Enantioselective Michael addition of malonates to aromatic nitroalkenes catalyzed by monosaccharide-based chiral crown ethers

The asymmetric Michael addition of diethyl malonate and α-substituted diethyl malonates to aromatic nitroalkenes was carried out under mild reaction conditions in a solid–liquid phase transfer reaction in the presence of α-d-glucopyranoside- and α-d-mannopyranoside-based crown ethers as the catalysts. The use of d-glucose-based lariat ether 1 gave the best results. The substituents of the β-nitrostyrene and the diethyl malonate had a significant impact on the chemical yields and enantioselectivity. The addition of diethyl-2-acetamidomalonate to aromatic nitroalkenes afforded the corresponding Michael adducts in moderate to high enantiomeric excess (ee up to 99%). The reaction of diethyl-2-methylmalonate with 2-nitro-β-nitrostyrene gave the adduct with 93% enantiomeric excess in the presence of crown catalyst 1.     

Organocatalyzed enantioselective michael addition of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonatesθ

By employing a cinchonine-based thiourea as catalyst, highly enantioselective Michael addition reactions of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonates were realized. The reaction afforded the corresponding β-substituted carboxylates in excellent yields with high levels of enantioselectivities (94->99% ee) upon quenching the generated parent structures with DBU and MeOH as a second nucleophile.     

Copper-mediated 1,4-conjugation reaction of functionalized alkylzinc iodides with derivatives of β-nitrostyrene

Functionalized alkylzinc iodides will undergo 1,4-conjugation reaction with derivatives of β-nitrostyrene in the presence of Cu(OAc)₂/LiCl to afford a polyfunctional nitro-compound in high yield.     

Enantioselective synthesis of chiral γ-aryl α-keto ester by copper-catalyzed 1,4-conjugate addition using D2-symmetric biphenyl phosphoramidite ligand

Cu-catalyzed enantioselective 1,4-conjugate addition of β,γ-unsaturated α-keto ester compound was carried out to afford chiral γ-substituted γ-aryl α-keto ester, which could be conveniently converted to the potential skeleton of new Pril drugs. Up to 81% ee and 99% yield were afforded for the 1,4-conjugate addition using D₂-symmetric biphenyl phosphoramidite ligand.     

Enantioselective reduction of aromatic ketones catalysed by chiral ruthenium(II) complexes

The catalytic enantioselective reduction of aromatic ketones in 2-propanol is carried out by using ruthenium(II) complexes prepared from [Ru(p-cymene)Cl₂]₂ and a variety of chiral diamines and β-aminoalcohols derived from α-amino acids. Good conversions (>99%) and enantioselectivities (=96%) are observed under mild reaction conditions.     

Controlling the α/γ-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

The first regio-, diastereo-, and enantioselective direct Michael reaction of β,γ-unsaturated ketones with nitroolefins is enabled by Brønsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–98 % ee range.     

REACTION DES ENOLATES MASQUES DE SILICIUM ISSUS WESTERS DE TRIMETHYLSILYLE AVEC LES DERIVES CARBONYLES α,β-INSATURES

Abstract

Bis(trimethylsilyl) ketene acetals RCH[dbnd]C[OSi(CH₃)₃]₂ 1 add to PhCH[dbnd]CH[sbnd]COR¹ 2 in the presence of catalytic amounts (10%) of TiCl₄ leading, in good to excellent yields to the corresponding β-hydroxy or δ-ketoacids. Under kinetic control, the regioselectivity of the reaction markedly depends on the nature of R and R¹. Mixtures of 1,2 and 1,4 products are formed in some of the cases; in others, solely Michael or aldol adducts are obtained. On the contrary, the stereoselectivity, which ranges from zero to moderate, is slightly influenced by R and R¹.

It is also shown that trimethylsilyl ester of α-trimethylacetic acid (CH₃)₃SiCH₂CO₂Si(CH₃)₃ 5 add to 2 in the presence of TBAF (10%) in THF.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Catalytic Michael/Ring‐Closure Reaction of α,β‐Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (−)‐Paroxetine

A highly enantioselective tandem Michael/ring‐closure reaction of α,β‐unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′‐dioxide–Yb(OTf)₃ complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo‐ and enantioselectivities. Moreover, this methodology could be used for gram‐scale manipulation and was successfully applied to the synthesis of (?)‐paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L ‐PMe₂ –Yb³⁺ complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.     

TiCl2(OTf)-SiO2: A solid stable lewis acid catalyst for Michael addition of α-Aminophosphonates,Amines, Indoles and Pyrrole

TiCl₂(OTf)-SiO₂ is simply prepared by immobilization of TiCl₃(OTf) on silica gel surface and introduced as a non-hygroscopic Lewis acid catalyst for C-N and C-C bond formation via Michael addition reaction. A variety of structurally diverse nitrogen nucleophiles including α-aminophosphonates, aliphatic and aromatic amines and imidazole were evaluated as Michael donors. Friedel–Crafts alkylation of indoles and pyrrole was also investigated through Michael addition reaction in the presence of TiCl₂(OTf)-SiO₂ as a catalyst. The reactions were conducted at room temperature or 60 °C under solvent-free conditions and the desired Michael adducts were obtained in high to excellent yields.     

Schiff base derivatives of peptide esters: Relative abundance of N-terminal,C-terminal and ‘internal’ fragments as a function of the blocking group

Electron-impact (EI) mass spectrometry of peptide derivatives is usually interpreted in terms of fragmentation where the charge resides on the N-terminal fragments and to a lesser degree on the less common, charged C-terminal fragments. Substituted and unsubstituted benzylidene, cinnamylidene, α- and β-naphthylidene derivatives of a reference tripeptide, valileala, gave both N- and C-terminal fragments as well as molecular ions. The order of increasing ion current (normalized) in C-terminal fragments was: acetylacetonyl, 4-dimethylaminonaphthylidene, p-dimethyl-aminobenzylidene, 3-pyridylmethylidene, p-diethylaminocinnamylidene, benzylidene, 2-hydroxy-naphthylidene, 4-pyridylmethylidene, p-nitrobenzylidene, p-methoxybenzylidene, p-cyanobenzylidene, cinnamylidene, p-dimethylaminocinnamylidene, β-indolylmethylidene, β-naphthylidene, 2-pyridylmethylidene and α-naphthylidene. The order for this value among the N-terminal fragments is significantly different, however (Day, Falter, Lehman and Hamilton, J. Org. Chem. in press). In addition to N- and C-terminal fragments, many spectra contain internal fragments, arising from loss of fragments from both ends, which provide sequence information. These fragments are found in the mass spectra of Schiff bases formed from various aromatic aldehydes with peptide esters. The interpretation of the latter pattern is facilitate in some cases by deuterium labeling at the α-carbon of the N-terminal amino acid residue of peptides. Such a pattern provides sequence information supplemental to that available involving N- and C-terminal fragmentations. In derivatives of hexaglycine, tetraphenylalanine and tryptophylmethionylaspartyl (β-OEt) phenylalanine amide, for example, substantial sequence information was contained in the internal fragments; in some cases the sequence could be deduced only if the internal fragments were utilized. The 4-dimethylamino-naphthylidene derivatives have proven to be the most useful to date in terms of volatility, tendency to maximize cleavage into N-terminal fragments, intensity of molecular ions and generation of useful mass spectra of certain peptide esters refractory to mass spectrometry in the form of any other derivative investigated.     

Synthesis,characterization and catalytic performance in enantioselective reactions by mesoporous silica materials functionalized with chiral thiourea-amine ligand

Chiral heterogeneous catalysts have been synthesized by grafting of silyl derivatives of (1R, 2R)- or (1S, 2S)-1,2-diphenylethane-1,2-diamine on SBA-15 mesoporous support. The mesoporous material SBA-15 and so-prepared chiral heterogeneous catalysts were characterized by a combination of different techniques such as X-ray diffractometry (XRD), Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), field emission scanning electron microscopy (FESEM), and Brunauer–Emmett–Teller (BET) surface area. Results showed that (1R, 2R)- and (1S, 2S)-1,2-diphenylethane-1,2-diamine were successively immobilized on SBA-15 mesoporous support. Chiral heterogeneous catalysts and their homogenous counterparts were tested in enantioselective transfer hydrogenation of aromatic ketones and enantioselective Michael addition of acetylacetone to β-nitroolefin derivatives. The catalysts demonstrated notably high catalytic conversions (up to 99%) with moderate enantiomeric excess (up to 30% ee) for the heterogeneous enantioselective transfer hydrogenation. The catalytic performances for enantioselective Michael reaction showed excellent activities (up to 99%) with poor enantioselectivities. Particularly, the chiral heterogeneous catalysts could be readily recycled for Michael reaction and reused in three consecutive catalytic experiments with no loss of catalytic efficacies.

     

A New Strategy for Enantioselective Construction of Multisubstituted Five‐Membered Oxygen Heterocycles via a Domino Michael/Hemiketalization Reaction

A new highly enantioselective domino Michael/hemiketalization reaction of α‐hydroxyacetophenone with β,γ‐unsaturated α‐keto esters for the synthesis of 2,2,4,5‐tetrasubstituted chiral tetrahydrofurans is reported. With 2 mol % intramolecular dinuclear zinc‐AzePhenol complex prepared in situ from the reaction of multidentate semi‐azacrown ether ligand with ZnEt₂, the corresponding anti‐multisubstituted tetrahydrofuran products were obtained in up to 90 % yields, and 98 % enantiomeric excess (ee) at 0 °C for 45 min. Moreover, the products were easily converted to 2,3,5‐trisubstituted 2,3‐dihydrofurans without any loss in optical activity.     

Aza-Michael reaction of 12-N-carboxamide of (–)-cytisine under high pressure conditions

The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (–)-cytisine with α,β-unsaturated ketones, dimethyl acetylenedicarboxylate and β-nitrostyrene under high pressure condition has been described. It has been shown that the [4+2]-cycloaddition takes place in the case with N-phenylmaleimide.     

Environmental Friendly Synthesis of Novel Isatin Ketal and Isatin Schiff Base Derivatives Using Michael Addition Reaction under Solvent‐Free Conditions

An efficient and simple procedure for the synthesis of novel isatin derivatives is described. Michael addition of aniline Schiff bases of isatin or p‐toluidine Schiff bases of isatin to fumaric esters affords the Michael adduct compounds in good to high yields in the presence of K₂CO₃ and tetrabutylammonium bromide (TBAB) under solvent‐free conditions. Repeating of this reaction about spiro[1,3‐dioxolane‐2,3′‐indol]‐2′(1′H)‐one, as a Michael donor, in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) gives Michael adducts in remarkable yields under the same conditions.     

Mechanistic Aspects on [3+2] Cycloaddition (32CA) Reactions of Azides to Nitroolefins: A Computational and Kinetic Study

[3+2] cycloadditions of nitroolefins have emerged as a selective and catalyst-free alternative for the synthesis of 1,2,3-triazoles from azides. We describe mechanistic studies into the cycloaddition/rearomatization reaction sequence. DFT calculations revealed a rate-limiting cycloaddition step proceeding via an asynchronous TS with high kinetic selectivity for the 1,5-triazole. Kinetic studies reveal a second-order rate law, and ¹³C kinetic isotopic effects at natural abundance were measured with a significant normal effect at the conjugated olefinic centers of 1.0158 and 1.0216 at the α and β-carbons of β-nitrostyrene. Distortion/interaction-activation strain and energy decomposition analyses revealed that the major regioisomeric pathway benefits from an earlier and less-distorted TS, while intermolecular interaction terms dominate the preference for 1,5- over 1,4-cycloadducts. In addition, the major regioisomer also has more favorable electrostatic and dispersion terms. Additionally, while static DFT calculations suggest a concerted but highly asynchronous Ei-type HNO₂ elimination mechanism, quasiclassical direct-dynamics calculations reveal the existence of a dynamic intermediate.     

Organocatalytic Enantioselective Pictet–Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A

We report herein an asymmetric Pictet–Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]_D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.     

Heterogeneous versus Homogeneous Copper(II) Catalysis in Enantioselective Conjugate‐Addition Reactions of Boron in Water

We have developed Cu^II‐catalyzed enantioselective conjugate‐addition reactions of boron to α,β‐unsaturated carbonyl compounds and α,β,γ,δ‐unsaturated carbonyl compounds in water. In contrast to the previously reported Cu^I catalysis that required organic solvents, chiral Cu^II catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)₂ with chiral ligand L1 ; cat. 2: Cu(OH)₂ and acetic acid with ligand L1 ; and cat. 3: Cu(OAc)₂ with ligand L1 . Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β‐unsaturated carbonyl compounds and an α,β‐unsaturated nitrile compound, including acyclic and cyclic α,β‐unsaturated ketones, acyclic and cyclic β,β‐disubstituted enones, acyclic and cyclic α,β‐unsaturated esters (including their β,β‐disubstituted forms), and acyclic α,β‐unsaturated amides (including their β,β‐disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43 200 h^?1) for an asymmetric conjugate‐addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ‐unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4‐Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ‐unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ‐unsaturated carbonyl compounds with compound 2 , whereas 1,4‐addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6‐addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate‐addition reactions in water were investigated and we propose stereochemical models that are supported by X‐ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.     

Stereoselective synthesis of various α-selenoglycosides using in situ production of α-selenolate anion

A large variety of α-selenoglycosides, including alkyl and aryl selenoglycosides, selenoglycosyl amino acid and selenodisaccharide have been synthesized in a stereoselective manner. The key precursor of α-anomeric selenolate anion was designed as p-methylbenzoyl selenoglycoside, which was synthesized by the reaction of β-glycosyl chloride with potassium p-methylselenobenzoate. Upon the action of piperazine or methylhydrazine in the presence of Cs₂CO₃, the acyl selenoglycoside produced an anomeric selenolate anion, which reacted in situ with various electrophilic counterparts to yield α-selenoglycoside.     

Chemistry of trifluorostyrenes and their dimers: 2. Synthesis of substituted α, β, β-trifluorostyrenes and α, β, β-trifluoroethenylnaphthalenes. Hammett correlations of their NMR parameters and the concept of “distorted π-electron clouds”

Six α, β, β-trifluorostyrenes with the following substituents, viz., p-MeO, p-Me, m-Me, p-Cl, m-Cl, and m-CF₃, were synthesized by the reaction of the corresponding Grignard reagents with tetrafluoroethylene in tetrahydrofuran. Similarly, α-and β-trifluoroethenylnaphthalenes were prepared. The substituent electronic effects on the ¹⁹F-NMR parameters were investigated for the trifluorostyrenes (I). Linear correlations between the Hammett σ constants and the following ¹⁹F-NMR parameters were established, namely, chemical shifts δ. (F¹) and δ (F²), coupling constants J₁₂, differences of chemical shifts Δδ_3-1 (δ (F³)—δ(f¹) or Δδ_3-2. The results are consistent with previous expectations based on the simple concept of “distorted π-electron clouds”. Facts are presented which indicate that the Δδ_3-1 (or Δδ_3-2) values may serve as empirical measures of the degree of polarization of the π bonds of these fluoroolefins.