Addition of aromatic thiols to conjugated cycloalkenones, catalyzed by chiral .beta.-hydroxy amines. A mechanistic study of homogeneous catalytic asymmetric synthesis

Abstract

Reactions between aromatic thiols and conjugated cycloalkenones afford optically active 3-arylthiocycloalkanones, when chiral bases are used as catalysts. This paper reports a detailed investigation into the mechanism of this catalytic asymmetric synthesis. The reaction has been performed under a variety of conditions. Catalysts containing the 0-hydroxy amine moiety (cinchona and ephedra alkaloids) give higher reaction rates and higher enantiomeric excesses (ee's) (up to 75%) than catalysts without a hydroxyl function. Polar solvents, concentrated reaction solutions, and the presence of tetra-n-butylammonium salts lower the ee's substantially. Kinetic measurements on a quinine-catalyzed reaction in toluene solution point to a third-order reaction, first order in each of the reactants. Activation enthalpies are very low (~0 kcal/mol) and activation entropies highly negative (-62 cal/(mol K)). Models of the transition-state complexes of the thiol addition reactions are proposed, which account well for the experimental data on reaction rate, ee, and absolute configuration. The erythro cinchona and ephedra alkaloids catalyze the reaction via tight transition-state complexes, composed of three species: thiol, enone, and catalyst. Important for the geometry of these complexes are three stabilizing interactions: an electrostatic interaction between the thiol anion and the ammonium cation, a hydrogen bond between the catalyst hydroxyl group and the enone carbonyl group, and a dispersion interaction between the catalyst aromatic ring system and the thiol anion. Different steric conditions cause a free-energy difference between two possible orientations of the enone, resulting in formation of unequal amounts of R and S products. The threo cinchona alkaloids and the catalysts without a hydroxyl group lack at least one of the stabilizing interactions, leading to less structured transition states and consequently lower ee's. The suggestion is made that these mechanisms of asymmetric catalysis also hold for other reaction types, catalyzed by cinchona and ephedra alkaloids. The alkaloids having the erythro 0-hydroxy amine configuration can be viewed as bifunctional catalysts. The value of such chiral catalysts in catalytic asymmetric synthesis is discussed.

Receptors functionalized with chiral aza‐crown ether rings. Attempted enantioselective catalysis of a Michael addition reaction

“…For all receptors we found that the reaction is essentially complete after 15 hours. This result is in agreement with similar findings of Hiemstra et al 12 for the alkaloid catalysts. For most receptors the optical purity values of the reaction products were negligible.…”

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…Wynberg himself performed a detailed mechanistic study of the cinchonidine-catalyzed addition of thiophenols to cyclic enones (Scheme 16). [66] A bifunctional activation mode of the catalyst was proposed. The basic catalyst is supposed to deprotonate the thiol (58) as well as the electrophile to hydrogen bond to the catalyst β-hydroxy group and a ternary complex, formed by the protonated catalytic base, the thiolate anion and the enone, accounts for the transition state (60).…”

Process Optimization for Synthesis of Anti-Tuberculosis Drug Catalyzed by Fluor apatite Supported Potassium Fluoride

“…In classic methods, this reaction catalyzed by strong bases such as alkali metal alkoxides [6], hydroxides [7] and amines [8]. The employment of these strong bases and acids in these reactions [9], however, leads to two main problems affecting the environment; the necessity to dispose of huge amounts of organic waste due to formation of undesirable side products resulting from polymerization, bis-addition and self condensation, and total dissolved salts formed following the neutralization of soluble bases with acids.…”