S S symmetry Article Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters FeaturingArticle a Quaternary Stereocenter Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters Monica Fiorenza Boselli, Chiara Faverio, Elisabetta Massolo, Laura Raimondi, Alessandra Puglisi andFeaturing Maurizio Benaglia a Quaternary * Stereocenter Monica Fiorenza Boselli, ChiaraDipartimento Faverio, diElisabetta Chimica, UniversitMassolo,à Lauradegli Studi Raimondi, di Milano, Alessandra Via Golgi 19,Puglisi I-20133 and Milano, Maurizio Italy; Benaglia * monicafi[email protected] (M.F.B.); [email protected] (C.F.); [email protected] (E.M.); [email protected] (L.R.); [email protected] (A.P.) *DipartimentoCorrespondence: di Chimica, [email protected]; Università degli Studi di Milano, Tel.: Via +39-02-5031-4171; Golgi 19, I-20133 Milano, Fax: +39-02-5031-4159 Italy; [email protected] (M.F.B.); [email protected] (C.F.); [email protected] (E.M.); Abstract:[email protected] development (L.R.); of [email protected] new and efficient methods, (A.P.) reagents, and catalysts for the introduction * Correspondence: [email protected]; Tel.: +39-02-5031-4171; Fax: +39-02-5031-4159 of fluorine atoms or fluorinated moieties in molecular scaffolds has become a topic of paramount importanceAbstract: The in development organic synthesis. of new and In thisefficient framework, methods, thereagents, incorporation and catalysts of thefor SCFthe introduc-3 group into organic moleculetion of fluorine has oftenatoms ledor fluorinated to beneficial moieties effects in molecular on the drug’s scaffolds metabolic has become stability a topic andof para- bioavailability. Heremount we importance report ourin organic studies synthesis. aimed In to th theis framework, stereoselective the incorporation synthesis of of the chiral SCF3 αgroup-SCF into3-β −ketoesters featuringorganic molecule a tetrasubstituted has often led stereocenter.to beneficial effects The useon the of drug’s a chiral metabolic auxiliary stability was crucial and bioavaila- to synthesize enan- tiopurebility. Here enamines we report that were our reactedstudies with aimedN-trifluoromethylthio to the stereoselective saccharin synthesis or phthalimide,of chiral to afford α-SCF3-β−ketoesters featuring a tetrasubstituted stereocenter. The use of a chiral auxiliary was enantioenriched α-SCF3-tetrasubstitued β-keto esters. By using a readily available, inexpensive chiral crucial to synthesize enantiopure enamines that were reacted with N-trifluoromethylthio saccharin diamine, such as trans-1,2-diaminocyclohexane, the fluorinated products could be obtained in modest or phthalimide, to afford enantioenriched α-SCF3-tetrasubstitued β-keto esters. By using a readily toavailable, good yields, inexpensive and, afterchiral the diamine, removal such of theas trans- chiral1,2-diaminocyclohexane, auxiliary, α-substituted- the αfluorinatedtrifluoromethylthio- βproducts−ketoesters could werebe obtained isolated in modest with high to good enantioselectivity yields, and, after (upthe removal to 91% of ee). the chiral auxiliary, α-substituted- α trifluoromethylthio-β−ketoesters were isolated with high enantioselectivity (up to Citation: Boselli, M.F.; Faverio, C.; Keywords:91% ee). asymmetric synthesis; fluorinated compounds; chiral auxiliary; stereoselectivity; Massolo, E.; Raimondi, L.; Puglisi, trifluoromethylthio-substituted ketones A.; Benaglia, M. Stereoselective Keywords: asymmetric synthesis; fluorinated compounds; chiral auxiliary; stereoselectivity; tri- synthesis of chiral fluoromethylthio-substituted ketones Citation: Boselli, M.F.; Faverio, C.; α-SCF3-β-ketoesters featuring a Massolo, E.; Raimondi, L.; Puglisi, A.; quaternary stereocenter. Symmetry Benaglia,2020 M., 13 Stereoselective, x. Synthesis 1. Introduction of Chiralhttps://doi.org/10.3390/xxxxxα-SCF3-β-Ketoesters 1. IntroductionFluorine atoms or residues are essential constitutive elements in many pharmaceu- Featuring a Quaternary Stereocenter. ticals,Fluorine including atoms very or residues popular are drugs essential such constitutive as Lipitor, elements Odanacatib, in many andpharmaceu- Prozac, or fluoro- Received: 5 December 2020 Symmetry 2021, 13, 92. https:// ticals, including very popular drugs such as Lipitor, Odanacatib, and Prozac, or fluo- Accepted: 4 January 2021 hydrocortisone acetate [1,2]. Enhanced lipophilicity, membrane permeability, receptor- doi.org/10.3390/sym13010092 ro-hydrocortisone acetate [1–2]. Enhanced lipophilicity, membrane permeability, recep- Published: 7 January 2021 binding selectively, and oxidative resistance are some of the attractive features that explain thetor-binding increasing selectively, request and of new oxidative fluorinated resistance chemical are some entities, of the notattractive only infeatures medicinal that chemistry Received: 5 December 2020 explain the increasing request of new fluorinated chemical entities, not only in medicinal Publisher’s Note: MDPI stays neu- (Figure1) but also in agrochemicals and material chemistry [3–5]. Accepted:tral with 4 January regard to 2021 jurisdictional chemistry (Figure 1) but also in agrochemicals and material chemistry [3–5]. Published:claims 7 in January published 2021 maps and insti- tutional affiliations. O O O Publisher’s Note: MDPI stays neu- F3CS H SCF3 O H tral with regard to jurisdictional clai- F CS H 3 ms in published maps and institutio- H H Copyright: © 2021 by the authors. O nal affiliations.Submitted for possible open access α-SCF -carvone α-SCF -santonin α-SCF -cholestenone publication under the terms and 3 3 3 conditions of the Creative Commons Figure 1. Trifluoromethylthio containing chiral drug candidates. Attribution (CC BY) license Figure 1. Trifluoromethylthio containing chiral drug candidates. Copyright:(http://creativecommons.org/licenses© 2021 by the authors. Li- Modern organic chemists have, therefore, turned their attention to the development censee/by/4.0/). MDPI, Basel, Switzerland. Modern organic chemists have, therefore, turned their attention to the development of newof new and and efficient efficient methods, methods, reagents, and and catalysts catalysts for for the the introduction introduction of a fluorine of a fluorine atom This article is an open access article atom or fluorinated moieties. In this context, the incorporation of the SCF3 group into distributed under the terms and con- ororganic fluorinated molecules moieties. has led often In this to beneficial context, theeffects incorporation on the drug’s ofstability the SCF and3 groupbioavail- into organic ditions of the Creative Commons At- molecules has led often to beneficial effects on the drug’s stability and bioavailability. tribution (CC BY) license (https:// Being highly lipophilic (Hansch’s hydrophobic parameter π = 1.44) and a strong electron creativecommons.org/licenses/by/ withdrawing group (Hammett constant: σm = 0.40 and σp = 0.50), the SCF3 group has been Symmetry 2021, 13, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/symmetry 4.0/). employed to tune lipophilicity and modify metabolic properties in new drugs [6,7]. Symmetry 2021, 13, 92. https://doi.org/10.3390/sym13010092 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, 92 2 of 16 Not surprisingly, many SCF3-containing molecules have been recently synthesized [8,9], and different synthetic methods have been developed to realize the trifluoromethylth- iolation of organic compounds, exploiting electrophilic, nucleophilic, or radical trifluo- romethylthiolating reagents [10–12]. Alternative strategies can be used to accomplish the stereoselective synthesis of chiral molecules featuring a trifluoromethylthio group: one pos- sibility is to start from enantiopure, fluorine containing building blocks; alternatively, chiral reagents or chiral catalysts may be employed to accomplish the enantioselective synthesis of the target molecule [13–15]. Trifluoromethylthiolated carbonyl derivatives are particularly attractive for their application in medicinal chemistry and as starting building block for the synthesis of functionalized molecules. However, stereoselective strategies to synthetize enantioenriched α-SCF3-substituted carbonyl compounds are still very rare [16]. The first examples of a catalytic enantioselective approach were reported indepen- dently by Shen [17] and Rueping [18] in 2013. Both groups studied the trifluoromethylthio- lation of indanone-derived β-keto esters catalyzed by Quinine; however, the methodology suffers from severe substrate limitations and work only with cyclic five-membered β−keto esters. Later, Shen published the first chiral trifluoromethylthiolating agent based on the commercially available (1S)-(-)-N-2,10- camphorsultam scaffold. Stereoselective α- trifluoromethylthiolation of β-keto esters, oxindoles, and benzofuranones was successfully achieved in the presence of potassium carbonate as a catalytic base. Excellent results in terms of yield and enantioselection were achieved, with the major disadvantage re- lated to the use of a stoichiometric amount of enantiopure sulfenylating reagent [19]. In 2016, Wu and Sun described a reaction based on an enamine catalysis performed on dihy- drocinnamaldehyde in the presence of Hayashi–Jorgensen’s catalyst [20]. Unfortunately, although yields are excellent, the system presents low stereochemical efficiency. In 2018, Wan and co-workers published a diastereo and enantioselective Cu-catalyzed tandem 1,4-addition/trifluoromethylthiolation of