Cinchonidinium Bromide Research Articles

3‑Amino Oxindole Schiff Base Efficiently Paired with p‑Quinone Methide to Enable a New Diastereoselective and Enantioselective 1,6-Conjugated Addition in the Presence of a Cinchonidinium Phase Transfer Catalyst

3‑Amino oxindole Schiff base has been used as an efficient substrate company with p‑quinone methides for a new highly diastereoselective and enantioselective 1,6-conjugate addition in the presence of a O-allyl-N-(9-anthracenylmethyl) cinchonidinium bromide phase transfer catalyst under mild reaction conditions. A broad series of chiral quaternary 3-amino oxindoles with 4-hydroxybenzyl scaffold were smoothly obtained in good to excellent yields with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 99 % ee). A typical scale-up preparation and subsequent hydrolysis of a pyridine substrate was successfully performed and a potential valuable chiral amino-pyridine bifunctional chiral building block was obtained, which is structurally feasible as chiral ligand for asymmetric metallic catalysis.

Dynamic Thermodynamic Resolution of Racemic 1,1'-Binaphthyl-2,2'-diol (BINOL).

A dynamic thermodynamic resolution method for converting (R/S)-BINOL (1,1'-binaphthyl-2,2'-diol) into (R)-BINOL in 100% theoretical yield is reported. This technique involves mixing (R/S)-BINOL with N-benzyl cinchonidinium bromide (1 equiv) and a [Cu2(tmeda)2(μ-OH)2]Br2 (2.5 mol %) redox catalyst in acetonitrile. In the background of this process is the observation that the energy for atropoisomerization decreases significantly when an electron is removed from BINOL. Therefore, it is possible to convert both enantiomers into the thermodynamically favorable [N-benzyl cinchonidinium bromide·(R)-BINOL] adduct.

Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated Cinchona Alkaloid-Based Derivatives as Cholinesterase Inhibitors.

A series of 46 Cinchona alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (Ki) ranged from 3.9–80 µM, and 0.075–19 µM for BChE. The most potent AChE inhibitor was N-(para-fluorobenzyl)cinchoninium bromide, while N-(meta-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with Ki constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where N-(meta-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R2 (CD-derivatives) of 0.9932 and R2(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary Cinchona alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system.

Design and evaluation of selective butyrylcholinesterase inhibitors based on Cinchona alkaloid scaffold.

This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range. Five cinchonidine derivatives displayed 95–510 times higher inhibition selectivity to butyrylcholinesterase over acetylcholinesterase and four were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-para-bromobenzyl cinchonidinium bromide can be considered a lead for further modifications and optimizations for possible use in the treatment of neurodegenerative diseases.

A novel and practical asymmetric synthesis of eptazocine hydrobromide.

In order to prepare eptazocine hydrobromide effectively, a novel, mild and practical asymmetric process was developed starting from 1-methyl-7-methoxy-2-tetralone under the catalysis of N-(p-trifluoromethylbenzyl)cinchonidinium bromide. The reaction conditions were optimized to obtain the product in excellent overall yield and purity.

Polymeric Pseudo-Liquid Membranes from Polymethacrylate Derivative Bearing Oligodimethylsiloxane Unit

Novel liquid membrane system, which is named polymeric pseudo-liquid membrane was constructed from polymethacrylate derivative bearing oligodimethylsiloxane (PDMSMA), showing rubbery state under operating conditions, as a membrane matrix. In the present study, dibenzo-18-crown-6 (DB18C6), dibenzo-21-crown-7 (DB21C7) or O -allyl- N -(9-anthracenylmethyl)cinchonidinium bromide (AMCC) was adopted as a carrier for KCl transport, CsCl transport or optical resolution of racemic mixture of phenylglycine (Phegly), respectively. The results of KCl and CsCl transports revealed that the membrane transport was attained by carrier-diffusion mechanism like conventional liquid membranes. The present study led the conclusion that PDMSMA can be applicable not only to membrane transport of alkali metal ions, such as K + and Cs + , but also to chiral separation.

ChemInform Abstract: Highly Enantioselective Sulpha‐Michael Addition to α,β‐Unsaturated Carbonyl Scaffolds Catalyzed by Allyloxy‐N‐(1‐benzyl) Cinchonidinium Bromide in Water at Room Temperature.

ChemInform Abstract: Highly Enantioselective Sulpha‐Michael Addition to α,β‐Unsaturated Carbonyl Scaffolds Catalyzed by Allyloxy‐N‐(1‐benzyl) Cinchonidinium Bromide in Water at Room Temperature.

Highly enantioselective sulpha-Michael addition to α,β-unsaturated carbonyl scaffolds catalysed by allyloxy-N-(1-benzyl) cinchonidinium bromide in water at room temperature

Allyloxy-N-(1-benzyl) cinchonidinium bromide was found to be an effective organocatalyst for asymmetric Michael reactions of thiols with various α,β-unsaturated ketones, acids and esters to provide optically active sulphides with high enantiomeric excess (91–100% ee) and chemical yields (up to >98%). The reaction was performed with 2–8mol% of catalyst in water at room temperature using tetra-n-butyl ammonium fluoride as an additive.

Polymeric Pseudo-Liquid Membranes from Poly(N-oleylacrylamide).

A polymeric pseudo-liquid membrane (PPLM) was constructed from poly(N-oleylacrylamide) (PC18AAm), which exhibited a rubbery state under membrane transport conditions and used as the membrane matrix. In the present study, dibenzo-18-crown-6 (DB18C6) and dibenzo-21-crown-7 (DB21C7) were adopted as transporters for alkali metal ions. KCl was adopted as a model substrate for DB18C6 and CsCl the latter. Chiral transporter, O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (AAMC) was used as a transporter for chiral separation of a racemic mixture of phenylglycine (Phegly). The l-somer was transported in preference to the antipode. The present study revealed that PPLMs are applicable to membrane transport, such as metal ion transport and chiral separation.

Polymeric pseudo-liquid membranes from poly(octadecyl methacrylate)

The novel liquid membrane system, which is named polymeric pseudo-liquid membrane, was constructed from poly(octadecyl methacrylate) (PC18MA), which showed a rubbery state under operating conditions, as a membrane matrix, and dibenzo-18-crown-6 (DB18C6) for the transport of KCl or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (AAMC) for that of racemic mixture of phenylglycine (Phegly) as a carrier. The results of KCl transport revealed that KCl transport was attained by carrier-diffusion mechanism even though membrane matrix was composed of polymeric material. The polymeric pseudo-liquid membrane containing chiral carrier AAMC showed optical resolution ability, in other words, the membrane selectively transported l-Phegly and its permselectivity toward l-Phegly reached 1.48 at the operating temperature of 40°C. Chiral separation ability was greatly dependent on the operating temperature and a wide range of permselectivity from l-isomer to d-isomer permselectivity was attained by adjusting the operating temperature. The present study revealed that the polymeric pseudo-liquid membrane is a promising membrane system in membrane separation.

Polymeric pseudo-liquid membranes from poly(dodecyl methacrylate): KCl transport and optical resolution

A polymeric pseudo-liquid membrane (PPLM) was constructed from poly(dodecyl methacrylate) (PC12MA), which exhibited a rubbery state under membrane transport conditions and was used as the membrane matrix, and from dibenzo-18-crown-6 (DB18C6) or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (AAMC), which was used as a model transporter. Membrane performance was studied using KCl or a racemic mixture of phenylglycine (Phegly) as a model substrate. The PPLM with DB18C6 transported KCl. The membrane transport ability depended on the DB18C6 concentration, implying that DB18C6 worked as a transporter within the PC12MA membrane matrix. L-Phegly was preferentially transported over D-Phegly through the membrane with AAMC from the racemic mixture of Phegly, and the permselectivity was determined to be 1.55. The present results suggest that PPLMs are applicable not only in metal ion transport but also in optical resolution. Polymeric pseudo-liquid membrane (PPLM) was constructed from poly(dodecyl methacrylate), which showed rubbery state under membrane transport conditions, as a membrane matrix and dibenzo-18-crown-6 or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide as a model transporter. Membrane performance was studied adopting KCl or racemic mixture of phenylglycine as a model substrate. The present results suggest that PPLMs were applicable to not only metal ion transport but also optical resolution.

Synthesis of the Tripeptide Domain of Sanglifehrins Using Asymmetric Phase-Transfer Catalysis

The tripeptide (S)-valinyl-(S)-m-hydroxyphenylalanyl-(3S)-piperazate common to immunosuppressant sanglifehrins was synthesized from the constituent amino acid residues in nine steps and 42% overall yield. A key construction was the installation of (S) absolute configuration in m-hydroxyphenylalanine using asymmetric phase-transfer catalysis in the presence of N-(1-naphthyl)cinchonidinium bromide. Cbz-protected (S)-valine was first coupled to the amino group of (S)-m-triisopropylsilyloxyphenylalanine tert-butyl ester, and the resulting dipeptide after ester cleavage was linked to (3S)-methyl piperazate.

Enantioselective transport of D,L-phenylalanine and D,L-phenylglycine through a bulk liquid membrane containing cinchona alkaloid derivatives as chiral selectors

Different cinchona derivatives were tested as chiral mobile carriers for enantioselective transport of D,L-phenylglycine and D,L-phenylalanine through a bulk organic liquid membrane (BLM). The effects of several parameters such as carrier nature, membrane solvent, buffer, solute and carrier concentrations on BLM enrichment were evaluated. Only D,L-phenylglycine is subjected to enantioselective transport at a certain degree; the maximum enantioselectivity ratio (the initial transport rates of the L-enantiomer relative to the antipode) was reached by employing O-allyl-N-(9-anthracenylmethyl) cinchonidinium bromide as carrier. In all cases the highest selectivity was observed during the initial stages of the process, indicating the rate of amino acid release from the source phase (SP) to the membrane organic phase (MP) as the driving factor. Chiral enrichment appeared to depend on thermodynamic factors more than on kinetic ones, since the complex formation was observed at (SP)/MP) interface, while complex decomposition was evidenced at (RP)/(MP) interface, where RP is receiving phase. The last phenomenon was promoted by H+ ions present in the RP.

Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation, Investigation of the Scope, and Application to the Synthesis of (−)-Ragaglitazar

[Reaction: see text]. Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst 9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities using a wide range of electrophiles (80-90% ee). Alkylated products were elaborated to useful alpha-hydroxy intermediates 3 using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification reactions. The ester products have been enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of the new methodology, the anti-diabetes drug (-)-ragaglitazar 24 was synthesized in six steps from a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.

Synthesis and evaluation of new antimalarial analogues of quinoline alkaloids derived from Cinchona ledgeriana moens ex trimen

In the course of attempts to develop antimalarial drugs, we have designed and synthesized a series of quinoline alkaloide derivatives. Three of them, N-(4-methoxy-3,5-di- tert-butylbenzyl)cinchonidinium bromide (OSL-5), O-benzyl- N-(3,5-di- tert-butyl-4-methoxybenzyl)cinchonidinium bromide (OSL-7), and N-(3,5-di- tert-butyl-4-methoxybenzyl)quininium bromide (OSL-14) show potent activity against Plasmodium falciparum.

Asymmetric alkylation of tert-butyl glycinate Schiff base with chiral quaternary ammonium salt under micellar conditions.

[reaction: see text] The asymmetric alkylation of the tert-butyl glycinate-benzophenone Schiff base 1 with various arylmethyl bromides catalyzed by O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (2) proceeded smoothly under micellar conditions (5 equiv of 1 M KOH and 0.4 equiv of Triton X-100) to give the alkylated products in good yields and with good enantioselectivity (72-85% ee), depending on the electrophiles.