Michael Cascade Research Articles

Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

Fluorinated Chiral Pyrans Obtained via Mechanochemical Organocatalytic Michael/oxa‐Michael Cascade

Fluorine‐containing compounds are important in medicine or crop‐protection. Herein, we show asymmetric organocatalytic Michael/oxa‐Michael cascade leading to chiral fluorinated pyrans under mechanochemical conditions. Formal oxa‐Diels‐Alder reaction between fluorine containing unsaturated keto esters and β,γ‐unsaturated ketones afforded a range of drug‐like pyran derivatives in short times and good to high yields. Ball‐milling convey the reaction in short times and high product yields, while keeping high enantiomeric purities of products. The reaction is diastereodivergent depending on the use of either monofunctional amine catalysts or bifunctional thiourea or squaramide.

A Catalyst-Free One-Pot Multicomponent Green Strategy for the Synthesis of Spiroindene-1,3dione-Benzochromene/ Thio-Chromene Derivatives under Neat/Aqueous Conditions

An efficient, facile, and catalyst-free one-pot multicomponent green strategy under neat or aqueous conditions has been developed to synthesize a series of spiro compounds that contain two biologically active pharmacophores, benzochromenes/thio-chromenes and indan-1,3-dione, in a single molecular framework. The desired Spiroindene-1,3dione-benzochromene/thio-chromene derivatives were yielded through a one-pot, three-component reaction between ninhydrin, substituted 1,3-dicarbonyls, and 2-naphthol/2-naphthalene thiol via the Knoevenagel–Michael cascade. The advances of this strategy include high product yields (94–82%), the formation of a new asymmetric center, cost-effectiveness, atom economy, and a straightforward workup procedure that does not require any additional purification steps.

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

AbstractSpiro derivatives are important scaffolding substances found in many natural products and pharmaceuticals. In the last decade, numerous new approaches based on multicomponent reactions have been explored for the selective and efficient development of new spiro derivatives using various organocatalytic and transition metal‐based catalytic systems. This Review discusses pioneering advances in the field of catalytic stereoselective multicomponent reactions for the preparation of various spiro derivatives. These include stereoselective Michael cascade cyclization reactions, cycloadditions, diastereoselective reactions, and miscellaneous reactions for the synthesis of spiro‐hetero/carbocycles. Advances in the last decade have made it possible to synthesize various spiro compounds with good to excellent stereoselectivity under appropriate reaction conditions. However, achieving high regioselectivity in several described multicomponent reactions remains a challenge. Organocatalysts and transition‐metal‐based catalysts play a crucial role in achieving this milestone. Proposed catalytic mechanisms and supporting evidence are highlighted in this Review. The progress described in catalytic stereoselective approaches for spiro derivatives is immense. However, it is expected that new stereoselective synthetic methods will soon be developed that can be widely used for the preparation of spiro‐heterocycles/carbocycles.

Organocascade Synthesis of Spiro[chroman‐3,2′‐indanedione] Scaffolds via [4+2] or [1+1+4] Cyclisation

AbstractA simple and convenient protocol has been demonstrated for the construction of spiro[chroman‐3,2′‐indanedione] via Oxa‐Michael/Michael cascade reaction sequence using 2‐arylidene‐1,3‐indanedione and (E)‐2‐(2‐nitrovinyl)phenol. This [4+2] cyclisation protocol results in the generation of two stereocentres along with an all carbon quaternary centre in good to high chemical yields of upto 93 %. A triple cascade reaction approach was carried out for the construction of spiro[chroman‐3,2′‐indanedione] using [1+1+4] cyclisation protocol.

Formal Synthesis of (-)-Quinagolide: Diastereoselective Ring Expansion via a Bicyclic Aziridinium Ion Strategy to Access the Octahydrobenzo[g]quinoline Architecture.

The diastereoselective formal synthesis of (-)-quinagolide, a D2 receptor agonist, has been achieved. The synthesis started from l-pyroglutamic acid and relied on utilization of (a) a stereospecific catalytic hydrogenation and diastereoselective Horner-Emmons-Michael cascade to obtain functionalized prolinate, (b) a Lewis acid mediated Pummerer cyclization to construct a tricyclic fused ring system, and (c) a diastereoselective ring expansion via a bicyclic aziridinium intermediate to access the required 3-substituted piperidine scaffold.

A Concise Total Synthesis of (−)‐Berkelic Acid

AbstractReported here is a concise total synthesis of (−)‐berkelic acid in eight linear steps. This synthesis features a Catellani reaction/oxa‐Michael cascade for the construction of the isochroman scaffold, a one‐pot deprotection/spiroacetalization operation for the formation of the tetracyclic core structure, and a late‐stage Ni‐catalyzed reductive coupling for the introduction of the lateral chain. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process. Stereocontrol of the intriguing deprotection/spiroacetalization process is supported by DFT calculations.

Bronsted Acidic Ionic Liquids (BAILs)-Catalyzed Synthesis of 1,8-Dioxo-Octahydroxanthene and 2,2′-Arylmethylene Bis(3-Hydroxy-5,5-Dimethyl-2-Cyclohexene-1-One) Derivatives Under Eco-Friendly Conditions

A simple and efficient one-pot process for the synthesis of 1,8-dioxo-octahydroxanthene and 2,2′-arylmethylene bis(3-hydroxy-5,5-dimethyl-2-cyclohexene-1-one) derivatives via the Knoevenagel–Michael cascade reactions of aromatic aldehydes and dimedone catalyzed by Bronsted acidic ionic liquids (BAILs) in solvent-free and aqueous conditions is described in this study. These heterocycles were prepared in the presence of Bronsted acidic ionic liquids as a suitable, economical, readily synthesized and eco-friendly catalyst. This method offers several advantages such as high yields, simplicity of the workup, low cost, short reaction times, green conditions and use of a reusable catalyst.

Asymmetric Synthesis of Spirocyclopentane Oxindoles Containing Four Consecutive Stereocenters and Quaternary α-Nitro Esters via Organocatalytic Enantioselective Michael-Michael Cascade Reactions.

An enantioselective domino Michael–Michael reaction of nitroolefins and 2-nitro-3-arylacrylates has been established, which provided a series of spirocyclopentane oxindoles with four consecutive stereocenters including quaternary α-nitro esters with good yields (up to 73%) and excellent enantioselectivities (up to 97% ee). The reaction was realized and optimized with the aid of a chiral squaramide-amine catalyst. The structures of 11 products were confirmed by single-crystal X-ray diffraction analysis.

A bifunctional pyrazolone–chromone synthon directed organocatalytic double Michael cascade reaction: forging five stereocenters in structurally diverse hexahydroxanthones

The merging of two or more known natural product-based scaffolds is a powerful and routine strategy to develop bioactive small molecules.

Highly efficient synthesis of benzodioxins with a 2-site quaternary carbon structure by secondary amine-catalyzed dual Michael cascade reactions.

Salicylic acids and substituted ynones were employed as substrates to afford a class of valuable 4H-benzo[d][1,3]dioxin-4-ones with a 2-site quaternary carbon structure in up to 92% yield by secondary amine-catalyzed dual Michael cascade reactions under mild reaction conditions. The α,β-unsaturated ketone as the key intermediate in the cascade process was successfully separated and characterized. As a result, a new reaction route for ynone species is demonstrated, which is totally different from the existing allenamine activation model.

Ethyl 2-[2-(4-Nitrobenzoyl)-1H-indol-3-yl]acetate

Ethyl 2-[2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate was prepared in good yield and characterized by the aza-alkylation/intramolecular Michael cascade reaction of (E)-ethyl 3-[2-(tosylamino)phenyl]acrylate with 2-bromo-4′′-nitroacetophenone, followed by desulfonative dehydrogenation with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) The structure of the newly synthesized compound was determined using 1H-,13C-NMR, IR and mass spectral data.

Synthesis of 18‐Demethoxy Analogues of the Aglycon of Saundersiosides A and B, Based on a Cascade Process

AbstractA deprotection/retro‐vinylogous aldol/vinylogous aldol/intramolecular transesterification/O‐Michael cascade triggered by Bu4NF was found to lead to a hexacyclic lactone in high yield on gram scale. This intermediate was used to prepare several 18‐demethoxy analogues of the aglycon of saundersiosides A and B.

ChemInform Abstract: Current Advances of Organocatalytic Michael—Michael Cascade Reaction in the Synthesis of Highly Functionalized Cyclic Molecules

AbstractReview: [47 refs.

Recent Advances in Dynamic Kinetic Resolution by Chiral Bifunctional (Thio)urea- and Squaramide-Based Organocatalysts.

The organocatalysis-based dynamic kinetic resolution (DKR) process has proved to be a powerful strategy for the construction of chiral compounds. In this feature review, we summarized recent progress on the DKR process, which was promoted by chiral bifunctional (thio)urea and squaramide catalysis via hydrogen-bonding interactions between substrates and catalysts. A wide range of asymmetric reactions involving DKR, such as asymmetric alcoholysis of azlactones, asymmetric Michael–Michael cascade reaction, and enantioselective selenocyclization, are reviewed and demonstrate the efficiency of this strategy. The (thio)urea and squaramide catalysts with dual activation would be efficient for more unmet challenges in dynamic kinetic resolution.

Enantioselective Construction of Spirocyclic Oxindoles via Tandem Michael/Michael Reactions Catalyzed by Multifunctional Quaternary Phosphonium Salt.

The enantioselective construction of five-membered spirocyclic oxindoles via a double Michael cascade reaction is described by using dipeptide-based multifunctional quaternary phosphonium salt catalysts. The desired products were obtained in excellent yields (up to 94%) and good to high stereoselectivities (up to >19:1 dr and 99% ee).

Natural phosphate as an efficient and green catalyst for synthesis of tetraketone and xanthene derivatives

Natural phosphate was applied as an efficient and ecofriendly catalyst for the synthesis of tetraketones (2–2.5 h, 90–100 %) and xanthenes (6.5–8.5 h, 84–95 %) via Knoevenagel–Michael cascade reaction of aromatic aldehydes with 1,3-cyclic diketones in water and ethanol, respectively. This protocol provides several advantages over the traditional chemical synthesis, such as simple work-up, easy handling procedure, non-toxicity and stability of catalyst, low cost and environmental friendliness.

ChemInform Abstract: An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction.

AbstractAn optimized synthesis of the glyoximide is developed which is used for a completely regio‐ and highly diastereoselective three‐component coupling with nitrostyrenes and vinylmagnesium bromide to give compounds (VII).

ChemInform Abstract: Synthesis of Alkaloid‐Mimicking Tricyclic Skeletons by Diastereo‐ and Regioselective Ugi/Ipso‐Cyclization/Aza‐Michael Cascade Reaction in One‐Pot.

AbstractThe scalable, operationally simple method generates complex functionalized azaspirofused tricyclic scaffolds with three stereogenic centers one of which is quaternary.

An Asymmetric Vinylogous Michael Cascade of Silyl Glyoximide, Vinyl Grignard, and Nitroalkenes via Long Range Stereoinduction.

A diastereoselective auxiliary-mediated vinylation/[1,2]-Brook rearrangement/vinylogous Michael cascade of silyl glyoximide, vinylmagnesium bromide, and nitroalkenes is described. The reaction occurs with complete regio- and diastereocontrol in good yield. The diastereoselectivity is induced by a rare instance of 1,7-chirality transfer that is hypothesized to arise from a trans-multihetero-decalin transition state.