Search results for: enantioselective

Authors: Jasneet Kaur, Swapandeep Singh Chimni

Abstract:

The unfavorable use of metal-based catalysts that are often extortionate and toxic can be overcome by using small organic molecules known as organocatalysts. A variety of small organic molecules, including Brønsted/Lewis bases and acids, based on sulfonic acids, phosphoric acids, amines, phosphines or carbenes, Cinchona alkaloids, have been used as organocatalysts. One of the key reasons for using organocatalysis is their ability to be effectively removed from the final product in comparison to the metallic counterparts, which are exceedingly difficult to remove. The present investigation seeks to explore the catalytic nature of Cinchona alkaloids as an organocatalyst for enantioselective synthesis of 3-substituted-3-aminooxindole, which is known to exhibit a variety of biological activities and pharmacological activities. In this context, an organocatalytic asymmetric route for the synthesis of 3-aminooxindoles via reaction of isatin imine with α-acetoxy-β-ketoesters has been developed. The bifunctional Cinchona derived thiourea catalyzed the reaction of α-acetoxy-β-ketoesters derivatives with isatin imine to afford 3-substituted-aminooxindole derivatives in up to 93% yield, 95% enantiomeric excess and >20:1 diastereomeric ratio. The reaction was performed at room temperature for two hours using 10 mol% of catalyst, in the presence of 4Å molecular sieves in tetrahydrofuran as a solvent at ambient temperature. After the completion of the reaction, the pure product could be easily separated by using column chromatography using hexane and ethyl acetate as solvents. In conclusion, the catalytic potential of Cinchona derived chiral thiourea-tertiary amine catalyst was explored for an organocatalytic enantioselective Mannich reaction of β-ketoester derivatives with various isatin imine derivatives under mild conditions.

Keywords: asymmetric synthesis, aminooxindoles, enantioselective, isatin imine

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Authors: Maki Mizogami, Hironori Tsuchiya, Yoshiroh Hayabuchi, Kenji Shigemi

Abstract:

Since drugs exhibit significant structure-dependent differences in activity and toxicity, their differentiation based on the mechanism of action should have implications for comparative drug efficacy and safety. We aimed to differentiate drug stereoisomers by their stereostructure-selective membrane interactions underlying pharmacological and toxicological effects. Biomimetic lipid bilayer membranes were prepared with phospholipids and sterols (either cholesterol or epicholesterol) to mimic the lipid compositions of neuronal and cardiomyocyte membranes and to provide these membranes with the chirality. The membrane preparations were treated with different classes of stereoisomers at clinically- and pharmacologically-relevant concentrations (25-200 μM), followed by measuring fluorescence polarization to determine the membrane interactivity of drugs to change the physicochemical property of membranes. All the tested drugs acted on lipid bilayers to increase or decrease the membrane fluidity. Drug stereoisomers could not be differentiated when interacting with the membranes consisting of phospholipids alone. However, they stereostructure-selectively interacted with neuro-mimetic and cardio-mimetic membranes containing 40 mol% cholesterol ((3β)-cholest-5-en-3-ol) to show the relative potencies being local anesthetic R(+)-bupivacaine > rac-bupivacaine > S(‒)-bupivacaine, α2-adrenergic agonistic D-medetomidine > rac-medetomidine > L-medetomidine, β-adrenergic antagonistic R(+)-propranolol > rac-propranolol > S(–)-propranolol, NMDA receptor antagonistic S(+)-ketamine > rac-ketamine, analgesic monoterpenoid (+)-menthol > (‒)-menthol, non-steroidal anti-inflammatory S(+)-ibuprofen > rac-ibuprofen > R(‒)-ibuprofen, and bioactive flavonoid (+)-epicatechin > (‒)-epicatechin. All of the order of membrane interactivity were correlated to those of beneficial and adverse effects of the tested stereoisomers. In contrast, the membranes prepared with epicholesterol ((3α)-chotest-5-en-3-ol), an epimeric form of cholesterol, reversed the rank order of membrane interactivity to be S(‒)-enantiomeric > racemic > R(+)-enantiomeric bupivacaine, L-enantiomeric > racemic > D-enantiomeric medetomidine, S(–)-enantiomeric > racemic > R(+)-enantiomeric propranolol, racemic > S(+)-enantiomeric ketamine, (‒)-enantiomeric > (+)-enantiomeric menthol, R(‒)-enantiomeric > racemic > S(+)-enantiomeric ibuprofen, and (‒)-enantiomeric > (+)-enantiomeric epicatechin. The opposite configuration allows drug molecules to interact with chiral sterol membranes enantiomer-selectively. From the comparative results, it is speculated that a 3β-hydroxyl group in cholesterol is responsible for the enantioselective interactions of drugs. In conclusion, the differentiation of drug stereoisomers by their stereostructure-selective membrane interactions would be useful for designing and predicting drugs with higher activity and/or lower toxicity.

Keywords: chiral membrane, differentiation, drug stereoisomer, enantioselective membrane interaction

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Authors: Koilpitchai Sivamuthuraman, Venkitasamy Kesavan

Abstract:

3-substituted 3-amino-2-oxindole skeleton bearing adjacent tetrasubstituted stereogenic centers is of great importance because of these heterocyclic motifs possess a wide range of pharmacological activity. The catalytic asymmetric construction of multi functionalised heterocyclic compound with adjacent tetrasubstituted stereocenters is one of the most difficult tasks in organic synthesis. To date, the most straightforward methodologies have been developed for synthesis of chiral 3-substituted 3-amino-2-oxindoles through the addition of carbon nucleophiles to isatin-derived ketimines. However, only a few successful examples have been described for the assembly of vicinal tetrasubstituted stereocenters using isatin derived ketimines as electrophiles. On the other hand, 2,2-Disubstituted benzofuran-3(2H)-ones and related frameworks are characteristic of a quaternary stereogenic center at C2 position present in quite a number of natural products and bioactive Molecules.Despite the intensive efforts devoted for the construction of 2,2-Disubstituted Benzofuran-3[2H]-one, there are only a few asymmetric methods such as organocatalytic Michael addition and enantioselective halogenations were reported till now. Due to the biological importance of oxindole and benzofuran-3-one, it is proposed here with the synthesis of hybrid molecule containing tetrasubstituted stereo centers through asymmetric organocatalysis. The addition of 2-substituted Benzofuran-3-one(1a) to isatin-derived ketimines(2a) using a bifunctional organocatalyst(catalyst IV or V), leading to chiral heterocyclic compounds containing both 3-amino 2-oxindole and benzofurn-3-one bearing vicinal quaternary stereocenters with good yields and excellent enantioselectivity. The present study extends the scope of the catalytic asymmetric Mannich reaction with isatin-derived ketimines, providing a new class of amino oxindole derivatives having benzofuran-3-one.

Keywords: asymmetric synthesis, benzofuran-3-one, isatin-derived ketimines, quaternary stereocenters

Procedia PDF Downloads 158