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Review

Organoselenium Compounds Derived from Natural Metabolites

by
Agata J. Pacuła-Miszewska
1,*,
Magdalena Obieziurska-Fabisiak
2 and
Jacek Ścianowski
2
1
Department of Toxicology, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. 107 Hallera Street, 80-416 Gdansk, Poland
2
Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100 Torun, Poland
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(11), 1749; https://doi.org/10.3390/ph18111749
Submission received: 20 October 2025 / Revised: 10 November 2025 / Accepted: 14 November 2025 / Published: 17 November 2025
(This article belongs to the Special Issue Organochalcogen Derivatives in Medicinal Chemistry)
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Abstract

Background/Objectives: Natural metabolites, due to their abundance, structural diversity, and availability in enantiomerically pure form, are broadly utilized in the synthesis of reagents, catalysts, building blocks, and potential therapeutics. To date, various organoselenium compounds, including selenides, diselenides, selenols, selenonium salts, and ylides, have been created based on the scaffold of primary and secondary metabolites like amino acids, sugars, nucleic bases, terpenes, and steroids. Their synthesis and application routes as reagents and catalysts in organic synthesis and biological systems are summarized in the presented review. Methods: The gathered material has been divided into two sections—naturally derived organoselenium compounds, such as antioxidants and GPx-mimetics, and reagents utilized in modern organic transformations. Results: The review summarizes the utility of natural scaffolds in the construction of organoselenium compounds with promising applications as antioxidant-type catalysts in biological systems (GPx-mimetics) and potent reagents for organic transformations, including asymmetric reactions. Conclusions: This review provides a comprehensive overview of known organoselenium reagents derived from natural compounds, discusses the advantages of their use in medicinal chemistry and modern organic synthesis, and outlines prospective directions for future development in this area.

Graphical Abstract

1. Introduction

Natural evolution is a one-of-a-kind phenomenon that continuously selects and modifies chemical structures to fit a specific biochemical process perfectly. The created metabolites enable the living cell to grow, reproduce, and survive in the surrounding environment. Naturally occurring molecules can be divided into those essential for survival, like amino acids, sugars, fatty acids, and nucleic bases (primary metabolites), and those involved in interacting with the surrounding environment, e.g., terpenes and alkaloids (secondary metabolites) [1,2]. The characteristic features of these compounds—structural diversity, fixed stereochemistry, and facile availability from recyclable sources—are highly desired properties in chemical syntheses dealing with the design of reagents, catalysts, or derivatives of medicinal value.
Interest of the scientific community in organoselenium chemistry has grown with the successful application of organoselenium compounds (OSeCs) in medicinal chemistry and material science and as reagents and catalysts in modern organic transformations [3,4,5]. The current development of green and environmentally friendly protocols for their preparation is an additional advantage when considering further extension of the scope of known OSeCs [6].
Selenization of natural scaffolds to modify and improve the reactivity of metabolites is currently a promising trend in organoselenium chemistry [7]. The selenium atom exists in nature, in the animal and plant kingdoms, and in both organic and inorganic forms [8,9,10]. As selenate (SeO42−) and selenite (SeO32−), which are highly soluble in soil, they are absorbed by plants and transformed into simple compounds like dimethyl selenide 1, dimethyl diselenide 2, methylselenol 3, dimethyl selenyl sulfide 4, and methyl selenone 5. Additionally, plants can convert mineral selenium into Se amino acids like selenomethionine (SeMet) 6 and methylselenocysteine (MSC) 7. Its presence in soil and plants is crucial for proper dietary intake as it is an essential micronutrient for animals and humans. Several Se-derivatives are necessary for important biochemical processes to occur. Selenocystamine 8 catalyses O2-mediated oxidation of an excess of glutathione to its disulfide, enabling protein folding. Selenodiglutathione 9 reduces oxidised thioredoxin in the thioredoxin/oxidoreductase dithiol-disulfide system. Finally, the 21st amino acid, selenocysteine (Sec) 10, along with its metabolites like diselenide 11 and methylated form 7, can be considered important biocatalysts that help maintain redox homeostasis at physiological levels. Sec 10 builds up the active side of the antioxidant Se-enzyme glutathione peroxidase (GPx). Highly reactive selenide anion RSe− 12 eliminates the excess of H2O2 according to the GPx-catalytic cycle presented in Scheme 1 [11]. The active selenol group 12 is initially oxidised to form selenenic acid 13. This intermediate then reacts with glutathione (GSH), leading to the formation of selenenyl sulfide 14. The original selenol 12 is regenerated through a subsequent reaction between compound 14 and another glutathione molecule, during which oxidized glutathione (GSSG) is released.
Besides their important biochemical role, the naturally derived organoselenium compounds have also been found to have applications in chemical synthesis and medicinal chemistry. Sec 10 is broadly used as a standard sample to evaluate the ability of OSeCs to mimic the activity of Se-enzymes. In mechanistic studies, it is commonly used to monitor selenium metabolism. Its methylated form, MSC 7, was found to act as an antioxidant agent and possess antiproliferative properties with respect to lung and thyroid cancer [12]. It was used as a wound healing stimulator [13], a building block, and a crosslinking initiator in synthesising peptides [14,15]. Selenodiglutathione 9 was also used to rebuild broken S-S bonds in peptides. Its physiological function allows it to be applied additionally as an efficient GPx mimetic and Trx substrate [16,17,18].
The reactivity of the selenium atom is broadly explored in chemical syntheses, enabling the design of efficient reagents, catalysts, and ligands for various reaction types. The advantages of Se-based transformations include the following: (1) mild reaction conditions (frequently fulfilling the rules of green chemistry); (2) diversified synthetic procedures to obtain OSeCs: selenol 15 (reaction of metal precursor and Se0), diselenide 16 (nucleophilic substitution of organic halide with M2Se2), and selenide 17 (reaction of RX with nucleophilic metal selenide MSeR); (3) transformation of selenide 17 to selenooxide 18, selenonium salt 19, and ylide 20 successfully used as chirality transfer agents; (4) simple cleavage of Se-Se bond and further transformation to electrophilic 21, nuleophilic 22, and radical 23 reagents; (5) facile introduction of the Se-moiety into the substrate compound (selenenylation 24 or selenocyclization product 25); (6) efficient transformation of the intermediate Se-compound into a radical molecule 26 (homolytic cleavage of the Se-C bond), alkene 27 (selenooxide syn-elimination), and nucleophile precursor 28; (7) broad possibility of application, e.g., drug design, materials science, and asymmetric synthesis as chiral catalysts and ligands (Scheme 2) [3,19,20,21,22,23,24,25].
In this context, constructing catalytically active molecules based on combining a chiral natural scaffold with a Se-moiety is an undeniably potent strategy for reagent design. In this review, we will present how incorporating a reactive selenium atom can enhance the reactivity of a natural compound or arm it with new, promising features. The collected material is divided to two sections: (2) naturally derived OSeCs as GPx-like catalysts, summarizing the most exploited field of application associated with the ability of OSeCs to act as oxygen transfer reagents mimicking the activity of GPx and (3) naturally derived OSeCs as reagents in organic synthesis, with subsections categorizing the gathered material according to the modified metabolites—amino acids and peptides (3.1), sugars (3.2), and terpenes (3.3).

2. Naturally Derived OSeCs as GPx-like Catalysts

Naturally derived organoselenium compounds (OSeCs) have emerged as promising oxygen transfer agents and glutathione peroxidase (GPx) mimetics due to their structural diversity, biocompatibility, and catalytic redox potential. Among the endogenous antioxidant defense systems, GPx enzymes play a pivotal role by catalyzing the reduction of hydrogen peroxide (H2O2) and organic hydroperoxides to water or corresponding alcohols using reduced glutathione (GSH) as the electron donor, which is concomitantly oxidized to glutathione disulfide (GSSG). As crucial components of the antioxidant defense system, they protect cells and tissues from oxidative damage that contributes to a multitude of diseases, e.g., cancer, diabetes, and neurodegenerative and cardiovascular disorders. [26,27,28,29,30,31]. The activity of GPx depends critically on the presence of the selenocysteine (Sec) residue at the active site, for which its selenol group (-SeH) possesses superior nucleophilicity and a lower pKa (~5.2) compared to cysteine’s thiol group, enhancing its reactivity under physiological conditions [32]. Substitution of this selenium center with sulfur (i.e., replacing Sec with Cys) drastically reduces enzymatic activity, confirming the essential catalytic function of selenium in redox biology [33,34]. Ebselen, a well-known synthetic organoselenium compound, is a benchmark GPx mimic. However, its poor aqueous solubility (logP ≈ 3.7) limits its bioavailability, necessitating specialized delivery strategies for biological evaluation [35].
In this context, various OSeCs derived from natural scaffolds such as amino acids, sugars, terpenes, steroids, or vitamins have been synthesized and studied for their GPx-like activity. Organoselenium compounds bearing amino acids, vitamins, and carbohydrate-based residues offer water solubility and potential for targeted delivery in biological systems. In contrast, terpene-derived organoselenium compounds benefit from conformational rigidity and stereocontrol, contributing to their catalytic performance [36]. These compounds effectively reduce peroxides and regenerate GSH, positioning them as valuable tools for modulating oxidative stress in biological systems. The exploration of naturally derived GPx mimetics thus holds great promise for developing antioxidant therapeutics with improved stability, selectivity, and pharmacological profiles.
Numerous review articles have summarized the state of the art in constructing OSeCs as efficient oxygen transfer reagents and GPx-like catalysts [25]. Herein, a summary of methods assessing the antioxidant potential of organoselenium compounds and the known naturally derived GPx mimetics will be presented.

2.1. Methods for Assessing GPx-like Antioxidant Activity

The table below (Table 1) summarizes the most commonly used methods for evaluating glutathione peroxidase (GPx) activity.

2.2. Examples of Organoselenium Compounds Mimicking GPx

Cholesterol, a well-known natural steroid, possesses unique structural features, such as a rigid framework with eight chiral centers and a high potential for structural derivatization [44,45,46]. In 2015, Braga et al. incorporated cholesterol into molecular systems by synthesizing selenides and diselenides. All synthesized diselenides exhibited strong GPx-like activity, with one compound, 29, demonstrating activity 3.3 times higher than the reference compound, Ebselen [47].
The vitamin B6 family of pyridine derivatives, including pyridoxine, pyridoxal, and pyridoxamine, functions as cofactors in numerous enzymatic reactions involving amino acids, such as transamination, deamination, racemization, decarboxylation, and β-elimination [48]. In 2015, Singh and co-workers modified one of the vitamin B6 vitamers, pyridoxine, by incorporating a selenium atom in place of the methyl group at position 2 and a bromine atom at position 6. As a result of this substitution, derivative 30 exhibited enhanced antioxidant activity, showing a 2-fold increase compared to Ebselen [49].
Incorporating amino acids into chemical structures can significantly improve their biocompatibility and water solubility. Moreover, such modifications often enhance the biological activity and selectivity of the resulting compounds [50,51,52]. In 2018, Braga and Rocha synthesized a novel chiral diselenoamino acid derivative derived from phenylalanine and valine. Diselenide 31, derived from L-valine, exhibited antioxidant activity comparable to (PhSe)2. The results indicated that the catalytic efficiency of the GPx mimetics described in this study is influenced by steric factors, which are affected by the length of the carbon chain separating the selenium atom from the amino acid residue and/or by the nature of the amino acid side chain [53]. In 2017, Ścianowski and co-workers synthesized a series of N-substituted benzisoselenazol-3(2H)-ones, functionalized at the nitrogen atom with amino acids, to improve Ebselen’s solubility. Among these derivatives, the compound 32 based on L-leucine was the most efficient peroxide scavenger, exhibiting 24-fold higher activity than ebselen [54].
Terpenes, widely occurring natural compounds in the plant kingdom, are characterized by a rich structural diversity and valuable properties. Traditionally employed as carriers of fragrance and flavor, they have also demonstrated significant pharmacological potential [55]. In recent years, in the research group led by Ścianowski, terpenes were effectively utilized as starting materials for the synthesis of a wide variety of chiral organoselenium compounds, including benzisoselenazol-3(2H)-ones [54,56], diselenides [55], phenylselenides [57], and selenides [58]. A notably high antioxidant potential was observed for benzisoselenazol-3(2H)-ones 33,34 and diselenides 35,36 containing the N-bornyl group. In the case of phenylselenides and selenides, high antioxidant potential was observed for N-pinanyl phenyl selenide 37 and O-menthyl selenide 38, respectively.
Furthermore, within the same research group, a series of novel chiral benzisoselenazol-3(2H)-ones was synthesized, featuring nitrogen substitution with three different monoterpene moieties—p-menthane, pinane, and carane. The synthesized compounds were designed as pairs of enantiomers, epimers, and regioisomers to further evaluate how the specific three-dimensional arrangement of substituents influences biological activity. The best antioxidant activity was observed for N-substituted benzisoselenazolones 39,40 with α-pinane skeletons. Interestingly, as anticipated, the compounds exhibited different antiproliferative capacity on human promyelocytic leukemia HL-60 cell lines. A recent publication by João P. Telo et al. reported a one-pot reaction of the natural monoterpenoid (−)-carvone with selenium bromide, yielding menthoselenophenone as the main product, along with minor amounts of phenolic by-products. A series of derivatives was also synthesized: an α,α-dimer, an oxime, and its Beckmann rearrangement product, lactam. Among the compounds obtained, dimer 41 exhibited the highest antioxidant activity [59].
Selenoneine, a selenium analogue of ergothioneine, is naturally found as the predominant organic selenium species in marine fish’s blood and muscle tissue, such as bluefin tuna and mackerel. This compound originates from marine food chains, being biosynthesized by microorganisms and bioaccumulated in predatory fish. It is then transferred to humans through dietary intake, which functions as a potent antioxidant [60]. For this reason, in 2023, Gaucher, da Silva Junior et al. focused on synthesising a series of molecules based on the selenoneine structure. Notably, compound 42 bearing a trifluoromethyl group exhibited GPx-mimetic activity similar to that of Ebselen [61]. The table below summarizes examples of all the naturally derived organoselenium compounds described above that exhibit the highest glutathione peroxidase (GPx)-mimicking activity and the methods used to evaluate this antioxidant activity (Table 2).

3. Naturally Derived OSeCs as Reagents in Organic Synthesis

The development of chiral reagents, catalysts, or ligands is highly valuable in modern organic synthesis, the total synthesis of natural products, and medicinal chemistry, where the enantioselectivity of the process is a major issue in many cases. The fixed stereochemistry of natural compounds like amino acids, sugars, and terpenes induced their broad applicability as synthetic tools in stereoselective organic synthesis. The additional incorporation of a Se-moiety has gained much attention, supported by the unique reactivity of the selenium atom. Until now, several organoselenium reagents (OSeRs) based on natural products like amino acids, sugars, and terpenes have been obtained and efficiently applied in various organic transformations.

3.1. Se Amino Acids and Peptides

Only 22 amino acids are what nature needed to form peptides fundamental to life. This group of compounds is considered essential primary metabolites and potential drug candidates and chiral reagents/catalysts in modern organic synthesis [62]. Some natural amino acids, as presented in Scheme 1, also possess an incorporated selenium atom, which makes them essential for several biochemical processes. Artificial Se amino acids can be synthesized by modifying the natural Se-metabolites or attaching a selected Se-moiety to the amino acid backbone. The catalytically potent Sec 1 was most thoroughly investigated—synthetic procedures and modification protocols were summarized in the review presented by Wessjohan [63]. More recent transformations included the conjugation of different aliphatic and aromatic substituents with the reactive selenol group. N-Boc-protected Sec 43, obtained from the L-serine methyl ester, was further modified into selenolanthionine 44a and selenocystine 44b, derivatives efficiently applied to synthesize Se-peptides [64]. Other SeH-conjugates 45 and 46 were proven to inhibit human cytochrome P450 [65,66] and possess anticancer properties, respectively [67]. Trifluoromethyl derivative of selenomethionine 47, synthesized from N-(tert-butoxycarbonyl)-L-aspartic acid tert-butyl ester by a seven-step procedure, was also evaluated as a cytotoxic agent towards colon cancer [68]. Lastly, a methylated form of selenocystine 48 was obtained to evaluate the release and bioavailability of the selenium atom from unnatural amino acids. As a result, Se accumulation in rats’ blood and liver was observed [69] (Scheme 3).
The possibility of Sec-modification enables the functionalization of proteins at these amino acid residues [70]. Modified proteins are essential for discovering biologics and investigating molecular mechanisms in biological processes. Thus, methods for precise peptide synthesis and functionalization are highly needed. The native chemical ligation (NCL), a tool for protein preparation, can occur 1000-fold faster for Sec than for the corresponding Cys residues. As the occurrence of Sec is also very low (>0.001% of protein residues) in comparison to Cys (about 0.3%), the reactions can be performed more selectively, leading to the total synthesis of proteins with particular modifications. An example of NCL utilizing Se-reagents is presented in Scheme 4. The Se-functionality of selenoester 49, an acyl group transfer agent, undergoes a nucleophilic substitution performed with Sec-peptide 50. Later, the undesired Se-moiety of 51 can be eliminated and transformed to alanine through anaerobic deselenization by tris (2-carboxyethyl) phosphine and DTT [71,72].
Other examples of using selenoesters as acyl group transfer agents in synthesizing peptides are presented in Scheme 5. Reagents 56 and 57 were generated from Fmoc-protected amino acids 53 and diphenyl diselenides 54 and 55. After forming the final amino acid 59, the eliminated organoselenium fragments can be efficiently regenerated [73,74].
The applicability of selenium in peptide chemistry was recently summarized in a review published by Stefanowicz et al. [75]. The presence of the Se-moiety enables the synthesis and post-synthetic modification of peptides based on the following: (a) formation of diselenide bridges (protein folding); (b) construction of selenolanthionie linkages (cyclisation and stapling); (c) and susceptibility of the diselenide bond to UV-irradiation, facilitating photochemical transformations [76,77,78,79].

3.2. Se-Sugars

The chemistry of carbohydrates is one of the most relevant research fields in organic synthesis. These polyfunctional compounds possess several advantages: They can be diversely manipulated to form new reactive centers or coordination sites; their attachment to other derivatives can enhance water solubility; as molecules vital for a multitude of biochemical processes, they can be considered potential pharmacophores for bioactive compounds [80,81]. A recent review by Santi et al. summarizes the synthesis of bioactive Se-containing sugars [82]. When considering the incorporation of selenium for OSeRs design, the phenylselanyl group dominates as the Se-sugar reactive center. Since the work of Pinto et al. [83] and the utility of phenylselenoglycosides as glycosyl group donors, this application route is continuously being fed with new selenosugar-based protocols. The RSePh derivatives are mainly used as glycosyl group transfer agents. Examples of phenylselenoglycosides 60–65, efficiently applied in the O-glycosylation reaction, are presented in Scheme 6 [84,85,86].
The construction of naturally derived compounds using Se-sugar reagents was also performed utilizing different types of Se-moieties. Szilayi et al. obtained a series of isoselenuronium bromides 66 or chlorides 67 that were further transformed to variously substituted Se-glycosides [87]. Under mild reaction conditions, the nucleophilic substitution with monosaccharide triflate 68 enabled the formation of Se-disaccharides 69 and 70 in good yields (Scheme 7).
Next, Ludtke and Wessjohann applied sugar diselenide 72 to synthesize steroidal selenoglycoconjugates 73 and 75 [88]. The reaction was performed with nucleophilic Se-reagent generated by the treatment of compound 72 with sodium borohydride. The further ring opening of steroidal epoxide 71 or the nucleophilic substitution of steroidal mesylate 74 furnished products 73 and 75, respectively (Scheme 8). The carbohydrate scaffold was further deprotected by the treatment with trifluoroacetic acid/methanol (9:1).
Lately, Misra et al. designed a reaction of appropriate glycosyl iodides or triflate 76 with potassium selenocyanate in water, which yielded a series of RSeCN-type reagents 77. These building blocks were further applied in synthesizing Se-pseudodisaccharide 79 (Scheme 9) [89].

3.3. Organoselenium Reagents Derived from Monoterpenes

Considering all enantiopure compounds creating the natural chiral pool, terpenes, with about 55,000 different structures, are the dominating contributors [90]. Depending on the number of isoprene units (C5)n that build up the isoprenoid skeleton, these derivatives are divided into mono- (C10), sesqui (C15), di- (C20), and polyterpenes (Cn≥40) [91]. The physicochemical properties of monoterpenes enable their feasible isolation from natural feedstocks by steam distillation. Bio-wastes from the orange juice and paper industry are the main sources for isoprenoid acquisition. Broad natural abundance, exceptional diversity of carbon skeletons, various functional groups, and stereogenic centers grounded their position as chirality transfer agents and building blocks in various organic transformations, stereoselective synthesis, and total synthesis of natural products [92].
Until now, the combination of a chiral monoterpene scaffold with a reactive selenium moiety has been well explored in the design of reagents for asymmetric transformations. Since the pioneering work of Sharpless—the synthesis of allylic alcohol linalool through the [2,3]-sigmatropic rearrangement of an allylic Se(IV) derivative—a multitude of chiral reactions have been designed utilizing Se-reagents constructed on the monoterpene skeleton. This subsection will be divided according to the appropriate transformation: monoterpene-based OSeRs in [2,3]-sigmatropic rearrangements (3.3.1); monoterpene-based OSeCs as electrophilic reagents (3.3.2); monoterpene-based OSeRs in asymmetric epoxidation and cyclopropanation (3.3.3); and other asymmetric transformations utilizing chiral monoterpene-based OSeRs (3.3.4).

3.3.1. Monoterpene-Based OSeRs in [2,3]-Sigmatropic Rearrangements

The discovery of [2,3]-sigmatropic rearrangement through allylic selenooxides, with subsequent selenooxide elimination, has popularised the utility of OSeCs in general organic synthesis. The reaction can be performed under mild conditions, much faster than with corresponding sulfoxides. When considering stereoselective versions, it can lead to high enantiomeric excess of the final products. The Se-reagent can generally undergo intermolecular rearrangement after oxidation or imidation via corresponding selenimides. These highly valuable reactions efficiently route chiral alcohol 80 and amine 81 (Scheme 10).
The first transformation of a monoterpene diselenide 82 to the corresponding allylic alcohol 83 was presented by Sharpless in 1972 [93,94,95]. Later, different types of chiral geranyl selenides, e.g., 84–86, were also successfully evaluated as precursors for the [2,3]-shift to afford compound 83 [96,97,98] (Scheme 11).
Several application examples of monoterpene OSeCs—monocyclic ((+)-carvotanacetyl, (−)-carvyl, perillyl), bicyclic (carane, pinane), and acyclic (geranyl, neryl) phenylselenides—in the synthesis of chiral amines and alcohols through [2,3]-shift were presented in the early 2000s by Ścianowski and co-workers [99,100,101,102,103]. The synthetic procedure is presented using (+)-10-phenylseleno-2-pinene 87 as an example. Treatment of precursor 87 with hydrogen peroxide, NCS, and chloramine-T led to selenooxide 88 and selenoimides 89 and 90, respectively. Subsequent rearrangement and hydrolysis furnished the final chiral products 91–93 (Scheme 12).
Similarly, terpenyl selenols were tested as [2,3]-shift precursors of chiral allylic alcohols. The obtained RSeH 94 was transformed to the corresponding allylic selenide 95 by treatment with butyl lithium and appropriate allylic chloride [104]. The oxidation with mCPBA following [2,3]-SR furnished the final chiral product 96 with moderate enantioselectivities (examples 97–99, Scheme 13).
Koizumi and co-workers also efficiently used terpene selenonium ylides as [2,3]-sigmatropic rearrangement precursors [105,106,107]. Allylic selenide 100 was transformed into allylic chloroselenurane 101, which, via the formation of corresponding selenooxides, selenimines, and aforementioned selenonium ylides, underwent rapid [2,3]-shifts to form chiral alcohol 102, amine 103, and selenide 104, respectively (Scheme 14).

3.3.2. Monoterpene-Based OSeCs as Electrophilic Reagents

The 1,2-addition to alkenes performed with electrophilic organoselenium reagents is a very well-examined field of research. The mechanistic features of this process include the reaction of RSe+X− (e.g., X = Cl, OTf, OSO3H) with alkene and the subsequent formation of a seleniranium ion. Further inter- or intramolecular ring opening with selected nucleophiles leads to acyclic or cyclic products [108]. Attachment of chiral moieties like terpenes to the reactive selenium center facilitates an asymmetric process. Back and co-workers performed one of the first enantioselective additions using a C3-camphor-based diselenide [109,110]. Methoxyselenenylation of trans-dec-5-ene with triflates 105 and 106 gave excellent d.r. values. The presence of an oxime enhances diastereoselectivity due to the coordination of the hydroxyl group with the selenium atom. Modified C3-camphor reagents were also applied in the cyclisation of unsaturated alcohols and carboxylic acids. Chloride 107 yielded the cyclic ether with d.r. 84:16 [111,112,113,114,115]. Later, Ścianowski et al. synthesized and transformed other terpene diselenides derived from carane, p-menthane, and pinane into selenenyl triflate analogs. The 1,2-addition to styrene with the highest diastereoselectivity was observed for hydroxycarane derivative 108. The selenocyclization of o-allylphenol bicyclic myrtenyl triflate 109 furnished the final benzofuran with d.r. 86:14 [116,117] (Table 3).
The group of Tiecco also performed several elegant asymmetric selenenylation–elimination transformations. The camphor diselenide 110 was converted to the corresponding sulfate 111 by the treatment with ammonium persulfate and triflic acid. The further utility of reagent 111 included the synthesis of (a) allylic ether 112 [118,119]; (b) oxazolines 113 and 114 and thiazolines 115 and 116 [120,121]; and (c) perhydrofuro [2,3-b]furans 117–119 [122] (Scheme 15).
The same group had also further exploited the utility of camphor diselenide 110 through its transformation to camphor selenenyl triflate in the synthesis of 1,6-dioxaspiro[4,4]nones [123] and (R)-camphorselenoacetone or methyl (R)-camphorselenoacetate as nucleophilic reagents in TiCl4-mediated aldol condensation [124,125].

3.3.3. Monoterpene-Based OSeCs in Asymmetric Epoxidation and Cyclopropanation

The design of efficient protocols to construct small rings like epoxides and cyclopropanes is crucial because of their exceptional reactivity and applicability as important building blocks. To date, several research groups have taken up the task of using terpenyl OSeRs in asymmetric epoxidation and cyclopropanation reactions. For the enantioselective synthesis of oxiranes, the camphor scaffold was modified by Huang [126] and Katanoka [127]. C3-camphor selenonium salt 120 and C2-camphor selenide 121 were obtained and applied to synthesize diphenyl oxiranes (up to 80% ee) and the Darzens reaction (up to 62% ee), respectively. Later, Midura and Ścianowski designed a series of bicyclic and acyclic terpenyl selenonium salts for the asymmetric epoxidation of benzaldehyde. The best result, acquired for (+)-limonene derivative 122, gave an enantiomeric ratio of 84:16 [128] (Scheme 16).
Application of terpenyl OSeRs in the synthesis of cyclopropanes covers two protocols presented by Huang in 2009 [129] and Ścianowski in 2014 [130] (Scheme 17). The first asymmetric synthesis of trimethylene derivatives performed with C3-camphor selenonium ylides 123 gave promising results with diastereomeric ratios up to 99:1. Later, excellent enantioselectivity (er cis 98:2, er trans 99:1) for the cyclopropanation of vinylphosphonate with (+)-limonene-derived selenonium ylides 124 confirmed the validity of using these types of reagents in the synthesis of small rings.

3.3.4. Other Transformations Utilizing Chiral Monoterpene-Based OSeCs

In addition to the well-established ways of utilizing naturally derived organoselenium reagents, new research protocols are emerging, expanding the scope of known reactions susceptible to Se-based transformations and catalysis. Examples of terpenyl OSeCs applied in different types of reactions are presented in Scheme 18. Allylic chlorination performed in the presence of pinene selenide 125 furnished the final chlorides in excellent yields [131]. Methylselenides with o-(S-caranyl)- and o-(S-isocaranyl) moieties 126 and 127 were evaluated as catalysts in the Tsuji–Trost allylic alkylation and Henry reaction [132]. Both reactions led to good yields but low enantioselectivities. A similar result was observed for the oxacyclization of alkenoic acids with the utility of dimenthyl diselenide 128 (yield: 95%, 28% ee) [133].

4. Conclusions

Natural metabolites serve as valuable starting materials in the design of organoselenium reagents and catalysts due to their inherent structural diversity and chirality. Numerous selenides, diselenides, selenols, selenonium salts, and ylides have been successfully synthesized using frameworks derived from amino acids, sugars, terpenes, and steroids. These compounds not only demonstrate considerable synthetic potential but also possess significant antioxidant properties and promising biological activity, aligning them closely with the goals of medicinal chemistry. Despite these advantages, the application of such selenium-containing reagents in modern organic synthesis remains underexploited. Their broader application could offer distinct benefits, including improved selectivity, biocompatibility, and access to enantiomerically pure products. This review highlights both the current achievements and the untapped potential of these compounds in synthesis, catalysis, and biomedical applications. Further exploration in this field may lead to the development of novel, efficient, and sustainable methodologies with broad implications for drug discovery and therapeutic innovation.

Author Contributions

Conceptualization, A.J.P.-M. and J.Ś.; methodology, A.J.P.-M.; formal analysis, A.J.P.-M., M.O.-F. and J.Ś. investigation, A.J.P.-M., M.O.-F. and J.Ś.; resources, A.J.P.-M., M.O.-F. and J.Ś.; data curation, A.J.P.-M. and M.O.-F.; writing—original draft preparation, A.J.P.-M. and M.O.-F.; writing—review and editing, A.J.P.-M. and J. Ś. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Pharmaceuticals 18 01749 sch001
Scheme 1. Naturally abundant organoselenium compounds 1–12.
Scheme 1. Naturally abundant organoselenium compounds 1–12.
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Scheme 2. Synthesis and transformations of organoselenium reagents.
Scheme 2. Synthesis and transformations of organoselenium reagents.
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Scheme 3. Modification of Se amino acids 43–48.
Scheme 3. Modification of Se amino acids 43–48.
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Scheme 4. Utility of Se amino acids in NCL.
Scheme 4. Utility of Se amino acids in NCL.
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Scheme 5. Se-esters as acyl group transfer agents.
Scheme 5. Se-esters as acyl group transfer agents.
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Scheme 6. Phenylselenoglycosides as glycosyl group transfer agents.
Scheme 6. Phenylselenoglycosides as glycosyl group transfer agents.
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Scheme 7. Isoselenuronium reagents in the synthesis of Se-disaccharides.
Scheme 7. Isoselenuronium reagents in the synthesis of Se-disaccharides.
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Scheme 8. Synthesis of steroidal selenoglycoconjugates.
Scheme 8. Synthesis of steroidal selenoglycoconjugates.
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Scheme 9. Synthesis of glycosyl selenocyanates in on-water conditions.
Scheme 9. Synthesis of glycosyl selenocyanates in on-water conditions.
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Scheme 10. The [2,3]-sigmatropic rearrangement of Se(IV) species to afford chiral alcohols and amines.
Scheme 10. The [2,3]-sigmatropic rearrangement of Se(IV) species to afford chiral alcohols and amines.
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Scheme 11. The [2,3]-sigmatropic rearrangement of geranyl diselenide 82.
Scheme 11. The [2,3]-sigmatropic rearrangement of geranyl diselenide 82.
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Pharmaceuticals 18 01749 sch012
Scheme 12. The [2,3]-sigmatropic rearrangement of pinanyl selenooxide 88 and selenoimides 89 and 90.
Scheme 12. The [2,3]-sigmatropic rearrangement of pinanyl selenooxide 88 and selenoimides 89 and 90.
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Scheme 13. Terpene selenols as [2,3]-sigmatropic rearrangement precursors.
Scheme 13. Terpene selenols as [2,3]-sigmatropic rearrangement precursors.
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Scheme 14. Synthesis of chiral alcohols, amines, and selenides from chloroselenourane 101.
Scheme 14. Synthesis of chiral alcohols, amines, and selenides from chloroselenourane 101.
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Scheme 15. The utility of camphor selenenyl sulfate 111 in asymmetric selenenylation–elimination transformations.
Scheme 15. The utility of camphor selenenyl sulfate 111 in asymmetric selenenylation–elimination transformations.
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Scheme 16. Synthesis of chiral epoxides using terpenyl OSeRs [126,127,128].
Scheme 16. Synthesis of chiral epoxides using terpenyl OSeRs [126,127,128].
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Scheme 17. Synthesis of cyclopropanes using terpenyl OSeRs [129,130].
Scheme 17. Synthesis of cyclopropanes using terpenyl OSeRs [129,130].
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Pharmaceuticals 18 01749 sch018
Scheme 18. Miscellaneous transformations utilizing chiral monoterpene-based OSeCs.
Scheme 18. Miscellaneous transformations utilizing chiral monoterpene-based OSeCs.
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Table 1. Methods for evaluating glutathione peroxidase (GPx) activity.
Table 1. Methods for evaluating glutathione peroxidase (GPx) activity.
Methods for Assessing GPx-like Antioxidant ActivityMethods for Assessing Radical-Trapping Antioxidant Activity
GSH/GR Coupled Assay (Enzymatic Method) [37]ABTS Assay [38]
The glutathione reductase (GR)-coupled assay was the pioneering indirect method for assessing GPx-mimic activity, created by Wilson et al. In this process, the GR enzyme utilizes the cofactor NADPH (β-nicotinamide adenine dinucleotide 2′-phosphate) to catalyse the conversion of oxidised glutathione (GSSG), produced during the catalytic reaction, back to its reduced form (GSH). The initial rates of NADPH reduction (νo) are measured using UV spectroscopy at a wavelength of 340 nm. The assay solution is prepared by mixing a potassium phosphate buffer, EDTA, sodium azide, GR, and a suitable amount of the test compound. The subsequent addition of H2O2 starts the reaction. The half and overall equations for the occurring reactions are as follows (Equations (1)–(3)):In the method introduced by Shaaban et al., the antioxidant activity of organoselenium compounds is evaluated based on their capacity to decolourise ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals. The corresponding radical-scavenging activity is determined by measuring the reduction in absorbance at 734 nm.
2 GSH + H 2 O 2   → G S H p e r o x i d a s e GSSG + 2 H 2 O (1)
G S S G + NADPH + H +     → G S H r e d u c t a s e 2 GSH + NADP + (2)
H 2 O 2 + NADPH + H +   → NADP + + 2 H 2 O (3)
PhSH assay [39]DPPH assay [40]
In this method, proposed by Iwaoka and Tomoda, benzenethiol (PhSH) is utilized as a GSH substitute. The reduction of hydrogen peroxide in the presence of PhSH, which leads to the concurrent production of diphenyl disulfide (PhSSPh), is evaluated using various methods: a. spectrophotometric analysis measures the increase in UV absorption at 305 nm resulting from the formation of PhSSPh; b. HPLC analysis determines the quantity of PhSSPh produced by measuring the time needed for 50% of PhSH to convert to PhSSPh (t1/2 values), calculated from the peak areas at different time intervals. The equation for the described reaction is as follows (Equation (4)):Shaaban et al. presented a straightforward method for evaluating the radical scavenging activities of organoselenium compounds and nutritional products. The antioxidant capacity of a compound is determined by its ability to convert the stable DPPH·radical (which appears purple in methanol) to DPPH (colourless), as indicated by a reduction in absorbance at 517 nm.
2 P h S H + H 2 O 2 → S e - c a t a l y s t P h S S P h + 2 H 2 O (4)
DTTred/DTTox NMR assay [41]HPLC Lipid Peroxidation assay [42,43]
The GPx-like antioxidant activity of compounds can be assessed using the protocol developed by Iwaoka et al. In this approach, the organoselenium catalyst reduces H2O2 and is subsequently regenerated in the presence of dithiothreitol (DTTred). The kinetics of this reaction are analysed using 1H NMR spectroscopy in either CD3OD or D2O. Signals corresponding to the disulfide (DTTox) produced at specific intervals are recorded. The chemical equation that describes the reaction is as follows (Equation (5)):To evaluate the antioxidant properties of organochalcogen compounds, Engman et al. routinely employed azo-initiated peroxidation of linoleic acid and its derivatives. A recent study described a refined experimental model for determining inhibition times (Tinh) and rates of peroxidation inhibition (Rinh) within a biphasic system. In this modified approach, the lipid phase contained linoleic acid and the test antioxidant, while the aqueous phase included a water-soluble co-antioxidant, such as N-acetylcysteine (NAC), capable of regenerating the active antioxidant species. The reaction mixture, chlorobenzene containing linoleic acid and the antioxidant, was vigorously stirred at 42 °C with the NAC solution. Peroxidation was initiated by 2,2′-Azobis(2,4-dimethylvaleronitrile) (AMVN), and the formation of conjugated dienes was monitored by HPLC with UV detection at 234 nm. The inhibition rate (Rinh) was subsequently calculated using least-squares analysis of absorbance versus time data.
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Table 2. Examples of naturally derived organoselenium compounds with the highest glutathione peroxidase (GPx)-mimicking activity.
Table 2. Examples of naturally derived organoselenium compounds with the highest glutathione peroxidase (GPx)-mimicking activity.
The Structure of the CompoundOriginMethod for Assessing GPx-like Antioxidant ActivityAuthor
Pharmaceuticals 18 01749 i002Cholesterol-derived diselenidePhSH assayBraga et al.
Pharmaceuticals 18 01749 i003Pyridoxine (vitamin B6)-derived diselenideGSH/GR coupled assaySingh et al.
Pharmaceuticals 18 01749 i004Amino acid (L-valine)-derived diselenidePhSH assayBraga, Rocha et al.
Pharmaceuticals 18 01749 i005Amino acid (L-leucine)-derived benzisoselenazoloneDTTred/DTTox NMR assayŚcianowski et al.
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Pharmaceuticals 18 01749 i007		Terpene (camphane)-derived benzisoselenazolones and diselenidesDTTred/DTTox NMR assayŚcianowski et al.
Pharmaceuticals 18 01749 i008Terpene (pinene)-derived phenylselenideDTTred/DTTox NMR assayŚcianowski et al.
Pharmaceuticals 18 01749 i009Terpene (O-menthyl)-derived selenideDPPH assayŚcianowski et al.
Pharmaceuticals 18 01749 i010Terpene (pinene)-derived benzisoselenazolones DTTred/DTTox NMR assayŚcianowski et al.
Pharmaceuticals 18 01749 i011Terpene carvone-derived selenophenesDTTred/DTTox NMR assayJoão P. Telo et al.
Pharmaceuticals 18 01749 i012Selenoneine-derived selenohydantoinGSH/GR coupled assayGaucher, da Silva Júnior et al.
Table 3. Electrophilic terpenyl OSeRs applied in the asymmetric 1,2-addition to alkenes.
Table 3. Electrophilic terpenyl OSeRs applied in the asymmetric 1,2-addition to alkenes.
ReagentSubstrateProductYield [%], d.r.Author
Pharmaceuticals 18 01749 i013Pharmaceuticals 18 01749 i014Pharmaceuticals 18 01749 i01588, 94:6Back et al.
Pharmaceuticals 18 01749 i016Pharmaceuticals 18 01749 i017Pharmaceuticals 18 01749 i01888, 98:2Back et al.
Pharmaceuticals 18 01749 i019Pharmaceuticals 18 01749 i020Pharmaceuticals 18 01749 i02187, 84:16Back et al.
Pharmaceuticals 18 01749 i022Pharmaceuticals 18 01749 i023Pharmaceuticals 18 01749 i02454, 90:10Ścianowski
et al.
Pharmaceuticals 18 01749 i025Pharmaceuticals 18 01749 i026Pharmaceuticals 18 01749 i02749, 86:14Ścianowski
et al.
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Pacuła-Miszewska, A.J.; Obieziurska-Fabisiak, M.; Ścianowski, J. Organoselenium Compounds Derived from Natural Metabolites. Pharmaceuticals 2025, 18, 1749. https://doi.org/10.3390/ph18111749

AMA Style

Pacuła-Miszewska AJ, Obieziurska-Fabisiak M, Ścianowski J. Organoselenium Compounds Derived from Natural Metabolites. Pharmaceuticals. 2025; 18(11):1749. https://doi.org/10.3390/ph18111749

Chicago/Turabian Style

Pacuła-Miszewska, Agata J., Magdalena Obieziurska-Fabisiak, and Jacek Ścianowski. 2025. "Organoselenium Compounds Derived from Natural Metabolites" Pharmaceuticals 18, no. 11: 1749. https://doi.org/10.3390/ph18111749

APA Style

Pacuła-Miszewska, A. J., Obieziurska-Fabisiak, M., & Ścianowski, J. (2025). Organoselenium Compounds Derived from Natural Metabolites. Pharmaceuticals, 18(11), 1749. https://doi.org/10.3390/ph18111749

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