Disubstituted Piperidines Research Articles

The Chemistry of van de Moer Test for Cytisine

Cytisine is an alkaloid with biological activity that is used as medication for smoking cessation treatment. It is a quinolizidine derivative, one ring being 2-pyridinone, and there is a third cycle, a disubstituted piperidine. Thus, the analytical chemistry of this compound is relevant. In this communication we provide the chemistry involved in the spot test for cytisine identification by means of ferric chloride/hydrogen peroxide. The electron flow, step by step, is given from the alkaloid to the final colored products. The sequence is based on the chemical properties of the substrate and reagents, disclosing the series of reactions occurring in this assay. The process is in accordance with the experimental results. We also give the mechanism of cytisine degradation, from a quinolizidine system to 6,8-dimethyl quinoline, which involves an interesting rearrangement.

Unusual behavior in di-substituted piperidine and piperazine anthraquinones upon protonation – Spectral, electrochemical, and quantum chemical studies

The objective of the study is to determine the influence of a substituent on the spectroscopic and electrochemical properties of a series of novel 9,10‑anthraquinone piperidine and piperazine derivatives. We conducted UV–Vis spectroscopy, pH-spectroscopic titration, and cyclic voltammetry measurements with an interesting phenomenon observed in the case of di-substituted quinones. Compounds with substituents in position 1 and 8 exhibit a significant increase in the absorption intensity of the monoprotonated form. Spectroscopic studies in the conjunction with time-dependent density functional theory (TD-DFT) calculations were employed to explore the unusual behavior. The state-of-the-art quantum chemistry calculations including bulk solvent in the polarizable continuum model (PCM) enabled the study of prototropic tautomerization and its influence on the position of absorption bands. The results of cyclic voltammetry measurements allowed us to determine the deciding factor influencing the reduction – the number of substituents and the possibility of the hydrogen bond formation of the charged states.

A Local-Desymmetrization-Based Divergent Synthesis of Quinine and Quinidine.

Herein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a "local-desymmetrization" approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.

A Local‐Desymmetrization‐Based Divergent Synthesis of Quinine and Quinidine

AbstractHerein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a “local‐desymmetrization” approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.

Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations.

In this study, six-membered N-acyliminium ions were generated by the “indirect cation pool” method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven’s hypothesis.

Increasing the Anti-Addictive Piperidine Alkaloid Production of In Vitro Micropropagated Indian Tobacco by Nitrate Treatments

Background: Lobelia inflata L. (Indian tobacco) is a traditional medicinal plant native to North America. It contains several piperidine alkaloids. Interest in Lobelia alkaloids, and in particular (-)-lobeline, the most active component, has increased in recent years due to their effect on the central nervous system. Thus, lobeline is currently the subject of renewed interest for its anti-addictive activity in the treatment of drug abuse, and neurological disorders. Our studies were aimed at introducing this species into cultivation in Hungary. Results: For direct characterization of di-substituted and mono-substituted piperidine alkaloids in extracts of L. inflata, a tandem mass spectrometric method was developed using electrospray ionization. The compounds (-) lobeline, norlobeline, lobelanidine, norlobelanine and other related structures were identified by HPLC-MS/MS. With the aim of increasing the alkaloid production, we have investigated the effect of changing the ammonium and potassium nitrate levels of the basic Murashige-Skoog medium. The highest dry mass, total alkaloid and lobeline content were measured in the herbs and roots cultured at 570 mg L-1 KNO3 content. Conclusions: The highest values for lobeline derivatives norlobeline and lobelidine were also recorded in the herba and roots of Lobelia inflata cultured on reduced KNO3 containing MS medium. The most sensitive response to media modification was observed in the case of lobelidine. Double-concentration of NH4NO3 had an inhibitory effect on plant growth, total alkaloid and lobeline content.

One-Pot Cascade Synthesis of Mono- and Disubstituted Piperidines and Pyrrolidines using Carboxylic Acid Reductase (CAR), ω-Transaminase (ω-TA), and Imine Reductase (IRED) Biocatalysts

Access to enantiomerically pure chiral mono- and disubstituted piperidines and pyrrolidines has been achieved using a biocatalytic cascade involving carboxylic acid reductase (CAR), ω-transaminase (ω-TA), and imine reductase (IRED) enzymes. Starting from keto acids or keto aldehydes, substituted piperidine or pyrrolidine frameworks can be generated in high conversion, ee, and de in one pot, with each biocatalyst exhibiting chemo-, regio-, and/or stereoselectivity during catalysis. The study also includes a systematic investigation of the effect of the position of a methyl group ring substituent on the IRED-catalyzed reduction of a chiral imine. Analysis of the selectivity observed in these reactions revealed an interesting balance between substrate versus enzyme control; the configurations of the products obtained were rationalized on the basis of minimizing 1,3- or 1,2-steric interactions with incoming NADPH.

ChemInform Abstract: Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights.

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

Access to 2,6-Disubstituted Piperidines: Control of the Diastereoselectivity, Scope, and Limitations. Applications to the Stereoselective Synthesis of (−)-Solenopsine A and Alkaloid (+)-241D

Scope and limitations in the diastereoselective preparation of 2,6-cis or 2,6-trans disubstituted piperidines are described, through intramolecular reaction of chiral β'-carbamate-α,β-unsaturated ketone. This methodology has been applied to the total synthesis of a few well chosen examples, such as (-)-solenopsine A and alkaloid (+)-241D.

Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists–serotonin reuptake transporter inhibitors for the treatment of depression

This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors

Alzheimer’s disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.

Tert-Butyl 1-hydroxypiperidine-2-carboxylate

The title compound, C10H19NO3, is a disubstituted piperidine bearing substituents in two equatorial positions. One of the substituents is a hy­droxy group bound to nitro­gen and the second a tert-butyl ester group bound to the carbon next to the endocyclic nitro­gen. Enanti­omers of the title compound form hydrogen-bridged dimers across a center of inversion.

ChemInform Abstract: Stereoselective Nucleophilic Addition to Conformationally Constrained Piperidines. An Efficient Route to 2-Axial-6-equatorial Disubstituted Piperidines.

Abstract Addition of RMgX to 2-methoxy-4-tert-butylpiperidine formamidine in dichloromethane or ether gives good to excellent yields of axial product.

ChemInform Abstract: Synthesis of Pharmaceutically Active Compounds Containing a Disubstituted Piperidine Framework.

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LC-DAD and LC–MS–MS Analysis of Piperidine Alkaloids of Lobelia inflata L. (In Vitro and In Vivo)

An LC-DAD method was developed for determination of lobeline from in vitro and in vivo cultures of Lobelia inflata. Samples were extracted with 0.1 N HCl–acetonitrile (1:1, v/v), and purified by solid-phase extraction. Optimized conditions resulted in high recovery. LC separations were performed on an Eurosphere C8 reversed-phase column using 30:70 (v/v) acetonitrile–0.1% trifluoroacetic acid as a mobile phase. Quantitative determination of lobeline was performed by external standard method at 250 nm, in the range of 2.4–80 μg mL−1. Validation studies proved that the repeatability of the method was good and the recovery was satisfactory. In vitro organized cultures contained considerable amount of lobeline (herb: 175 μg g−1, root: 100 μg g−1). When these cultures were transplanted into the open field, the lobeline content increased significantly (herb: 323 μg g−1, root: 833 μg g−1). Plants obtained from seed propagation contained 382 μg g−1 lobeline in the herb. For direct characterization of di-substituted piperidine alkaloids in extracts of L. inflata, tandem mass spectrometric method was developed using electrospray ionization. Analysis was performed in the positive ion mode on a triple quadropole LC–MS system. LC separations were achieved on Eurosphere C8 column with a modified mobile phase (acetonitrile–30 mM ammonium formate, pH 2.80) to ensure proper molecular ionization. The identification and structural elucidation of the alkaloids were performed by comparing their changes in molecular mass (ΔM), full-scan MS–MS spectra with those of lobeline, norlobelanine and lobelanidine. These alkaloids and ten other derivatives were identified in the plant extracts. Three piperidine alkaloids were reported in L. inflata for the first time.

Diastereoselective Synthesis of 2,6‐trans‐Disubstituted Piperidines via Sequential Cross‐Metathesis–Cationic Cyclisation

AbstractRuthenium‐catalysed cross‐metathesis of protected homoallylamine derivatives with vinyl carbinols furnished allylic alcohols, which underwent stereoconvergent cyclisation to trans‐tetrahydropyridines upon treatment with BF3⋅OEt2. The new methodology was used for the preparation of enantiopure piperidine and indolizidine natural products.

Stereoselective synthesis of chiral piperidine derivatives employing arabinopyranosylamine as the carbohydrate auxiliary

Stereoselective synthesis of 2-substituted dehydropiperidinones and their further transformation to variously disubstituted piperidine derivatives was achieved employing D-arabinopyranosylamine as the stereodifferentiating carbohydrate auxiliary. A domino Mannich–Michael reaction of 1-methoxy-3-(trimethylsiloxy)butadiene (Danishefsky's diene) with O-pivaloylated arbinosylaldimines furnished N-arabinosyl dehydropiperidinones in high diastereoselectivity. Subsequent conjugate cuprate addition gave 2,6-cis-substituted piperidinones, while enolate alkylation furnished 2,3-trans-substituted dehydropiperidinones. Electrophilic substitution at the enamine structure afforded 5-nitro- and 5-halogen dehydropiperidinones of which the latter were applied in palladium-catalyzed coupling reactions. The absolute configuration of the obtained products was proven by NMR and X-ray structure analysis as well as by syntheses of the alkaloids (+)-coniine and (+)-dihydropinidine.Key words: piperidine alkaloids, carbohydrate auxiliary, domino Mannich–Michael reaction, conjugate cuprate and hydride addition, electrophilic substitution of enamines.

The First Synthesis of 3,5-Dimethylene-4-phenylpiperidine-2,6-dione from Baylis-Hillman Adduct

Recently we reported the synthesis of N-benzyl 3,5disubstituted piperidines via double Michael addition strategy from the 1,4-pentadiene derivatives. During the investigations we found the formation of 3-methylenepiperidin-2-one derivatives in low yields. Lee and coworkers also reported the synthesis of benzylidenesuccinimide from methyl 2-cyanomethylcinnamates under FeCl3/ AcOH conditions. Many compounds containing piperidine-2,6-dione moiety (simply as glutarimide) have been found in a variety of biologically important compounds. The synthesis of methyleneor alkylideneglutarimide derivatives has been studied by Koomen and co-workers. In these respects, we intended to prepare 3,5-dimethylenepiperidine-2,6-dione derivatives, which could be used as Michael acceptors for further transformations. The requisite starting materials 1a and 1b were prepared according to the previous paper from the corresponding Baylis-Hillman adducts (Scheme 1). In order to hydrolyze the nitrile group of 1 into amide functionality of 2, we examined a variety of conditions. Among the conditions the use of excess amounts of H2SO4 in MeOH at low temperature gave the best yields of 2 (75-85%). With 2a and 2b in our hands, we tried the cyclization toward the desired glutarimide derivatives 3. Fortunately we found that the use of NaHCO3 in aqueous MeOH could afford the products 3a and 3b in reasonable yields (Scheme 2). However, due to the low nucleophilicity of the amide group of 2a and 2b the reaction rate for the cyclization reaction was slow. In addition, when we subjected methyl 3-phenyl-2-cyanomethyl-2-propenoate (4) under the same reaction conditions, we could obtain the benzylidenesuccinimide 6 via the corresponding amide derivative 5 in a slightly improved yield (51%) than the reported one (Scheme 3).

Synthesis of N‐Benzyl 3,5‐Disubstituted Piperidines via Double Michael Addition Strategy.

AbstractFor Abstract see ChemInform Abstract in Full Text.