**3.1 Spirodioxyselenuranes/spirodiazaselenurane and its analogues as GPx mimics/models**

Lesser and Weiss in 1914 reported the first example of a spirodioxyselenurane **13**. After this initial study, several spirodioxyselenuranes such as **14–19** have been reported in the literature [48–50]. This type of hypervalent selenium compounds attracted significant attention in recent years due to their interesting structural and stereochemical properties [51]. The selenium center in spirodioxyselenuranes generally shows trigonal bipyramidal geometry around central atom with the lone pair lying in the equatorial plane and the electronegative oxygen atoms occupying the apical positions [52]. In contrast to the well-studied spirodioxyselenuranes, spirodiazaselenuranes that contain two nitrogen substituents are extremely rare. Back and co-workers [53] few years ago, demonstrated the relative instability of spirodiazaselenuranes. They reported that the oxidation of the selenium center in 2,2′-selenobis(benzamide) by H2O2 does not produce the expected spirodiaza derivative 8, but it results in the formation of azaselenonium hydroxide **23** [54]. The azaselenonium cation contains one Se–N bond and the compound is stabilized by a noncovalent interaction between the selenium atom and the carbonyl oxygen atom of the other amide moiety (**Figure 6**).

**Figure 6.**

*Some representative examples of stable spirochalcogenuranes [47, 50, 53, 55].*

In continuation selenium compounds in 2004 Back and co-workers reported for the first time that spirodioxyselenurane and its tellurium analogue exhibit very good antioxidant activity by mimicking the glutathione peroxidase (GPx) enzyme which protects the organism from oxidative damage by catalyzing the reduction of peroxides using thiol as the cofactor [47, 56]. Subsequently, a series of spirodioxyselenuranes with different stereochemistry and ring size has been reported [50, 54]. Very recently, we have reported the first example of a hydrolytically stable spirodiazaselenurane **24** and its tellurium analogue **25** bearing two nitrogen substituents in the apical positions [57]. In continuation of our research work on selenium compounds we have synthesized different substituted spirodiazaselenurane and its analogues and its Antioxidant activity [58, 59]. Very recently, Singh and co-workers have synthesized and characterized a new pincer type bicyclic diazaselenurane **26** where the two amide groups are present in the same phenyl ring forming the bicycles [55].

#### **3.2 Glutathione peroxidase (GPx) activity**

Back and co-workers reported that spirodioxyselenurane **11** exhibit excellent antioxidant property by mimicking glutathione peroxidise enzyme [47]. The effect of different substituents attached to the nitrogen atom was one of the objectives of this study to understand the antioxidant activity of selenides and spirodiazaselenuranes. Therefore, the GPx-like catalytic activity of compounds **27** was studied using glutathione (GSH) as thiol cofactor and hydrogen peroxide (H2O2) as substrate [57, 58]. The reduction of H2O2 by the selenides mechanism may involve a redox shuttle between the selenides and spirodiazaselenuranes via the corresponding intermatidates selenoxides (**Figure 5**). As previously described, the reactions of compounds **27** with H2O2 produce the corresponding selenoxides **28** which upon elimination of a water molecule generate the spirodiazaselenuranes **29**. Selenides **27** regenerate by GSH due to the reductive

*Functional Mimics of Glutathione Peroxidase: Spirochalcogenuranes, Mechanism and Its… DOI: http://dx.doi.org/10.5772/intechopen.102430*

cleave of the Se-N bonds in compounds **30** (Path A, **Figure 7**). This pathway is particularly favored at higher concentrations peroxide.

The nucleophilic attack of the thiol at the selenium center may produce the intermediates **30** which upon reaction with GSH can regenerate the selenides at higher concentrations of GSH. The nucleophilic attack of GSH at the selenium center is expected to favor due to noncovalent interactions between the selenium and one of the carbonyl oxygen. It should be noted that the mechanism shown in **Figure 7** is different from that of GPx and other diselenide-based mimetics that utilize a selenol moiety for the reduction of peroxides.

#### **3.3 Mechanism of spirocyclization**

Detailed mechanistic studies of spirodiazaselenuranes and structural characterization were carried out by using 77Se NMR spectroscopy. It was observed in the previous studies the presence of aromatic substituents cyclization process is very rapid at room temperature (25°C) on the nitrogen atoms as apical position [58]. To detect intermediates at room temperature (25°C) the cyclizations of the selenides to

#### **Figure 7.** *Proposed mechanism for GPx activity of compounds* **27–30** *[57, 58].*

#### **Figure 8.**

*Formation of spirodioxyselenurane from diaryl selenide by an oxidation-elimination mechanism [58].*

**Figure 9.** *Stepwise mechanism for the formation of Spirodiazachalcogenuranes from diaryl selenide [58, 60].*

the corresponding spiro compounds were too fast. However, the formation of selenoxide could be observed when the cyclization is blocked by replacing the N-H moiety in compound **29** with an N-Et group. Therefore, the oxidation of selenide **29** by H2O2 produced the selenoxide **30** with very good yield.

However, it was observed when a solution of compound **31** in acetonitrile with H2O2 was kept for a week, formation of the corresponding spirodioxyselenurane **32**. The mechanism for the formation of **33** may proceed via the initial attack of a water molecule at the selenium center in compound **31** followed by a nucleophilic attack of the selenium-bound oxygen atom at the carbonyl carbon of one of the amide moieties, leading to the formation of an intermediate **32** (**Figure 8**) [59]. Although the formation of a spirodioxyselenurane has been proposed for a selenide having an *N*-methyl-*N*-phenylamide moiety [55, 58, 59] the conversion of **31** into **33** suggests that such mechanism can be generalized for diaryl selenides having different substituents on the amide nitrogen atom as mentioned in **Figure 9**.
