent enantio- and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio- and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt‐Catalyzed Enantioselective Intermolecular C−H Annulation

AbstractInherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt‐catalyzed C−H activation/annulation strategy in high yield with excellent enantio‐ and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio‐ and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.

Stereoselective synthesis of geminal bromofluoroalkenes by kinetically controlled selective conversion of oxaphosphetane intermediates.

Geminal bromofluoroalkenes are an important subclass of versatile organic interhalide, which can serve as useful synthetic precursors to monofluoroalkenes that are valuable amide group isosteres. Nonetheless, despite the vast advancement of olefination methodologies, the broadly applicable stereoselective synthesis remained elusive for geminal bromofluoroalkenes before our work. In particular, the seemingly straightforward Wittig-type approach with interhalogenated phosphorus ylide has been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Here, we describe a conceptually distinctive strategy, by which the stereoselectivity is gained via the selective decomposition of the oxaphosphetane intermediates. The suitably identified phosphorus(III) reagent and reaction medium enabled efficient kinetic differentiation, which was supported by nuclear magnetic resonance analysis and density functional theory calculation. Through our method, the highly diastereoselective synthesis of geminal E-bromofluoroalkenes was accomplished in one step. Furthermore, the generality was demonstrated by accommodating a wide range of readily available carbonyl compounds, including ketones and pharmaceutical substrates.

Dipeptidic Proline Amide–Isothiouronium Salt Organocatalysts for Enantiodivergent Conjugate Addition Reactions Between Aldehydes and Nitroolefins

AbstractWe rationally designed and successfully developed novel dipeptidic proline amide–isothiouronium catalysts for asymmetric conjugate addition reactions between various aldehydes and nitroolefins, which generated 1,4‐addition products with up to 95% yields, 92:8 syn‐diastereoselectivity, and 96% enantiomeric excess. The catalysts, which were prepared via simple methylation of the corresponding thiourea, can provide the desired enantiomeric syn‐1,4‐adducts by exchanging the configuration of the N‐terminal proline moiety.

A Linear and Stereoselective Approach for the Synthesis of Dapoxetine from Benzaldehyde

Abstract: In addition to providing a succinct pathway for the stereoselective synthesis of dapoxetine, a potent SSRI employed in the treatment of premature ejaculation, this study highlights the strategic use of Ellman's sulfinamide as a chiral auxiliary. The key method involves the diastereoselective allylation of (S,E)-N-Benzylidenesulfinamide, resulting in the desired S-configuration critical for the pharmacological activity of dapoxetine. The utilization of readily available benzaldehyde as the starting material and 1-naphthol as a late-stage coupling partner contributes to the economic feasibility of the synthesis. Especially, the linear synthetic approach adopted in this study employs simplified and more efficient protocols for various transformations, culminating in an overall yield of 26%. This research not only presents a practical synthetic route for dapoxetine, but also underscores the importance of cost-effective and streamlined methodologies in drug development processes.

Enantioselective Synthesis of Chiral Isoindolines via Palladium-Catalyzed Asymmetric Allylic C–H Amination

Enantioselective Synthesis of Chiral Isoindolines via Palladium-Catalyzed Asymmetric Allylic C–H Amination

Recent advances toward the catalytic enantioselective synthesis of planar chiral cyclophanes

Recent advances toward the catalytic enantioselective synthesis of planar chiral cyclophanes

Catalytic Asymmetric Synthesis of Bicyclic Isothioureas from a Common Enolizable Template.

While bicyclic isothiourea (ITU) moieties are found in biologically active molecules and organocatalysts, a catalytic asymmetric synthesis of ITUs is pending. Here, we report the catalytic, enantioselective functionalization of enolizable template II with a variety of electrophiles, including unsaturated ketones, esters, sulfones, nitro compounds, and thiolating reagents, as an entry to enantioenriched bicyclic ITUs III. Scope and limitations are shown, as well as examples of product derivatization.

Lamiide and Ipolamiide: A Comprehensive Review of Their Bioactive Properties and Therapeutic Potential.

There is an increasing interest in using iridoids and secoiridoids as major targets for chemical synthesis and biosynthesis. Iridoids can be found in numerous species of Lamiaceae, Verbenaceae, Scrophulariaceae, and other families. Iridoids possess a chemical structure characterized by a cyclopentane ring with oxidative substituents, forming a six-membered ring. Various research groups have used these structures as valuable starting materials for regioselective and stereoselective synthesis. This approach has enormous potential for the production of bioactive alkaloids, prostaglandin analogues, and other bioactive natural compounds. Because there is currently no review on lamiide and ipolamiide, this review intends to pique researchers' interest in this vital topic of natural science for drug discovery from naturally occurring iridoids. Lamiide and ipolamiide have the potential to be useful tools in the pharmaceutical sector, enabling the use of these plant metabolites in a variety of medicinal compositions. Given that these molecules appear to be potential natural substances for treating human ailments, we get light on them as alternative therapeutic approaches using these compounds alone or in combination with other substances which will potentially lead to future (pre)-clinical investigations.

Stereoselective Synthesis of (Z)‐β‐Thioenamide from (Z)‐Enamide‐Iodines and Thiols under Mild Conditions

AbstractThe (Z)‐β‐thioenamides is a valuable motif in many drugs. However, it's stereoselective synthesis is still facing challenge. Herein, we firstly reported a general and efficient approach for highly stereoselective synthesis of them by using (Z)‐enamide‐iodines with thiols under transition metal‐free conditions.

Stereoselective Synthesis of AB‐5,15‐Porphyrinquinone Platinum(II) Complexes

Abstract5,15‐Porphyrinquinone is a non‐aromatic and electron‐deficient porphyrinoid that acts as an important framework for the synthesis of porphyrinoid derivatives. Generally, meso‐functionalized A2‐porphyrinquinone is synthesized via the oxidation of A2‐porphyrin. Herein, we present the stereoselective synthesis of AB‐porphyrinquinone Pt(II) complexes using the corresponding dipyrrinato‐Pt complexes and bisformyldipyrrins. The reaction involves cyclization and oxidative aromatization induced by the Pt template, followed by oxidation using a mild MnO2 oxidant.

Enantioselective Synthesis of Benzylic Boronic Esters via Photoredox/Nickel-Catalyzed Multicomponent Cross-Couplings.

As a class of versatile building blocks, chiral benzylic boronic esters are important intermediates employed in modern organic chemistry. We describe herein the first stereoconvergent multicomponent cross-coupling reaction of vinyl boronates, alkyltrifluoroborates, and aryl halides through a dual photoredox/nickel catalysis methodology. This synergistic platform permitted the benign construction of various enantioenriched benzylic boronic esters with broad substrate tolerance and moderate to excellent enantioselectivity (up to 98:2 er) from commercially available starting materials. Moreover, experimental and computational studies shed light on the nickel catalytic transformation and the origin of the enantioselectivity.

Total Synthesis of (-)-Aspidospermidine via an Enantioselective Palladium-Catalyzed Allylic Substitution Strategy.

A total synthesis of (-)-aspidospermidine via an enantioselective Pd-catalyzed allylic substitution strategy is reported. This represents the first application of a Pd-catalyzed allylic substitution with a 3-substituted indole derivative in the synthesis of Aspidosperma alkaloids. In our synthetic route, the allylic substitution reaction was the stereo defining step. The pentacyclic framework was then constructed in a fully diastereoselective sequence. This culminated in the shortest enantioselective synthesis of aspidospermidine reported to date, in seven linear steps.

Silver/Segphos‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition for the Enantioselective Synthesis of Pyrrolidine Spirooxindoles

AbstractEnantioselective synthesis of chiral heterocyclic derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, a silver‐catalyzed asymmetric 1,3‐dipolar cycloaddition of glycine iminoesters with 3‐isopropylidene‐2‐oxindoles was developed. The DTBM‐Segphos‐induced spirooxindole cycloaddition reaction was used to synthesize a range of stereodivergent alkyl‐substituted 3‐methylene‐2‐oxindoles, achieving excellent enantioselectivities (up to 99 % ee), good diastereoselectivities (up to 20 : 1 dr), and high yields under mild reaction conditions. Computational insights from DFT calculations indicate that the Michael addition step is crucial in determining the reaction rate and enantioselectivity.

Biocatalytic Desymmetrization for the Atroposelective Synthesis of Axially Chiral Biaryls Using an Engineered Imine Reductase.

The enzymatic atroposelective synthesis of biaryl compounds is relatively rare, despite considerable attention received by biocatalysis in the academic and industrial sectors. Imine reductases (IREDs) are an important class of enzymes that have been applied in the asymmetric synthesis of chiral amine building blocks. In this study, two IREDs (IR140 and IR189) were identified to catalyze the efficient desymmetrization of biaryls utilizing various amine donors. Further protein engineering enabled the identification of variants (IR189 M8-M9 and IR189 M13-M14) that are able to catalyze the formation of both (R) and (S) atropisomers in excellent yields and atroposelectivities (24 examples, up to 99 % ee and yield). The absolute configuration and rotational barriers were confirmed, and the reactions were readily scaled up to allow isolation of the atropisomeric product in 99 % ee and 82 % yield. The optically pure biaryl amines were further derivatized into various synthetically useful atropisomers. To shed light on the molecular recognition mechanisms, molecular dynamics (MD) simulations were performed, offering plausible explanations for the improved atroposelectivity and enzymatic activity. The current strategy expands the scope of the IRED-catalyzed synthesis of axially chiral biaryl amines, contributing significantly to the field of atroposelective biocatalysis.

Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Ketones Involving Free Phenolic Hydroxyl Group(s).

A straightforward asymmetric transfer hydrogenation for accessing enantiomerically enriched secondary benzyl alcohols involving free phenolic hydroxyl group(s) under mild conditions was developed. Various of optical pure aryl alcohols with a remarkable functional group compatibility were achieved with 78 %-97 % yields, 84 %->99 % ee's and up to 10 000 TON. This rhodium-catalyzed reaction could be performed in a gram-scale without loss of the efficiency. Furthermore, the synthetic utility has also been demonstrated in the asymmetric synthesis of (S)-adrenaline and (S)-phenylephrine.

Enantioselective Intramolecular Oxidative Aminoacetoxylation from Aryl-Substituted Alkene via Chiral Triazole-oxazoline Palladium Complexes.

Here, we describe an enantioselective intramolecular oxidative aminoacetoxylation reaction using a palladium catalyst and an aryl-substituted internal alkene compound as the substrate under mild conditions in several hours. The triazole-oxazoline ligand was selected for the asymmetric catalyst. A range of enantioenriched pyrrolidine-derived vicinal amino acetate compounds were synthesized, showing yields from 47% to 84%, diastereomer ratios from 57:43 to 95:5, and enantiomer excesses from 67% to 92%.

Recycling of Rare Earth Elements: From E-Waste to Stereoselective Catalytic Reactions.

Raw mixtures of Rare Earths Elements, REE, recovered by E-waste, were used as catalysts to promote the (stereoselective) synthesis of highly valuable compounds. Y2O3, the major species that is recovered by the E-waste, can be easily converted into the catalytically active Y(OTf)3 that is able to efficiently promote the Michael addition of indoles to benzylidene malonates and the stereoselective Diels-Alder cycloaddition between cyclopentadiene and 4-(S)-3 acryloyl 4-tert-butyl 2-oxazolidinone. Additionally, the raw mixtures were immobilissed onto silica and used to construct packed reactors, resulting in values for Productivity and Space-Time Yields that were significantly higher than those of the corresponding batch conversions. Notably, the prepared cartridge employed in the model Michael reaction maintained its catalytic efficiency for more than 4 days of continuous running.