Synthesis of octahydroquinolines through the Lewis acid catalyzed reaction of vinyl allenes and imines

The reaction of vinyl allenes with imines under Lewis acid catalysis has been explored. Vinyl allenes in which the allenic portion of the molecule is tri- or tetrasubstituted gave octahydroquinoline derivatives as single isomers together with a minor compound formed by an ene reaction of the imine with the allene. Compounds in which the allene is 1,3-disubstituted do not react under the conditions assayed.     

The 4-oxalocrotonate tautomerase- and YwhB-catalyzed hydration of 3E-haloacrylates: implications for the evolution of new enzymatic activities

4-Oxalocrotonate tautomerase (4-OT) catalyzes the conversion of 2-oxo-4E-hexenedioate to 2-oxo-3E-hexenedioate through the intermediate, 2-hydroxy-2,4E-hexadienedioate. 4-OT and a homologue found in Bacillus subtilis (designated YwhB) share sequence identity and two key catalytic groups, Pro-1 and Arg-11, with the two subunits comprising trans-3-chloroacrylic acid dehalogenase (CaaD). 4-OT and YwhB have now been found to display a low-level hydratase activity, resulting in the dehalogenation of 3E-haloacrylates. The enzymes are highly selective for the (E)-isomer, and Pro-1 is critical for the activity while an arginine is likely required. Two mechanisms are proposed in which Pro-1 functions as a general base or a general acid catalyst and, along with the arginine, facilitates the Michael addition of water. Both mechanisms suggest an intriguing route for the evolution of the CaaD activity. One or more mutations could decrease the hydrophobic environment of the active site, which would make it more favorable for a hydrolytic reaction, thereby raising the pKa of Pro-1 and increasing the concentration of enzyme in the reactive form.     

Theoretical investigations on the stereoselectivity of the proline catalyzed Mannich reaction in DMSO

The stereocontrol steps of the (S)-proline catalyzed Mannich reaction of cyclohexanone, formaldehyde, and aniline were theoretically investigated. The geometries of reactants, products, and transition states were optimized using density functional theory using the B3LYP functional with the 6-31++G(d,p) basis set. The energies of these compounds were then more accurately determined at the MP2 level, and the effect of DMSO as the solvent was included using a polarizable continuum model (PCM). The reaction was modeled from the previously proposed mechanism that cyclohexanone reacts with (S)-proline to generate an enamine, while formaldehyde reacts with aniline to produce an imine, and that the conformation around the C-N bond of the enamine 1 is crucial for the further enantioselective step. The formation of two conformations of the enamine via a proton transfer process was examined, revealing activation barriers for syn- and anti-enamine proton transfer of 10.2 and 17.9 kcal/mol, respectively. The transformation of syn- to anti-enamine through C-N bond rotation, however, was predicted to require only 4.2 kcal/mol, while the (S)- and (R)-intermediates could be obtained from subsequent reactions between enamine and imine with energy barriers of 8.5 and 12.4 kcal/mol, respectively. The difference between these barriers, but not the C-N rotation energy, becomes larger at the MP2 level and when DMSO as a solvent is included. This predicted enantioselective reaction, through the kinetic and thermodynamic favoring of the (S)-pathway, is in agreement with experimental results, which have reported the (S)-configuration as the major product.     

Design of a conformationally restricted analogue of the antiepilepsy drug Vigabatrin that directs its mechanism of inactivation of gamma-aminobutyric acid aminotransferase

The antiepilepsy drug vigabatrin (1, 4-aminohex-5-enoic acid, gamma-vinylGABA) is known to be a mechanism-based inactivator of the pyridoxal phosphate (PLP)-dependent enzyme gamma-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9341-9349). The major pathway involves gamma-proton removal, tautomerization into the PLP ring, followed by Michael addition of an active site lysine residue at the conjugated vinyl group to give a stable covalent adduct with the protein (Scheme 2, pathway a). The minor inactivation mechanism also involves gamma-proton removal, but tautomerization occurs through the vinyl group, followed by an enamine rearrangement that leads to attachment of the inactivator to the PLP, which is bound to the protein (Scheme 2, pathway b). The cause for the two different inactivation pathways was hypothesized to be potential overlap of the incipient carbanion with the pi-orbitals of both the PLP and the vinyl group. With use of the crystal structure data for GABA-AT recently reported (Storici, P.; Capitani, C.; De Biase, D.; Moser, M.; John, R. A.; Jansonius, J. N.; Schirmer, T. Biochemistry 1999, 38, 8628-8634) a computer model of vigabatrin bound to the PLP was constructed and energy minimized. This model indicated that the major Michael addition pathway could only occur if the vinyl group were allowed to rotate by 180 degrees. A conformationally rigid analogue of vigabatrin, cis-3-aminocyclohex-4-ene-1-carboxylic acid (9), was designed to prevent bond rotation and block the Michael addition pathway. A detailed study of the mechanism of inactivation of GABA-AT by 9 revealed that it inactivates by a single mechanism, the enamine pathway.     

Nitrogen-rich porous covalent imine network (CIN) material as an efficient catalytic support for C-C coupling reactions

In an effort to expand the realm of possibilities of nitrogen-rich porous materials that could be used in catalysis, herein we report the synthesis of a new highly nitrogen rich (ca. 45%) porous covalent imine network (CIN-1) material employing simple Schiff base chemistry and further grafting its surface with palladium. Pd-loaded CIN-1 support acts as a truly heterogeneous catalyst towards Suzuki C-C coupling reaction between aryl halides with arylboronic acids. High surface area and excellent accessibility of the catalytic sites make it very efficient for heterogeneous catalysis. The stability of the catalyst due to intimate contact between nitrogen-rich organic support and metal allows several reuses with only a minor loss in catalytic activity.     

Development and evaluation of conditions for the kinetic quantitation of acetoacetate in body fluids

This paper describes a detailed study of the kinetic behavior of reactions used in the quantitation of acetoacetate in body fluids. Reactions studied are those between acetoacetate and glycine to form a transiently stable enamine intermediate, reaction of the enamine intermediate with nitroprusside, and simultaneous reaction of acetoacetate, glycine, and nitroprusside (nitrosopentacyanoferrate(III). Variables studied include pH, temperature and concentrations of all reactants. The primary reaction between acetoacetate and glycine follows pseudo-first-order kinetics at high pH (ρ 8.6) at which the enamine is transiently stable; the other reactions deviate from first-order behavior at longer times because the reaction product is unstable. Several options involving nonlinear curve-fitting methods applied to all reaction sequences above and an initial-rate method applied to the combined reactions are evaluated. Also, the two-step and combined-reaction sequences are evaluated for quantitation of acetoacetate in urine and serum samples. For acetoacetate in the concentration range 0.5–4.25 mmol l^?1, the methods yield relative standard deviations in the range 1.0–1.8% with absolute standard deviations of 3.5–35 μmol l^?1.     

Aqueous aldol catalysis by a nicotine metabolite

Nornicotine, an endogenous tobacco alkaloid and minor nicotine metabolite, can catalyze aldol reactions at physiological pH. Catalysis appears to be due to a covalent enamine mechanism, an unprecedented reaction with small organic molecule catalysts in aqueous buffer. Kinetic parameters for nornicotine as well as other related alkaloids were measured and demonstrate that both the pyrrolidine and pyridine rings are critical for optimal catalysis. Substrate compatibility of this catalyst and its implications in vivo are discussed.     

Vinylamine—XVIII : Sterische untersuchungen an enaminen und iminen mit hilfe der 3J(15NH)-Kopplung

The ¹⁵N-labelled imine enamine tautomeric systems 1–3 are studied by NMR-spectroscopy. The configuration of the isomers is determined by ³J(¹⁵NH)-coupling constants.     

Phototransformation products of the alkaloid lappaconitine: Multinuclear NMR study

The NMR technique has been applied to characterize the phototransformation products of the natural alkaloid lappaconitine. It was demonstrated that the photolysis of lappaconitine 1 results in cleavage of the ester bond with elimination of N-acetylanthranilic acid. The final reaction product was found to be an immonium salt 4 of N-acetylanthranilic acid and enamine 3. An equilibrium between the imine cation and the enamine 3 was detected.     

6-氨基-2-取代吲哚-3-羧酸乙酯及其衍生物的合成与生物活性评价

以2,4-二硝基氯苯和乙酰乙酸乙酯为原料, 经过亲核置换、还原-环化协同反应, 合成了6-氨基-2-甲基吲哚-3-羧酸乙酯, 而后在催化剂作用下, 与乙酰乙酸乙酯反应生成烯胺, 环化合成9-羟基-2,7-二甲基吡咯(2,3-f)喹啉-3-羧酸乙酯; 类似地, 合成了6-氨基-2-苯基吲哚-3-羧酸乙酯和6-氨基-2-(呋喃-2'-基)吲哚-3-羧酸乙酯. 其结构均由¹H NMR, IR以及MS波谱数据表征. 所得化合物具有抑制肺癌A549细胞生长的活性, 其抑制效果具有浓度依赖性.     

Synthesis and tautomeric behavior of 3-(pyrazolylhydrazonomethyl)-2-oxo-1, 2-dihydroquinoxalines. Specification of hydrazone imine and diazenyl enamine forms

3-(Pyrazolylhydrazonomethyl)-2-oxo-1, 2-dihydroquinoxalines were synthesized, and their tautomer ratios between hydrazone imine and diazenyl enamine forms were specified by pmr spectral data.     

Dual mechanisms of an organocatalytic homodimerization reaction

The l-proline organocatalytic homodimerization of 2-cyclohexenone has been studied and it is concluded that the mechanism of the reaction follows competing pathways involving either a two-step imine/enamine addition or a concerted Diels-Alder cycloaddition where the ultimate product distribution is dependent upon the ratio of the organocatalyst to 2-cyclohexenone and a base present.     

Enantioselective aerobic oxidative cross-dehydrogenative coupling of glycine derivatives with ketones and aldehydes via cooperative photoredox catalysis and organocatalysis

The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and simple ketones or aldehydes, which provides an efficient approach for the rapid synthesis of enantiopure unnatural α-alkyl α-amino acid derivatives in good yield with excellent diastereo- (up to >99 : 1) and enantioselectivities (up to 97% ee). This process includes the direct photoinduced oxidation of glycine derivatives to an imine intermediate, followed by the asymmetric Mannich-type reaction with an enamine intermediate generated in situ from a ketone or aldehyde and a chiral secondary amine organocatalyst. This mild method allows the direct formation of a C–C bond with simultaneous installation of two new stereocenters without wasteful removal of functional groups.

A visible-light-induced enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and simple ketones or aldehydes is achieved.     

How to drive imine–enamine tautomerism of pyronic derivatives of biological interest – A theoretical and experimental study of substituent and solvent effects

An investigation of the tautomerism of five series of aminated pyronic compounds of pharmacological interest was carried out using NMR experiments and standard quantum mechanical B3LYP/6-311+G** calculations. The obtained results indicate that among four possible tautomers, imine and enamine forms are the two predominating ones in the gas phase as well as in solution. Depending on the nature of the substituting group, the enamine or the imine form is the most stable tautomer, the calculations being in agreement with experiment. The calculated equilibrium constants in the gas phase and in solution show that the enamine form is stabilized by polar solvents, in all cases. NBO analysis explains well the predominance of a form over another one when changing a substituting group. We give indications on how to favour the imine form which is preferred for synthesis purposes.     

Anion-π transaminase mimics

Abstract

The possibility to stabilise anionic transition states on π-acidic aromatic surfaces has been explicitly demonstrated first in 2013. Since then, anion-π catalysis has been introduced to asymmetric enamine and iminium chemistry and to cascade processes, and the first anion-π enzyme has been created. Moving beyond systems that operate with nitronate-π interactions, this report adds transamination to the repertoire of anion-π catalysis. Whereas bioinspired approaches to transamination with pyridoxalphosphate appeared less obvious in this context, the base-catalyzed isomerisation of trifluoromethylimines contains suitable anionic transition states. Run on increasingly π-acidic aromatic surfaces in covalent and supramolecular trifunctional systems, we find that both rate and enantioselectivity of this reaction increase. These results support that anion-π interactions with 2-azaallyl anion intermediates catalyse the isomerisation of trifluoromethylimines by cumulative asymmetric umpolung on π-acidic surfaces.     

Theoretical and experimental study of imine-enamine tautomerism of condensation products of propanal with 4-aminobenzoic acid in ethanol

The tautomerism of the reaction products of propanal with 4-aminobenzoic acid in ethanol was studied by J-modulated spin-echo (JMOD) ¹³C NMR spectroscopy and gradient-enhanced heteronuclear (ge-2D) ¹H–¹³C HSQC spectroscopy. The existence of imine and enamine tautomeric forms of the reduced compounds in solution was established. The tautomeric equilibrium of the condensation product of propanal with 4-aminobenzoic acid in ethanol was found to be shifted toward the imine form. Quantum chemical calculations by the density functional theory (DFT) method demonstrated that the 4-(N-propylidene)aminobenzoic acid molecule forms a stronger hydrogen bond with an ethanol solvent molecule compared to the enamine molecule, resulting in a higher stability of the ethanol adduct of azomethine compared to the adduct of enamine.     

Organomagnesium‐Catalyzed Isomerization of Terminal Alkynes to Allenes and Internal Alkynes

Organomagnesium complexes 2 were synthesized from N,N‐dialkylamineimine ligands 1 and dibenzylmagnesium by benzylation of the imine moiety. 3‐Aryl‐1‐propynes reacted with 2 to form the corresponding tetraalkynyl complexes, which acted as catalysts for the transformation of these terminal alkynes into allenes and further to internal alkynes under mild conditions. To the best of our knowledge, this example is the first of an organomagnesium‐catalyzed isomerization of alkynes. Notably, the reactions proceeded through temporally separated autotandem catalysis, thus allowing the isolation of the allene or internal alkyne species in good yields. Mechanistic experiments suggested that the catalytically active tetraalkynyl complexes consist of a tautomeric mixture of alkynyl‐, allenyl‐, and propargylmagnesium species.     

The biosynthesis of the thiazole phosphate moiety of thiamin (vitamin B1): the early steps catalyzed by thiazole synthase

Thiazole synthase (ThiG) catalyzes an Amadori-type rearrangement of 1-deoxy-d-xylulose-5-phosphate (DXP) via an imine intermediate. In support of this, we have demonstrated enzyme-catalyzed exchange of the C2 carbonyl of DXP. Borohydride reduction of the enzyme DXP imine followed by top-down mass spectrometric analysis localized the imine to lysine 96. On the basis of these observations, a new mechanism for the biosynthesis of the thiazole phosphate moiety of thiamin pyrophosphate in Bacillus subtilis is proposed. This mechanism involves the generation of a ketone at C3 of DXP by an Amadori-type rearrangement of the imine followed by nucleophillic addition of the sulfur carrier protein (ThiS-thiocarboxylate) to this carbonyl group.     

The oxidation of compounds capable of imine-enamine tautomerism with lead tetraacetate

Compounds capable of imine-enamine tautomerism react preferentially via their enamine tautomer giving a 2-acetoxyaldehyde which equilibrates with the starting imine. This derives from the extra nucleophilicity of the β-carbon of the enamine tautomer. The reaction of the imine isomer to form an aryl- or an alkylnitrenoid species is a minor pathway.     

The chemistry of polycyclic arene imine. VI. 1-[N,N-di-(2-propenyl)-9-phenanthreneamine-10-yl]-1a,9b-dihydrophenanthro[9,10-b]azirine an unusual allylation product of phenanthrene 9,10-imine

Phenanthrene 9,10-imine (1) was shown to react with allyl bromide and 50% aqueous sodium hydroxide under phase transfer catalysis conditions to give the title compound 3 as the only product. The starting imine 1 is assumed to undergo initially bis alkylation to form an N,N-di-(2-propenyl)phenanthrene 9,10-iminium salt (4) which, in turn, is attacked by a deprotonated phenanthrene imine anion (5). The structure of 3 has been determined by a single crystal X-ray diffraction analysis.