molecules Review Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry Franz Steppeler 1 , Dominika Iwan 1, El˙zbietaWojaczy ´nska 1,* and Jacek Wojaczy ´nski 2 1 Faculty of Chemistry, Wrocław University of Science and Technology, Wybrze˙zeWyspia´nskiego 27, 50 370 Wrocław, Poland; [email protected] (F.S.); [email protected] (D.I.) 2 Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50 383 Wrocław, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-71-320-2410 Academic Editors: Zbigniew Czarnocki and Joanna Szawkało Received: 29 December 2019; Accepted: 16 January 2020; Published: 18 January 2020 Abstract: For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asymmetric organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development. Keywords: asymmetric synthesis; chirality; isothiocyanates; organocatalysis; stereoselectivity; thioureas 1. Introduction The replacement of the electronegative oxygen atom of urea by sulfur (with electronegativity comparable to carbon) results in a significant change of properties. Thioureas (thiocarbamides) exhibit higher acidity and are stronger hydrogen bond donors [1–3]. This ability to participate in hydrogen bonding, which can be further modified by the appropriate substitution of nitrogen atoms, is essential for numerous applications of this class of organic compounds, mainly in organocatalysis and molecular recognition. Thioureas are also widely applied in agriculture and medicine [4–7], and as corrosion inhibitors [8–11]. For almost 20 years they have been used as catalysts in organic synthesis, especially in stereoselective reactions [12–14]. They also serve as valuable starting materials for the synthesis of heterocycles [15–17], and are used as ligands in coordination chemistry (particularly when additional donors are present in their molecules) [18–22], as well as in the field of anion binding and recognition [2,23]. Structurally thioureas can be classified depending on the number of substituents of nitrogen atom (Figure1)[ 6,7]. Not surprisingly, derivatives with one and two organic groups (either 1,1 or 1,3-disubstituted) are most common, though trisubstituted (with limited, but still preserved possibility to act as hydrogen bond donors) and fully substituted (mainly cyclic) thioureas are also prepared and used for various purposes. The first thiocarbamides were prepared ca. 150 years ago [24,25], and their chiral derivatives have been long known [26,27], but a great interest in the latter has arisen with the development of enantioselective organocatalysis. Molecules 2020, 25, 401; doi:10.3390/molecules25020401 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 57 Molecules 2020, 25, 401x 22 of of 57 56 (a) (b) (c) (d) (e) (a) (b) (c) (d) (e) Figure 1. TypesTypes of of thioureas; thioureas; (a) ( amonosubstituted;) monosubstituted; (b) (b1,1-disubstituted;) 1,1-disubstituted; (c) 1,3-disubstituted; (c) 1,3-disubstituted; (d) (Figuretrisubstituted;d) trisubstituted; 1. Types (e )of tetrasubstituted. (e )thioureas; tetrasubstituted. (a) monosubstituted; (b) 1,1-disubstituted; (c) 1,3-disubstituted; (d) trisubstituted; (e) tetrasubstituted. 2. Synthesis of Chiral Thioureas 2. SynthesisSince the of thioureaChiral Thioureas skeleton is notnot intrinsicallyintrinsically chiral, the existence of enantiomersenantiomers typically originatesSince fromthe thiourea its substituents.substituents. skeleton isExamples Examples not intrinsicall of of va variousriousy chiral, groups the bearingexistence stereogenic of enantiomers centers typically will be presentedoriginates ininfrom thethe subsequentitssubsequent substituents. section. section. Examples Desymmetrisation Desymmetrisation of various resulting groupsresulting bearing from from less less stereogenic common common axial centersaxial (biphenyl (biphenyl will be or binaphthylpresentedor binaphthyl in derivatives) the derivatives) subsequent [28 [28–30]– 30section.] or or planar planarDesymmetrisation chirality chirality [ 31[31–33]–33 resulting] is is also also from worth worth less mentioning.mentioning. common axial Consequently, (biphenyl theor binaphthyl methods of derivatives) synthesis of [28–30] chiral or thioureas planar chiral are essentiallyesseityntially [31–33] the is alsosame worth as for mentioning. their achiral Consequently, counterparts, but,the methods typically, of thethe synthesis reactants reactants of fromchiral from a thioureas achiral chiral pool pool are are esse are usedntially used in inenantiomerically the enantiomerically same as for their pure pure achiral form. form. However,counterparts, However, the thebut,preparation preparation typically, of the the of reactants thedesired desired productfrom product a chiral as asracemic racemicpool are mixture mixtureused in followed followedenantiomerically by by separation separation pure ofform. of enantiomers enantiomers However, was the reportedpreparation in selectedof the desired cases, e.g.,product bis-thiourea as racemic derivativesderiva mixturetives offollowed Tröger’s by base separation werewere obtained of enantiomers as racemates was andreported resolved in selected on a chiralchiral cases, stationarystationary e.g., bis-thiourea phasephase [[34].34 deriva]. Similarly,tives of enantiomersenantiomers Tröger’s base ofof we norbornanenorbornanere obtained thiocarbamidethiocarbamide as racemates formedand resolved as 1:1 on mixture a chiral in astationary two-step phase protocol [34]. from Similarly, norbornene enantiomers were separated of norbornane either by thiocarbamide chiral HPLC orformed by crystallizationcrystallization as 1:1 mixture of in diastereomericdiastere a two-stepomeric protocol salts ofoffrom thethe norbornene amineamine intermediatesintermediates were separated [[35].35]. Theeither advantage by chiral ofHPLC this approachor by crystallization lays in the of fact diastere that bothomeric optical salts antipodes of the amine of chiral intermediates thiourea can[35]. be The isolated advantage and used of this as organocatalystsapproach lays in or the for fact chiralchiral that recognition.recognition. both optical antipodes of chiral thiourea can be isolated and used as organocatalystsThe choice ofofor a afor particularparticular chiral recognition. method method of of preparation preparation of of the the desired desired stereoisomer stereoisomer depends depends mainly mainly on on its structureits structureThe choice (number (number of a and particular typeand oftype substituents)method of substituents) of preparation and availability and of availabilitythe ofdesired necessary stereoisomerof necessary startingmaterials. dependsstarting mainlymaterials. Certainly, on oneitsCertainly, structure should one also (number should consider andalso possible typeconsider of inconveniences substituents) possible inco (bothandnveniences availability for the (both person of for conductingnecessary the person starting the conducting synthesis materials. andthe forCertainly,synthesis the environment) and one for should the environment) connectedalso consider with connected possible the use withinco of certain nveniencesthe use reactants:of certain (both reactants:for their the limited person their stability, limitedconducting stability, toxicity, the flammability,synthesistoxicity, flammability, and orfor simply the environment) or an simply unpleasant an connected unpleasant odor. In withmost odor. the preparations, In use most of certainpreparations, reactants reactants: containingreactants their limited containing C=S bondstability, C=S are used—mainlytoxicity,bond are flammability, used—mainly isothiocyanates, or isothiocyanates, simply but an alsounpleasant dithiocarbamates, but also od or.dithiocarbamates, In most carbon preparations, disulfide, carbon reactants disulfide, thiophosgene containing thiophosgene and their C=S equivalents.bondand theirare used—mainly equivalents. Less frequently, isothiocyanates,Less inorganic frequently, sources but inorga also of sulfurdithiocarbamates,nic sources are useful of forsulfur carbon a given are disulfide, transformation—P useful thiophosgenefor a given4S10 orandtransformation—P Lawesson’s their equivalents. reagent4S10 toor Less convertLawesson’s frequently, urea intoreagent thioureainorga to nicconvert [ 36sources,37] sulfidesurea of intosulfur or elementalthiourea are useful [36,37] sulfur. for Aminessulfides a given areor thetransformation—Pelemental most usual sulfur. source Amines4S10 ofor thiourea areLawesson’s the mo nitrogenst usualreagent atoms; source tohowever, ofconvert thiourea isocyanidesurea nitrogen into thioureaatoms; and azides however, [36,37] are also isocyanidessulfides found or in variouselementaland azides protocols. sulfur. are also Amines An found alternative are in variou the mo routesst protocols. usual involves source An modification alternativeof thiourea ofroute nitrogen already involves atoms; constructed modification however, achiral isocyanides of thiourea already withandconstructed azides optically are achiral