molecules Article Atom Efficient Preparation of Zinc Selenates for the Synthesis of Selenol Esters under “On Water” Conditions Luca Sancineto 1, Jaqueline Pinto Vargas 2, Bonifacio Monti 1, Massimiliano Arca 3, Vito Lippolis 3, Gelson Perin 4, Eder Joao Lenardao 4,* and Claudio Santi 1,* 1 Catalysis and Organic Green Chemistry Group, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06100 Perugia, Italy; [email protected] (L.S.); [email protected] (B.M.) 2 Universidade Federal do Pampa—Unipampa, Av. Pedro Anunciação, 111, Caçapava do Sul-RS 96570-000, Brazil; [email protected] 3 Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, S.S. 554 bivio per Sestu, 09042 Monserrato, Cagliari, Italy; [email protected] (M.A.); [email protected] (V.L.) 4 Laboratório de Síntese Orgânica Limpa-LASOL-CCQFA, Universidade Federal de Pelotas-UFPel, P.O. Box 354, Pelotas-RS 96010-900, Brazil; [email protected] * Correspondence: [email protected] (E.J.L.); [email protected] (C.S.); Tel.: +55-53-3275-7533 (E.J.L.); +39-075-585-5112 (C.S.) Academic Editor: Derek J. McPhee Received: 11 May 2017; Accepted: 3 June 2017; Published: 8 June 2017 Abstract: We describe here an atom efficient procedure to prepare selenol esters in good to excellent yields by reacting [(PhSe)2Zn] or [(PhSe)2Zn]TMEDA with acyl chlorides under “on water” conditions. The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence of other functionalities in the starting material. Keywords: selenium; selenol esters; zinc; TMEDA; water 1. Introduction Selenol esters are versatile tools in organic synthesis, once they can be easily converted to a sort of more complex molecules, acting as acyl-transfers, and in other important functional groups modifications [1]. Aromatic selenol esters, such as I, are stable liquid crystals with a large nematic mesophase range [2–4]. In contrast to their sulfur analogues, selenol esters only recently have attracted the attention to their pharmacological potential; the thiazolidine-4-carboselenoate II is a potent antioxidant [5], while the polyfunctionalized selenol esters III and IV presented high cytotoxic and antiproliferative activities against MCF-7 human cancer cells [6,7] (Figure1). The synthetic usefulness of selenol esters goes far beyond the transfer of acyl group [8], or its use as a protecting group for selenium compounds [9]. Selenol esters were explored in the total synthesis of several complex molecules [10–14], such as the marine alkaloid amphimedime [10], apparicine [11], (+)-geissoschizine [12], ciguatoxin CTX3C7d [13] and the peach moth (Carposia niponensis) pheromone [14]. More recently, selenol esters have gained even more importance, after the discovery that they can be used in native chemical ligation (NCL) reactions where the traditional thioester ligation chemistry is prohibitive [15,16]. Molecules 2017, 22, 953; doi:10.3390/molecules22060953 www.mdpi.com/journal/molecules Molecules 2017, 22, 953 2 of 13 Molecules 2017, 22, 953 2 of 13 Figure 1. Examples of molecules bearing the selenol ester moiety. Figure 1. Examples of molecules bearing the selenol ester moiety. As a consequence of the increasing demand for selenol esters, the number of methods to prepare As a consequencethis class of compounds of the has increasing been increased demand along the years for selenol[1,17–43] Among esters, the the strategies number to prepare of methods to prepare thisselenol class esters of compounds there are the reactions has been of nucleophil increasedic alongselenium the reagents years with [1,17 an– acyl43] group Among source, the strategies such as N-acyl benzotriazoles [17,18] activated carboxylic acids (using DCC [3] or PBu3 [4,5,19,20]), to prepareenol selenol esters esters[21], anhydrides there are [22–24 the], esters reactions [25], carbon of nucleophilic monoxide [26,27], selenium aldehydes reagents[28,29] or acyl with an acyl group source,chlorides such [2,7,30–43]. as N-acyl Other benzotriazoles approaches to selenol [17 esters,18] involve activated the alkylation carboxylic of selenocarboxylate acids (using DCC [3] anions with alkyl halides [6,44–46] or the acidic hydration of selenoalkynes [47,48]. The acyl or PBu3 [4,5,19,20]), enol esters [21], anhydrides [22–24], esters [25], carbon monoxide [26,27], substitution of acyl chlorides is by far the most explored method to access selenol esters, mainly aldehydesbecause [28,29] of or its acylversatility, chlorides since the [2 ,diversity7,30–43 of]. acyl Other chlorides approaches that can be toprepared selenol is practically esters involve the alkylationendless. of selenocarboxylate The pivotal step in this anions reaction with is the alkylgeneration halides of the nucleophilic [6,44–46] selenium or the species acidic and hydration a of selenoalkynesrange [ 47of ,reagents48]. The have acyl been substitutionused for this purpose, of acyl including chlorides Se°/ArMgBr is by [2], far (NH the2)2 mostC=Se/Et explored3N [30], method to access selenolSe°/NaBH esters,4 [6], InI/(PhSe) mainly2 because[31,39,40], ofSe°/LiAlH its versatility,4 [32,37], (RSe) since2/Zn/AlCl the diversity3 [33], Ph(NH of2)C=Se acyl [34], chlorides that (Bu3Sn)2/(PhSe)2/hv [35,36], Se°/R2C=CZrCp2Cl [38], (RSe)2/Zn°/[bmim]PF6 [41], (PhSe)2/Hg°/dioxane [42] can be preparedand (PhSe) is2/SnCl practically2/CuBr2/[bmim]BF endless.4 [43]. The Despite pivotal these stepreaction in syst thisems reaction afforded a is range the of generation selenol of the nucleophilicesters, selenium they suffer species from one and or more a range of the followin of reagentsg drawbacks: have use been of VOCs used as forsolvent, this strong purpose, bases, including ◦ strong and moisture sensible reducing agents,◦ expensive reagents and low atom-economy. ◦ Se /ArMgBr [2], (NH2)2C=Se/Et3N[30], Se /NaBH4 [6], InI/(PhSe)2 [31,39,40], Se /LiAlH4 [32,37], Significant progress towards the greenness of the synthesis of selenol esters has◦ been recently (RSe)2/Zn/AlCldescribed3 [ 33[49,50].], Ph(NH Braga and2)C=Se co-workers [34], described (Bu3Sn) the2/(PhSe) solvent-free2/hv, microwave [35,36], accelerated Se /R2C=CZrCp reaction 2Cl [38], ◦ ◦ (RSe)2/Zn of/[bmim]PF diorganyl diselenides6 [41], (PhSe) with 2acyl/Hg chlorides;/dioxane good [ 42yields] and of (PhSe)selenol 2esters/SnCl were2/CuBr obtained2/[bmim]BF after 4 [43]. Despite theseirradiation reaction at 80 systems °C for only afforded 2 min [49]. a rangeIn the same of selenol year, some esters, of us theydescribed suffer the use from of the one bench or more of the following drawbacks:stable nucleophilic use species, of VOCs PhSeZnX as solvent, (X=Br, Cl), strong in the synthesis bases, strong of a range and of selenol moisture esters sensible in good reducing yields at room temperature and using water as medium [50]. It was observed that the reaction was agents, expensiveaccelerated reagents when it andwas performed low atom-economy. under “on water” conditions and, in addition, the water was Significantreused progressfor subsequent towards cycles of the reactions. greenness of the synthesis of selenol esters has been recently described [49,50Nine]. Braga years andago, we co-workers introduced describeda simple method the solvent-free, to prepare in microwavesitu nucleophilic accelerated sulfur and reaction of selenium reagents by reducing dichalcogenides with elemental zinc in an acidic biphasic system [51]. diorganyl diselenidesThis protocol withhas been acyl more chlorides; recently used good by us yields and others of selenol to effect estersa series wereof selenylation obtained reactions after irradiation ◦ at 80 C forinvolving only 2 nucleophilic min [49]. substitutions, In the same ring year, opening some and ofhydrochalcogenations us described the [51–53] use and ofthe it was bench stable nucleophilicadopted species, by Flemer PhSeZnX in the (X=Br, synthesis Cl), of peptides in the synthesis[54,55]. of a range of selenol esters in good yields at room temperatureThe actual and using reactive water specie asin mediumthis protocol [50 was]. Itsupposed was observed to be a zinc that bis-selenate the reaction [(PhSe) was2Zn] accelerated probably in equilibrium with the corresponding selenol. Considering that [(PhSe)2Zn] is when it wascharacterized performed by a under higher “onatom water”economy conditionsrespect to the and, PhSeZn-halides in addition, in the the insertion water of wasPhSe reused for subsequentgroups, cycles the of possibility reactions. to obtain it in a bench stable form is desirable. It could improve the versatility Nine yearsof its synthetic ago, we application introduced (avoiding a the simple strong methodacidic conditions to prepare of the biphasic in situ system), nucleophilic controlling sulfur and or preventing undesired side reactions like those observed when it was prepared and used in situ in selenium reagentsthe presence by of reducing THF [56]. dichalcogenides with elemental zinc in an acidic biphasic system [51]. This protocol has been more recently used by us and others to effect a series of selenylation reactions involving nucleophilic substitutions, ring opening and hydrochalcogenations [51–53] and it was adopted by Flemer in the synthesis of peptides [54,55]. The actual reactive specie in this protocol was supposed to be a zinc bis-selenate [(PhSe)2Zn] probably in equilibrium with the corresponding selenol. Considering that [(PhSe)2Zn] is characterized by a higher atom economy respect to the