Optically Active Selenoxides: Structural and Synthetic Aspects Optically Active Selenoxides: Structural and Synthetic Aspects

: Synthetic approaches to the preparation of non-racemic selenoxides and the problem of their optical stability are discussed in this mini review. general structures 1 and 2 (Figure 1) is dominated mainly by the presence of a highly polarized heteroatom–oxygen bond, and their optical activity is associated with their tetrahedral geometry, which induces the optical activity of compounds in which two di ﬀ erent carbon chains and / or rings are bonded to a stereogenic heteroatom. Abstract: Synthetic approaches to the preparation of non-racemic selenoxides and the problem of their optical stability are discussed in this mini review.


Introduction
Sulfoxides are the logical and obvious reference point when one is considering the reactivity and optical activity of selenoxides. This is due to the fact that the reactivity of both groups of heterorganic derivatives of general structures 1 and 2 ( Figure 1) is dominated mainly by the presence of a highly polarized heteroatom-oxygen bond, and their optical activity is associated with their tetrahedral geometry, which induces the optical activity of compounds in which two different carbon chains and/or rings are bonded to a stereogenic heteroatom.

Introduction
Sulfoxides are the logical and obvious reference point when one is considering the reactivity and optical activity of selenoxides. This is due to the fact that the reactivity of both groups of heterorganic derivatives of general structures 1 and 2 (figure 1) is dominated mainly by the presence of a highly polarized heteroatom-oxygen bond, and their optical activity is associated with their tetrahedral geometry, which induces the optical activity of compounds in which two different carbon chains and/or rings are bonded to a stereogenic heteroatom.

Scheme 1. Deprotonation and elimination reactions of selenoxides and sulfoxides.
When considering the optical activity of unsymmetrical selenoxides, it should be noted that their pyramidal configuration at selenium was for the first time proved only in 1946 by mixed crystal studies [13,14] and that the first attempts to resolve 4-carboxydiphenyl selenoxide 8 and 4-carboxyphenyl methyl selenoxide 9 ( Figure 2) via diastereoisomeric salts with enantiomerically pure amines were unsuccessful [15]. When considering the optical activity of unsymmetrical selenoxides, it should be noted that their pyramidal configuration at selenium was for the first time proved only in 1946 by mixed crystal studies [13,14] and that the first attempts to resolve 4-carboxydiphenyl selenoxide 8 and 4-carboxyphenyl methyl selenoxide 9 (figure 2) via diastereoisomeric salts with enantiomerically pure amines were unsuccessful [15].  The failure to observe resolution, which was in sharp contrast with the ease of resolution of the related sulfoxides [16] (due to the addition of water to unsymmetrical selenoxides, which should give rise to symmetrical dihydroxides) was mentioned in this paper. However, it was rejected by the authors because specific rotation of a dry sample of diastereoisomeric salts of the selenoxide 8 with enantiomerically pure α-phenylethylamine was observed by recrystallizing it from dry ethyl acetate was not changed. An open suggestion that the inability to isolate selenoxide enantiomers is due to the rapid formation of hydrates in the presence of water was formulated only in 1952 in a review paper [17]. This reaction is illustrated for the selenoxide 1a and the formed dihydroxyselenuranes 10 in Scheme 2. The failure to observe resolution, which was in sharp contrast with the ease of resolution of the related sulfoxides [16] (due to the addition of water to unsymmetrical selenoxides, which should give rise to symmetrical dihydroxides) was mentioned in this paper. However, it was rejected by the authors because specific rotation of a dry sample of diastereoisomeric salts of the selenoxide 8 with enantiomerically pure α-phenylethylamine was observed by recrystallizing it from dry ethyl acetate was not changed. An open suggestion that the inability to isolate selenoxide enantiomers is due to the rapid formation of hydrates in the presence of water was formulated only in 1952 in a review paper [17]. This reaction is illustrated for the selenoxide 1a and the formed dihydroxyselenuranes 10 in Scheme 2. According to a current terminology, dihydroxyselenuranes such as 10 can be considered as hypervalent molecules [21][22][23] Due to the presence of two apical hydroxyl groups in the trigonal bipyramid formed as an intermediate, they are achiral [24]. It can be expected, that the isolation of selenoxides in enantiomerically pure, or at least enriched form, could be possible when the formation of hydrated form is slowed down. This can be realized most easily by introduction at least a single, sterically demanding substituent. Successful experiments on the isolation of optically active selenoxides, described after 1970, fully confirmed this assumption. It is the intent of this mini review to present the available information on the preparation and optical stability of selenoxides, in order to stimulate the additional research on this topic. It should be noted here that in the years 1987-1995 short reviews were published in Japanese by Japanese authors conducting research on this topic. [25][26][27]. There are also two brief accounts in English that describe experiments on the synthesis, stereochemical aspects and the application in asymmetric synthesis of chiral chalcogen oxides carried out in the laboratories of authors, in which optically active selenoxides are also mentioned [28,29]. A few year later, a brief discussion devoted to optically active selenoxides was included into the Chapter 16 of "The Chemistry of Organic Selenium and Tellurium Compounds" from Patai's "Chemistry of Functional Groups" [30].
Below, we are going to discuss the synthesis of optically active selenoxides, which have been obtained in the form of diastereomeric mixtures or in enantiomeric form since 1970 using the following procedures: a) reaction of diastereoisomerically pure precursors; b) asymmetric oxidation of prochiral selenides; c) chromatographic and nonclassical resolution of racemates by forming complexes with an optically active hydrogen bond donor; Scheme 2. Rapid hydrate formation by selenoxides in the presence of water.
This proposal was later supported by NMR experiments using benzyl phenyl selenoxide 11 as the model compound according to which the chemical shift between the nonequivalent methylene protons H A and H B disappeared in an aqueous solution, which indicates the apparent loss of stereogenity of the selenium atom in this medium due to the formation of the corresponding dihydroxyselenurane [18]. The configurational instability in aqueous media was also observed for selenoxides 12 [19] and 13 ( Figure 3) [20]. It is interesting to note that racemic and meso forms of selenoxide 13 were separated. This proposal was later supported by NMR experiments using benzyl phenyl selenoxide 11 as the model compound according to which the chemical shift between the nonequivalent methylene protons HA and HB disappeared in an aqueous solution, which indicates the apparent loss of stereogenity of the selenium atom in this medium due to the formation of the corresponding dihydroxyselenurane [18].The configurational instability in aqueous media was also observed for selenoxides 12 [19] and 13 ( Figure 3) [20]. It is interesting to note that racemic and meso forms of selenoxide 13 were separated. According to a current terminology, dihydroxyselenuranes such as 10 can be considered as hypervalent molecules [21][22][23] Due to the presence of two apical hydroxyl groups in the trigonal bipyramid formed as an intermediate, they are achiral [24]. It can be expected, that the isolation of selenoxides in enantiomerically pure, or at least enriched form, could be possible when the formation of hydrated form is slowed down. This can be realized most easily by introduction at least a single, sterically demanding substituent. Successful experiments on the isolation of optically active selenoxides, described after 1970, fully confirmed this assumption. It is the intent of this mini review to present the available information on the preparation and optical stability of selenoxides, in order to stimulate the additional research on this topic. It should be noted here that in the years 1987-1995 short reviews were published in Japanese by Japanese authors conducting research on this topic. [25][26][27]. There are also two brief accounts in English that describe experiments on the synthesis, stereochemical aspects and the application in asymmetric synthesis of chiral chalcogen oxides carried out in the laboratories of authors, in which optically active selenoxides are also mentioned [28,29]. A few year later, a brief discussion devoted to optically active selenoxides was included into the Chapter 16 of "The Chemistry of Organic Selenium and Tellurium Compounds" from Patai's "Chemistry of Functional Groups" [30].
Below, we are going to discuss the synthesis of optically active selenoxides, which have been obtained in the form of diastereomeric mixtures or in enantiomeric form since 1970 using the following procedures: a) reaction of diastereoisomerically pure precursors; b) asymmetric oxidation of prochiral selenides; c) chromatographic and nonclassical resolution of racemates by forming complexes with an optically active hydrogen bond donor; According to a current terminology, dihydroxyselenuranes such as 10 can be considered as hypervalent molecules [21][22][23] Due to the presence of two apical hydroxyl groups in the trigonal bipyramid formed as an intermediate, they are achiral [24]. It can be expected, that the isolation of selenoxides in enantiomerically pure, or at least enriched form, could be possible when the formation of hydrated form is slowed down. This can be realized most easily by introduction at least a single, sterically demanding substituent. Successful experiments on the isolation of optically active selenoxides, described after 1970, fully confirmed this assumption. It is the intent of this mini review to present the available information on the preparation and optical stability of selenoxides, in order to stimulate the additional research on this topic. It should be noted here that in the years 1987-1995 short reviews were published in Japanese by Japanese authors conducting research on this topic. [25][26][27]. There are also two brief accounts in English that describe experiments on the synthesis, stereochemical aspects and the application in asymmetric synthesis of chiral chalcogen oxides carried out in the laboratories of authors, in which optically active selenoxides are also mentioned [28,29]. A few year later, a brief discussion devoted to optically active selenoxides was included into the Chapter 16 of "The Chemistry of Organic Selenium and Tellurium Compounds" from Patai's "Chemistry of Functional Groups" [30].
Below, we are going to discuss the synthesis of optically active selenoxides, which have been obtained in the form of diastereomeric mixtures or in enantiomeric form since 1970 using the following procedures: a) reaction of diastereoisomerically pure precursors; b) asymmetric oxidation of prochiral selenides; c) chromatographic and nonclassical resolution of racemates by forming complexes with an optically active hydrogen bond donor; Symmetry 2020, 12, 349 4 of 24 d) kinetic resolution of racemates; e) reaction of enantiopure, cyclic seleninic esters with organometallic reagents.

Diastereoisomeric Selenoxides
The first selenoxides whose optical activity results from the presence of a stereogenic selenium atom constitute diastereoisomeric, steroidal selenoxides 14 and 15, which were described in 1970 [31]. Their synthesis was based on the oxidation of 6β-phenylseleno-5α-cholestane 17 which contains a prochiral divalent selenium atom (prepared by the reaction of 6α-methanesulphonyloxy-5α-cholestane 16 with sodium benzeneselenolate) with ozone [32]. It was found that this asymmetric oxidation, carried out in dichloromethane at −78 • C, gave a mixture of the selenoxides (R)-6β-14 and (S)-6β-15 in the ratio 2:1. Separated p by chromatography at −50 • C did not interconvert at temperatures between −78 • C and 25 • C in organic solvent in the presence of water. This indicates that their racemization via reversible hydrate formation (or pyramidal inversion) is not observed under these conditions. However, both diastereoisomerically pure selenoxides 14 and 15 were found to decompose at room temperature, affording only 5-α-cholest-6-ene 18 and benzeneseleninic acid 19 (Scheme 3). It is interesting to note that the (S)-6β-15 gave the olefin 18 after 4 h at 0 • C, while the other one remains unchanged. These difference i in the decomposition rate was proposed to be related with the cyclic intramolecular mechanism common to syn-eliminations [33]. In line with this mechanism, the transition state 20a which leads from the (S)-6-β-phenylselenoxide 15 to 5a-cholest-6-ene 18 is appreciably less sterically compressed than that of the transition state 20b responsible for the formation of the unsaturated steroid 18 from the (R)-isomer 14 (Scheme 3).

Diastereoisomeric Selenoxides
The first selenoxides whose optical activity results from the presence of a stereogenic selenium atom constitute diastereoisomeric, steroidal selenoxides 14 and 15, which were described in 1970 [31]. Their synthesis was based on the oxidation of 6β-phenylseleno-5α-cholestane 17 which contains a prochiral divalent selenium atom (prepared by the reaction of 6α-methanesulphonyloxy-5α-cholestane 16 with sodium benzeneselenolate) with ozone [32]. It was found that this asymmetric oxidation , carried out in dichloromethane at −78 °C, gave a mixture of the selenoxides (R)-6β-14 and (S)-6β-15 in the ratio 2:1. Separated p by chromatography at −50 °C did not interconvert at temperatures between −78 °C and 25 °C in ,organic solvent in the presence of water. This indicates that their racemization via reversible hydrate formation (or pyramidal inversion) is not observed under these conditions. However, both diastereoisomerically pure selenoxides 14 and 15 were found to decompose at room temperature,affording only 5-α-cholest-6-ene 18 and benzeneseleninic acid 19 . (Scheme 3). It is interesting to note that the (S)-6β-15 gave the olefin 18 after 4 h at 0 °C, while the other one remains unchanged.. These difference i in the decomposition rate was proposed to be related with the cyclic intramolecular mechanism common to syn-eliminations [33]. In line with this mechanism, the transition state 20a which leads from the (S)-6-β-phenylselenoxide 15 to 5a-cholest-6-ene 18 is appreciably less sterically compressed than that of the transition state 20b responsible for the formation of the unsaturated steroid 18 from the (R)-isomer 14 (Scheme 3). Generation of diastereoisomeric steroidal selenoxides 21 and 22, which were too labile to be isolated was observed during the oxidation of 7β-phenylselenocholesteryl benzoate 23, (prepared by the reaction of 7α-bromocholesteryl benzoate 24 with sodium benzeneselenolate), with ozone at −70 °C in a methylene chloride solution. Their configurational stability and the absolute configuration at the newly generated stereogenic center on a selenium atom was suggested, taking into account an observation that the 3-benzoate of coprost-6-en-3b,5-diol 26 and 7-dehydrocholesteryl benzoate 25 were formed in approximately equal yields of 45%. Interestingly, when temperature was slowly raised, the presence of 26 was detected by thin layer chromatography (TLC )at about −25 °C whilst 25 appeared only at about −5 to 0 °C (Scheme 4). If the selenoxides 21 and 22 were configurationally unstable it the interconversion of 22 to 21 should lead predominantly to the product 26, which was not detected [34]. The sequential treatment of 4-aza-5-pregnene-3,20-dione 27 with benzeneselenenyl chloride 28 and 1 equivalent of m-chloroperbenzoic acid (MCPBA) was found to afford a 2:1 mixture of selenoxide diastereomers (R)-30 and (S)-31 (Scheme 5). This Generation of diastereoisomeric steroidal selenoxides 21 and 22, which were too labile to be isolated was observed during the oxidation of 7β-phenylselenocholesteryl benzoate 23, (prepared by the reaction of 7α-bromocholesteryl benzoate 24 with sodium benzeneselenolate), with ozone at −70 • C in a methylene chloride solution. Their configurational stability and the absolute configuration at the newly generated stereogenic center on a selenium atom was suggested, taking into account an observation that the 3-benzoate of coprost-6-en-3b,5-diol 26 and 7-dehydrocholesteryl benzoate 25 were formed in approximately equal yields of 45%. Interestingly, when temperature was slowly raised, the presence of 26 was detected by thin layer chromatography (TLC) at about −25 • C whilst 25 appeared only at about −5 to 0 • C (Scheme 4). If the selenoxides 21 and 22 were configurationally unstable it the interconversion of 22 to 21 should lead predominantly to the product 26, which was not detected [34]. The sequential treatment of 4-aza-5-pregnene-3,20-dione 27 with benzeneselenenyl chloride 28 and 1 equivalent of m-chloroperbenzoic acid (MCPBA) was found to afford a 2:1 mixture of selenoxide diastereomers (R)-30 and (S)-31 (Scheme 5). This mixture of selenoxide stereoisomers It was suggested that the 2:1 ratio reflects the relative thermodynamic stabilities of the two diastereoisomers [35]. The abnormally low field of the NMR signals of the enamidic hydrogen atoms in the stereoisomers 30 and 31 was related to the presence of strong intramolecular hydrogen bonds between the selenoxide oxygens and these hydrogen atoms.. . A series of diasteroisomeric hydroxyselenoxides 40-43 containing the bornyl moiety was prepared by hydrolysis at 0 °C of diasteroisomeric chloroselenuranes 36-39 (X = Cl) which were formed rapidly (10 min at 0 °C) as single stereoisomers (89-100% yield) upon the reaction of bicyclic hydroxyselenides 32-35 with t-butyl hypochlorite (Scheme 6). It was found that the treatment of selenoxide 40a with a base afforded an equilibrium mixture of 40a and 40b (2:1) whereas the treatment with an acid (HCIO4) of selenoxide 40a or a mixture of the selenoxides 40a and 40b predominantly gave 40a, and that selenurane 36 was formed both from 40a and a mixture of 40a and 40b. The starting chloroselenurane 36 was recovered as a single diastereomer (100% yield) upon treatment of the selenoxide 40 with HCl, . A similar reaction of 40 with HBr gave bromoselenurane 44 (96% yield). The reaction of the hydroxyselenoxide 40 with strong organic acids (3,5-dinitrobenzoic , It was suggested that the 2:1 ratio reflects the relative thermodynamic stabilities of the two diastereoisomers [35]. The abnormally low field of the NMR signals of the enamidic hydrogen atoms in the stereoisomers 30 and 31 was related to the presence of strong intramolecular hydrogen bonds between the selenoxide oxygens and these hydrogen atoms.. . A series of diasteroisomeric hydroxyselenoxides 40-43 containing the bornyl moiety was prepared by hydrolysis at 0 °C of diasteroisomeric chloroselenuranes 36-39 (X = Cl) which were formed rapidly (10 min at 0 °C) as single stereoisomers (89-100% yield) upon the reaction of bicyclic hydroxyselenides 32-35 with t-butyl hypochlorite (Scheme 6). It was found that the treatment of selenoxide 40a with a base afforded an equilibrium mixture of 40a and 40b (2:1) whereas the treatment with an acid (HCIO4) of selenoxide 40a or a mixture of the selenoxides 40a and 40b predominantly gave 40a, and that selenurane 36 was formed both from 40a and a mixture of 40a and 40b. The starting chloroselenurane 36 was recovered as a single diastereomer (100% yield) upon treatment of the selenoxide 40 with HCl, . A similar reaction of 40 with HBr gave bromoselenurane 44 (96% yield). The reaction of the hydroxyselenoxide 40 with strong organic acids (3,5-dinitrobenzoic , It was suggested that the 2:1 ratio reflects the relative thermodynamic stabilities of the two diastereoisomers [35]. The abnormally low field of the NMR signals of the enamidic hydrogen atoms in the stereoisomers 30 and 31 was related to the presence of strong intramolecular hydrogen bonds between the selenoxide oxygens and these hydrogen atoms. A series of diasteroisomeric hydroxyselenoxides 40-43 containing the bornyl moiety was prepared by hydrolysis at 0 • C of diasteroisomeric chloroselenuranes 36-39 (X = Cl) which were formed rapidly (10 min at 0 • C) as single stereoisomers (89-100% yield) upon the reaction of bicyclic hydroxyselenides 32-35 with t-butyl hypochlorite (Scheme 6). It was found that the treatment of selenoxide 40a with a base afforded an equilibrium mixture of 40a and 40b (2:1) whereas the treatment with an acid (HCIO4) of selenoxide 40a or a mixture of the selenoxides 40a and 40b predominantly gave 40a, and that selenurane 36 was formed both from 40a and a mixture of 40a and 40b. The starting chloroselenurane 36 was recovered as a single diastereomer (100% yield) upon treatment of the selenoxide 40 with HCl, A similar reaction of 40 with HBr gave bromoselenurane 44 (96% yield). The reaction of the hydroxyselenoxide 40 with strong organic acids (3,5-dinitrobenzoic, p-toluenesulfonic or trifluoromethanesulfonic )in the presence of MgSO 4 gave the corresponding selenuranes 44-47, respectively (Scheme 6) [36,37]. It is well known that allyl selenoxides undergo very fast [2,3] sigmatropic rearrangement, producing allylic alcohols (Scheme 7), while vinyl selenoxides are able to eliminate selenic acid, which leads to the cumulene system (Scheme 8). The asymmetric version of both methods can be used to synthesize optically active alcohols or allenes, respectively [38][39][40][41]. It is well known that allyl selenoxides undergo very fast [2,3]sigmatropic rearrangement, producing allylic alcohols (Scheme 7), while vinyl selenoxides are able to eliminate selenic acid, which leads to the cumulene system (Scheme 8). The asymmetric version of both methods can be used to synthesize optically active alcohols or allenes, respectively [38][39][40][41]. It is well known that allyl selenoxides undergo very fast [2,3] sigmatropic rearrangement, producing allylic alcohols (Scheme 7), while vinyl selenoxides are able to eliminate selenic acid, which leads to the cumulene system (Scheme 8). The asymmetric version of both methods can be used to synthesize optically active alcohols or allenes, respectively [38][39][40][41].  It is well known that allyl selenoxides undergo very fast [2,3] sigmatropic rearrangement, producing allylic alcohols (Scheme 7), while vinyl selenoxides are able to eliminate selenic acid, which leads to the cumulene system (Scheme 8). The asymmetric version of both methods can be used to synthesize optically active alcohols or allenes, respectively [38][39][40][41]. The first example of this methodology, which was used in the preparation of optically active allylic alcohol, was reported in 1991 [42] and was based on the in situ generation of the optically active, diastereoisomerically enriched, geranyl [2.2]paracyclophanyl selenideoxide 49 by treatment of the corresponding optically active geranyl selenide 48 with meta-chloroperbenzoic acid (MCPBA). This protocol gave linalool 51 with 67% enantiomeric excess (ee) via selenenic ester 50 which was formed as a result of the [2,3]sigmatropic rearrangement of selenoxide 49 (Scheme 9).

Asymmetric Oxidation
Among the different approaches to the synthesis of enantiomeric selenoxides, asymmetric oxidation of the prochiral, unsymmetrical selenides with optically active oxidizing agents can be considered the method of choice. The first asymmetric oxidations of methyl phenyl selenide 81 by chiral 2-sulfonyloxaziridines 89a or 89b, carried out in the Davis laboratory, was found to give the corresponding methyl phenyl selenoxide 85 with ee only around 9% ee under anhydrous conditions [47]. Later, N-(phenylsulfonyl) (3,3-dichlorocamphoryloxaziridine) 89c was found to be more efficient reagent for the enantioselective oxidation of prochiral selenides 81-84 Using this reagent, the corresponding alkyl aryl selenoxides 85-88 were isolated for the first time with ee hagher than 90%..(Scheme 16) [48,49].

Asymmetric Oxidation
Among the different approaches to the synthesis of enantiomeric selenoxides, asymmetric oxidation of the prochiral, unsymmetrical selenides with optically active oxidizing agents can be considered the method of choice. The first asymmetric oxidations of methyl phenyl selenide 81 by chiral 2-sulfonyloxaziridines 89a or 89b, carried out in the Davis laboratory, was found to give the corresponding methyl phenyl selenoxide 85 with ee only around 9% ee under anhydrous conditions [47]. Later, N-(phenylsulfonyl) (3,3-dichlorocamphoryloxaziridine) 89c was found to be more efficient reagent for the enantioselective oxidation of prochiral selenides 81-84 Using this reagent, the corresponding alkyl aryl selenoxides 85-88 were isolated for the first time with ee hagher than 90%..(Scheme 16) [48,49].

Asymmetric Oxidation
Among the different approaches to the synthesis of enantiomeric selenoxides, asymmetric oxidation of the prochiral, unsymmetrical selenides with optically active oxidizing agents can be considered the method of choice. The first asymmetric oxidations of methyl phenyl selenide 81 by chiral 2-sulfonyloxaziridines 89a or 89b, carried out in the Davis laboratory, was found to give the corresponding methyl phenyl selenoxide 85 with ee only around 9% ee under anhydrous conditions [47]. Later, N-(phenylsulfonyl) (3,3-dichlorocamphoryloxaziridine) 89c was found to be more efficient reagent for the enantioselective oxidation of prochiral selenides 81-84 Using this reagent, the corresponding alkyl aryl selenoxides 85-88 were isolated for the first time with ee hagher than 90%..(Scheme 16) [48,49]. Diastereoisomeric (+) and (-)-(camphorylsulfonyl)oxaziridines 89d [50] were used for the enantioselective oxidation of 1-phenylselenyl-8-methylselenylnaphthalene 96. It was found that this reaction afforded regioselectively enantiomerically enriched 1-phenylselenyl-8-methylseleninylnaphthalene 97, which maintains, in a standard laboratory environment, stereochemical integrity at a stereogenic seleninyl selenium atom at room temperature for several days (Scheme 18) [51]. A relatively high optical stability of the selenoxide 97 results from stabilization to racemization by intramolecular coordination between the dicoordinated, divalent selenium atom of the phenylselenenyl group at position 1 and a stereogenic seleninyl selenium atom at position 8 of the naphthalene ring. A few enantiomerically enriched alkyl aryl selenoxide 86 and 102-105 were synthesized by the asymmetric oxidation of the corresponding alkyl aryl selenides 82 and 98-101 using a mixture of t-butylhydroperoxide with optically active dialkyl tartrates and titanium or aluminium tetraalkoxides such as the Lewis acids (Sharpless reagent) (Scheme 19) [52]. It was found that the most effective combination was that of diethyl tartrate (DET) and titanium tetraisopropoxide (TTIP). It gave the highest ee value (32.7%) for methyl 2,4,6-tri-t-butylphenyl selenoxide 98 when the oxidation was carried out in methylene chloride at −15 °C.  [50] were used for the enantioselective oxidation of 1-phenylselenyl-8-methylselenylnaphthalene 96.

Diastereoisomeric (+) and (-)-(camphorylsulfonyl)oxaziridines 89d
It was found that this reaction afforded regioselectively enantiomerically enriched 1-phenylselenyl-8methylseleninylnaphthalene 97, which maintains, in a standard laboratory environment, stereochemical integrity at a stereogenic seleninyl selenium atom at room temperature for several days (Scheme 18) [51]. A relatively high optical stability of the selenoxide 97 results from stabilization to racemization by intramolecular coordination between the dicoordinated, divalent selenium atom of the phenylselenenyl group at position 1 and a stereogenic seleninyl selenium atom at position 8 of the naphthalene ring. Diastereoisomeric (+) and (-)-(camphorylsulfonyl)oxaziridines 89d [50] were used for the enantioselective oxidation of 1-phenylselenyl-8-methylselenylnaphthalene 96. It was found that this reaction afforded regioselectively enantiomerically enriched 1-phenylselenyl-8-methylseleninylnaphthalene 97, which maintains, in a standard laboratory environment, stereochemical integrity at a stereogenic seleninyl selenium atom at room temperature for several days (Scheme 18) [51]. A relatively high optical stability of the selenoxide 97 results from stabilization to racemization by intramolecular coordination between the dicoordinated, divalent selenium atom of the phenylselenenyl group at position 1 and a stereogenic seleninyl selenium atom at position 8 of the naphthalene ring.

Scheme 18. Enantioselective oxidation of 1-phenylselenyl-8-methylseleninylnaphthalene 96.
A few enantiomerically enriched alkyl aryl selenoxide 86 and 102-105 were synthesized by the asymmetric oxidation of the corresponding alkyl aryl selenides 82 and 98-101 using a mixture of t-butylhydroperoxide with optically active dialkyl tartrates and titanium or aluminium tetraalkoxides such as the Lewis acids (Sharpless reagent) (Scheme 19) [52]. It was found that the most effective combination was that of diethyl tartrate (DET) and titanium tetraisopropoxide (TTIP). It gave the highest ee value (32.7%) for methyl 2,4,6-tri-t-butylphenyl selenoxide 98 when the oxidation was carried out in methylene chloride at −15 °C.

Chromatographic and Non-Classical Resolution of Racemates by Forming Complexes with an Optically Active Hydrogen Bond Donor
The first optical resolution by column chromatography using a chiral column was applied for diaryl selenoxides that possess no functional groups. I By this approach the racemic diaryl selenoxides 143-149 ( figure 4) were partially resolved on a medium pressure column chromatography system [(R)-iV-(3,5-dinitrobenzoyl) phenylglycine/aminopropylsilica (particle size 40 μ) columne]. Enantiomeric excess for fast eluting enantiomers ranged from 12 to 66%, and for slowly eluting enantiomers from 4 to 41% [47,48]. Later on, column chromatography on a chiral column was applied to separate enantiomers selenoxides configurationally stabilized by intramolecular coordination to the stereogenic selenium atom. Thus, racemic 2-((dimethylamino)methyl)phenyl alkyl (or aryl) selenoxides 150-152(figure5), containing an amino group able to coordinate with the selenium atom, were resolved into enantiomers by means of HPLC chromatography using an chiral column It is interesting to note that the. vthe stabilization energy (ca. 3 kcal mol −1 ) for this interaction was determined by variable temperature 1 H-NNMR experiments . [59]. Scheme 23. Asymmetric oxidation of phenyl tri-t-butylphenyl selenide 142.

Chromatographic and Non-Classical Resolution of Racemates by Forming Complexes with an Optically Active Hydrogen Bond Donor
The first optical resolution by column chromatography using a chiral column was applied for diaryl selenoxides that possess no functional groups. I By this approach the racemic diaryl selenoxides 143-149 ( Figure 4) were partially resolved on a medium pressure column chromatography system [(R)-iV-(3,5-dinitrobenzoyl) phenylglycine/aminopropylsilica (particle size 40 µ) columne]. Enantiomeric excess for fast eluting enantiomers ranged from 12 to 66%, and for slowly eluting enantiomers from 4 to 41% [47,48].

Kinetic Resolution of Racemates
In fact, the first optically active, enantiomerically enriched selenoxides were isolated in a kinetic resolution reaction when racemic methyl phenyl selenoxide 85 or methyl tri-isopropylphenyl selenoxide 86 were subjected to the reaction with a half molar equivalent of (-)-or (+)-camphorsulfonamide 173 (Scheme 24) [64].

Kinetic Resolution of Racemates
In fact, the first optically active, enantiomerically enriched selenoxides were isolated in a kinetic resolution reaction when racemic methyl phenyl selenoxide 85 or methyl tri-isopropylphenyl selenoxide 86 were subjected to the reaction with a half molar equivalent of (-)-or (+)-camphorsulfonamide 173 (Scheme 24) [64].
selenoxides 85 and 162-167 in the complex with 171 was found to be almost 100%. Moreover, dynamic kinetic resolution (DKR) of selenoxides via hydrate formation gave in some cases enantiomerically pure selenoxides in yields above 100%. [63].

Absolute Configurations and Enantiomeric Excesses of Optically Active Selenoxides
The absolute configuration of the levorotatory enantiomer of selenoxide 78 was established to be S, taking into accounts the result of X-ray crystallographic analysis of the diastereoisomerically pure, levorotatory selenoxide 76a and the lack of inversion of configuration around the stereogenic selenium atom during the transesterification from (-)-(Sse)-76 to methyl esters (-)-78 (Scheme 14) [45]. This determination was also supported by the presence of negative Cotton effects at the same wavelength region (284 nm) in the circular dichroism CD spectra of (-)- (76)  [52] was determined by 1 H-NMR using tris[3-(heptafluoropropylhydroxymethylene d-camphorate]-europlum (III), Eu(hfc)3 as chiral shift reagent (CSR). Their absolute configurations were suggested based upon comparison with circular dichroism spectra of the appropriate alkyl aryl sulfoxides. The S absolute configuration of the levorotatory enantiomers of 2-(dimethylamino)methyl)phenyl alkyl (or aryl) selenoxides 150-152 was suggested by comparison of their specific rotations, circular dichroism spectra, and behavior on the optically active column with those of the sulfur analogue [44]. The common features that exist between the CD spectra of selenoxides 143-149 and optically active p-tolyl mesityl sulfoxide and p-tolyl 2,4,6-triisopropylphenyl sulfoxide were used to assign the absolute configuration of the dextrarotatory selenoxide enantiomers [57,58]. The relationship between the absolute configurations around a stereogenic selenium atom of 2-(methylchalcogenomethyl)diphenyl selenoxides 153-154 and 2-{2-(N,N-dimethylamino)ethyl}-phenyl alkyl (or aryl) selenoxides 156-158 and the chiroptical properties of the enantiomers of was clarified by comparing with those of sulfur analogues [60]. Earlier, the absolute configurations of the optically active chalcogen oxides 159-161 were assigned by comparison of their specific rotations and CD spectra with those of their sulfur analog [61,62]. Similarly, the absolute configuration of dextrorotatory 2-(hydroxymethyl) phenyl methyl selenoxide (+)-177 was determined to be R by comparison of its specific rotations and CD spectra with those of that (R)-2-(hydroxymethyl) phenyl methyl sulfoxide. Enantiomeric excess of selenoxides 85 and 162-Scheme 25. Reaction of optically active seleninate ester (+)-(R)-176 with methylmagnesium bromide.

Absolute Configurations and Enantiomeric Excesses of Optically Active Selenoxides
The absolute configuration of the levorotatory enantiomer of selenoxide 78 was established to be S, taking into accounts the result of X-ray crystallographic analysis of the diastereoisomerically pure, levorotatory selenoxide 76a and the lack of inversion of configuration around the stereogenic selenium atom during the transesterification from (-)-(S se )-76 to methyl esters (-)-78 (Scheme 14) [45]. This determination was also supported by the presence of negative Cotton effects at the same wavelength region (284 nm) in the circular dichroism CD spectra of (-)-(76) and (-)-(78). The (S) absolute configurations around the stereogenic selenium atom of the other selenoxides (-)-(77) and (-)-(79) were deduced from their CD spectra in which also negative Cotton effects in this region (292 nm) were observed. The enantiomeric excesses of the selenoxides mentioned above were determined by HPLC using a chiral column. The extent of the asymmetric induction during the asymmetric oxidation of methyl phenyl selenide 81 to the corresponding selenoxide 85 (Scheme 16) was determined by adding to their solution successive amounts of tris[3-(heptafluoropropylhydroxymethylene d-camphorate]-europlum (III), Eu(hfc) 3 . The absolute configuration around the stereogenic selenium atom of the selenoxide 85 was determined by the analysis of 1 H-NMR spectra recorded for the reaction mixture or for the isolated sample in the presence of (+)-2,2,2-trifluoro-l-(9-anthryl)ethanol. The extent of the asymmetric induction during the enantiselective oxidation of 1-phenylselenyl-8-methylselenylnaphthalene 96 to the corresponding, enantiomerically enriched 1-phenylselenyl-8-methylseleninylnaphthalene 97 (Scheme 18) was determined by analyzing 1 H-NMR spectra of the isolated selenoxide 97 measured in the presence of enantiomerically pure BINOL or t-butylphenylphosphinothioic acid as a chiral solvating agent (CSA). The extent of the asymmetric induction during the asymmetric oxidation of alkyl aryl selenides 82 and 98-101 to the corresponding selenoxides 86 and 102-105 with Sharpless reagent (Scheme 19) [52] was determined by 1 H-NMR using tris[3-(heptafluoropropylhydroxymethylene d-camphorate]-europlum (III), Eu(hfc) 3 as chiral shift reagent (CSR). Their absolute configurations were suggested based upon comparison with circular dichroism spectra of the appropriate alkyl aryl sulfoxides. The S absolute configuration of the levorotatory enantiomers of 2-(dimethylamino)methyl)phenyl alkyl (or aryl) selenoxides 150-152 was suggested by comparison of their specific rotations, circular dichroism spectra, and behavior on the optically active column with those of the sulfur analogue [44]. The common features that exist between the CD spectra of selenoxides 143-149 and optically active p-tolyl mesityl sulfoxide and p-tolyl 2,4,6-triisopropylphenyl sulfoxide were used to assign the absolute configuration of the dextrarotatory selenoxide enantiomers [57,58]. The relationship between the absolute configurations around a stereogenic selenium atom of 2-(methylchalcogenomethyl)diphenyl selenoxides 153-154 and 2-{2-(N,N-dimethylamino)ethyl}-phenyl alkyl (or aryl) selenoxides 156-158 and the chiroptical properties of the enantiomers of was clarified by comparing with those of sulfur analogues [60]. Earlier, the absolute configurations of the optically active chalcogen oxides 159-161 were assigned by comparison of their specific rotations and CD spectra with those of their sulfur analog [61,62]. Similarly, the absolute configuration of dextrorotatory 2-(hydroxymethyl) phenyl methyl selenoxide (+)-177 was determined to be R by comparison of its specific rotations and CD spectra with those of that (R)-2-(hydroxymethyl) phenyl methyl sulfoxide. Enantiomeric excess of selenoxides 85 and 162-167 in their complexes with BINOL 171 was determined from the 1 H-NMR spectra [48]. The optical excesses of 2-methoxy-2, 2-diphenylethyl aryl selenoxides 108-109 were determined by HPLC using a chiral column [53].

Configurational Stability of Optically Active Selenoxides
Bearing in mind the very close structural similarity between sulfoxides and selenoxides it can be expected, simply by analogy, that the same racemization mechanisms will operate for different selenoxides. Three basic mechanism of thermally induced racemization of sulfoxides, including a pyramidal inversion, are very well understood, mainly due to the classical studies of the Mislow's group [66][67][68]. At the same time, extensive studies, mainly from the Oae group, explained in detail various chemically induced racemization of the reach family of sulfoxides [68,69]. In contrast to sulfoxides, mechanistic studies on thermally and chemically induced racemization of selenoxides are rather limited. There is only a single paper devoted to thermal racemization of selenoxides by a pyramidal inversion mechanism. In this publication, the free energies of activation (AG*) for the epimerization of a few diastereoisomeric, optically active diaryl selenoxides have been reported. They were calculated on the basis of the coalescence temperature of signals of two nonequivalent 77 Se nuclei observed in the 77 Se-NMR spectra of a series of diasteroisomeric 4-[(-)-menthyloxycarbonyl] phenyl 2,4,6-tri-alkylphenyl selenoxides 76, 77 and 178-180 ( Figure 9). These values, ranging from 61 to 85.8 kJ mol −1 , clearly indicate that the rate of epimerization of the selenoxides is strongly dependent on the bulkiness of the ortho substituents [70]. It should be noted here that the activation barriers for alkyl aryl and diaryl sulfoxides are considerably higher (150-180 kJ/ mol) [66][67][68].

Configurational Stability of Optically Active Selenoxides
Bearing in mind the very close structural similarity between sulfoxides and selenoxides it can be expected, simply by analogy, that the same racemization mechanisms will operate for different selenoxides. Three basic mechanism of thermally induced racemization of sulfoxides, including a pyramidal inversion, are very well understood, mainly due to the classical studies of the Mislow's group [66][67][68]. At the same time, extensive studies, mainly from the Oae group, explained in detail various chemically induced racemization of the reach family of sulfoxides [68,69]. In contrast to sulfoxides, mechanistic studies on thermally and chemically induced racemization of selenoxides are rather limited. There is only a single paper devoted to thermal racemization of selenoxides by a pyramidal inversion mechanism. In this publication, the free energies of activation (AG*) for the epimerization of a few diastereoisomeric, optically active diaryl selenoxides have been reported. They were calculated on the basis of the coalescence temperature of signals of two nonequivalent 77 Se nuclei observed in the 77 Se-NMR spectra of a series of diasteroisomeric 4-[(-)-menthyloxycarbonyl] phenyl 2,4,6-tri-alkylphenyl selenoxides 76, 77 and 178-180(figure9). These values, ranging from 61 to 85.8 kJ mol −1 , clearly indicate that the rate of epimerization of the selenoxides is strongly dependent on the bulkiness of the ortho substituents [70]. It should be noted here that the activation barriers for alkyl aryl and diaryl sulfoxides are considerably higher (150-180 kJ/ mol) [66][67][68]. The facile formation of achiral hydrates, mentioned for the first time in the paper which reported the first unsuccessful attempts to resolve 4-carboxydiphenyl selenoxide 8 and 4-carboxyphenyl methyl selenoxide 9 via diastereoisomeric salts with brucine, L-menthylamine, and enantiomerically pure α-phenylethylamine [18], can be considered as an oldest example of the chemically induced racemization of selenoxides. Later, racemization of selenoxides 143-144, 147-148 and 150-152 was studied in detail by CD measurements [57,58] In a chloroform solution, the CD spectra of selenoxides 150-152 were unchanged even after five days. However, racemization was observed in methanol and addition of water to the methanol solution accelerated this racemization. These results indicate that the racemization in methanol was caused by a trace amount of water. The half-lives of racemization for selenoxide (S)-(-)-152 corresponded well with those for selenoxide (R)-(+)-148. Moreover, racemization of (S)-(-)-150-152, was accelerated by the addition of p-toluenesulfonic acid or sodium hydroxide, especially in the case of (S)-(-)-150, whereas the racemization of selenoxide (R)-(+)-148 was not accelerated by the addition of sodium hydroxide. This results can be explained if one assumes operation of the mechanism shown for selenoxide 1a on Scheme 26. According to this mechanism the formation of hydroxyselenonium salt 181 is the rate determining step (RDS) in acidic media, whereas racemization in basic media is caused by the addition of hydroxide ion to a selenium atom in 1a followed by protonation of the oxygen atom in 182 to give an achiral hydrate 10. The facile formation of achiral hydrates, mentioned for the first time in the paper which reported the first unsuccessful attempts to resolve 4-carboxydiphenyl selenoxide 8 and 4-carboxyphenyl methyl selenoxide 9 via diastereoisomeric salts with brucine, L-menthylamine, and enantiomerically pure α-phenylethylamine [18], can be considered as an oldest example of the chemically induced racemization of selenoxides. Later, racemization of selenoxides 143-144, 147-148 and 150-152 was studied in detail by CD measurements [57,58] In a chloroform solution, the CD spectra of selenoxides 150-152 were unchanged even after five days. However, racemization was observed in methanol and addition of water to the methanol solution accelerated this racemization. These results indicate that the racemization in methanol was caused by a trace amount of water. The half-lives of racemization for selenoxide (S)-(-)-152 corresponded well with those for selenoxide (R)-(+)-148. Moreover, racemization of (S)-(-)-150-152, was accelerated by the addition of p-toluenesulfonic acid or sodium hydroxide, especially in the case of (S)-(-)-150, whereas the racemization of selenoxide (R)-(+)-148 was not accelerated by the addition of sodium hydroxide. This results can be explained if one assumes operation of the mechanism shown for selenoxide 1a on Scheme 26. According to this mechanism the formation of hydroxyselenonium salt 181 is the rate determining step (RDS) in acidic media, whereas racemization in basic media is caused by the addition of hydroxide ion to a selenium atom in 1a followed by protonation of the oxygen atom in 182 to give an achiral hydrate 10. Symmetry 2020, 12, x FOR PEER REVIEW 20 of 24 Scheme 26. The mechanism of racemization of selenoxides by the formation of hydrates in the presence of water.
The half-lives of racemization for selenoxides 162-166 complexed with BINOL 171, determined by polarymetric measurements at 19 °C, was found to be in the range of minutes (from 6.5 to 19.5) in methanol, while for the complex of the selenoxide 164 dissolved in chloroform was equal to 3.7 h [63].

Conclusions
In the present review, synthetic approaches to the preparation of non-racemic selenoxides and the problem of their optical stability are described. The purpose of this mini review is to provide available information on both topics in order to stimulate additional research in this field. The rationale for this research topic is the structural similarity between selenoxides and sulfoxides, which play a very important role as new synthetic reagents, biologically active compounds and new functional materials [71]. Therefore, it is reasonable to expect that optically active selenoxides should be just as useful as sulfoxides when they have sufficiently high optical stability. The literature data discussed in this review show how this goal can be achieved, and this is the main reason for publishing it in its current form. It is reasonable to expect that further research will allow the preparation of model compounds containing sterically demanding substituents, which in turn enable the preparation of optically active selenoxides with optical stability comparable to sulfoxides. Experimental works currently carried in our laboratories, focused on methodological and stereochemical aspects of flow processes [72} and mechanochemical procedures, allow us to have legitimate hope for reaching this goal. The half-lives of racemization for selenoxides 162-166 complexed with BINOL 171, determined by polarymetric measurements at 19 • C, was found to be in the range of minutes (from 6.5 to 19.5) in methanol, while for the complex of the selenoxide 164 dissolved in chloroform was equal to 3.7 h [63].

Conclusions
In the present review, synthetic approaches to the preparation of non-racemic selenoxides and the problem of their optical stability are described. The purpose of this mini review is to provide available information on both topics in order to stimulate additional research in this field. The rationale for this research topic is the structural similarity between selenoxides and sulfoxides, which play a very important role as new synthetic reagents, biologically active compounds and new functional materials [71]. Therefore, it is reasonable to expect that optically active selenoxides should be just as useful as sulfoxides when they have sufficiently high optical stability. The literature data discussed in this review show how this goal can be achieved, and this is the main reason for publishing it in its current form. It is reasonable to expect that further research will allow the preparation of model compounds containing sterically demanding substituents, which in turn enable the preparation of optically active selenoxides with optical stability comparable to sulfoxides. Experimental works currently carried in our laboratories, focused on methodological and stereochemical aspects of flow processes [72] and mechanochemical procedures, allow us to have legitimate hope for reaching this goal.