A series of aliphatic diselenides and selenides containing coordinating substituents was tested for glutathione peroxidase (GPx)-like catalytic activity in a model system in which the reduction of tert-butyl hydroperoxide with benzyl thiol to afford dibenzyl disulfide and tert-butyl alcohol was performed under standard conditions and monitored by HPLC. Although the diselenides showed generally poor catalytic activity, allyl selenides proved more effective. In particular, allyl 3-hydroxypropyl selenide (25) rapidly generated 1,2-oxaselenolane Se-oxide (31) in situ by a series of oxidation and [2,3]sigmatropic rearrangement steps. The remarkably active cyclic seleninate 31 proved to be the true catalyst, reacting with the thiol via a postulated mechanism in which the thioseleninate 32 is first produced, followed by further thiolysis to selenenic acid 33 and oxidation-dehydration to regenerate 31. In contrast to catalysis with GPx, formation of the corresponding selenenyl sulfide 34 comprises a competing deactivation pathway in the catalytic cycle of 31, as a separate experiment revealed that authentic 34 was a much less effective catalyst than 31. 1,2-Oxaselenane Se-oxide (37), the six-membered homologue of 31, was formed similarly from allyl 4-hydroxybutyl selenide (26), but proved a less effective catalyst than 31. Compounds 31 and 37 are the first examples of unsubstituted monocyclic seleninate esters.

Oxidative stress results from the formation of peroxides and other reactive oxygen species during the course of normal aerobic metabolism.[1] These reactive intermediates and the free radicals they produce cause damage to various biologically important molecules present in cells. Peroxides have been implicated in a number of degenerative processes and disease states, including inflammation, mutagenesis, and cancer, atherosclerosis, Alzheimer's disease, and the aging process.[2] Glutathione peroxidase (GPx) is a selenoenzyme that protects cells by catalyzing the reduction of peroxides with the stoichiometric reductant glutathione.[3] The catalytic cycle of the enzyme is shown in Scheme 1 and involves the reduction of a peroxide molecule by the selenol moiety of a selenocysteine residue of the enzyme, followed by reduction of the corresponding selenenic acid with glutathione. The resulting selenenyl sulfide then reacts with a second mole equivalent of glutathione to regenerate the original selenol and the disulfide of glutathione.In view of the biological importance of GPx as a natural protective agent against oxidative stress, considerable effort has been expended to discover small-molecule selenium compounds that emulate GPx.[4] One such compound, ebselen (1), [5] has undergone clinical trials as an antiinflammatory agent. Ebselen and many other GPx mimetics that have been studied contain a covalent SeÀN bond or an amino substituent capable of coordinating with the selenium atom at various stages of its redox cycle. [6,7] Aryl selenides generally display poor catalytic activity in the thiol-mediated reduction of peroxides, [7] while alkyl selenides are prone to decomposition by syn elimination of their corresponding selenoxides. However, we recently reported that allyl 3-hydroxypropyl selenide (2) possesses remarkably high GPx-like activity (ca. one order of magnitude greater than that of ebselen) by producing the corresponding cyclic seleninate 3 in situ by a series of oxidation and [2,3] sigmatropic rearrangement steps.[8] Seleninate 3 then serves as the true catalyst and is recovered at the end of the catalytic cycle. These experiments revealed that OSe compounds can be even more effective catalysts than the more widely studied N-Se analogues. We now report that di(3-hydroxypropyl) selenide (4) [9] serves as a highly effective GPx mimetic and functions by a remarkable mechanism that involves a novel spirodioxaselenanonane as an intermediate.In the course of our studies on GPx mimetics, we have employed a model system in which excess tert-butyl hydroperoxide (tBuOOH) is treated with benzyl thiol (BnSH), which serves as the sacrificial reductant, in the presence of 10 mol % of the selenium-containing catalyst at 18 8C.[6g, 8] The reaction is easily followed by HPLC with naphthalene as an internal standard, and the time (t 1/2 ) required for the oxidation of 50 % of the thiol to its disulfide (BnSSBn) provides a convenient means for comparing the effectiveness of various catalysts. Thus, under identical condition...

1,2-Oxaselenolane Se-oxide is a novel cyclic seleninate ester that functions as a remarkably efficient glutathione peroxidase mimetic by catalyzing the reduction of tert-butyl hydroperoxide to tert-butyl alcohol in the presence of benzyl thiol. The seleninate ester can be conveniently generated in situ by oxidation of allyl 3-hydroxypropyl selenide with tert-butyl hydroperoxide. Its catalytic activity surpasses that of several other known GPx mimetics containing cyclic selenenamide structures, which were also tested for comparison.

Nonenzymatic exogenous and endogenous antioxidants play an important role in human health and act as preservatives for cosmetics, pharmaceuticals, and food products. This chapter will discuss the chemical structure and mechanism of action of the most important nonenzymatic small exogenous and endogenous organic molecules that act as antioxidants. The chapter will focus on the structural features, functional groups, properties, biosynthetic origin, and mechanism of action of such antioxidants. It also covers damages that free radicals create and the mechanisms by which they are neutralized by the various antioxidants. The scope of this chapter will be limited to nonenzymatic exogenous and endogenous antioxidants since enzymatic antioxidants have been discussed extensively in several reviews.

The first total synthesis of the marine toxin (−)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels–Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki–Hiyama–Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide and a few additional steps provided (−)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.