Michael-aldol Cascade Research Articles

Stereoselective formal [3 + 3] annulation of 3-alkylidene-2-oxindoles with β,γ-unsaturated α-keto esters.

1,4-Diazabicyclo[2.2.2]octane (DABCO)-catalyzed [3 + 3] cycloaddition reaction of 3-alkylidene-2-oxindole and β,γ-unsaturated α-keto esters under mild reaction conditions afforded the spirocyclohexene-oxindole with excellent diastereoselectivity. The [3 + 3] annulation is found to proceed through a vinylogous Michael-aldol cascade reaction and it allows rapid access to a diverse set of highly functionalized spirocyclohexene-oxindoles. Also, a bioactivity study of the compounds on mammalian sarcoma cells has reflected cell growth inhibitory/anti-cancer properties.

Protecting Group-Directed Diastereodivergent Synthesis of Chiral Tetrahydronaphthalene-Fused Spirooxindoles via Bifunctional Tertiary Amine Catalysis.

A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids bearing a quaternary carbon center at the β-position of THN has been developed. The diastereodivergent direct catalytic Michael-aldol reaction between 3-ylideneoxindole and 2-methylbenzaldehyde was accomplished by using bifunctional tertiary amine. Simply changing the protecting group on the substrate in the organocatalytic cascade reaction led to inverted diastereoselectivity in good yields with a high ee value. To explain the diastereodivergence of the organocatalytic Michael-aldol cascade, we also proposed plausible transition-state models for [4 + 2] annulation based on the observed stereochemistry of the products.

First synthesis of (±)-pseudohygrophorone A12, an anti-fungal cyclohexenone derivative isolated from Hygrophorus abieticola

Pseudohygrophorones A12 and B12 are cyclohexenone derivatives isolated from Hygrophorus abieticola (Basidiomycete) as anti-phytopathogenic compounds. In this study, the first synthesis of (±)-pseudohygrophorones A12 is reported, utilizing Michael–aldol cascade reaction for constructing the 3,3-dimethyl-2,4-dioxabicyclo[3.1.1]nonan-9-one skeleton and the diastereoselective addition of alkyllithium to the one-side blocked ketone as the key steps.

Solvent-free Synthesis of Novel Spirocyclic Oxindole Derivatives via a Michael-Aldol Cascade by Grinding

A simple and novel synthesis of spirocyclic oxindole derivatives by the reaction of ( E)-3-arylideneindole-2-ones and 1,4-dithiane-2,5-diol via a Michael-aldol cascade under solvent-free reaction conditions is reported. This method provides a new practical and facile approach to 4′-hydroxy-2′-aryl-4’,5′-dihydro-2' H-spiro[oxindole-3,3′-thiophen]-2-ones in moderate to good yields. The structures of all the products were characterised by NMR, infrared spectroscopy and HRMS.

Synthesis of spiro-tetrahydrothiopyran-oxindoles by Michael-aldol cascade reactions: discovery of potential P53-MDM2 inhibitors with good antitumor activity.

Using proline as the catalyst, an organocatalytic Michael-aldol cascade reaction was developed for the synthesis of spiro-tetrahydrothiopyran oxindoles. The highly functionalized scaffold was assembled in moderate to good yields (51-78%) and excellent diastereoselectivities (>20 : 1 dr). Interestingly, the oxindoles displayed moderate to good in vitro antitumor activities and were validated as p53-MDM2 inhibitors, which represented promising lead compounds for antitumor drug discovery.

Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds.

Enantioselective synthesis of pyrazolone-fused spirocyclohexenols by the secondary amine-catalyzed cascade reaction of α,β-unsaturated aldehydes with α-arylidene pyrazolinones is reported. This formal [3 + 3] organocascade reaction proceeds through a vinylogous Michael-aldol sequence to furnish the spiroheterocycles with three stereocenters including an all-carbon quaternary center in good yields and selectivities. The catalytic generation of α,β-unsaturated iminium ions from enals and tandem dienolate/enolate formation from pyrazolinones are the key for the success of this spiroannulation reaction.

Primary-Secondary Diamine Catalyzed Enantioselective Synthesis of Substituted Cyclohex-2-enones by Cascade Michael–Aldol–­Dehydration of Ketones with Chalcones

A simple primary-secondary diamine organocatalyst catalyzes the cascade Michael–aldol–dehydration of chalcones and unmodified ketones to produce substituted cyclohex-2-enones under mild conditions with good yields and high enantio- and/or diastereoselectivities. The success of the catalyst system is possibly due to simultaneous activation of the electrophilic chalcone by iminium formation and the nu­cleophilic ketone by enamine formation with an overall intramolecular iminium–di-enamine mechanism.

Cascade Michael-Aldol reaction: efficient annulation of sulfonamide chalcones into novel cyclohexenones under solvent-free conditions

Cascade Michael-Aldol reaction: efficient annulation of sulfonamide chalcones into novel cyclohexenones under solvent-free conditions

ChemInform Abstract: Diastereoselective Synthesis of Biheterocyclic Tetrahydrothiophene Derivatives via Base‐Catalyzed Cascade Michael‐Aldol [3 + 2] Annulation of 1,4‐Dithiane‐2,5‐diol with Maleimides.

A highly diastereoselective intermolecular [3 + 2] annulation of 1,4-dithiane-2,5-diol to maleimides has been developed by using DABCO as a catalyst, which provides a series of highly functionalized biheterocyclic tetrahydrothiophene derivatives containing tetrahydrothiophene and pyrolidine backbones in excellent yields and diastereoselectivities (up to 98% yield and >20:1 d.r.). The cascade Michael-aldol reaction is capable of tolerating organic solvents as well as water.

Total synthesis of norleucosceptroids F and G

Abstract First total synthesis of norleucosceptroids F and G has been achieved through key steps of Michael–Aldol cascade, oxa-Michael cyclization–dehydration–deprotection cascade and cross metathesis (CM), this work developed a general and concise method to the synthesis of leucosceptroid and norleucosceptroid.

Diastereoselective Synthesis of Biheterocyclic Tetrahydrothiophene Derivatives via Base-Catalyzed Cascade Michael-Aldol [3 + 2] Annulation of 1,4-Dithiane-2,5-diol with Maleimides.

A highly diastereoselective intermolecular [3 + 2] annulation of 1,4-dithiane-2,5-diol to maleimides has been developed by using DABCO as a catalyst, which provides a series of highly functionalized biheterocyclic tetrahydrothiophene derivatives containing tetrahydrothiophene and pyrolidine backbones in excellent yields and diastereoselectivities (up to 98% yield and >20:1 d.r.). The cascade Michael-aldol reaction is capable of tolerating organic solvents as well as water.

Highly diastereoselective synthesis of spiropyrazolones.

We report a highly diastereoselective synthesis of spiropyrazolones catalyzed by secondary amines. The reported Michael-Aldol cascade reaction affords the desired spiropyrazolones bearing four chiral centers as a single diastereomer in excellent yields.

ChemInform Abstract: Formation of Dihydronaphthalenes via Organocatalytic Enantioselective Michael—Aldol Cascade Reactions with Arylalkanes.

AbstractA new organocatalytic highly enantioselective nucleophilic carbon initiated Michael—aldol cascade reaction for one‐pot construction of chiral dihydronaphthalenes is developed.

ChemInform Abstract: Organocatalytic Formal [5 + 1] Annulation: Diastereoselective Cascade Synthesis of Functionalized Six‐Membered Spirocyclic Indane‐1,3‐diones/oxindoles via Michael—Aldol Reaction.

Abstract An efficient cascade protocol has been developed for the diastereoselective synthesis of functionalized six-membered spirocyclic compounds. The reaction proceeded smoothly between indane 1,3-diones/oxindoles/coumaranone as the dinucleophilic components and (E)-5-nitro-6-aryl-hex-5-en-2-one as the dielectrophile to give the desired products with reasonable to high chemical yields (30–84%) and high levels of diastereoselectivities (upto >95:5 dr). The reaction proceeded smoothly via cascade Michael–aldol reaction.

Formation of Dihydronaphthalenes via Organocatalytic Enatioselective Michael–Aldol Cascade Reactions with Arylalkanes

An organocatalytic highly enantioselective Michael-aldol cascade access to valuable chiral dihydronaphthalenes has been realized. Notably, the strategy via activation of nucleophilic alkyl chains by introducing nitro, chloro, or CF3 group(s) at the ortho- and/or para-position(s) on an aromatic ring renders them readily deprotonated to produce highly reactive nulecophilic species in the cascade process under mild conditions.

Organocatalytic formal [5+1] annulation: diastereoselective cascade synthesis of functionalized six-membered spirocyclic indane-1,3-diones/oxindoles via Michael–aldol reaction

An efficient cascade protocol has been developed for the diastereoselective synthesis of functionalized six-membered spirocyclic compounds. The reaction proceeded smoothly between indane 1,3-diones/oxindoles/coumaranone as the dinucleophilic components and (E)-5-nitro-6-aryl-hex-5-en-2-one as the dielectrophile to give the desired products with reasonable to high chemical yields (30–84%) and high levels of diastereoselectivities (upto >95:5 dr). The reaction proceeded smoothly via cascade Michael–aldol reaction.

Metallic chalcogenolates mediated modular Michael-aldol cascade reaction: an easy route to multi-functionalized chalcogenides and Morita–Baylis–Hillman adducts

Chalcogenolate mediated Michael-aldol cascade reactions consists of a very efficient route to multi-functionalized γ-hydroxichalcogenides. Although, when selenolates are employed, these γ-hydroxichalcogenides can be readily converted into the corresponding Morita–Baylis–Hillman adducts by oxidative elimination of the selenium moiety. In this context, herein we present a complete study on the scope and limitations of this reaction.

ChemInform Abstract: An Organocatalytic Michael—Aldol Cascade: Formal [3 + 2] Annulation to Construct Enantioenriched Spirocyclic Oxindole Derivatives.

AbstractThe presented approach provides a facile access to a new family of polyfunctionalized spirooxindoles bearing three consecutive stereogenic centers.

An organocatalytic Michael-aldol cascade: formal [3+2] annulation to construct enantioenriched spirocyclic oxindole derivatives

An efficient organocatalytic Michael-aldol cascade reaction for the asymmetric synthesis of spirocyclic oxindole derivatives fused with tetrahydrothiophenes has been developed through a formal [3+2] annulation strategy.

“One-Pot” Access to 4H-Chromenes with Formation of a Chiral Quaternary Stereogenic Center by a Highly Enantioselective Iminium-allenamine Involved Oxa-Michael−Aldol Cascade

An unprecedented organocatalytic highly enantioselective cascade Michael-aldol reaction has been developed in high yields under mild reaction conditions. The "one-pot" process affords an efficient approach to the synthetically and biologically important chiral 4H-chromenes bearing a quaternary stereogenic center. The study significantly expands the scope of less explored organocatalytic iminium-allenamine chemistry.