Organoselenium Chemistry: Between Synthesis and Biochemistry

Organoselenium compounds attracted in the last twenty years a growing scientific interest. From a chemical point of view, organoselenium reagent can be used in mild conditions to effect chemio, regio and stereoselective reactions and, in a number of examples as efficient and selective catalysts.

More recently also the biological aspect has been deeply explored and some organoselenium derivatives showed interesting and evaluable pharmacological properties.

Addition reactions of electrophilic selenium reagents to the double bonds, selenocyclizations, and their stereochemical aspects are described. The synthesis of electrophilic organoselenium reagents, including optically active examples, the formation of new carbon-oxygen, carbon-nitrogen, carbon-carbon bonds, and applications in the synthesis of heterocycles are presented.

Nucleophilic selenium compounds are useful for a number of functional group transformations. The aim of this chapter is to present the various aspects of the preparation and the synthetic utility of the most recently used nucleophilic selenium reagents now available to academic and industrial chemists.

Radical reactions with the participation of selenium compounds have been described here in the point of view of the source of selenium radicals. Consequently, the following groups have been reviewed: alkyl phenyl selenides, acyl phenyl selenides, imidoyl phenyl selenides, benzeneselenol and other selenides as the source of radicals.

The chapter covers the literature from early 90s until 2012.

Selenium forms a very large number of inorganic and organic compounds showing different reactivity and structural properties. Among them there are hypervalent compounds, selenuranes - the derivatives in which the central selenium atom has expanded its valence shell from 8 to 10 or 12 electrons. Such compounds are presented in the chapter using the criterion of classification which is based on the formal oxidation state and number (N) of ligands bonded to selenium. For each class, the methods of synthesis, complemented with the mechanistic and stereochemical studies, are comprehensively discussed.

This chapter has overviewed the stability of selenocarbonyl compounds that have been classified based on the substituents attached to their selenocarbonyl carbon atom. Focus has then been laid on the synthetic methods for selenoamides, whose chemistry has grown much more than that of other selenocarbonyl compounds in the last ten years. As starting materials leading to selenoamides, ordinary amides, nitriles and terminal acetylenes are mainly used. As a final part of this review, recent application of selenoamides to synthetic reactions has been introduced. Nucleophilic characters of selenium and nitrogen atoms in selenoamides have enabled several types of intermolecular cyclizations. The carbon atom of selenoamides can accept nucleophilic attack and selenium atom can formally work as a leaving group.

The peculiar reactivity and the interesting biological properties of chiral organoselenium compounds inspired organic chemists to develop new methodologies for their synthesis. In recent years, interesting catalytic protocols have been found for the asymmetric synthesis of organoselenium compounds starting from prochiral or racemic starting materials. This chapter summarizes these novel strategies based on the use of chiral organometallic catalysts, organocatalysts and biocatalysts.

In recent years, an increasingly broad array of applications has been found for new eco-friendly protocols related to the synthesis of organoselenium compounds. One of the most important challenges in this field is the development of new procedures that involve the use of alternative and/or recyclable solvents or solvent-free conditions. In this context, ionic liquids, water, glycerol, ethanol and polyethylene glycol have been used as ‘green’ solvents. The advantages of using these solvents will be discussed, mainly with regard to their reusable and easily separable systems. Solvent-free methodologies will also be described in detail. Additionally, catalytic amounts of selenium-containing organic molecules can be applied to effect several chemical transformations, leading to their use as organocatalysts within a “greener perspective” and this probably represents the most important recent advance in this field. Other important selective contributions in this field will also be addressed.

Selenium (Se) is an essential micronutrient with proposed role in the protection of DNA, proteins and lipids from oxidative damage, and in the homeostasis of the immune system, thyroid gland and spermatogenesis. Environmental (soil and water) availability influences Se food content and thus the Se status of the different populations. Recommended daily intake in USA and Europe is 55 and 60 μg/day, with tolerable upper intake levels of 400 and 300 μg, respectively. Biological activities are dependent on the organization of the elemental form in the structure of the amino acids selenomethionine and selenocysteine, with the latter as functional component of endogenous proteins with role in redox catalysis (glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases), signaling, storage, transport and structural activities. A series of epidemiology and intervention studies have suggested that populations exposed to high levels of intake may benefit of health promoting effects and this has made Se supplements quite popular. However, such positive effects are not always supported by sufficient evidence and a number of studies, on the other hand, have suggested that higher intakes may cause adverse effects increasing the risk of cancer and diabetes. Chronic toxicity of Se remains in fact matter of concern representing a valid reason for further clinical investigation on the safety of current supplementation and food fortification protocols. This chapter provides a systematic analysis of the literature available on these aspects particularly focusing on nutritional and biochemistry features of Se.

Selenium (Se) is a key component of a number of selenoproteins required for the normal human metabolism. Se is considered a scavenger of free radicals; it has been studied for its ability to improve the immune system functions and to prevent cancer. The initial studies on anti-inflammatory and antimicrobial activities of ebselen, an organoselenium compound, have furthered the research to identify new molecules with antimicrobial activities. The antimicrobial potential of many organoselenium compounds was studied in in vitro and in vivo assays against a wide range of microorganisms and suggested a potential use for them in different medical applications such as treatment of drug resistant microorganisms, and as an adjuvant in healing wounds. The interesting results observed for the Se-containing organic compounds also suggest their potential use to enhance the safety and the shelf life of food products. Another interesting application of organoselenium compounds is their use as a herbicide because of their activity against parasites and plant pathogens, although the residual toxicity of the compounds in food has to be investigated.

The discovery in the early sixties of the fundamental role that selenium plays in many living systems has led to investigate the chemical mechanisms of action of the most important selenoenzymes. These mechanisms together with the possibility to develop biomimetic molecules to be used as useful catalysts in green synthetic protocols will be explored in this chapter.

A number of selenoenzyme mimics, mostly of glutathione peroxidase (GPx), have been developed in decades so as to probe the molecular mechanism of the catalytic cycle as well as to utilize them as selenium antioxidants (SeAO), expecting that those organoselenium compounds would reduce reactive oxygen species (ROS) in living cells. Meanwhile, the design of antioxidant selenoenzyme mimics has encountered several problems relating to the biologically multimodal functions of SeAO. In this chapter, recent progress in the development of SeAO as ROS scavengers is overviewed. After brief explanation for the regulation of oxidative stress by SeAO, biological effects of SeAO and the proposed action mechanisms are described. Possible prooxidant (PO) effects of selenium compounds are also surveyed. Finally, the SeAO are classified in two types, i.e., type A which is easily reducible to selenolate species (RSe^-) and type B which is not easily reducible, on the basis of their AO and PO functions in order to summarize the current status in the SeAO design and give some guidelines for the future study.

⁷⁷Se NMR spectroscopy has been established as a powerful tool in the study of the selenium chemistry. ⁷⁷Se NMR chemical shifts (δ(Se)) are sharply sensitive to the structural changes in selenium compounds. Therefore, they are widely applied to analyze the chemical bonds around Se atoms and to determine the structures. On the other hand, the calculated absolute magnetic shielding tensors of Se (σ(Se)) become much reliable. It is now possible to assign the spectra based not only on the empirical rules but also on the theoretical supports. Interpretation of the shift values separately by the contributions from the occupied orbitals and the orbital-orbital transitions is the typical example of the theoretical treatment. The theoretical background for the chemical shifts is explained, together with the coupling constants (J(Se, X)), although briefly. ⁷⁷Se NMR spectra are measured on a daily basis and the structures of selenium compounds are determined through the assignment of the spectra. Applications of ⁷⁷Se NMR are mainly discussed so as to give good hints when the spectra are assigned, for the better understanding of the selenium chemistry. Orientational effect on σ(Se) and δ(Se) by aryl groups, mechanisms for J(Se, X), NICS and relativistic effect on σ(Se) are also discussed, together with the usual applications.