Synthesis and evaluation of some novel selenium-based chiral auxiliaries and glutathione peroxidase mimetics.

摘要

This thesis describes the preparation of several novel C(3)- and C(10)-camphorseleno chiral auxiliaries, as well as their evaluation in the asymmetric methoxyselenenylation of alkenes and cyclization of unsaturated alcohols and carboxylic acids. This represents one of two main topics and is discussed in Chapter Two. This thesis also describes the synthesis and glutathione peroxidase (GPx) activity of some novel ω-functionalized alkyl diselenides, dialkyl selenides and allyl selenides. This is the subject of Chapter Three.;Modification of C(2) of di(endo-3-camphoryl) diselenide, an optically active compound previously prepared in our group, generated a series of novel chiral auxiliaries. In addition, two other camphor-based diselenides were prepared from (R)-10-bromocamphor. While many of the chiral auxiliaries afforded low asymmetric induction in cyclization reactions of unsaturated alcohols and carboxylic acids and in the methoxyselenenylations of alkenes, di[(1R)-2-oximo-endo-3-camphoryl] diselenide and its O-benzoyl derivative proved particularly effective in the process of methoxyselenenylation, affording high diastereoselectivities (up to 98:2), with the former consistently giving very high diastereomeric ratios with all examples studied. This marks a significant improvement over existing selenium-based chiral auxiliaries, since the earlier results have generally been inconsistent with respect to the diastereomeric ratios obtained with different types of alkene substitution patterns. In particular, methoxyselenenylations of cis-disubstituted and symmetrical cyclic alkenes were considerably improved with the present system. When di[(1R)-2-oximo- endo-3-camphoryl] diselenide was brominated in situ to generate the reactive electrophile 2-oximo-endo-3-bornaneselenenyl bromide, the latter underwent intramolecular cyclization to form a stable heterocycle, the structure of which was confirmed by X-ray crystallography. This confirms the strong intramolecular coordination of selenium with nearby heteroatoms and highlights the role played by proximal functional groups in asymmetric induction.;While dialkyl diselenides proved generally ineffective as GPx mimetics, the corresponding allyl ω-hydroxyalkyl selenides and di(ω-hydroxyalkyl) selenides were remarkably active, with allyl 3-hydroxypropyl selenide and di(3-hydroxypropyl) selenide affording the highest catalytic activities in the reduction of t-butyl hydroperoxide in the presence of a sacrificial thiol reductant. When allyl 3-hydroxypropyl selenide and allyl 4-hydroxybutyl selenide were oxidized with t-butyl hydroperoxide, they produced 1,2-oxaselenolane Se-oxide and 1,2-oxaselenane Se-oxide, respectively. Similarly, when di(3-hydroxypropyl) selenide and di(4-hydroxybutyl) selenide were oxidized, they underwent intramolecular cyclizations to afford the corresponding five- and six-membered dialkoxyselenuranes, respectively. These species were found to exhibit remarkable catalytic activities in the reduction of t-butyl hydroperoxide in the presence of benzyl thiol. This finding highlights the positive role played by the coordination of the hydroxyl oxygen atom with the selenium center during the catalytic cycle.