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Asymmetric Synthesis of Spirooxindoles Via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts

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Asymmetric Synthesis of Spirooxindoles Via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts molecules Article Asymmetric Synthesis of Spirooxindoles via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts Martina Miceli 1, Andrea Mazziotta 1, Chiara Palumbo 1, Elia Roma 1, Eleonora Tosi 1, Giovanna Longhi 2 ID , Sergio Abbate 2, Paolo Lupattelli 3, Giuseppe Mazzeo 2 ID and Tecla Gasperi 1,* ID 1 Dipartimento di Scienze- Sezione di Nanoscienze e Nanotecnologie, Università degli Studi di Roma Tre, V.le G. Marconi 446, I-00146 Rome, Italy; [email protected] (M.M.); [email protected] (A.M.); [email protected] (C.P.); [email protected] (E.R.); [email protected] (E.T.) 2 Dipartimento di Medicina Molecolare e Traslazionale (DMMT), Università di Brescia, viale Europa 11, 25123 Brescia, Italy; [email protected] (G.L.); [email protected] (S.A.); [email protected] (G.M.) 3 Dipartimento di Scienze, Università degli Studi della Basilicata, via dell0Ateneo Lucano 10, I-85100 Potenza, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-3386711045 Received: 5 February 2018; Accepted: 12 February 2018; Published: 16 February 2018 Abstract: Taking into account the postulated reaction mechanism for the organocatalytic epoxidation of electron-poor olefins developed by our laboratory, we have investigated the key factors able to positively influence the H-bond network installed inside the substrate/catalyst/oxidizing agent. With this aim, we have: (i) tested a few catalysts displaying various effects that noticeably differ in terms of steric hindrance and electron demand; (ii) employed α-alkylidene oxindoles decorated with different substituents on the aromatic ring (11a–g), the exocylic double bond (11h–l), and the amide moiety (11m–v). The observed results suggest that the modification of the electron-withdrawing group (EWG) weakly conditions the overall outcomes, and conversely a strong influence is unambiguously ascribable to either the N-protected or N-unprotected lactam framework. Specifically, when the NH free substrates (11m–u) are employed, an inversion of the stereochemical control is observed, while the introduction of a Boc protecting group affords the desired product 12v in excellent enantioselectivity (97:3 er). Keywords: epoxidation; organocatalysis; epoxyoxindole; alkylidenoxindoles; H-bond network; non-covalent catalysis; chiroptical properties 1. Introduction “If carbonyl compounds have been said to be virtually the backbone of organic synthesis, the epoxides correspond to at least one of the main muscles” (Prof. D. Seebach) [1]. As an irreplaceable muscle, over the years, chiral epoxides have proved to be highly valuable intermediates and outstanding building blocks in fine organic synthesis. Indeed, the oxirane ring easily undergoes several stereoselective chemical transformations into a variety of multi-functionalized compounds that directly led to advanced precursors of both natural products and biologically active molecules [2–7]. Among them, spiro-epoxyoxindoles, featured with a spiro-carbon and unstable oxirane motif, have piqued the interest of a growing number of research groups [8–10]. Such striking allure is mainly due not only to their recognised medicinal effectiveness [11–17], but also to their role providing direct access to architecturally complex heterocycles [18–22]. Although various fascinating approaches have been developed for their preparation, only few are efficient and effective strategies to achieve Molecules 2018, 23, 438; doi:10.3390/molecules23020438 www.mdpi.com/journal/molecules Molecules 2018, 23, 438 2 of 18 this notable framework with high optical purity. For instance, since the seminal work of Brière and MetznerMolecules [ 232018],, stereoselective23, x Darzen-type processes have been the object of several investigations.2 of 18 In 2014 Xiao et al. succeeded in the synthesis of epoxyoxindoles from isatines [8]. Likewise, Metzner [23], stereoselective Darzen-type processes ha0 ve been the object of several investigations. In Feng and co-workers investigated a Co(acac)2-N,N -dioxide-catalyzed Darzens reaction to afford 2014 Xiao et al. succeeded in the synthesis of epoxyoxindoles from isatines [8]. Likewise, Feng and benzyl-substituted trans-spirooxirane-oxindoles [10], while, more recently, Wong has focused his co-workers investigated a Co(acac)2-N,N′-dioxide-catalyzed Darzens reaction to afford benzyl- efforts on the use of (R)-BINOL and Ti(iOPr) as catalysts reaching a high level of stereoselectivity substituted trans-spirooxirane-oxindoles [10], 4while, more recently, Wong has focused his efforts on involving chiral sulfur ylides in situ generated from camphor-derived sulfonium salts [24]. Conversely, the use of (R)-BINOL and Ti(iOPr)4 as catalysts reaching a high level of stereoselectivity involving lesschiral explored sulfur have ylides been in the situ stereoselective generated from epoxidation camphor-derived of α-ylidenoxindoles sulfonium salts with [24]. peroxide, Conversely, which less even thoughexplored these have furnished been the stereoselective the titled products epoxidation with of excellent α-ylidenoxindoles diastereomeric with peroxide, ratios, which provided even the correspondingthough these spiroepoxides furnished the only titled with products moderate with to goodexcellent enantioselectivity diastereomeric [25ratios,–27]. provided the correspondingIn the past few spiroepoxides years, we have only been with engaged moderate in to the good development enantioselectivity of the nucleophilic [25–27]. epoxidation of α-ylidenoxindolesIn the past few as wellyears, as we in have the improvement been engaged ofin thethe correspondingdevelopment of organocatalyticthe nucleophilic versionepoxidation [25,26 ], whichof α-ylidenoxindoles mostly relies on as thewell catalyst’s as in the abilityimprovement to install of the in corresponding the transition organocatalytic state a strong version network with[25,26], substrate which andmostly oxidizing relies on agentthe catalyst’s (Figure abilit1A).y Pursuingto install in our the transiti researchon state and a prompted strong network by the continuouswith substrate interest and concerning oxidizing agent spiroepoxy (Figure derivatives, 1A). Pursuing we our envisaged research enhancing and prompted the previouslyby the reportedcontinuous procedure interest by introducingconcerning spiroepoxy further additional derivatives, groups we capable envisaged of installing enhancing more the H-bonds previously inside thereported substrate/catalyst/oxidant procedure by introducing system further by modifying additional both groups the substratecapable of and installing the catalyst. more Specifically,H-bonds sinceinside the the first substrate/catalyst/oxidant step of our nucleophilic system epoxidation by modifying involved both an oxathe-Michael substrate addition and the and,catalyst. taking Specifically, since the first step of our nucleophilic epoxidation involved an oxa-Michael addition and, into account the analogous activation process of the enoyl-CoA hydratase in fatty acid metabolism, taking into account the analogous activation process of the enoyl-CoA hydratase in fatty acid we envisaged the possibility of employing a catalyst bearing two hydrogen donor groups that should metabolism, we envisaged the possibility of employing a catalyst bearing two hydrogen donor increase the α,β-unsaturated bond electrophilicity and make stronger the H-bond network in the groups that should increase the α,β-unsaturated bond electrophilicity and make stronger the H-bond postulated transition state A. network in the postulated transition state A. Ph N Ph H O H H chiral tBu O skeleton O Lewis O N X Acid N X R1 H H X Lewis EtO C N Acid 2 Bronsted Bronsted H H base base 3 R BC R2 A HO O Ar N N Ph N H HN N Ar CO H N H OH N 2 H HN N H Ph HO 1 Ar = C6H5 5 67 2 Ar = 4-NO2-C6H4 3 Ar = 4-MeO-C6H4 4 Ar = 3,5-(tBu)2-C6H3 N CF O S 3 N S OMe H N N HN H H NH F C N N 3 H H HO N 89 10 FigureFigure 1. 1.Postulated Postulated transition transition state state ((AA)) ofof the previously optimized optimized or organocatalyticganocatalytic epoxidation epoxidation that that highlightshighlights the the substrate/catalyst/oxidant substrate/catalyst/oxidant H-bond H-bond network. network. Hypothesized Hypothesized catalyst catalyst structures structures (B,C (B). ,C). Organocatalysts examined in this study (1–10). Organocatalysts examined in this study (1–10). Molecules 2018, 23, 438 3 of 18 2. Results and Discussion 2.1. EvaluationMolecules 2018 of the, 23, Catalystx Modification 3 of 18 Initially, considering the efficiency of the α, α-diarylprolinol 1, the catalyst scope was enlarged 2. Results and Discussion to various compounds in which: (i) either the aromatic rings or the pyrrolidine framework were decorated2.1. withEvaluation substituents of the Catalyst different Modification in terms of hindrance- and electron demand (2–5, Figure1); (ii) the BrønstedInitially, basic considering site was the preserved, efficiency of whereas the α, α-diarylprolinol the Lewis acidic 1, the sitecatalyst was scope changed was enlarged to a tetrazolic ring (6,to Figure various1); compounds (iii) the Brønsted in which: basic (i) either site wasthe ar preserved,omatic rings while or the two pyrrolidine hydrogen framework bond donors were were introduceddecorated (7 and with8, substituents e.g., an hydroxyl different group in terms and of hindrance- an amide and moiety, electron Figure demand1); ( (iv)2–5, theFigure Brønsted 1); (ii) basic site wasthe preserved, Brønsted basic and site linked was preserved,
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