Chiral Sulfoxides Coenzyme Nadh Model Compound Synthesis And Reaction

Coenzyme NADH plays an important role in biological oxidation and reduction reactions. It can reduce many prochiral carbonyl compounds and other unsaturated compounds with high enantioselectivity. The stereochemistry and reaction mechanism of the reduction with NADH mimics have been of great interest in the field of physical organic chemistry and biological chemistry. This thesis is concerned with the synthesis of new chiral sulfinyl NADH models, whose key step is the synthsis of chiral R-3-pyridyl sulfoxides. There are three parts of work following a brief review in the area.Part I: Liquid-phase chromatographic resolution of racemic R-3-pyridyl sulfoxides on chiral stationary phase. A series of R-3-pyridyl sulfoxides are synthesized and the resolution is carried out on the chiral stationary phase (OB-H). The chromatographic conditions are optimized and the the best resolution conditions are with 30% iso-propanol in the mobile phase and the column temperature at 25℃. This part is the preliminary work for the synthesis of chiral R-3-pyridyl sulfoxides.Part II: Synthesis of chiral sulfinyl NADH models. Three synthetic routes are adopted, i.e. asymmetric oxidation of prochiral sulfides, inclusion resolution of racemic sulfoxides and nucleophilic substitution of optical active sulfinates. It was found that the former two methods can give ethyl-3-pyridyl sulfoxide only, with good enatioselectivity (89% ee, 73% ee), but not other chiral R-3-pyridyl sulfoxides. The two methods also have other drawbacks, such as low yields and poor repeatability, so they are not good choices for the synthesis of chiral NADH models. A new optical active sulfoxide, (R_S)-tert-butyl-3-pyridyl sulfoxide (>99% ee) is synthesized using cinchona alkaloid (-)-quinine as chiral auxiliary, and its absolute structure is determined by X-ray diffraction. With the compound as an intermediate, a novel chiral NADH model: N-methyl-(R_S)-3-(tert-butyl)-sulphinyl-1,4-dihydropyridine is synthesized, and its reactivity proved by the reduction of methyl benzoylformate, producing (S)-methyl mandelate in >99% ee. In addition, N-methyl-(S_S)-3-(tert-butyl)-sulphinyl-1,4-dihydropyridine is also synthesized using Ellman's method to produce (S_S)-tert-butyl tert-butanethiosulfinate as the chiral auxiliary.Part III: Catalytic hydrogenation ofα,β-epoxyketones toβ-hydroxyketones with two sulfinyl analogues of coenzyme NADH models. An efficient method for the selective hydrogenation of a series ofα,β-epoxyketones toβ-hydroxyketones using catalytic amount of two sulfinyl analogues of NAD~+ model compounds is reported. The lack of any diastereoselectivity for the formation ofβ-hydroxyketones with optically active sulfinyl analogue of NAD~+ model supports the radical mechanism proposed previously.