materials Article Novel Selenoureas Based on Cinchona Alkaloid Skeleton: Synthesis and Catalytic Investigations Mariola Zieli ´nska-Błajet 1,* and Joanna Najdek 2 1 Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeze˙ Wyspia´nskiego27, 50-370 Wrocław, Poland 2 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany; [email protected] * Correspondence: [email protected]; Tel.: +48-71-3202128 Abstract: An efficient approach to the synthesis of chiral selenoureas consisting of Cinchona alkaloid scaffolds was described. The new selenoureas were assessed as bifunctional organocatalysts in the asymmetric Michael addition reactions under mild conditions. The best results were obtained for selenoureas bearing the 4-fluorophenyl group. These catalysts promoted the reactions with enantioselectivities of up to 96% ee. Additionally, the catalytic performance of the thiourea and selenourea counterpart was compared. Keywords: Cinchona alkaloids; selenoureas; isoselenocyanates; organocatalysis; Michael addition; asymmetric synthesis 1. Introduction In recent years, growing attention has been focused on the synthesis and applications Citation: Zieli´nska-Błajet,M.; of selenourea derivatives. The structures of selenoureas are closely related to those of Najdek, J. Novel Selenoureas Based analogs of oxygen and sulfur compounds [1–3], but the presence of larger, more polarizable on Cinchona Alkaloid Skeleton: selenium results in a change of significant properties. They possess various biological Synthesis and Catalytic properties, such as antioxidant [4,5], antibacterial and antifungal [6], antileishmanial [7], Investigations. Materials 2021, 14, 600. pesticidal [8], and anti-urease activity [9]. Selenoureas also demonstrate enzyme inhibition, https://doi.org/10.3390/ma14030600 free-radical scavenging, and anticancer activity [10,11]. These compounds are very useful starting materials for the synthesis of selenium-containing heterocycles [12,13] and are Academic Editor: Erika Bálint used for anion binding and recognition [14,15]. To the best of our knowledge, only a Received: 31 December 2020 few examples of chiral selenoureas have been reported in the literature [16,17]. Currently, Accepted: 23 January 2021 chiral bis-selenourea is used as a strong hydrogen-bonding donor for highly efficient Published: 28 January 2021 chiral recognition of a diverse range of tertiary alcohols [18]. Still, little is known about the application of selenoureas as hydrogen-bond donors in organocatalysis. Bolm and co- Publisher’s Note: MDPI stays neutral workers were the first to apply a selenourea derivative as a chiral catalyst in the asymmetric with regard to jurisdictional claims in α published maps and institutional affil- Michael addition of -nitrocyclohexane to aryl nitroalkenes [19]. iations. Chiral bifunctional organocatalysts, which incorporate a thiourea group as H-bond donors with Lewis base, are commonly used in asymmetric catalysis. Both parts of the catalysts simultaneously activate the electrophile and nucleophile leading to the high stereocontrol of the reaction [20,21]. Nowadays, thioureas are widely recognized as highly useful and powerful organocatalysts that promote a diverse range of reactions with ex- Copyright: © 2021 by the authors. cellent enantioselectivity [22–24]. Cinchona alkaloids with an exceptionally good chiral Licensee MDPI, Basel, Switzerland. backbone have been used for the synthesis of many successful catalysts [25]. Inspired by This article is an open access article distributed under the terms and the improved catalytic activity of the thioureas in comparison to ureas, we have taken conditions of the Creative Commons interest in the modification of the “privileged” Cinchona alkaloid scaffolds by substituting Attribution (CC BY) license (https:// the thiourea with a selenourea moiety. creativecommons.org/licenses/by/ 4.0/). Materials 2021, 14, 600. https://doi.org/10.3390/ma14030600 https://www.mdpi.com/journal/materials Materials 2021, 14, x FOR PEER REVIEW 2 of 13 Materials 2021, 14, 600 2 of 13 Materials 2021, 14, x FOR PEER REVIEW 2 of 13 Here, we report the approach to the efficient synthesis of a series of novel Cinchona alkaloid-derived selenoureas, and we also demonstrate their organocatalytic potential in Here, we report the approach to the efficient synthesis of a series of novel Cinchona Here, we report the approach to the efficient synthesis of a series of novel Cinchona asymmetricalkaloid-derived Michael selenoureas, additions. and we also demonstrate their organocatalytic potential in alkaloid-derived selenoureas, and we also demonstrate their organocatalytic potential in asymmetric Michael additions. 2.asymmetric Results and Michael Discussion additions. 2.1.2. Results Preparation and Discussionof Compounds 2. Results and Discussion 2.1. Preparation Cinchona alkaloid of Compounds-based selenoureas were prepared by coupling reactions of 9-epi- 2.1. Preparation of Compounds aminoalkaloidsCinchona alkaloid-based with aryl isoselenocyanates. selenoureas were Although prepared there by are coupling some methods reactions in of the 9- epilit-- Cinchona alkaloid-based selenoureas were prepared by coupling reactions of 9-epi- eratureaminoalkaloids for the preparation with aryl isoselenocyanates.of selenoureas [4,10,26] Although, the best there procedure are some still methods turns out in to the be aminoalkaloids with aryl isoselenocyanates. Although there are some methods in the lit- theliterature reaction for of the isoselenocyanates preparation of selenoureas with amines. [4,10 The,26], crucial the best step procedure is the pre stillparation turns out of erature for the preparation of selenoureas [4,10,26], the best procedure still turns out to be isoselenocyanates,to be the reaction ofwhich isoselenocyanates, unlike their sulfur with analogs amines., are The not crucial commercially step is the available. preparation Sev- the reaction of isoselenocyanates with amines. The crucial step is the preparation of eralof isoselenocyanates, strategies towards which, their synthesis unlike their have sulfur been analogs,reported are[27– not29]. commercially The oxidation available. of corre- isoselenocyanates, which, unlike their sulfur analogs, are not commercially available. Sev- spondingSeveral strategies isocyanides towards with elemental their synthesis black haveselenium been in reported a suitable [27 solvent–29]. The seems oxidation to be the of eral strategies towards their synthesis have been reported [27–29]. The oxidation of corre- corresponding isocyanides with elemental black selenium in a suitable solvent seems to be mostsponding reliable isocyanides method [13,16,30,31]with elemental. black selenium in a suitable solvent seems to be the the most reliable method [13,16,30,31]. most The reliable first methodcoupling [13,16,30,31] partner for. the synthesis of desired selenoureas was Cinchona al- Cinchona kaloidThe The-based firstfirst amines coupling 2a –partner partnere, which for for were the the synthesis prepared synthesis of in desired of good desired yieldsselenoureas selenoureas (65–75%) was Cinchonafrom was naturally al- occurringalkaloid-basedkaloid-based Cinchona amines amines alkaloi 2a–2ae,– ds,whiche, whichnamely were were quinineprepared prepared (QN), in good incinchonidine goodyields yields (65– 75%)(CD), (65–75%) from quinidine naturally from (QD), natu- andrallyoccurring the occurring respective CinchonaCinchona alkaloi dihydroalkaloids,ds, namelyderivatives namely quinine (dihydroquinine quinine (QN), cinchonidine (QN), cinchonidine (DHQN)/dihydroquinidine (CD), quinidine (CD), quinidine (QD), (QD), and the respective dihydro derivatives (dihydroquinine (DHQN)/dihydroquinidine (DHQD))and the inrespective a three-step dihydro sequence derivatives via mesylation (dihydroquinine [32], azidation (DHQN)/dihydroquinidine with NaN3 in warm DMF (DHQD)) in a three-step sequence via mesylation [32], azidation with NaN in warm followed(DHQD)) byin a threeSN2 -displacementstep sequence via[33 mesylation], and then [32 ],treat azidationment withwith NaN triphenylphosphine3 in warm3 DMF DMF followed by S 2 displacement [33], and then treatment with triphenylphosphine (Staudingerfollowed by reduction) SN2 displacementN to amine (Scheme[33], and 1) [then34]. treatment with triphenylphosphine (Staudinger(Staudinger reduction)reduction) to amine amine (Scheme (Scheme 1)1)[ [3434].]. SchemeScheme 1. 1. General General synthetic routeroute for for compounds compounds 7a 7a–g–.g . NonNon-commercialNon--commercialcommercial aryl isoselenocyanatesisoselenocyanates 6a 6a–c–,c the,, the the second second second coupling coupling coupling partner partner partner,, were, were were syn- syn- syn- thesizedthesized in inin good good yieldsyields (46(46 (46–68%)––68%)68%) inin in aa athree three three-step-step-step protocol protocol (Scheme (Scheme 2) 22)that) thatthat involved involvedinvolved N- N-- formylationformylation of ofof the the commercially availableavailable available aryl aryl aryl amines amines amines 3a 3a3a–c– –withcc with formic formic acid acid in toluene,in toluene, conversionconversion ofof thethe formamides 4a4a––cc into into isocyanides isocyanides 5a 5a–c– uponcc upon dehydration dehydration with withwith POCl POClPOCl3 in3 3 in thethe presence presence ofofof NEtNEtNEt33 inin dichloromethanedichloromethane (DCM)( DCM(DCM) [) 35 [35].]. ].The The The last last last step step step included included included