A Tetradentate Ligand for the Enantioselective Ti(IV)-Promoted Oxidation of Sulfides to Sulfoxides: Origin of Enantioselectivity

Abstract

A detailed stereomechanistic analysis has led to the design of a new tetradentate ligand for the enantioselective Ti(IV)-catalyzed oxidation of unsymmetrical sulfides to sulfoxides with high selectivity. The pathway of this oxidation and the closely related and long-known Kagan-Modena oxidation have been clarified to identify the likely origin of the enantioselectivity.

Extreme Synergistic Mutational Effects in the Directed Evolution of a Baeyer–Villiger Monooxygenase as Catalyst for Asymmetric Sulfoxidation

“…WT PAMO shows 90% ee in favor of the ( S )-sulfoxide, while the best ( R )-selective mutant ZGZ-2, characterized by four point mutations I67Q/­P440F/­A442N/­L443I, leads to 95% ee , which means a change in free energy of ΔΔ G ‡ = 16.4 kJ/mol. This mutant also displays high enantioselectivity in the reaction of several other thioethers, and consequently constitutes an alternative to other catalysts in asymmetric sulfoxidation. − The four new point mutations do not impair the high thermostability of the enzyme, which is of practical importance. This also means that, if necessary, ZGZ-2 can be used as a template in future protein engineering studies.…”

“…The catalytic asymmetric sulfoxidation of prochiral thioethers constitutes an important transformation in organic chemistry, mediated by chiral synthetic transition metal complexes, organocatalysts, or enzymes of the type Baeyer–Villiger monooxygenases (BVMOs). , These flavin-dependent enzymes react with molecular oxygen to form an intermediate flavin-hydroperoxide (Fl-OOH) which reacts electrophilically with either one of the two enantiotopic lone electron pairs (or both) of the sulfur functionality . In contrast, the Baeyer–Villiger reaction is initiated by nucleophilic addition of deprotonated flavin-hydroperoxide (Fl-OO – ) to the carbonyl function of ketones with formation of a short-lived Criegee intermediate. , Stereodifferentiation between the two lone electron pairs of prochiral thioethers can be achieved by using wildtype (WT) cyclohexanone monooxygenase (CHMO) , or mutants for “difficult” substrates, but this BVMO is only moderately thermostable, requiring immobilization and other biotechnological techniques for practical applications .…”

Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds

“…The long puzzling origin of the Kagan/Modena oxidation system based on Ti(IV) complexes of diethyl tartrate and tertbutyl hydroperoxide (TBHP) or cumene hydroperoxide (CHP) was studied by Corey's group. 41 DFT calculations were applied to compare geometries and energies of possible isomeric helical complexes formed in the course of reaction: the more stable P diastereomer was shown to preferentially yield one of the enantiomers of sulfoxide. This analysis led to design and synthesis of a chiral tetraol containing two tartrate moieties 5, which was found superior in the enantioselective oxidation of alkyl aryl sulfides in comparison with the original Kagan's system (Scheme 2).…”

“…The long puzzling origin of the Kagan/Modena oxidation system based on Ti­(IV) complexes of diethyl tartrate and tert -butyl hydroperoxide (TBHP) or cumene hydroperoxide (CHP) was studied by Corey’s group . DFT calculations were applied to compare geometries and energies of possible isomeric helical complexes formed in the course of reaction: the more stable P diastereomer was shown to preferentially yield one of the enantiomers of sulfoxide.…”

“…Scheme 2. Enantioselective Oxidation of Sulfides Catalyzed by Ti(IV) Complex with Chiral Tetraol 541 …”