Selenium-Epoxy ‘Click’ Reaction and Se-Alkylation—Eﬃcient Access to Organo-Selenium and Selenonium Compounds

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Communication Selenium-Epoxy ‘Click’ Reaction and Se-Alkylation—Eﬃcient Access to Organo-Selenium and Selenonium Compounds

Taejun Eom and Anzar Khan * Department of Chemical and Biological Engineering, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul 02841, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-3290-4859

Received: 3 September 2020; Accepted: 29 September 2020; Published: 5 October 2020

Abstract: This work establishes the ‘click’ nature of the base-catalyzed oxirane ring opening reaction by the selenolate nucleophile. The ‘click’-generated ß-hydroxy selenide can be alkylated to aﬀord cationic selenium species. Hemolytic studies suggest that selenonium cations do not lyse red blood cells even at high concentrations. Overall, these results indicate the future applicability of the developed organo-selenium chemistry in the preparation of a new class of cationic materials based on the seleno-ether motif.

Keywords: ‘click’ chemistry; oxirane ring opening reaction; organo-selenium; organo-selenonium

1. Introduction Selenium was discovered in early 1800 [1,2]. The chemistry of organo-selenium nucleophiles, however, only began in 1973 with Sharpless and Lauers’ report on the preparation of phenylselenolate and its application in converting epoxides into allylic alcohols [3]. Since then a wide range of reactions based on nucleophilic selenium reagents have been developed for use in organic synthesis [1,2]. Inspired by Sharpless’ selenium reagent and the growing interest in organoselenium materials [4], we began to examine the full scope of the ring opening reaction of epoxides by the selenolates in context of ‘click’ chemistry—another area of research pioneered by Sharpless [5]. ‘Click’ chemistry entails modular and wide in scope reactions that can be carried out under simple experimental conditions and produce quantitative yields and inoffensive byproducts [6]. This philosophy has been quickly adapted in the arena of materials science and application of ‘click’ reactions has revolutionized the way functional soft materials are being created [7–12]. The copper catalyzed azide-alkyne cycloaddition reaction has been at the forefront of this revolution since its advent in 2002 [6]. However, other potential ‘click’ processes originally identified by Sharpless, such as thiol and amine-based ring opening of the epoxide group, are also making a considerable impact in the protective-group-free synthesis of reactive and functionalizable polymers [13], hydrogels [14] and patterned surfaces [15]. The addition of selenium to this list would enhance the repertoire of nucleophilic ring opening ‘click’ reactions. Simple and efficient access to the ß-hydroxy selenide motif would also help in evaluating its applicability in terms of creating new bio-relevant materials. In examining previous studies, it becomes clear that the most successful method to access ß-hydroxy selenides relies on stoichiometric amounts of metal-hydrides (e.g., LiAlH4, NaH, LiBEt3H, Na/NH3, Bu3SnH, NaBH4) or reducing agents such as zinc metal to create selenolate from diselenide precursors [16–20]. Often, selenolate is used in excess, reaction times range in hours at elevated temperatures (>50 ◦C), the isolated yields are moderate to high (<90%) and inert conditions are required. A strong reducing atmosphere also compromises functional group tolerance in such reactions. These attributes do not satisfy the ‘click’ chemistry criteria.

Chemistry 2020, 2, 827–836; doi:10.3390/chemistry2040054 www.mdpi.com/journal/chemistry Chemistry 2020, 2, x 2 required.Chemistry 2020 A, 2strong reducing atmosphere also compromises functional group tolerance in such828 reactions. These attributes do not satisfy the ‘click’ chemistry criteria. Since selenols possess a relatively low pKa (5.2) [21], we hypothesized that simple organic and Since selenols possess a relatively low pKa (5.2) [21], we hypothesized that simple organic and inorganicinorganic bases bases such such as as triethylamine triethylamine (TEA), (TEA), di diazabicycloundeceneazabicycloundecene (DBU) (DBU) or or lithium lithium hydroxide hydroxide (LiOH)(LiOH) may may catalyze catalyze selenolate selenolate formation formation under under mild mild conditions conditions and and may may lead lead to to the the development development ofof simple simple protocols protocols in in epoxide epoxide ring ring opening opening reactions. reactions. Herein, Herein, we we show show that that indeed indeed small small amounts amounts (0.01–0.05(0.01–0.05 eq./SeH) eq./SeH) of of the the aforementioned aforementioned bases bases in an in organic an organic or aqueous or aqueous medium medium can catalyze can catalyze regioselective formation of ß-hydroxy selenides in >95% yield in 15 min of reaction time under ambient regio-selective formation of ß-hydroxy selenides in >95% yield in 15 min of reaction time under conditions. Due to a mild and fast nature, the reaction tolerates a variety of electrophiles and ambient conditions. Due to a mild and fast nature, the reaction tolerates a variety of electrophiles and nucleophiles in the system. The selenium atom in the formed ß-hydroxy selenides can be nucleophiles in the system. The selenium atom in the formed ß-hydroxy selenides can be quantitatively quantitatively transformed into selenonium-based cationic species with full compatibility towards transformed into selenonium-based cationic species with full compatibility towards mammalian red mammalian red blood cells. Overall, these results indicate that the base-catalyzed selenium-epoxy blood cells. Overall, these results indicate that the base-catalyzed selenium-epoxy reaction meets reaction meets the requirements of a ‘click’ reaction. The strength of this chemistry is also the the requirements of a ‘click’ reaction. The strength of this chemistry is also the reactivity of the reactivity of the ‘click’-generated motif that allows for further installation of an alkyl group and ‘click’-generated motif that allows for further installation of an alkyl group and cationization of cationization of the structure. the structure.

2.2. Results Results

2.1.2.1. Selenol Selenol Nucleophile Nucleophile in in Organic Organic Medium Medium Initially,Initially, commerciallycommercially available available benzene benzene selenol selenol (1) and (1) glycidoland glycidol (2) were (2 chosen) were as chosen the precursors as the precursors(Scheme1)[ (Scheme22–25]. 1) The [22–25]. reaction The was reaction performed was pe underrformed ambient under ambient conditions conditions in chloroform in chloroform and the andcrude the reaction crude mixturereaction was mixture analyzed was withanalyzed the help with of 1theH-NMR help spectroscopyof 1H-NMR spectroscopy (Figure1, Figures (Figure S1–S3). 1, FiguresAmbient S1–S3). conditions Ambient were conditions chosen to were fulfill chosen one ofto fu thelfill criteria one ofof the ‘click’ criteria chemistry, of ‘click’ chemistry, which entails which the entailsreactions the toreactions be tolerant to be oftolerant moisture of moisture and oxygen. and oxygen. A 1:1 stoichiometryA 1:1 stoichiometry between between the reactants the reactants was wasemployed. employed. From From the the1H-NMR 1H-NMR data, data, it it became became clear clear that that prolonging prolonging thethe reactionreaction (from(from 15 min to to 3030 min) min) did did not not improve improve the the yield yield of ofthe the product product 3 significantly3 significantly (Table (Table 1).1 Instead,). Instead, thethe nature nature and and the amountthe amount of the of catalyst the catalyst influenced influenced the reaction the reaction in a more in a profound more profound way. The way. relatively The relatively stronger stronger bases, DBUbases, and DBU LiOH, and LiOH,led to 94 led and to 94 97% and ring 97% opening ring opening reaction reaction within within 15 min 15 of min reaction of reaction time with time with0.03 eq./SeH0.03 eq. /(4.76SeH mol%) (4.76 mol%) loading. loading. In all cases, In all diselenide cases, diselenide 4 (PhSeSePh)4 (PhSeSePh) was produced was produced as the side as product. the side Itproduct. appears It that appears stronger that catalysts stronger and catalysts short andreaction short times reaction are timesrequired are to required facilitate to a facilitate fast ring a opening fast ring reactionopening and reaction to hinder and tothe hinder formation the formation of diselenide of diselenide through oxidative throughoxidative dimerization dimerization of selenol of reactant selenol underreactant ambient under conditions. ambient conditions.

SchemeScheme 1. 1. Base-catalyzedBase-catalyzed epoxide epoxide ring ring opening opening reaction reaction with with selenol selenol nucleophile. nucleophile.

Chemistry 2020, 2 829 Chemistry 2020, 2, x 3

1 FigureFigure 1. H-NMR 1. 1H-NMR of the reactants of the reactants and the reaction and the mixture reaction (bottom) mixture in deuterated (bottom) in chloroform deuterated (CDCl 3). chloroform (CDCl3). Table 1. Ring opening reaction in chloroform.

Selenol TableEpoxide 1. Ring opening reactionCatalyst in chloroform.Catalyst Time Ring Opening Entry Solvent Catalyst (1) (2) (mol%) (eq./SeH) (min) (%) Ring Selenol Epoxide Catalyst Catalyst Time Entry1 Solvent CHCl3 1 1Catalyst TEA 0.99 0.01 15Opening 75 2 CHCl (1)1 (2) 1 TEA(mol%) 0.99 (eq./SeH) 0.01 30(min) 77 3 (%) 3 CHCl3 1 1 TEA 2.91 0.03 15 81 14 CHCl CHCl33 11 1 1 TEA TEA 0.99 2.91 0.03 0.01 3015 83 75 25 CHCl CHCl33 11 1 1 TEA TEA 0.99 4.76 0.05 0.01 1530 87 77 6 CHCl 1 1 TEA 4.76 0.05 30 87 3 CHCl33 1 1 TEA 2.91 0.03 15 81 7 CHCl3 1 1 DBU 0.99 0.01 15 88 4 CHCl3 1 1 TEA 2.91 0.03 30 83 8 CHCl3 1 1 DBU 0.99 0.01 30 89 5 CHCl3 1 1 TEA 4.76 0.05 15 87 9 CHCl3 1 1 DBU 2.91 0.03 15 89 610 CHCl CHCl33 11 1 1 TEA DBU 4.76 2.91 0.03 0.05 3030 90 87 711 CHCl CHCl33 11 1 1 DBU DBU 0.99 4.76 0.05 0.01 15 15 94 88 12 CHCl 1 1 DBU 4.76 0.05 30 94 8 CHCl33 1 1 DBU 0.99 0.01 30 89 13 CHCl3 1 1 LiOH 0.99 0.01 15 94 9 CHCl3 1 1 DBU 2.91 0.03 15 89 14 CHCl3 1 1 LiOH 0.99 0.01 30 94 10 CHCl3 1 1 DBU 2.91 0.03 30 90 15 CHCl3 1 1 LiOH 2.91 0.03 15 95 1116 CHCl CHCl33 11 1 1 DBU LiOH 4.76 2.91 0.03 0.05 30 15 96 94 1217 CHCl CHCl33 11 1 1 DBU LiOH 4.76 4.76 0.05 0.05 15 30 97 94 18 CHCl 1 1 LiOH 4.76 0.05 30 97 13 CHCl33 1 1 LiOH 0.99 0.01 15 94 19 CHCl3 1.1 1 TEA 3.19 0.03 15 91 14 CHCl3 1 1 LiOH 0.99 0.01 30 94 20 CHCl3 1.1 1 DBU 3.19 0.03 15 >99 3 1521 CHCl CHCl3 1.11 1 1 LiOH LiOH 2.91 3.19 0.03 0.03 15 15 >99 95 16 CHCl3 1 1 LiOH 2.91 0.03 30 96 2.2.17 Selenol CHCl Nucleophile3 in1 Water 1 LiOH 4.76 0.05 15 97 18 CHCl3 1 1 LiOH 4.76 0.05 30 97 19Water CHCl is clearly3 a better1.1 reaction 1 mediumTEA than chloroform3.19 (Table2, 0.03 Figures S4–S6)15 [ 26,27]. The 91 best results20 wereCHCl obtained3 with1.1 the help 1of LiOH that DBU produces 3.19 near quantitative 0.03 ring opening 15 reaction >99 even when21 usedCHCl in 0.993 mol%1.1 (0.01 eq./SeH) 1 loading. LiOH DBU required 3.19 2.91mol% 0.03 (0.03 eq. 15 /SeH) to >99 achieve similar results. Interestingly, TEA also led to near full conversion with 2.91 mol% loading. 2.2. Selenol Nucleophile in Water Water is clearly a better reaction medium than chloroform (Table 2, Figures S4–S6) [26,27]. The best results were obtained with the help of LiOH that produces near quantitative ring opening reaction even when used in 0.99 mol% (0.01 eq./SeH) loading. DBU required 2.91 mol% (0.03 eq./SeH) to achieve similar results. Interestingly, TEA also led to near full conversion with 2.91 mol% loading.

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Table 2. Ring opening reaction in water.

Selenol Epoxide Catalyst Catalyst Time Ring Opening Entry Solvent Catalyst (1) (2) (mol%) (eq./SeH) (min) (%)

1 H2O 1 1 TEA 0.99 0.01 15 94 2 H2O 1 1 TEA 0.99 0.01 30 95 3 H2O 1 1 TEA 2.91 0.03 15 >99 4 H2O 1 1 TEA 2.91 0.03 30 >99 5 H2O 1 1 TEA 4.76 0.05 15 >99 6 H2O 1 1 TEA 4.76 0.05 30 >99 7 H2O 1 1 DBU 0.99 0.01 15 94 8 H2O 1 1 DBU 0.99 0.01 30 95 9 H2O 1 1 DBU 2.91 0.03 15 >99 10 H2O 1 1 DBU 2.91 0.03 30 >99 11 H2O 1 1 DBU 4.76 0.05 15 >99 12 H2O 1 1 DBU 4.76 0.05 30 >99 13 H2O 1 1 LiOH 0.99 0.01 15 >99 14 H2O 1 1 LiOH 0.99 0.01 30 >99 15 H2O 1 1 LiOH 2.91 0.03 15 >99 16 H2O 1 1 LiOH 2.91 0.03 30 >99 17 H2O 1 1 LiOH 4.76 0.05 15 >99 18 H2O 1 1 LiOH 4.76 0.05 30 >99 19 H2O 1.1 1 TEA 3.19 0.03 15 >99 20 H2O 1.1 1 DBU 3.19 0.03 15 >99 21 H2O 1.1 1 LiOH 3.19 0.03 15 >99

2.3. Non-Stoichiometric System In general, the reaction performs very well in water (>99%) under stoichiometric conditions. In an organic medium, however, it is relatively sluggish (75%–97%). Therefore, a slight excess of selenol (1.1 eq./epoxide) was employed to further push the reaction in an organic medium. These results indicated that even in the case of TEA in chloroform, a reaction that typically underperformed, conversions exceeding 90% could be obtained with stoichiometry imbalance (Figures S7 and S8). In all other catalysts/solvent combinations, a quantitative ring opening reaction was observed (Tables S1 and S2).

2.4. Regio-Chemistry Depending upon electronic and steric situation as well as reaction conditions, two isomers can form upon ring opening reaction (Scheme2)[ 28]. Compound 3 is formed when the nucleophile attacks the least substituted carbon atom. Conversely, 5 is formed if the new bond is established between the nucleophile and the most substituted carbon atom. To examine whether the present reaction led to the formation of one or more regio-isomers, 3 was synthesized from a different synthetic route. In this scheme, a commercially available compound 6 with the known structure was allowed to react to benzene selenol through selenium-halide reaction. The proton resonances from the compounds prepared by the selenium-epoxy and selenium-halide reactions were identical (Figure2). In addition, no extra signals could be observed from the isomer 5. 1 The H-NMRs were recorded in deuterated dimethylsulfoxide (DMSO-d6), which allows for observing the hydroxyl protons too and indicate that one hydroxyl group is located adjacent to a tertiary carbon atom and the other to a secondary carbon atom. Hence, a doublet and a triplet arise and the doublet is downfield shifted due to its vicinity to the selenium atom. In isomer 5, the hydroxyl groups are both secondary and would only produce one (triplet) signal for the hydroxyl group. The signal assignment was further confirmed by esterification with acetic acid (7), which produces two different types of acetyl groups and the signals from the hydroxyl groups disappear upon acetylation. From these experiments, it can be concluded that regio-isomer 3 forms exclusively under basic conditions. The carbon (Figures S9 and S10) and selenium NMRs discussed later further reinforces this notion. ChemistryChemistry 2020 2020, ,2 2, ,x x 55 differentdifferent types types of of acetyl acetyl groups groups and and the the signals signals from from the the hydroxyl hydroxyl groups groups disa disappearppear upon upon acetylation. acetylation. FromFrom thesethese experiments,experiments, itit cancan bebe concludedconcluded thatthat regio-isomerregio-isomer 33 formsforms exclusivelyexclusively underunder basicbasic conditions.Chemistryconditions.2020 The, The2 carbon carbon (Figures (Figures S9 S9 and and S10) S10) and and selenium selenium NMRs NMRs discussed discussed later later further further reinforces reinforces831 thisthis notion. notion.

SchemeScheme 2. 2. The TheThe regio-isomers regio-isomersregio-isomers 3 3 andand and 55 5 thatthat that can cancan form formform upon uponupon ring ringring opening openingopening reaction. reaction. reaction. The TheThe bottom bottombottom shows showsshows an anan alternativealternative synthesis synthesis of of 3 3 through through the the alkylation alkylation route. route.

1 FigureFigure 2. 2. Crude Crude H-NMRs1H-NMRs of of 3 3 produced producedproduced by by ring ring ring opening opening opening reaction reaction reaction ( top( top)) )and and alkylation alkylation alkylation reaction reaction (middle) and after acetylation (bottom) in deuterated dimethylsulfoxide (DMSO-d6). ((middlemiddle) and) and after after acetylation acetylation (bottom (bottom) in deuterated) in deuterated dimethylsulfoxide dimethylsulfoxide (DMSO- (DMSO-d6). d6).

2.5.2.5. Chemo-Selectivity Chemo-SelectivityChemo-Selectivity TheThe mild mild and and fast fast reaction reaction indicated indicated that that the the selenium-epoxyselenium-epoxy reaction reaction might might tolerate tolerate other other functionalfunctionalfunctional groups. groups.groups. For ForFor this, this,this, initially, initially,initially, epoxides epoxidesepoxides 8 88 and and 9 9 carrying carrying terminal terminal acetylene acetylene and and allyl allyl groups groups werewere chosenchosen (Scheme(Scheme 3 3).).3). TheseThese groupsgroups cancan bebebe involvedininvolvedvolved ininin azide-alkyne azide-alkyneazide-alkyne andandand thiol-enethiol-ene/ynethiol-ene/yne/yne ‘click’ ‘click’‘click’ reactionsreactionsreactions [ [29–33],29[29–33],–33], respectively. respectively.respectively. In In theseIn thesethese cases, cases,cases, complete cocompletemplete preservation preservationpreservation of the of acetyleneof thethe acetyleneacetylene and allyl andand moieties allylallyl were observed (Figures S11–S14). Encouraged by this, epoxide 10 with a more reactive methacrylate group was chosen. In this case as well, the methacrylate was not involved in a Michael-type of addition Chemistry 2020, 2, x 6 moieties were observed (Figures S11–S14). Encouraged by this, epoxide 10 with a more reactive methacrylate group was chosen. In this case as well, the methacrylate was not involved in a Michael- type of addition reaction with benzeneselenolate (Figures S15 and S16) [34]. A further increase in the reactivity of the second electrophilic site in the molecule was sought with the help of an alkyl halide (11). Surprisingly, even in this case, no substitution reaction was observed (Figures S17 and S18). These results indicated that the selenium-epoxy reaction tolerated a number of other electrophilic sites in the system and only the ring-opened products 12–15 were obtained. ChemistryTo2020 examine, 2 tolerance for other nucleophilic sites in the system, competing reactions were832 Chemistry 2020, 2, x 6 performed (Scheme 4, Figures S19–S22). Initially, phenol, benzoic acid and aniline were employed in moietiesa 1:1 ratio were with observed selenol 1 .(Figures Although S1 these1–S14). nucleophiles Encouraged are by known this, epoxideto open the10 withepoxide a more ring, reactivethey fail reaction with benzeneselenolate (Figures S15 and S16) [34]. A further increase in the reactivity of the methacrylatedue to a faster group ring opening was chosen. reaction In this with case the as selenolate well, the nucleophile.methacrylate This was led not us involved to employ in athiophenol Michael- second electrophilic site in the molecule was sought with the help of an alkyl halide (11). Surprisingly, typeas the of nucleophile.addition reaction It is one with of benzeneselenolate the best nucleophile (Figuress that organicS15 and chemistry S16) [34]. Acan further offer. increaseAs expected, in the it even in this case, no substitution reaction was observed (Figures S17 and S18). These results indicated reactivitycan compete of the with second selenol electrophilic and 18% thio-ether site in the canmolecule form under was sought LiOH withcatalysis. the help In this of ancase, alkyl therefore, halide that the selenium-epoxy reaction tolerated a number of other electrophilic sites in the system and only (11milder). Surprisingly, systems employing even in this DBU case, and no TEA substituti wereon also reaction explored was and observed led to (Figures16 and 11%S17 andthio-ether S18). the ring-opened products 12–15 were obtained. Theseformation, results respectively. indicated that the selenium-epoxy reaction tolerated a number of other electrophilic sites in the system and only the ring-opened products 12–15 were obtained. To examine tolerance for other nucleophilic sites in the system, competing reactions were performed (Scheme 4, Figures S19–S22). Initially, phenol, benzoic acid and aniline were employed in a 1:1 ratio with selenol 1. Although these nucleophiles are known to open the epoxide ring, they fail due to a faster ring opening reaction with the selenolate nucleophile. This led us to employ thiophenol as the nucleophile. It is one of the best nucleophiles that organic chemistry can offer. As expected, it can compete with selenol and 18% thio-ether can form under LiOH catalysis. In this case, therefore, milder systems employing DBU and TEA were also explored and led to 16 and 11% thio-ether formation, respectively.

SchemeScheme 3.3. RingRing openingopening reactionreaction inin thethepresence presenceof of other other electrophiles electrophiles in in the the system. system.

To examine tolerance for other nucleophilic sites in the system, competing reactions were performed (Scheme4, Figures S19–S22). Initially, phenol, benzoic acid and aniline were employed in a 1:1 ratio with selenol 1. Although these nucleophiles are known to open the epoxide ring, they fail due to a faster ring opening reaction with the selenolate nucleophile. This led us to employ thiophenol as the nucleophile. It is one of the best nucleophiles that organic chemistry can oﬀer. As expected, it can compete with selenol and 18% thio-ether can form under LiOH catalysis. In this case, therefore, milder systems employing DBU and TEA were also explored and led to 16 and 11% thio-ether formation, respectively. Scheme 3. Ring opening reaction in the presence of other electrophiles in the system.

Scheme 4. Ring opening reaction in the presence of other nucleophiles in the system.

2.6. Selenium Alkylation

Methylation of the selenium atom in 3 and 7 could be achieved with the help of AgBF4 as a catalyst and methyl iodide as an alkylating agent in acetonitrile at 50 °C for 24 h (Scheme 5, Figures S23–S26) [35]. This reaction proceeds cleanly and requires just precipitation for isolation of the cationic products 16 and 17. Interestingly, the addition of a substituent on selenium adds one more stereogenic center to the molecule and the 1H- and 13C-NMR becomes relatively complex due to the formation of four diastereomers (Figure 3). Scheme 4. RingRing opening reaction in the presence of other nucleophiles in the system.

2.6. Selenium Selenium Alkylation Alkylation

Methylation ofof thethe selenium selenium atom atom in 3inand 3 and7 could 7 could be achieved be achieved with thewith help the of help AgBF of4 asAgBF a catalyst4 as a catalystand methyl and iodide methyl as iodide an alkylating as an alkylating agent in acetonitrile agent in acetonitrile at 50 ◦C for at 24 50 h (Scheme °C for 245, Figuresh (Scheme S23–S26) 5, Figures [ 35]. ThisS23–S26) reaction [35]. proceeds This reaction cleanly proceeds and requires cleanly just and precipitation requires just for precipitation isolation of the for cationic isolation products of the 16cationicand 17 products. Interestingly, 16 and the 17. additionInterestingly, of a substituent the addition on of selenium a substituent adds oneon selenium more stereogenic adds one centermore 1 13 stereogenicto the molecule center and to thethe moleculeH- and C-NMRand the 1 becomesH- and 13 relativelyC-NMR becomes complex relatively due to the complex formation due of to four the formationdiastereomers of four (Figure diastereomers3). (Figure 3).

Chemistry 2020, 2 833 Chemistry 2020, 2, x 7 Chemistry 2020, 2, x 7

SchemeScheme 5. 5.Alkylation Alkylation ofof seleno-ethers seleno-ethers to to access access selenonium selenonium cations. cations. Scheme 5. Alkylation of seleno-ethers to access selenonium cations.

Figure 3. Formation of diastereomers upon Se-alkylation (E = enantiomer, D = diastereomer). FigureFigure 3. 3.FormationFormation of of diastereomers diastereomers upon Se-alkylationSe-alkylation (E (E= =enantiomer, enantiomer, D =Ddiastereomer). = diastereomer). 2.7. Selenium NMR 2.7.2.7. SeleniumSelenium NMRNMR Among six natural isotopes,77 77Se with spin quantum number l = ½1 is active in nuclear magnetic AmongAmong sixsix naturalnatural isotopes,isotopes, 77Se with spinspin quantumquantum numbernumber ll == ½2 isis activeactive inin nuclearnuclear magneticmagnetic resonance spectroscopy. A common reference, however, is not established in the field. Historically, a resonanceresonance spectroscopy.spectroscopy. A common reference, reference, however, however, is is not not established established in in the the field. field. Historically, Historically, a number of compounds have been used as standards [36]. A practical standard is diphenyldiselenide anumber number of of compounds compounds have have been been used used as as standard standardss [36]. [36]. A A practical practical standard is diphenyldiselenidediphenyldiselenide (4) with a chemical shift of δ = 463 ppm. This standard allows for fathoming the chemical shifts of ((44)) withwith aa chemicalchemical shiftshift ofofδ δ= =463 463 ppm.ppm. ThisThis standardstandard allowsallows forfor fathomingfathoming thethe chemicalchemical shiftsshifts ofof other selenium compounds (Figure 4 and Figures S27–S30). As can be seen in Figure 4, selenium in 3 otherother seleniumselenium compoundscompounds (Figure(Figure4 4and and Figures Figures S27–S30). S27–S30). As As can can be be seen seen in in Figure Figure4 ,4, selenium selenium in in3 3 resonates at 262 ppm. The single signal once again confirms one regio-isomer. Upon esterification of resonatesresonates atat 262262 ppm.ppm. TheThe singlesingle signalsignal onceonce againagain confirmsconfirms oneone regio-isomer.regio-isomer. UponUpon esterificationesterification ofof this compound into 7, a downfield shift in the selenium is observed by 10 ppm due to the electron thisthis compoundcompound intointo 77,, aa downfielddownfield shiftshift inin thethe seleniumselenium isis observedobserved byby 1010 ppmppm duedue toto thethe electronelectron withdrawing nature of the carbonyl groups. In compounds 16 and 17 in which the selenium atom withdrawingwithdrawing naturenature ofof thethe carbonylcarbonyl groups.groups. InIn compoundscompounds 1616 andand 1717 inin whichwhich thethe seleniumselenium atomatom becomes a cation and electron poor, a downfield shift of >100 ppm is observed. Interestingly, as becomesbecomes a a cation cation and and electron electron poor, poor, a downfield a downfield shift ofsh>ift100 of ppm >100 is observed.ppm is observed. Interestingly, Interestingly, as expected as expected1 from the13 1H and 13C-NMRs, two signals for two diastereomers were observed in the case of fromexpected the Hfrom and theC-NMRs, 1H and 13 twoC-NMRs, signals two for twosignals diastereomers for two diastereomers were observed were in the observed case of 17in. the However, case of 17. However, 16 only exhibited one broad signal, perhaps due to an overlap of the two expected 1617only. However, exhibited 16 oneonly broad exhibited signal, one perhaps broad duesignal, to an perhaps overlap due of the to twoan overlap expected ofsignals. the two expected signals. signals.

Chemistry 2020, 2 834 Chemistry 20202020,, 22,, xx 88

FigureFigure 4. 4. 777777Se-NMRSe-NMR of of 3,, 7 andand 16–17. 16–17.

2.8. Hemolysis Hemolysis A hemolysis assay was performed to to evaluate the the lytic lytic activity activity of of 1616 andand 17 usingusing sheep sheep red red blood cells (RBCs). In In this this study, study, the released hemo hemoglobinglobin was detected with the help of a microplate readerreader at at thethe wavelengthwavelength ofof 540540 nmnmnm andandand comparedcomparcompared toto controlcontrol systems.systems. The negative control was phosphate buffered buffered salinesaline (PBS)(PBS) inin whichwhich the RBCs do not rupture due to the isotonic effect effect and a net zero movement of molecules across the cell membranemembrane [37]. [37]. The The positive positive control control is is represented by deionized (DI) water in which cells rupture fully du duee to a hypotonic effect effect and movement of pure water into the RBCs through osmosis. In In the case case of of 1616 andand 1717,, however,however, no no hemolysis hemolysis was was observed observed µ even at a concentrationconcentration of 1000 μgg/mL/mL (Figure(Figure5 5).). ThisThis indicatesindicates thatthat selenoniumselenonium cationscations 1616 andand 17 have no toxic effects effects onon thethe mammalianmammalian cellcell membranes.membranes.

Figure 5. DigitalDigital picture picture showing showing the the release release of of hemoglobin hemoglobin from from red red blood cells in DI water and completecomplete orthogonality orthogonality with with PBS, PBS, 16 andand 17.17.

3. Conclusions Conclusions InIn summary,summary,summary, by byby tweaking tweakingtweaking the thethe nature naturenature of the ofof base-catalyst thethe babase-catalystse-catalyst and reaction andand reactionreaction medium, medium,medium, high (>95%) highhigh yields (>95%)(>95%) of yieldsß-hydroxy of ß-hydroxy selenides selenides can be obtained can be in obtained a 15 min in of a reaction 15 min timeof reaction under ambienttime under conditions. ambient The conditions. reaction The reaction is regio-selective and tolerates many electrophilic and nucleophilic sites in the system. A post-synthesis alkylation of the ‘click’-generated seleno-ether linkage furnishes selenonium-based

Chemistry 2020, 2 835 is regio-selective and tolerates many electrophilic and nucleophilic sites in the system. A post-synthesis alkylation of the ‘click’-generated seleno-ether linkage furnishes selenonium-based cationic structures with hemocompatibility. Overall, the presented chemistry is anticipated to become a practical synthetic tool in accessing selenium-based materials of ever increasing demand in biological applications.

Supplementary Materials: The synthesis and characterization details are available online at http://www.mdpi. com/2624-8549/2/4/54/s1. Author Contributions: Conceptualization, T.E. and A.K.; methodology, T.E.; validation, T.E.; formal analysis, T.E.; investigation, T.E.; writing—original draft preparation, T.E. and A.K.; writing—review and editing, T.E. and A.K.; supervision, A.K.; project administration, T.E. and A.K.; funding acquisition, A.K. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by National Research Foundation of Korea grant funded by the Korean government (MSIP) (NRF-18R1D1A1B07048527). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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