Asymmetric Synthesis and Applications of Chiral Organoselenium Compounds: A Review

Abstract

The synthesis and application of organoselenium compounds have developed rapidly, and chiral organoselenium compounds have become an important intermediate in the field of medicine, materials, organic synthesis. The strategy of developing a green economy is still a challenge in the synthesis of chiral organoselenium compounds with enantioselective properties. This review covers in detail the synthesis of chiral organoselenium compounds from 1979 to 2024 and their application in the fields of asymmetric synthesis and catalysis.

1. Introduction

Selenium is a non-metal element, that was discovered by Swedish chemist Berzelius in 1818 [1]. It is generally found in different inorganic forms in the soil as Se (Se⁰), selenide (Se²⁺), selenate (SeO₄²⁻), or selenite (SeO₃²⁻) [2]. Selenium is important to human health and exists in the human body as a trace element in the form of selenocysteine [3]. In recent decades [4], studies have found that organoselenium has antiviral, anti-inflammatory, antitumor, antidepressant, antioxidant, and anticonvulsant activities (Figure 1).

Research in the field of organoselenium began in 1836 with the synthesis of diethyl selenide by Löwig [5,6,7], which was isolated and purified by Rathke 33 years later [8,9]. Because organoselenium compounds are highly malodorous and difficult to purify, the development of organoselenium was slow during this period [10]. During this time only a few simple aliphatic organoselenium compounds were identified such as selenol (RSeH), selenide (RSeR) and diselenide (RSeSeR). From the 1970s, the discovery and identification of different types of organoselenium compounds has increased and has attracted the attention of scientists [11,12,13,14]. Organoselenium compounds has become an emerging field of research.

Organoselenium compounds are used in supramolecular chemistry. Supramolecular chemistry integrates the four fundamental disciplines of chemistry (organic, inorganic, analytical, and physical) into one. Supramolecular behavior is exhibited through electrostatic action between anions and cations or via hydrogen bonding [15,16,17,18]. Selenium’s unique reactivity ensures regioselectivity and stereoselectivity is achieved. Selenium is often used in organic synthesis as nucleophilic selenophiles, electrophilic selenophilic reagents and free radical selenium reagent [19,20,21,22]. Selenium has a lower bond energy and electronegativity than sulfur, which belongs to the same group in the periodic table. Due to its redox properties, it is easy to remove as well as substitute selenium atoms in a reaction. Hence, current research is mostly focused on the synthesis of non-chiral organic selenium compounds. The main reason is the rapid racemization of intermediates, which hinder the formation of chiral organic selenium compounds.

In the past decade, the importance of organoselenium compounds, especially chiral organoselenium compounds has been the focus and several groups are committed to developing new strategies for the synthesis of chiral organoselenium compounds. Organoselenium compounds are important building blocks in materials chemistry [23,24,25,26,27]. Chiral organoselenium compounds are indispensable intermediates [28] that can serve as the core backbone of a drug [29,30,31,32]. They also play an important role in organic asymmetric synthesis, for example, chiral catalysts and chiral ligands are used to regulate enantioselectivity, as shown in (Figure 2). Although extensive research has been conducted on various preparation methods and applications of chiral organoselenium compounds, there are few reviews related to the study of chiral organoselenium compounds. As early as 2007, Zhu [33] reported in detail the synthesis strategy of asymmetric organoselenium compounds. However, with the rapid development of asymmetric synthesis in recent years, the synthetic strategy of asymmetric organoselenium compounds has also grown. The review of asymmetric organic selenium compounds needs updating, and the classification should be more comprehensive. Zeng [34] and Back [35] have recently collated literature in this topic, which includes asymmetric processes catalyzed by chiral selenium-based reagents, auxiliaries, and catalysts Selenium-containing catalysts play an important part in numerous reactions. Examples include selenium-ligated palladium (II) complexes as Heck reaction catalysts, organoselenium catalysis in Michael-Type reactions, and organoselenium compounds that catalyze organic asymmetric synthesis. Rodríguez [36] discussed the use of selenium in catalysis and proposed reaction mechanisms.

There are three general methods (Figure 3) for the synthesis of chiral organic selenium compounds: (a) chiral substrate-controlled methods; (b) chiral ligand-controlled methods, a chiral auxiliary primarily controls enantioselectivity through complex interactions between chiral ligands and metals [37,38]; (c) chiral catalyst-controlled methods: enantioselectivity is controlled through electronic effects and steric hindrance [39,40,41]. However, no visible boundaries exist, such as asymmetric olefin addition and cyclization, which are frequently aided by chiral ligands or chiral catalysts.

Some chiral auxiliaries, for example, can be utilized as chiral catalysts in asymmetric synthesis as well. Our goal is to summarize progress in the synthesis of enantioselective organoselenium compounds based on their reaction type, which is divided into the following groups: asymmetric cycloaddition, seleniolactonizations, selenioaminations and amides, asymmetric addition reaction, asymmetric selenizing of aldehydes/ketones, asymmetric ring-opening reaction, asymmetric substitution reaction, and asymmetric decarboxylation reaction. The first section of this review covers the synthesis of chiral organic selenium compounds, while the second section discusses the use of chiral organic compounds as catalysts in organic asymmetric synthesis. Enantioselective synthesis of chiral selenium compounds is a rapidly growing topic in modern organic synthesis. Furthermore, chiral selenium compounds have gained considerable attention because to their high potential in catalytic asymmetric synthesis.

Our research group has focused on asymmetric catalytic processes, including asymmetric hydrogenation [42,43,44,45,46], asymmetric radical reaction, and asymmetric C–H activation [47]. Organoselenium compounds have been used in a variety of applications and industries. We began our research on organoselenium compounds in 2020 and published the first example of a selenium-directed C-H borylation procedure for the synthesis of diverse organoselenium compounds [22]. Later in 2022, we reported the first example of radical cyclization and ring-opening of oxime esters using diselenides to synthesize a variety of functionalized organoselenium compounds [21]. To the best of our knowledge, there have been no reports of asymmetric hydrogenation to create chiral organoselenium compounds. Based on our previous research findings, we are focusing on asymmetric hydrogenation and an asymmetric radical strategy for the simple synthesis of organoselenium compounds. So far, we’ve made good progress in the lab.

2. Asymmetric Synthesis of Organoselenium Compounds

Stereoselective processes involving C-Se, Se-Se, Se-O, and Se-N bonds have grown in diversity, efficiency, and applicability [19,48,49,50]. In general, chiral organoselenium compounds are synthesized via three routes. In this section, we describe the asymmetric synthesis of organoselenium compounds using substrate manipulation, chiral additives, and chiral catalysts, that result in a series of optically active organoselenium derivatives.

2.1. Chiral Catalyst or Ligand-Controlled Method

2.1.1. Asymmetric Cycloaddition

In 1996, Yamazaki and coworkers [51] reported the reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene 1 and α-unsaturated ketone 2 in the presence of TiCl₄, Ti(OiPr)₄, (R)-(BINOL) Cat.1 chiral Lewis acids. The result was a cis-cyclopropane product 3 (Scheme 1) with moderate enantioselectivity (40–57% ee) and yields of 4–45%.

Scheme 1 depicts a probable reaction mechanism for the asymmetric [2 + 1] cycloaddition reaction. The first step is to combine vinyl ketone 2 with chiral titanium to generate a chiral titanium-vinyl ketone complex (I), which will be attacked by selenosilyl nucleophile 1. The titanium-vinyl ketone complex (I) can take either s-cis or s-trans configuration. Because of the stable secondary orbital interaction (Se---C=O), synclinal stereoselective addition may have an effect on face selectivity. The succeeding 1,2-silicon migration generates selenium-bridged intermediate (IV) by minimum motion and ring closure, yielding cyclopropane 3.

2.1.2. Selenolactonizations

In 2010, Denmark and coworkers [52] used Lewis base to catalyze the asymmetric intramolecular selenoetherification of unsaturated alcohols 4. An extensive study of chiral Lewis bases showed that 1,1′-binaphthalene-2,2′-diamine (BINAM)-derived thiophosphoramides catalyzed cyclization of unsaturated alcohols 4 in the presence of N-(2-nitrophenylselenenyl) succinimide 5 and methanesulfonic acid (Scheme 2). A variety of cyclization products 6 were synthesized with good chemical yield (97%) and moderate to good enantioselectivity (70% ee). The catalytic and enantioselective selenium functionalization of unactivated olefins were achieved for the first time. The authors investigated the reaction mechanism, revealed that the cycle begins with the reversible binding of Lewis bases to selenimide to create adducts (I). Succinimidyl protonation in (I) generated the intermediate (II). This was followed by the formation of cyclic selenium ions (III), which underwent nucleophilic trapping, releasing the product and regenerating the Lewis base catalyst. A mechanism for inhibiting the racemization of selenium ion intermediates (II) was discovered. When aryl selenium cation transfer cyclization (III) occurs quicker than substrate racemization, high enantioselectivity might be expected.

In 2014, Jacobsen and coworkers [53] reported a novel chiral squaramide catalyst Cat.3 in combination with mineral acids and achiral Lewis bases capable of high enantioselective selenocyclization (Scheme 3). The authors selected o-allyl-substituted phenol 7 as the substrate because it can form a chroman-type product with two contiguous stereogenic centers; N-p-anisylselenyl succinimide (NPASS) as the selenium donor; and hydrogen chloride as a co-catalyst. Activating the electrophilic selenium reagent with Lewis bases and Brønsted acids gave a reactive ion pair that may be linked to the squaramide catalyst. Tris-(dimethylamino)phosphorus sulfide (HMPA(S)) promoted selenocyclization and the products 8 were obtained in excellent enantioselectivity (up to 92% ee). The enantioselectivity of recrystallized products increased to 99% ee. The strategy had good substrate applicability, and most of the substrates yielded the target products with good to excellent yields and high enantioselectivity. The mechanistic studies revealed that the enantioselectivity of selenium ions was caused by dynamic kinetic resolution via anion-binding catalysis.

In 2015, Yeung and coworkers [54] reported a catalytic and highly enantioselective selenolactonization of olefinic acids using (DHQD)₂PHAL Cat.4 as a bifunctional organocatalyst (Scheme 4). Treatment of olefinic acids 9 and N-phenylselenophthalimide(N-PSP) 10, used as the electrophilic selenium reagent, gave the corresponding selenolactones 11 with up to 96% ee. The substrates scope was extended to include different skeletons 12 under the standard conditions, and gave 13 in 74% ee. This catalytic system was applied to diene carboxylic acid 14 where desymmetrization-asymmetric selenolactonization occurred, affording 15 in 90% ee with 12:1 dr.

In 2018, Yeung, Wong and Ke [55] developed asymmetric selenocyclization and desymmetrization of olefinic 1,3-diol, This is promoted by a unique chiral pairing between a C₂-symmetric cyclic selenide Cat.5 catalyst as the Lewis base and a chiral BINOL-derived phosphoric acid Cat.6 as the Brønsted acid cocatalyst (Scheme 5). In this study olefinic 1,3-diol 16 was the substrate and N-phenylselenophthalimide (N-PSP) 10 was the electrophilic selenium reagent. A range of phenylseleno-functionalized tetrahydrofuran 17 were synthesized with good to excellent diastereo- and enantioselectivity (up to 98% yield; up to 98:2 er and >99:1 dr). The tetrahydrofuran products 17 contained a phenylselenoether moiety, that was further transferred to useful synthetic compounds, such as aldehydes. Mechanistic studies and theoretical calculations show that chiral Cat.5/(R)-Cat.6 pairs form a supramolecular catalytic system via hydrogen bonds in the selenocyclization reaction.

2.1.3. Selenoaminations and Amidations

In 2013, Gong and coworkers [56] reported selenofunctionalization of tryptamine derivatives catalyzed by chiral phosphoric acid to afford 3a-(phenylselenyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole derivatives (Scheme 6). Treatment of tryptamine derivatives 18 and N-(phenylseleno)phthalimide (N-PSP) 10 in the presence of chiral phosphoric acid Cat.6 yielded 3a-(phenylselenyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole derivatives 19 in good yield (up to 85%) and with good enantioselectivity (up to 89% ee). Furthermore under alkaline conditions, the oxidative deselenation of 19-a with m-CPBA produced the corresponding alcohol 20 in 95% yield, which could be subsequently converted to the chiral precursor (+)-alline. The alcohols exhibited the same stereochemistry as the parent selenide.

In 2022, Chen and coworkers [57] reported the first enantioselective selenocyclization of 1,1-disubstituted alkenes 21. They achieved this by combining chiral BINAM-derived sulfides Cat.7 and achiral Lewis acids BF₃▪THF to produce chiral oxaquaternary stereocenters (Scheme 7). Various selenium-containing 4H-3,1-benzoxazine derivatives 21 were obtained in moderate to good yields (up to 93%) and good to excellent enantioselectivities (up to 96% ee). Product 22-a was oxidised to selenoxide 22-b with m-chloroperbenzoic acid with excellent yield (>99%). Product 22-b generated product 23 (77% yield and 93% ee) via reductive deselenenylation using AIBN/Bu₃SnH. The Seleno−Pummerer reaction with TFAA and TMSN₃ gave product 24 (67% yield, >25:1 dr, 94% ee).

2.1.4. Asymmetric Addition Reaction

In 1979, Wynberg and Pluim [58] reported the first enantioselective synthesis of organoselenium compounds using (−) cinchonidine Cat.8 (Scheme 8). The asymmetric catalytic addition between aryl selenol 26 and 2-cyclohexen-1-ketone 25 was achieved. The target products 27 were generated in excellent yields (>95%) and enantioselectivity (11–43% ee).

In 2000, Uemura and coworkers [59] reported aryl benzyl selenide 28 reacted with N-(p-toluenesulfonyl)imino]phenyliodinane [TSN = IPH] in toluene or acetonitrile to give the corresponding N-p-toluene selenimide 29 in yields of 31–64% and 20–36% ee (Scheme 9). Enantioselective imidation was used in the presence of chiral bis (oxazoline) ligands Lig.1 and molecular sieve to produce N-p-toluene selenimide, with best being 2-naphthylbenzylselenimide (64% yield, 36% ee). The addition of molecular sieves remove water in the reaction. This stops the equilibrium between selenimide and selenium oxide, which is known to racemize rapidly [60,61,62,63]. Hence, removing water is a key step to control the enantioselectivity of the reaction.

In 2011, Alemán and Marini [64] described a new strategy for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides 32. Addition of α-selenocarbonyl derivatives 30 and catalyzed by thiourea or squaramide cinchona catalysts gave nitroalkenes 31 (Scheme 10). This reaction was carried out at low catalyst loading with excellent chemoselectivity (up to >99% ee, up to >98:2 dr).

In 2012, Shi and coworkers [65] used N-triflyl phosphoramide Cat.11 via Brønsted acid catalysis for enantioselective oxyselenenylation of olefins (Scheme 11). Olefins 33 were enantioselectively desymmetrized with N-phenylselenophthalimide 10 and benzoic acid 34 in the presence of Cat.11, generating the chiral selenide target product 35 with moderate to good enantioselectivities (25–84% ee). Surprisingly, when compared to sulfenamide, the Se reagent displayed higher reactivity toward olefins.

In 2018, Yan and coworkers [66] reported the first organo-catalyzed enantioselective addition of selenosulfonate 36 to α, β-unsaturated ketones 2 (Scheme 12). A chiral bifunctional squaramide produced from quinine Cat.12 are an efficient catalyst. The desired α-selenylated ketones 37 were obtained in good yield with high enantioselectivity (up to 87% yield and 89% ee). They can be efficiently transformed into useful building blocks with a propenylic stereocenter.

Later, Qin and Mao [67] also reported the use of chiral squaramide Cat.13 in the enantioselective catalysis of selenosulfonate 38 to α, β-unsaturated ketones 39 in saturated NaCl solution (Scheme 13). High yields and enantioselectivity were achieved for a series of α-selenyl and β-sulfonyl ketones, with two contiguous stereogenic centers, (up to 85% yield, 90% ee and dr > 20:1). Furthermore, they demonstrated effective stereocontrol in transforming chiral α-selenyl and β-sulfonyl ketones 40 into their corresponding alcohols.

In 2020, Wang and Bian [68] developed the Rh(I)/(S)-Xyl-Binap catalytic system for the asymmetric hydroselenation of various nonpolar olefins 41 with diselenides 42 to produce selenol-incorporated adducts 43 (Scheme 14). By overcoming self-promoted racemic hydroselenation, a number of heterobicyclic alkenes produced selenol-incorporated adducts with high yields (up to 96%) and exceptional enantioselectivities (up to 97% ee). The approach was also used for kinetic resolution of unsymmetric oxabenzonorbornadiene.

In 2021, Peregrina and coworkers [69] reported the first entirely chemo- and diastereoselective 1,4 conjugate additions of various Se-nucleophiles. These were generated in situ from diselenide derivatives by the action of sodium borohydride, to chiral bicyclic dehydroalanine (Dha) 44 (Scheme 15). Only single diastereomers 45 were formed in the Se-Michael addition reaction on Dha 44. The results proved that the reaction was completely diastereoselectivity controlled. Acidic hydrolysis of Se-Michael adduct 45 resulted in the formation of enantiopure selenocysteine (Sec) derivatives 46, that have significant potential for chemical biology applications [70].

In 2022, Huang and Chen [71] reported a chiral bifunctional N-heterocyclic carbine (NHC)/thiourea catalyzed Se-Michael conjugate addition reaction between α, β-unsaturated ketones 39 and alkyl selenol 26 (Scheme 16). Synthesis of various chiral β-selenol carbonyl derivatives 48 were achieved with excellent yields (up to 98%) and enantioselectivities (up to 99% ee). The (NHC)/thiourea catalyst addresses the issue of reversibility due to the high nucleophilicity and leaving group ability of selenols, which was the main challenge in the development of asymmetric Se-Michael addition reactions. Both the NHC and thiourea moiety were required to achieve high enantioselectivity.

In 2022, Yang and Dong [72] reported the first Rh(cod)₂BF₄/MeO-BIPHEP Lig.3 catalyzed enantioselective Markovnikov hydroselenation of selenols 26 with styrene 49 (Scheme 17). The desired chiral selenides were obtained in moderate to high yield (up to 91%) with good enantioselectivities (up to 98:2 er) and excellent regioselectivity (>20:1 rr). Based on their previous mechanistic studies, it was speculated that the reaction forms C-Se bonds with excellent regio- and enantiocontrol via a Rh-hydride pathway. Rh(I) catalysts can undergo oxidative addition to Se−H bonds to form Rh hydrides [73]. Here Rh(I) catalysts are added to ArSeH 26 to generate the Rh complex (I) to yield Rh−H (II), a resting state of the catalytic cycle validated by NMR studies. The olefin coordinates to intermediate (II) and provides (III). Olefin migration to the Rh−H bond, providing intermediate (IV). Intermediate (IV) is reductively eliminated to yield intermediate (V), which is subsequently dissociated with product 50 to regenerate the Rh catalyst (I).

In 2022, Feng and Liu [74] reported a novel asymmetric [2,3]-sigmatropic rearrangement of allylic selenides 52 with α-diazo pyrazoleamides 51 catalyzed by chiral N,N′-dioxide cobalt(II) complex. It is an efficient synthetic method for the preparation of optically active selenide with a quaternary C-Se stereocenter (Scheme 18). The reactions were done with 0.5–5 mol% catalyst loading and afforded chiral selenides 53 in up to 99% yield and 97% ee. The control experiments revealed that allyl selenide had high reactivity. Chiral N, N′-cobalt dioxide ligands and α-diazo pyrazoleamide had obvious superiority in the [2,3]-sigmatropic rearrangement reaction. The mechanistic studies have shown that the key to asymmetric rearrangement of allyl selenium ylides involves the transfer of chirality from the stable chiral selenium to the carbon of the product.

In 2023, Yin and coworkers [75] reported a Cu(CH₃CN)₄PF₆/(R,R_p)-TANIAPHOS Lig.5 catalyzed asymmetric conjugation/protonation with α -substituted α,β-unsaturated thioamide 54 and selenols 26 (Scheme 19). More than 40 examples of α-chiral β-selenothioamide 55 were generated in high to excellent yields (up to 99%) and enantioselectivities (up to >99% ee). The catalytic system was also successfully applied to the asymmetric selenization of β-substituted α, β-unsaturated thioamides (2 examples) with high yields (up to 86%) and excellent enantioselectivities (up to 99% ee).

2.1.5. Asymmetric Selenization of Aldehydes/Ketones

In 2004, Toru and colleagues [76] reported that α-seleno carbanions derived from bis (phenylseleno) acetal 56 and bis (2-pyridylseleno) acetal 56 react enantioselectively in the presence of chiral bioxazoline Lig.6 with electrophiles giving products 57 with excellent reactivity and high enantioselectivity (Scheme 20). The authors evaluated the reactivity of several electrophiles and found good enantioselectivity (95% ee), demonstrating the method’s viability.

In 2007, Melchiorre and Marini [77] reported the application of an enamine activation strategy in the first highly enantioselective α-selenenylation of aldehydes 58 using a chiral secondary amine as catalyst and N-(phenylseleno)phthalimide 10 as the electrophilic selenium source (Scheme 21). Diarylprolinol silyl ethers salt (Cat.15·p-NO₂PhCOOH) exhibited excellent selectivity and had higher catalytic activity. Various aldehydes, including alkyl, alkenyl, and hetero-substituted groups were tolerated in the reaction and afforded α-seleno aldehyde 59, which was further reduced, in situ with NaBH₄, to the corresponding chiral alcohol 60 (up to 99% yields, up to 99% ee) without loss of optical purity. Later, a similar approach was undertaken by Córdova and coworkers [78] who reported a highly enantioselective α-selenenylation between aldehydes 58 and N-(phenylseleno)phthalimide 10. The reaction was directed using diarylprolinol silyl ethers (Cat. 16) as catalyst and gave the desired product α-selenoaldehydes and β-selenoalcohols in 63–93% yield with up to 96% ee.

In 2010, Posner and coworkers [79] reported the application of α-seleno aldehyde 59 for the synthesis of α-hydroxy-(E)-β,γ-unsaturated esters 63 in a two-step method (Scheme 21). The highly enantioselective α- seleno aldehyde 59, synthesized in one step by asymmetric organocatalytic α-selenylation of aldehydes, was directly subjected to in situ Wittig reaction to give allylic selenide 61. This was oxidized to selenoxide 62 using H₂O₂ which resulted in the spontaneous [2,3]-sigmatropic rearrangement, giving the target compound 63 in 43–65% overall yield and in 94–97% ee. Posner and coworkers [80] soon reported the application of α-seleno aldehyde 59 for the synthesis γ-substituted-α, β-ethylenic esters. Chiral γ-seleno-α, β-ethylenic esters 61, were, prepared using the Wittig reaction, and treated with sulfonyl chloride and ethyl vinyl ether in hexane to give α-chloro-β, γ-ethylenic esters 64 in 65–75% yield and with 95–97% ee. These allyl chloride compounds react with Me₂-CuMgBr and sodium azide to yield γ-substituted-α, β-ethylenic esters 65. The allylic chlorides 64 were treated with sodium azide to produce the azide-substituted product 66, which was then reduced in situ using stannous chloride to the amine. This was then treated with di-tert-butyl dicarbonate affording the N-Boc-γ-amino-α, β-ethylenic tert-butyl esters 67. Chiral racemic allyl chloride is a multifunctional, stereochemically stable electrophilic chiral compound with good chiral control and that can perform various nucleophilic substitution and olefin addition reactions.

In 2011, Armstrong and his coworker [81] developed a method to synthesize chiral α-alkyl, α-vinyl amino acids 70 and 71(quaternary vinyl glycine derivatives) using allylic selenimides as the raw material via [2,3]-sigmatropic rearrangement (Scheme 22) with excellent enantioselectivity (90–97% ee). The trisubstituted allylic selenides 68 and 69 were prepared by asymmetric organocatalytic α-selenenylation reaction of aldehydes 58 and Horner-Wadsworth-Emmons (HWE) olefination. Both enantiomers 70 and 71, which were obtained after rearrangement of the (E)- and (Z)- geometric isomers 68 and 69, exhibit excellent enantioselectivity.

In 2014, Armstrong and coworkers [82] then developed the NCS-mediated amination/[2,3]-sigmatropic rearrangement of enantioenriched allylic selenides 68, and provided a novel strategy that uses N-protected amino acid amides to synthesize a series of peptides containing unnatural vinyl glycine amino acids resides 70-a (Scheme 23). This strategy was applied to N-unprotected amino acid esters to generate N, N-dicarboxymethylamines 70-b, which is a motif found in several pharmaceuticals. Furthermore, it was modified for the aromatic amines to provide a pathway to obtain a variety of high-enantioenriched N-arylamino acids 70-c. These three product categories highlights the versatility of the amination of allyl selenide [2,3]-sigmatropic rearrangement as a method for synthesizing enantioenriched allyl amine derivatives and broadens the substrate range to previously unreported carbamates, alkyl amines, and aromatic amines.

In 2022, Wang and coworkers [83] developed a CrCl₂/(S,R)-Lig.7 catalyzed three-component reaction, for the preparation of valuable chiral β-hydroxy selenides 74 having adjacent stereocenters from vinyl selenide 72, iodide 73, aldehydes 58 (Scheme 24). A series of chiral β-hydroxy selenides 74 had good functional compatibility and were obtained in moderate to good yields (up to 86%), high diastereoselectivity (up to > 20:1 dr) and enantioselectivity (up to 96% ee). Mechanistic investigations suggest that the reaction may occur through a secondary alkyl Cr intermediate stabilized by α-selenide groups.

2.1.6. Asymmetric Ring-Opening Reaction

In 2005, Zhu and coworkers [84] used a novel chiral Ti^IV-Ga^III-Salen heterometallic catalytic system 77 and obtained the optically active β-arylseleno alcohols 76 via an asymmetric ring-opening reaction with meso-epoxides 75 and aryl selenols 26 (up to 97% ee) (Scheme 25). The catalytic process revealed a strong synergistic effect of different Lewis acids in the system. The method has a good substrate scope, and a series of β-arylseleno alcohols derivatives was obtained in good to excellent enantioselectivities for both cyclic and acyclic meso-epoxides. However, the reaction mechanism remains unclear. Epoxides are likely to coordinate and activate the hard Lewis acid titanium, while nucleophilic reagent selenophenol coordinates with the relatively soft Lewis acid gallium, thereby effectively and selectively directing the attack of the selenophenol to the epoxide.

2.1.7. Asymmetric Substitution Reaction

In 2015, Yuan and coworkers [85] used commercial cinchonidine Cat.8 under mild conditions to synthesize 3,3-disubstituted oxindoles 79 via asymmetric selenenylation of 3-pyrrole-oxyindole 78 with good to excellent enantioselectivity (up to 93% ee) (Scheme 26). Various optically active 3-seleno-3-pyrrole-oxindoles 79 were successfully obtained. Substrate expansion experiments showed that the electronic and steric hindrance effect had little effect on the reactivity and enantioselectivity.

In 2020, Chen and coworkers [86] reported Ni(OTf)₂ as a Lewis acid catalyzed asymmetric selenocyanation of β-ketoesters 80 using a new selenocyanation reagent N-selenocyanatosaccharin 81 in the presence Lig.8 (R,R)-DBFOX/Ph (Scheme 27). A series of α-selenocyanato-β-keto esters 82 were synthesized with good yields (up to 99%) and good ees values (up to 92%). This approach is straightforward, highly enantioselective, and appropriate for the synthesis of chiral selenocyanates. This is the first report on the asymmetric formation of the C(sp³)-SeCN bond.

In 2024, You and coworkers [87] achieved rhodium(III)-catalyzed Cat.18 atroposelective C−H selenylation of 1-aryl isoquinolines 83 (Scheme 28). The C−H selenylation reaction between 1-aryl isoquinolines 84 and 2- (phenylselanyl)isoindoline-1,3-dione in 10 the presence of the chiral SCpRh(III) complex afforded a series of axial chiral 1-aryl isoquinoline selenides 84 in up to 95% yield and 96% ee. DFT calculations show that the C-Se bond formation step is via the S_N2 pathway.

2.1.8. Asymmetric Decarboxylation Reaction

In 2008, Tunge and coworkers [88] reported the Pd₂dba₃/Np-Trost Lig.9 catalyzed decarboxylation of selenocarbonates which afforded enantioenriched allyl selenides 86 (Scheme 29) in good yields (44–46%) and excellent enantioselectivities (89–96% ee). The remaining unreacted selenocarbonate 87-a/b were also isolated with excellent enantioselectivities (92–99% ee). The allyl selenide 86-b underwent a [2,3]-sigmatropic rearrangement to form allylic amine 88 with high enantioselectivity (92% ee), or was converted to allyl chloride 90 by treatment with NCS in CH₂Cl₂ under mild conditions.

2.2. Substrate Control Enantioselectivity

In 2012, García Ruano and Degl’Innocenti [89] reported the synthesis of enantiomerically pure 1,2-selenoamines with two stereocenters using (S)-α-(phenylselenyl)-2-(p-tolylsulfiny) toluene 91 and (S)-N-(p-tolylsulfiny) imide 92 (Scheme 30). The character of the aliphatic or aromatic N-sulfinylimines 92 that are obtained is closely related to the syn or anti stereochemistry of the 1,2-Selenoamines (up to >98% ee, up to >98% dr, up to 80% yield). LDA was added to a THF solution of (S)-91, forming a delocalized benzylcarbanion. Then (S)-92 was added to afford diastereomerically enriched 93-a and 93-b. To synthesize enantiomerically pure 1,2-selenoamines compounds 94-a and 94-b should be desulfinylated without affecting the C−Se bond nor their configurational integrity. This synthetic transformation was carried out for 94-a and 94-b, derived from aryl- and alkyl imines 93-a and 93-b, using a two-step sequence consisting of initial C-desulfinylation with t-BuLi and subsequent N-desulfinylation with TFA.

In 2015, Liao and coworkers [90] reported a novel asymmetric synthesis of dihydronaphthoquinone incorporating adjacent quaternary and tertiary stereocenters via a Se-Michael addition triggered ring-expansion method (Scheme 31). Treatment of chiral phthalide 95 with lithium selenophenolate (PhSeLi), which was generated in situ from selenophenol and n-butyllithium, gave the desired chiral organoselenium 96 in good yield (64%), excellent enantioselectivity (96% ee) and diastereoselectivity (>19:1 dr). Although the precise mechanism by which magnesium cations control the reaction’s selectivity is not well understood, we could refer to the mechanism for the sulfonamide-Michael addition/nucleophilic addition tandem reaction [91,92,93]. The assumption is: the magnesium cation coordinates favorably to both the oxygen atom of the lactone and the enolate units of intermediate (I) to form a chelating structure which may contribute the current high diastereoselectivity in this tandem process.

In 2016, Fu and coworkers [94] developed an efficient method for the synthesis of chiral α-selenoamino acids 98 using visible light photoredox (Scheme 32). N-Acetoxyphthalimide derivatives of two genetically coded proteinogenic amino acids, including L-aspartic acid and glutamic acid, where the carboxyls on the side chains of N-Bis(Boc)-Asp(OPht)-OMe (97, n = 1) and N-Bis(Boc)-Glu(OPht)-OMe (97, n = 2), were reacted with various diorganyl diselenides 42. The reaction was carried out in the presence of diisopropylethylamine (DIPEA), Hantzsch ester (HE) and irradiation of 40 W compact fluorescent light (CFL) under argon atmosphere at room temperature using [Ru(bpy)₃]Cl₂ as the photocatalyst to afford chiral α-selenoamino acids 98. They also proved that the visible-light photoredox decarboxylative coupling maintained the chirality of the desired products α-selenoamino acids 98 (n = 1, R = Ph, >99% ee).

In 2018, Punniyamurthy and coworkers [95] described a new approach that involved Al-catalyzed stereospecific tandem C-N/C-Se bond formation of chiral aziridines 100 with isoselenocyanates 101 giving 90–99% ee and 77–91% yields (Scheme 33). The energy profile diagram for the reaction (Scheme 33, bottom right) clearly shows that it is a one-step S_N2-type reaction. The observed experimental and DFT studies indicate that chelation of isoselenocyanate 99 with Al-salen may result in the formation of an Al-complex (I), which can couple with aziridine 100 via a concerted S_N2 pathway b to produce the target products 101.

In 2020, Zeng and coworkers [96] developed a new method to synthesize (enantioenriched) selenoethers 103 from (chiral) benzylic trimethylammonium salts 102 and di(hetero)aryl diselenides 42 (Scheme 34). Benzyl selenyl ether was synthesized under weak basic conditions without transition metal catalysis with good to excellent yields (up to 93%) and high enantiomeric purity (up to 99% ee). Later in 2021 they developed a novel approach for the synthesis of (enantio-enriched) dibenzyl diselenides 105 via S_N2 nucleophilic substitution of (enantiomerically enriched) benzyl quaternary ammonium salt 104 and diselenide dianion (Se²⁻) [97].

3. Application of Chiral Organoselenium Compounds in the Asymmetric Catalysis

Organoselenium compounds exhibit a wide range of chemical properties. Their use in catalysis is very relevant and well documented. Furthermore, a number of synthetic approaches to access diverse chiral organoselenium are reported. A number of chiral selenide compounds were produced and employed as catalysts in a variety of asymmetric reactions (Scheme 35).

In 2003, Braga and coworkers [98] synthesized a series of chiral aliphatic aminodiselenide Cat.21 by the ring-opening reaction of azidine 107 which was then used as a catalyst for the enantioselective addition of diethylzinc to aldehydes (Scheme 36). The chiral secondary alcohol derivatives 109 were produced in good to excellent yields (up to 93%) and enantioselectivities (up to >99% ee). In substrate expansion experiments, the effect of alkyl substituents and aryl substituted aldehydes on stereoselectivity was examined, and the results showed moderate to excellent enantioselectivities (45 - > 99% ee). Notably, alkyl chains have a greater effect on enantioselectivity, resulting in a significant decrease in enantioselectivity from hexanal (>99% ee) to decanal (45% ee).

In 2013, Yeung and coworkers [39] used a C₂-symmetric mannitol-derived cyclic selenium to catalyze asymmetric bromocyclization of trisubstituted olefinic amides 110 (Scheme 37, up to 95% ee). The resulting enantioenriched pyrrolidine derivatives, with two stereogenic centers, can undergo rearrangement to yield 2,3-disubstituted piperidines 111 with good diastereoselectivity and enantiospecificity. It is hypothesized that the mechanism of this cyclic-selenium-catalyzed bromocyclization reaction (Scheme 37) is as follows: coordination of Lewis basic selenium Cat. 20 to NBP forms activated electrophilic brominating species (I). Subsequent interaction between (I) and the olefinic substrate 110 would give selenium coordinated bromonium intermediate species (II).

In 2017, Zhao and coworkers [99] developed a new bifunctional chiral selenide Cat.22-a for catalyzing the enantioselective CF₃S aminocyclization of olefins 112 to construct a series of saturated azaheterocycles 114-a/b in good yields (up to 99%) high diastereo-and enantioselectivities (Scheme 38, up to 97% ee, >99:1 dr). This method provides a new approach for the synthesis of chiral saturated pyrrolidines and piperidines. The indane-based chiral amino aryl chalcogenide catalysts can give acceptable H-bonding by varying the amino protecting groups. They can also produce good Lewis basicity and steric hindrance by modifying the substituents on the aryl chalcogenide motifs. These features allow them to produce a chiral environment while also meeting the reactivity requirements. Notably, they have been effectively applied to several asymmetric electrophilic reactions involving alkenes, alkynes, and arenes, thus broadening the field of electrophilic reactions [100].

In 2018, Zhao and coworkers [101] again reported the use of chiral selenide Cat.22-a for oxytrifluoromethylthiolation of aliphatic internal alkenes 115, for the synthesis of CF₃S-substituted 1,3-amino alcohol 116 (up to 98% yield and up to 94% ee) and 1,3-diol derivatives 117 (86% yield, and 95% ee) with high regio-, enantio-, and diastereoselective (Scheme 39, up to >99:1 dr). In this approach, the alkenes were functionalized regioselective, with the surrounding imide or ester group providing a functional group.

In another investigation in 2018, Zhao and coworkers [102] reported the use of chiral selenide Cat.22-a for allylic trifluoromethylthiolation of alkenes 118, affording the chiral allylic CF₃S-substituted products 119 in good to excellent yields (up to 95%) and excellent enantioselectivities (Scheme 40, up to 95% ee). The unactivated alkenes 118 also achieved intermolecular difunctionalization in the presence of a nucleophile reagent, generating the corresponding difunctionalized chiral CF₃S-substituted products 120 in moderate to good yields (up to 80%) with excellent enantio- and diastereoselectivities (up to 93% ee, >99:1 dr). This method provided a new approach for the synthesis of C-SCF₃ stereogenic compounds, where alkenes do not require directing group assistance for enantiocontrol.

In the same year, Zhao and coworkers [103] reported the use of efficient chiral bifunctional selenide Cat.22-a for enantioselective desymmetrization and trifluoromethylthiolation of gem-diaryl tethered alkenes 121, which gave the corresponding CF₃S-tetrahydronaphthalene derivatives 122 in good to excellent yields (up to >99%) with excellent enantio- and diastereoselectivities (Scheme 41, up to >99% ee, >99:1 dr). Remarkably, diphenyl-tethered alkynes 123 also worked well in the reaction and gave the desired chiral dihydronaphthalenes compounds 124 in good yields (68% and 73%) with excellent enantioselectivities (up to 95% ee).

In 2019, Zhao and coworkers [104] discovered a new application for chiral bifunctional selenide Cat.22-b, which was used for enantioselective trifluoromethyl thiolation of 1,1-disubstituted olefins 125 (Scheme 42). Various chiral trifluoromethylthiolated 2,5-disubstituted oxazoles 126 were synthesized in good yields (up to 76% yield) with good to excellent enantioselectivities (up to 94% ee), providing a new approach for the synthesis of chiral oxazolines.

In 2019, Zhao and his coworker [105] reported the use of new chiral bifunctional selenide Cat.22-c for electrophilic azidothiolation and oxythiolation of N-allyl sulfonamides 127, to construct chiral vicinal azidosulfides and oxysulfides 129 in good yields (up to 95%) with excellent enantio- and diastereoselectivities (Scheme 43, up to 97% ee, up to >99:1 dr). This is the first example of chiral bifunctional selenide-catalyzed enantioselective electrophilic azidothiolation and long-chain-alkylthiolation of alkenes, which indicates the possible application of this method to other alkenes. The key arylthiiranium ion intermediate in the reaction is depicted as an anion bridge Tf₂NH which binds to the substrate and the catalyst (Scheme 42).

In 2020, Zhao and coworkers [106] reported the use of chiral bifunctional selenide Cat.22-d or Cat.22-a for desymmetrizing enantioselective electrophilic aromatic halogenation of 130 (Scheme 44), to construct P-chirogenic triaryl phosphine oxide compounds 132 or 133 in high yields (up to 98%) with excellent enantioselectivities (up to >99% ee). Interestingly, chlorination switches from ortho to para positions, when the substrates were changed from triaryl phosphine oxides to alkyl diaryl phosphine oxides and diaryl phosphinates, depending on the structure of the phenols. Control experiments were carried out and the results showed that H-binding could strengthen the interaction between the catalyst and substrate to control the reactivities and racemization.

In 2021,Chein and coworkers [107] reported the use of a new type of chiral tetrahydroselenophene Cat.23-a or Cat.23-d (Scheme 45), which were synthesized from (R)-3-(3-bromopropyl)-2,2-diphenyloxirane, for asymmetric cyclopropanations of (E)-chalcones 134, giving the cyclopropanes 136 with moderate to excellent yields (up to 95%) and excellent enantioselectivities (up to 99% ee). This is the first example of chiral selenide-catalyzed enantioselective cyclopropanation reaction. The proposed catalytic cycle (Scheme 45) shows selenide catalyst I is initially converted into selenonium salt II, and then transformed into the corresponding ylide III-b under basic conditions. The ylide carbanion’s unshared electrons are delocalized in the selenium atom’s 4d orbitals, forming the benzene system. Thus, the resonance structure of betaine adopts a conformation [108,109,110,111], in which the lone electron pair on the selenium remains orthogonal to the π-system of ylene III-a, while the phenyl group occupies a sterically relaxed pseudoequatorial position. The bulky side chain in III is positioned so that it blocks the si face of the ylide carbon, forcing the Michael receptor to be approached from the re face resulting in intermediate (V) with a preferred anti-anti-conformation.

In 2022, Zhao and coworkers [112] reported the use of chiral bifunctional selenide, including Cat.22-a, Cat.22-c, Cat.22-e, and Cat.22-f, for enantioselective electrophilic hydrothiolation of alkenes, which was a new approach for constructing chiral sulfides (Scheme 46). In the presence of electrophilic sulfur reagents 128 and silanes, the cyclic and acyclic unactivated alkenes 137 or 138 efficiently provided various chiral sulfide products 139 or 140 with good to excellent yields (up to 92% and 89%) and excellent enantioselectivities (up to 97% ee and 95% ee). Mechanistic studies indicated a relatively stable chiral thiiranium ion is considered the key reactive intermediate.

In 2023, Breder and coworkers [41] developed a new catalyst, which was chiral and nonracemic spirobiindane selenium-π-acid catalysts Cat.24, for asymmetric, photoaerobic lactonization and cycloamination of non-directing alkenes 141 (Scheme 47). 2,4,6-Tris(p-anisyl)pyrylium tetrafluoroborate was worked as photoredox catalyst and 4,4′-Dichlorodiphenyldisulfide was worked as cocatalyst. Enoic acids 141a or unsaturated sulfonamides 141b were exposed to photoredox catalyst in combination with Se-π-acid catalysts Cat.24 and sulfur cocatalyst under air and 465 nm irradiation for 5–24 h. Butenolides 142a and 3-pyrrolines 142b were obtained in good to excellent yields (up to 97%) and high enantioselectivities (up to 97:3 er). The authors investigated the impact of structural modifications on the catalysts 24. The electronic effect of the benzylic Se-protecting groups (7/7′position, Scheme 46) did not show a specific trend with regards to the er values (Cat.24 a-f). However, changing the Se-protecting group from benzylic to aliphatic protecting group had a significant effect (Cat.24 g-i). Modifications at position 6/6′ indicated that the oxygen atoms may play an important role in stereoinduction (Cat.24 j-p). The results were consistent with that reported by Wirth and Tomoda et al. They demonstrated that nonbonding interactions between n → σ* O···Se typically lead in rigid catalyst−substrate conformations, resulting in higher levels of stereoinduction [113,114]. Continuing with modification at the distal 5/5′ position had no significant effect on the reaction outcome (Cat.24 q-r). Making the catalyst skeleton more rigid by adding substituents (1s/t) led to weaker stereoinduction (Cat.24 s-t). For Cat.24-s, the author interpreted this as a result of conformational restrictions at the 6/6′O atoms, which potentially prevents n → σ* O···Se overlap.

In 2024, Zhao and coworkers [115] reported an efficient strategy of enantioselective thiolative azidation of sulfone-tethered alkenes 143 or 144 via a chiral chalcogenide Cat.22-g catalyzed electrophilic reaction (Scheme 48). A series of enantioenriched sulfones 146 or 147 bearing remote stereogenic centers was synthesized with good to excellent yields (up to 99%) and high enantioselectivities (up to 98% ee) with linear unsaturated sulfones and cyclic unsaturated sulfones.

4. Conclusions

In conclusion, the synthesis of chiral organoselenium compounds and their application as a catalyst in asymmetric synthesis over the past decade was summarized in this review. The common approach is to use chiral catalysts or chiral ligands to regulate enantioselectivity for asymmetric synthesis. Another method is to use the chiral structure of the raw material to control the stereoselectivity of the reaction process. In recent years, chiral organoselenium compounds have been developed as catalysts in asymmetric synthesis, facilitating the synthesis of a variety of target products with high enantioselectivity.

Although the synthesis of chiral organoselenium compounds has achieved significant progress, there are limited reactions for the use of chiral catalysts or chiral ligands. The synthetic route for these reactions is complex or not commercialized, which represents a further limitation of this method. Currently, controlling enantioselectivity through chiral catalysts or chiral ligands is still the principal method in asymmetric synthesis. Therefore, the development of a green and economical method [75] for the preparation and synthesis of chiral selenium compounds has a bright prospect.