One-pot Cascade Research Articles

Access to 2-Alkenyl-furans via a Cascade of Pd-Catalyzed Cyclization/Coupling Followed by Oxidative Aromatization with DDQ.

An unprecedented DDQ-mediated oxidative aromatization of 2-bezylidene-dihydrofurans yielding 2-alkenyl-furans is disclosed. Integration of this transformation with a prior Pd-catalyzed reaction of α-propargylic-β-ketoesters and (hetero)aryl halides into a one-pot cascade process opens a direct modular route to highly substituted 2-vinyl-furans. Experimental and computational studies reveal that the crucial step of the oxidative-aromatization involves facile hydride transfer from the dihydrofuran ring to the O-center of DDQ.

Adaptive maleimide-fused macrocyclic clamps: Synthesis, structures, and complexations with polycyclic aromatic hydrocarbons

The photoactive macrocyclic molecules attract attention because of their important roles in supramolecular chemistry as well as photoelectronic applications. Herein, two D-A conjugated macrocycles containing two maleimide nodes have been successfully obtained via an one-pot cascade reaction of Perkin and imidization condensations. Owing to the incorporation of two bulky 1,4-dimethoxybenzene moieties at the narrow maleimide corners, the obtained conjugated macrocycles have been equipped with two adaptive clamps, which can adjust to the guest sizes to capture the guest molecules. Interestingly, the co-crystallization with larger-sized polycyclic aromatic hydrocarbons (PAHs) leads to the 1:1 host-guest complexes, while with smaller-sized solvents results in the 1:2 complexes. Furthermore, the rotatable 1,4-dimethoxybenzene moieties endowed such macrocyclic fluorophores with pronounced solvatochromic and aggregation-induced emission enhancement (AIEE) phenomena.

Synthesis of Fluorine-Containing Multisubstituted Oxa-Spiro[4,5]cyclohexadienones via a Fluorinated Alcohol-Catalyzed One-Pot Sequential Cascade Strategy.

In recent years, the application of fluorinated alcohols as solvents, cosolvents, or additives has become important in modern organic synthesis. However, their potential as efficient catalysts in organic synthesis has not been well-explored. In this article, we report on the development of a one-pot sequential cascade reaction of p-quinone methides with difluoroenoxysilanes using hexafluoroisopropanol as catalyst. This reaction allows for the preparation of fluorinated multisubstituted oxa-spiro[4,5]cyclohexadienones. By using 50 mol % 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP), the reaction proceeds smoothly to yield 1,6-conjugated products, which are then subjected to oxidative dearomatization/hemiacetalization using PhI(OAc)2. The overall process affords moderate to high yields and excellent diastereoselectivities.

Identification and Characterization of Glycosyltransferases Involved in the Biosynthesis of Neodiosmin.

Glycosylation plays a very important role in plant secondary metabolic modifications. Neodiosmin, identified as diosmetin-7-O-neohesperidoside, not only acts to mitigate bitterness and enhance the flavor of food but also serves as a pivotal metabolite that reinforces plant immunity. Investigating its biosynthetic pathway in plants is crucial for optimizing fruit quality and fortifying plant immune responses. In this study, through analysis of transcriptomic data from Astilbe chinensis, we identified two novel uridine diphosphate (UDP)-glycosyltransferases (UGTs): Ach14791 (AcUGT73C18), responsible for flavonoid 7-O-glycosylation and Ach15849 (AcUGT79B37), involved in flavonoid-7-O-glucoside-2″-O-rhamnosylation. By delving into enzymatic properties and catalytic promiscuity, we developed a biosynthesis route of neodiosmin by establishing a one-pot enzyme-catalyzed cascade reaction. Simultaneously, lonicerin and rhoifolin were also successfully synthesized using the same one-pot dual-enzyme catalytic reaction. Taken together, our findings not only identified two novel UGTs involved in neodiosmin biosynthesis but also provided important biocatalytic components for the microorganism-based biosynthesis of flavonoid-7-O-disaccharide compounds.

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile.

The unmatched chemo-, regio-, and stereoselectivity of enzymes renders them powerful catalysts in the synthesis of chiral active pharmaceutical ingredients (APIs). Inspired by the discovery route toward the LPA1-antagonist BMS-986278, access to the API building block (1S,3R)-3-hydroxycyclohexanecarbonitrile was envisaged using an ene reductase (ER) and alcohol dehydrogenase (ADH) to set both stereocenters. Starting from the commercially available cyclohexene-1-nitrile, a C-H oxyfunctionalization step was required to introduce the ketone functional group, yet several chemical allylic oxidation strategies proved unsuccessful. Enzymatic strategies for allylic oxidation are underdeveloped, with few examples on selected substrates with cytochrome P450s and unspecific peroxygenases (UPOs). In this case, UPOs were found to catalyze the desired allylic oxidation with high chemo- and regioselectivity, at substrate loadings of up to 200 mM, without the addition of organic cosolvents, thus enabling the subsequent ER and ADH steps in a three-step one-pot cascade. UPOs even displayed unreported enantioselective oxyfunctionalization and overoxidation of the substituted cyclohexene. After screening of enzyme panels, the final product was obtained at titers of 85% with 97% ee and 99% de, with a substrate loading of 50 mM, the ER being the limiting step. This synthetic approach provides the first example of a three-step, one-pot UPO-ER-ADH cascade and highlights the potential for UPOs to catalyze diverse enantioselective allylic hydroxylations and oxidations that are otherwise difficult to achieve.

One-pot cascade conversion of ethyl levulinate to 1,4-pentanediol over CuZr/CoOx catalyst

Catalytic hydrogenation of ethyl levulinate (EL) to 1,4-pentanediol (1, 4-PDO) could provide a potential approach to obtain valuable chemicals from renewable biomass. In this study, a CuZr/CoOx catalyst was developed based on a structural topotactic transformation process of layered double hydroxides. The prepared CuZr/CoOx catalysts possess a double functionality of metal-acid sites and showed superior catalytic activity in the production of 1, 4-PDO from cascade conversion of EL. A complete EL conversion (100 %) and 93.1 % 1, 4-PDO yield were obtained under optimized conditions over catalyst CuZr/CoOx-400. The co-existence of Cu0 and Cu+ on the surface of catalyst CuZr/CoOx was confirmed by XRD and XAES characterizations. In addition, the XPS results suggested a strong interaction between Co and Cu, which would effectively stabilize the Cu+ species in the catalyst. The Cu0 was believed to activate hydrogen, while the Cu+ could promote the adsorption of carbonyl group of the substrate thus facilitating the hydrogenolysis. The introducing of Zr in the catalyst greatly improved the dispersion of Cu species and increased the abundance of the acid sites as revealed by the TEM and NH3-TPD analysis. Catalyst CuZr/CoOx-400 also exhibited highly catalytic activity after five reaction cycles. Together with the low cost of the non-precious metals, the CuZr/CoOx catalysts demonstrate a potential for the scaled-up application in the biomass refinery process.

One-pot redox cascade paired electrosynthesis of gamma-butyrolactone from furoic acid

The catalytic valorisation of biomass to afford synthetically useful small molecules is essential for sustainable biorefinery processes. Herein, we present a mild cascaded electrochemical protocol for converting furoic acid, a common biomass-derived feedstock, into a versatile platform chemical, gamma-butyrolactone. In the platinum(+)|nickel(−) electrode paired undivided cell, furoic acid is electrochemically oxidised with 84.2% selectivity to 2(5H)-furanone, the olefin of which is then hydrogenated to yield gamma-butyrolactone with 98.5% selectivity. The final gamma-butyrolactone yield is 69.1% with 38.3% Faradaic efficiency and 80.1% carbon balance when the reaction is performed with 100 mM furoic acid at 80 °C at +2.0 VAg/AgCl. Mechanistic investigation revealed the critical temperature and electrolyte pH conditions that maximise the production and protection of the key intermediate, furan radical, promoting its transition to 2(5H)-furanone rather than self-polymerising. The reaction is scalable, as 2.1 g of 98.1% pure gamma-butyrolactone is isolated through a simple solvent extraction.

Microbial-Driven Synthesis and Hydrolysis of Neohesperidin Dihydrochalcone: Biotransformation Process and Feasibility Investigation.

A novel yeast-mediated hydrogenation was developed for the synthesis of neohesperidin dihydrochalcone (NHDC) in high yields (over 83%). Moreover, whole-cell catalytic hydrolysis was also designed to hydrolyze NHDC into potential sweeteners, hesperetin dihydrochalcone-7-O-glucoside (HDC-G) and hesperetin dihydrochalcone (HDC). The biohydrogenation was further combined with whole-cell hydrolysis to achieve a one-pot two-step biosynthesis, utilizing yeast to hydrogenate C═C in the structure, while Aspergillus niger cells hydrolyze glycosides. The conversion of NHDC and the proportion of hydrolysis products could be controlled by adjusting the catalysts, the components of the reaction system, and the addition of glucose. Furthermore, yeast-mediated biotransformation demonstrated superior reaction stability and enhanced safety and employed more cost-effective catalysts compared to the traditional chemical hydrogenation of NHDC synthesis. This research not only provides a new route for NHDC production but also offers a safe and flexible one-pot cascade biosynthetic platform for the production of high-value compounds from citrus processing wastes.

N,O-Bidentated difluoroboron complexes based on pyridine-ester enolates: Facile synthesis, post-complexation modification, optical properties, and applications

An array of pyridine-ester enolate based organoboron complexes has been designed and synthesized via a one-pot cascade of Pd-catalyzed α-arylation and BF2 complexation. The rapid structure-activity relationship (SAR) studies indicated that unsymmetrical N,O-chelated BF2 complexes were highly fluorescent in solid state, and exhibited large Stokes shifts, excellent photostability, along with insensitivity to pH. The α-aryl group could not only modulate the electronic effect but also inhibit the intermolecular π-π stacking to promote the aggregation-induced emission (AIE) effect. DFT calculations and experiments identified that the intramolecular charge transfer properties of these N,O-chelates could be switched by the modification of substituents, resulting tunable fluorescence wavelengths. Furthermore, post-complexation modification was accomplished, including Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination, oxidative cleavage, along with a unique triple substitution reaction involving propargyl Grignard reagents. The exemplificative application of dimethylamine substituted boron complex as a reversible acidic vapor sensor was also demonstrated.

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade.

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7(R)-geissoschizol oxindole/(±)-7(S)-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations.

Visible-Light-Induced Decarboxylative Aminosulfonylation of (Hetero)aryl Carboxylic Oxime Esters.

Sulfonamides are important structures in pharmaceuticals, agrochemicals, and organocatalysts, yet the rapid and benign synthesis of these compounds is still a great challenge. Herein we report a photoinduced method for synthesizing sulfonamides from (hetero)aryl carboxylic acid oxime esters. This reaction proceeds via one-pot cascade radical-radical cross-coupling by energy-transfer-mediated photocatalysis. A wide substrate scope including (hetero)aryl substrates and late-stage modification of pharmaceutical molecular entities reveal its generality.

Preparation of Spirocyclic Vinylic Carbonates from Allylic Alcohols.

We present the synthesis of exo- and endo-spirovinylethylene carbonates, starting from various cyclic allylic alcohols. This one-pot cascade reaction to the spirocyclic scaffold was optimized using a design of experiments approach. The introduction of spirovinylethylene carbonates broadens the scope of using these in catalytic applications and provides an easy synthetic entry into spirocyclic scaffolds of various ring sizes.

Asymmetric α-benzylation of cyclic ketones enabled by concurrent chemical aldol condensation and biocatalytic reduction

Chemoenzymatic cascade catalysis has emerged as a revolutionary tool for streamlining traditional retrosynthetic disconnections, creating new possibilities for the asymmetric synthesis of valuable chiral compounds. Here we construct a one-pot concurrent chemoenzymatic cascade by integrating organobismuth-catalyzed aldol condensation with ene-reductase (ER)-catalyzed enantioselective reduction, enabling the formal asymmetric α-benzylation of cyclic ketones. To achieve this, we develop a pair of enantiocomplementary ERs capable of reducing α-arylidene cyclic ketones, lactams, and lactones. Our engineered mutants exhibit significantly higher activity, up to 37-fold, and broader substrate specificity compared to the parent enzyme. The key to success is due to the well-tuned hydride attack distance/angle and, more importantly, to the synergistic proton-delivery triade of Tyr28-Tyr69-Tyr169. Molecular docking and density functional theory (DFT) studies provide important insights into the bioreduction mechanisms. Furthermore, we demonstrate the synthetic utility of the best mutants in the asymmetric synthesis of several key chiral synthons.

KI mediated one-pot cascade reaction for synthesis of 1,3,4-selenadiazoles.

An efficient catalytic system consisting of KI and K2S2O8 for a one-pot pseudo three-component cascade reaction in the preparation of a diverse array of 1,3,4-selenadiazole derivatives from easily accessible precursors aldehydes, hydrazine and elemental selenium is demonstrated in this paper. Here, KI is used as the surrogate of iodine and K2S2O8 as the oxidant. The key advantages of this protocol include an easy reaction set up, operational simplicity, high functional group tolerance and utilisation of low toxicity chemicals. Further, a radical quenching reaction was also performed to confirm the mechanistic pathway.

One-pot Multi-enzyme Cascade Synthesis of Bifunctional Compounds from Vegetable Oils

One-pot Multi-enzyme Cascade Synthesis of Bifunctional Compounds from Vegetable Oils

One-pot enzymatic synthesis of L-5-methyltetrahydrofolate from folic acid using enzyme cascades

L-5-methyltetrahydrofolate (L-5-MTHF) is an active form of folate and widely used as a nutraceutical due to its high bioavailability. Herein, we report an efficient one-pot three-enzymes cascade reaction for production...

An electrochemical multicomponent cascade annulation and functionalization reaction to enable C(sp3)–H trifluoromethylation

Herein, we describe a novel electrochemistry facilitated one-pot multicomponent cascade annulation and bi-functionalization reaction that enables the efficient synthesis of highly functionalized 3,4-dihydroquinazolinones, realising indirect C(sp3)–H trifluoromethylation of aromatic ketones.

Electrochemical one-pot cascade synthesis of thio(seleno)cyanato-substituted thiazolidine-2-imines without external electrolyte.

A novel synthetic method has been developed for generating thio(seleno)cyanato-substituted thiazolidine-2-imines via an electrochemical one-pot cascade reaction. This reaction employs isothiocyanates, N-2-en-1-amines, and KSCN (or KSeCN) under mild conditions, obviating the need for metals, chemical oxidants, and external electrolytes. The protocol is effective with unactivated alkenes and facilitates the synthesis of five- and six-membered thio(seleno)cyanato-substituted thiazolidine-2-imines. The versatility is demonstrated by its straightforward operation and scalability to gram-scale production, underscoring its potential for broader application.

Pd(II)-catalyzed cascade annulation of N-substituted anilines with CO, NH4OAc and aldehydes to N1-substituted 2,3-dihydroquinazolin-4(1H)-ones.

A facile and direct approach to N1-substituted 2,3-dihydroquinazolin-4(1H)-ones has been developed via Pd(II)-catalyzed one-pot cascade annulation of N-substituted anilines with CO, NH4OAc and aldehydes, and it features an intrinsic directing strategy, cheap and easily obtainable raw materials, low cost, high step economy and efficiency, broad substrate scope and good product diversity. This protocol has been successfully applied to the synthesis of glycozolone A and gram-level experiments. Based on the control experiments and the literature, the reaction mechanism was proposed.

Metal-free β,γ-C(sp3)-H difunctionalization of propanols: DMP-initiated asymmetric spirocyclopropanation.

A DMP-initiated metal-free effective β,γ-asymmetric spirocyclopropanation of propanols strategy using oxidative iminium activation is described. This process has been realized by a synergistic amine-catalyzed one-pot cascade oxidation-Michael addition cyclopropanation for "one-pot" access to various spirocyclopropyl propionaldehydes/propanols from diverse 3-arylpropanols and α-brominated active methylene compounds under mild conditions and with high enantioselectivity (ee up to >99%).