Cinchona Alkaloid Derivatives Research Articles

Study of Mechanism to Asymmetric Mannich Reaction of Diethyl Malonate and Benzothiazol Imine Catalyzed by Applying Chiral Quinidine

Benzothiazol-β-amino esters, acted as β-amino acids derivatives, perform excellent bioactivity in antibacterial and antivirus. To gain highly and purely optical single enantioisomer of benzothiazol-β-amino esters with simple organocatalyst, recently, the development for a classic Mannich reaction of diethyl malonate (Nu) with benzothiazol imine (EI) in the pres- ence of cinchona alkaloid derivatives as organocatalyst has been made. The study for mechanism of applying unmodified cinchona alkaloid-chiral quinidine as potent organocatalyst to asymmetric Mannich reaction of benzothiazol-β-amino esters plays a vital role in asymmetric synthesis. In this work, the mechanism for Mannich reaction of benzothiazol-β-amino esters catalyzed by simple chiral quinidine organocatalyst was investigated through a combination of experiment with theoretical approaches (DFT). All geometry structures of reactants (Nu and EI), intermediates and product were optimized completely with the moderate approach M06-2X/6-311G (d,p) basis set in the gas phase. Afterward, the effect of solvent for DCM was took into consideration, and CPCM was used as polarization continuum model. Frequency calculations were performed at the same level of 6-311G (d,p) basis set as the geometry optimizations to confirm stable transition state (TS), which was verified further by means of IR vibrating frequency calculations (zero and only one imaginary frequency respectively). As comparison of (R)TS pathway with (S)TS pathway in potential energy profile, it enables to elaborate that (S)TS pathway executes to af- ford unique enatioisomer (S). The calculating results indicate that (1) Active sites of quinidine have been confirmed, that are 9-hydroxyl and tertiary amine; (2) The product exhibits S enantiomer as major configuration; (3) Moreover, the results of DFT calculation indicated that the stereo selectivity of the reaction could be improved by lower reaction temperature. The lower temperature is, the more distereoselectivity is upgraded. The calculation demonstrated that all of results are able to be in agreement with experimental data that β-amino acid esters derivatives carrying S as major configuration could arrive to range of 81%~95% ee. Keywords chiral quinidine; benzothiazol-β-amino esters; DFT; transition state; mechanism

Enantioselective synthesis of β-amino esters bearing a quinazoline moiety via a Mannich-type reaction catalyzed by a cinchona alkaloid derivative

The cinchona alkaloids catalyzed the direct asymmetric Mannich reactions of 1, 3-dicarbonyl compounds with acyl imines to produce novel β-amino ester derivatives containing a quinazoline moiety. The adducts were isolated with high enantiomeric excess (up to 99%).

Enantioselective Michael reaction of nitroalkanes onto nitroalkenes catalyzed by cinchona alkaloid derivatives

An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the direct Michael addition of nitroalkanes onto nitroalkenes has been described. In the presence of readily modified cinchona alkaloid derivatives, nitroethane reacted well with a variety of aromatic and heterocyclic aromatic nitroalkenes to afford products with good diastereoselectivities (dr up to 72/28) and enantioselectivities (ee up to 94%). The catalyst loading can be decreased to 2mol% without compromising the asymmetric induction or the reaction rate.

Cinchona Alkaloid Derivatives Catalyzed Asymmetric [4+2] Cycloaddition

Cinchona Alkaloid Derivatives Catalyzed Asymmetric [4+2] Cycloaddition

Asymmetric Aldol Reaction Catalyzed by Modularly Designed Organocatalysts

AbstractThe self‐assembly of the precatalyst modules, which are amino acids and cinchona alkaloid derivatives, leads to the direct formation of the desired organocatalysts without any synthesis. These modularly designed organocatalysts (MDOs) may be used for catalyzed asymmetric aldol reaction. Depending on structure of the aldehyde substrates, the corresponding aldol products may be obtained in mediocre to excellent ee values (up to 92% ee) with moderate diastereoselectivities (up to 79:21 dr).

Evaluation of Antibacterial and Anti-biofilm Activities of Cinchona Alkaloid Derivatives against Staphylococcus aureus

Bacterial biofilms are resistant to most of the commonly available antibacterial chemotherapies. Thus, an enormous need exists to meet the demands of effective anti-biofilm therapy. In this study, a small library of cinchona alkaloids, including the naturally occurring compounds cinchonidine and cinchonine, as well as various synthetic derivatives and analogues was screened for antibacterial and anti-biofilm activity against the Staphylococcus aureus biofilm producing strain ATCC 25923. Two methods were used to evaluate activity against biofilms, namely crystal violet staining to measure biomass and resazurin assay to measure biofilms viability. Cinchonidine was found to be inactive, whereas a synthetic derivative, 11-triphenylsilyl-10,11-dihydrocinchonidine (11-TPSCD), was effective against planktonic bacteria as well as in preventing biofilm formation at low micromolar concentrations. Higher concentrations were required to eradicate mature biofilms.

Asymmetric Direct Vinylogous Michael Reaction Catalyzed by Self-Assembled Organocatalyst

The self-assembled organocatalyst of cinchona alkaloid derivatives and amino acids has been applied to a direct asymmetric vinylogous Michael addition of α,α-dicyanoolefins to nitroolefins; the corresponding products could be obtained in moderate to good yields and enantioselectivities.

Organocatalytic Asymmetric Fluorination/Semipinacol Rearrangement: An Efficient Approach to Chiral β‐Fluoroketones

An asymmetric fluorination/semipinacol rearrangement of 2-oxa allylic alcohols, as catalyzed by cinchona-alkaloid derivatives, gives chiral β-fluoro ketones with moderate to high levels of enantioselectivity (see scheme). Both enantiomers of the product could be obtained by using the appropriate catalyst.

ChemInform Abstract: A New Family of Cinchona‐Derived Bifunctional Asymmetric Phase‐Transfer Catalysts: Application to the Enantio‐ and Diastereoselective Nitro‐Mannich Reaction of Amidosulfones.

AbstractSome new cinchona alkaloid derivatives are prepared and tested as catalysts.

Antibacterial and anti-biofilm activities of cinchona alkaloid derivatives against Staphylococcus aureus

Antibacterial and anti-biofilm activities of cinchona alkaloid derivatives against Staphylococcus aureus

Natural products as butyrylcholinesterase inhibitors - Screening of a small compound collection

Investigation of the involvement of butyrylcholinesterase (BChE) in diseases such as Alzheimer's disease (AD), type 2 diabetes mellitus (T2DM) and multiple sclerosis (MS) makes it a valuable target for drug discovery. Cholinesterase inhibitors of natural origin have shown success in AD therapy and have encouraged further exploration of nature as a source of cholinesterase inhibitors. Using the Ellman's reaction a collection of 111 compounds containing commercially available compounds e.g. flavonoids and coumarins, as well as a subset of cinchona alkaloid derivatives synthesized by our group, were screened for anti-cholinesterase activity. Two cinchona alkaloids were found to inhibit the hydrolase activity of BChE in the micromolar range (IC50 ≤10µM) and were further characterized. Considering their wide medical use (mostly as antimalarials) the cinchona alkaloid scaffold may serve as an advantage in drug development for various diseases.

Advances and Applications in Organocatalytic Asymmetric aza‐Michael Addition

Asymmetric aza-Michael Addition The back cover shows an array of asymmetric organocatalysts and the CN bond-containing enantioenriched products formed from nitrogen-based nucleophiles and a,bunsaturated carbonyl systems. In their “Minireview Advances and Applications in Organocatalytic Asymmetric aza-Michael Addition” on p. 917 ff., F. Y. Kwong, A. S. C. Chan, P. Li et al. describe progress in the field of inter- and intramolecular aza-Michael additions, covering catalysis with primary and secondary amines and Brnsted acids, as well as miscellaneous catalyst systems, such as cinchona alkaloid derivatives and phase-transfer catalysts.

ChemInform Abstract: Asymmetric Nitroaldol Reactions of Nitroalkanes with Isatins Catalyzed by Bifunctional Cinchona Alkaloid Derivatives.

The enantioselective nitroaldol reactions of isatins with nitroalkanes were smoothly carried out by organocatalysis. A C6′-OH cinchona alkaloid derivative bearing a C9-OBn group exhibited outstanding catalytic efficiency as an acid–base bifunctional catalyst for the nitroaldol reaction of isatins with nitromethane, providing 3-hydroxy-3-(nitromethyl)indolin-2-ones in good yields (90–98 %) and with good to high enantiomeric excess values (72–95 %). The resultant oxindole derivatives are highly important for the synthesis of related natural products and pharmaceutically active compounds.

Bifunctional organo/metal cooperative catalysis with cinchona alkaloid scaffolds

Cooperative catalysis, inspired by the early findings on enzymatic activation, is a fast growing research area. It refers to the combination of two or more catalytic species that operate together within the same molecular environment to achieve an overall transformation via mutual activation of reaction partners. In this field, cinchona derived scaffolds play a major role. Their combination with a wide range of metal ions and complexes has led to the development of unprecedented transformations in terms or reactivity and stereocontrol. This review discusses recent developments (the last 10 years) in the field of cooperative catalysis using cinchona alkaloid derivatives in combination with metal ions, highlighting the potential of this new research area and the many challenges that still remain for the future.

ChemInform Abstract: Enantioselective Synthesis of β‐Amino Esters Bearing a Benzothiazole Moiety via a Mannich‐Type Reaction Catalyzed by a Cinchona Alkaloid Derivative.

Novel β-amino esters bearing a bioactive benzothiazole moiety were obtained with high enantioselectivities (up to 95 % ee) through a Mannich-type reaction of different imines with malonate in the presence of a new chiral cinchona alkaloid thiourea catalyst. Imines derived from both aromatic and heterocyclic aldehydes were found useful in this conversion.

ChemInform Abstract: Enantioselective Dichlorination of Allylic Alcohols.

The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration of the substrate scope, and a model for stereoinduction are presented.

Synthesis of α-Amino Acid Derivatives by Biomimetic Transamination

Shi and co-workers have developed a methodology to synthesize α-amino acid derivatives 3 from α-keto esters 2, catalyzed by cinchona alkaloid derivative 1. This is the first catalytic highly enantioselective synthesis of α-amino acid derivatives 3 via biomimetic transamination. The proton of the ammonium ion in the transition state is delivered to the si-face of the substrate, affording the (R)-α-amino ester as the major enantiomer.

Asymmetric Nitroaldol Reactions of Nitroalkanes with Isatins Catalyzed by Bifunctional Cinchona Alkaloid Derivatives

AbstractThe enantioselective nitroaldol reactions of isatins with nitroalkanes were smoothly carried out by organocatalysis. A C6′‐OH cinchona alkaloid derivative bearing a C9‐OBn group exhibited outstanding catalytic efficiency as an acid–base bifunctional catalyst for the nitroaldol reaction of isatins with nitromethane, providing 3‐hydroxy‐3‐(nitromethyl)indolin‐2‐ones in good yields (90–98 %) and with good to high enantiomeric excess values (72–95 %). The resultant oxindole derivatives are highly important for the synthesis of related natural products and pharmaceutically active compounds.

Enantioselective Synthesis of β‐Amino Esters Bearing a Benzothiazole Moiety via a Mannich‐Type Reaction Catalyzed by a Cinchona Alkaloid Derivative

AbstractNovel β‐amino esters bearing a bioactive benzothiazole moiety were obtained with high enantioselectivities (up to 95 % ee) through a Mannich‐type reaction of different imines with malonate in the presence of a new chiral cinchona alkaloid thiourea catalyst. Imines derived from both aromatic and heterocyclic aldehydes were found useful in this conversion.

Highly Enantio‐ and Diastereoselective Synthesis of β‐Methyl‐γ‐monofluoromethyl‐Substituted Alcohols

Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.