Enantioselective synthesis of 3,4-dihydropyran derivatives via organocatalytic Michael reaction of α,β-unsaturated enones

A simple chiral diamine catalyst (1a) was successfully applied in the asymmetric Michael reaction between cyclic dimedone and α,β-unsaturated ketones. Both acyclic enones with aryl or alkyl β-substituents and cyclic enones were tolerated well in the reaction. The desired adducts were obtained in high yields (up to 98%) with excellent enantioselectivities (up to 97% ee). The additives were found to increase the reactivity dramatically. The biologically active 2,4-disubstituted polyhydroquinoline scaffold was conveniently prepared through an ammoniation from the generated 3,4-dihydropyran product.     

Investigating the reaction mechanism and organocatalytic synthesis of α,α'-dihydroxy ketones

A biomimetic TK one-pot reaction using hydroxypyruvate and aldehydes to generate α,α'-dihydroxy ketones in water has recently been described. To investigate this tertiary-amine mediated reaction mechanism two approaches were used. Firstly, (13)C labelled lithium hydroxypyruvate was synthesised and used to establish where hydroxypyruvate is incorporated in the product. In separate experiments reaction intermediates were also successfully intercepted and structurally identified using ESI-MS with tandem mass spectrometry ESI-MS/MS. These studies indicated that two mechanisms appear to be operating, one involving the addition of the tertiary amine catalyst to hydroxypyruvate, the other an aldol-based mechanism. Since the first mechanism may enable facial stereodifferentiation in the addition of intermediates to the aldehyde, a preliminary study on the use of chiral catalysts was performed and the first asymmetric organocatalytic synthesis of α,α'-dihydroxy ketones in aqueous media achieved, in up to 50% ee, using a quinine ether catalyst.     

Enantioselective formal synthesis of (−)-aurantioclavine using Pd-catalyzed cascade cyclization and organocatalytic asymmetric aziridination

The enantioselective formal synthesis of (?)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatalytic asymmetric aziridination reaction.     

Asymmetric organocatalytic cascade Michael/acyl transfer reaction of 2-hydroxychalcones with α-nitroketones

A highly enantioselective (84–97% ee) cascade Michael/acyl transfer reaction of α-nitroketones to a wide range of 2-hydroxychalcones was established in the presence of a bifunctional squaramide. Although aliphatic α-nitroketones were revealed to be a class of challenging substrates with unsatisfactory reactivity or enantioselectivity by previous reports, good isolated yields and excellent enantiopurities have been achieved via our catalytic protocol. γ-Nitroketones created by this new methodology were versatile building blocks possessing profound further synthetic utility.     

Enantioselective synthesis of gabapentin analogues via organocatalytic asymmetric Michael addition of α-branched aldehydes to β-nitroacrylates

Michael addition reaction of α-branched aldehydes to β-nitroacrylates was successfully carried out by using a mixed catalyst consisting of a primary amino acid, L-phenylalanine, and its lithium salt to give β-formyl-β'-nitroesters having a quaternary carbon centre in good yields (up to 85%) with high enantioselectivity (up to 98% ee). By using benzyl β-nitroacrylates as Michael acceptors, the obtained β-formyl-β'-nitroesters were converted into various 4,4-disubstituted pyrrolidine-3-carboxylic acids including analogues of gabapentin (Neurotin(?)) in one step from the Michael adducts in high yields.     

Rongalite-promoted synthesis of β-keto sulfones via radical cascade reaction

Direct arylsulfonylation of arylethenes with aryl iodides and sodium metabisulfite to access β-keto sulfones is described. In this reaction, rongalite (sodium hydroxymethanesulfinate) and sodium metabisulfite serve as the radical promoter and the sulfur dioxide surrogate, respectively.     

Aqueous microwave-assisted DMAP catalyzed synthesis of β-phosphonomalonates and 2-amino-4H-chromen-4-ylphosphonates via a domino Knoevenagel-phospha-Michael reaction

An aqueous microwave (mw)-assisted DMAP catalyzed one-pot highly efficient route to synthesize β-phosphonomalonates and 2-amino-4H-chromen-4-yl phosphonates has been demonstrated via the domino Knoevenagel-phospha-Michael reaction of aryl aldehyde/salicylaldehyde, malononitrile/ethyl cyanoacetate and alkyl phosphite ester. Optimization of reaction conditions were performed by using conventional and microwave synthetic approaches. This conversion proceeded smoothly to deliver the desired product in good to excellent yields (75–95%) in a short reaction time (10–12 min). The present methodology is very simple, environmentally benign, high yielding and has very well demonstrated the synergistic effect of water and microwaves.     

Asymmetric synthesis of α-amino-1,3-dithianes via chiral N-phosphonyl imine-based Umpolung reaction without using chromatography and recrystallization

A series of α-amino-1,3-dithianes have been synthesized via the asymmetric Umpolung reaction of 2-lithio-1,3-dithianes with chiral N-phosphonyl imines in good chemical yields (up to 82%) and good to excellent diastereoselectivities (>99:1). The manner by which chiral N-phosphonyl imines are slowly added into the solution of 2-lithio-1,3-dithiane was found to be crucial for achieving excellent diastereoselectivity. The current synthesis was proven to follow the GAP chemistry (group-assistant-purification chemistry) process, which avoids traditional purification techniques of chromatography or recrystallization, i.e., the pure chiral α-amino-1,3-dithianes attached with the chiral N-phosphonyl group were readily obtained by washing the solid crude products with hexane or a mixture of hexane-ethyl acetate.     

Enantioselective synthesis of functionalized α-amino acids via a chiral guanidine catalyzed Michael addition reaction

Several chiral guanidines were evaluated as catalysts for the Michael reaction of glycine derivatives 7 with acrylic esters 8. The best result (30.4% ee) was obtained when 7b was reacted with 8b under the catalysis of guanidine 1 in THF.     

PEG-mediated catalyst-free expeditious synthesis of polysubstituted anilines and benzenes via the reaction of malononitrile and β-ketoester derivatives in the presence of activated acetylenes

Poly(ethylene glycol) (PEG) has been used as a sustainable, non-volatile, and environmentally friendly reaction solvent for synthesis of functionalized anilines and benzenes via the reaction of malononitrile and β-ketoester derivatives in the presence of activated acetylenes at 80° C. No additional solvent and catalyst are required.     

Enantioselective Michael addition of diethyl cyanomethylphosphonate to chalcones using bifunctional cinchona-derived organocatalysts: synthesis of chiral precursors of α-substituted β-aminophosphonates

An enantioselective Michael addition of diethyl cyanomethyl phosphonate to chalcones catalysed by bifunctional catalysts based on cinchona alkaloids has been developed, producing enantiomerically enriched cyanophosphonate precursors of α-substituted β-aminophosphonates.     

Enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a CF3 moiety

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary α-amino acids in excellent yields (up to 99%) and high enantioselectivities (up to 98:2 er).     

Catalyst-controlled torquoselectivity switch in the 4π ring-opening reaction of 2-amino-2-azetines giving β-substituted α,β-unsaturated amidines

The torquoselectivity of the 4π electrocyclic ring-opening reaction of 2-azetines can be controlled by the Br?nsted acidity of the catalyst and the polarity of the solvent. DFT calculations provided insight into the mechanism of this remarkable switch. Anti and syn stereoisomers of α,β-unsaturated amidines were selectively synthesized from ynamides and aldimines in the presence of Tf(2)NH and CSA, respectively.     

Enantioselective synthesis of β-lactams via the IndaBox-Cu(II)-catalyzed Kinugasa reaction

The enantioselective Kinugasa reaction of nitrones with terminal alkynes in the presence of 20 mol % of IndaBox-Cu(OTf)₂ and di-sec-butylamine (1.5 equiv) produced β-lactams with the highest level of enantiomeric excesses among the catalytic enantioselective Kinugasa reactions reported so far.     

Enantioselective synthesis of quaternary α-aminophosphonates via conjugate addition of α-nitrophosphonates to enones

Enantioselective Michael addition of α-nitrophosphonates to enones for the synthesis of α-aminophosphonates is reported for the first time. The reaction proceeds in good to high yields and moderate to high selectivity in the presence of a new quinine thiourea catalyst. The quaternary nitrophosphonates were conveniently transformed to cyclic quaternary α-aminophosphonates via in situ reduction-intramolecular cyclization or Baeyer-Villiger oxidation followed by in situ reduction-intramolecular cyclization.     

Diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Heck–Suzuki cascade reaction

A method for the diastereoselective synthesis of tetrahydroquinolines via a palladium-catalyzed Suzuki terminated Heck reaction is described. The reaction provides access to tetrahydroquinolines containing both quaternary and tertiary stereocenters. Ligand effects, a rationale for the high level of diastereoselectivity, and a mechanistic hypothesis are discussed.     

Multisubstituted pyrazole synthesis via[3+2]cycloaddition/rearrangement/N-H insertion cascade reaction of α-diazoesters and ynones

The cascade reactions of alkyl α-diazoesters and ynones using Al(OTf)₃ as the catalyst are described.A series of 4-substituted pyrazoles were obtained via [3+2] cycloaddition,1,5-ester shift,1,3-H shift,and N-H insertion process.Deuterium labelling experiments,kinetic studies and control experiments were carried out for the rationalization of the mechanism.     

Enantioselective synthesis of stimulus-responsive amino acid via asymmetric α-amination of aldehyde

Development of a methodology to control the function of peptides and proteins is an indispensable task in the field of chemical biology and drug delivery. Recently, we reported synthesis of racemic stimulus-responsive amino acids and their application for controlling peptidyl function. In this study, we report enantioselective synthesis of a key intermediate of stimulus-responsive amino acids via asymmetric α-amination reaction of an aldehyde. The obtained chiral intermediate was converted to an Fmoc protected UV-responsive amino acid with (S)-configuration, and it was successfully incorporated into a model peptide by Fmoc solid phase peptide synthesis.     

Enantioselective synthesis of α-stereogenic γ-keto esters via formal umpolung

A feasible method has been developed for the enantioselective synthesis of α-stereogenic γ-keto esters. By employing nitro(phenylsulfonyl)methane as an acyl anion equivalent, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various γ-keto esters with high optical purities.     

Highly efficient synthesis of polysubstituted 1,2-dihydroquinolines via cascade reaction of α-ketoesters with arylamines mediated by iodine

An efficient strategy enabling the construction of polysubstituted 1,2-dihydroquinoline derivatives mediated by the commercially available, economical, and environmentally benign iodine (3 mol %) under mild conditions was developed. Various arylamines and α-ketoesters could participate in this cascade reaction, and the desired products were obtained in excellent yields up to 98%.