Asymmetric Synthesis of Spirooxindoles Via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts

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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 H-bonds Speciﬁcally, 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, to a thiourea whereas through the Lewis a methylene acidic site was (9, Figure changed1); to (v) a tetrazolic the chiral ring skeleton (6, Figure 1); (iii) the Brønsted basic site was preserved, while two hydrogen bond donors were was changed to an epi-quinine, in which the basic site is a tertiary amine and the Lewis acid group is introduced (7 and 8, e.g., an hydroxyl group and an amide moiety, Figure 1); (iv) the Brønsted basic a thioureasite (Sowasó preserved,s catalyst and10, linked Figure to1 ).a thiourea through a methylene (9, Figure 1); (v) the chiral skeleton Thewas nucleophilic changed to an epoxidation epi-quinine, in reactionwhich the wasbasic site initially is a tertiary performed amine and using the Lewis the alkylidenacid group is oxindole 11a as modela thiourea substrate, (Soós catalyst testing 10, Figure catalysts 1). 2–10 and employing previously optimized conditions [25] (i.e., TBHP asThe oxidizing nucleophilic agent, epoxidation hexane reaction as solvent, was init andially roomperformed temperature). using the alkyliden The observed oxindole 11a outcomes were comparedas model substrate, with the testing simplest catalystsα,α 2-diphenyl–10 and employing prolinol previously1 (Table optimi1). Thezed presenceconditions of[25] an (i.e., electron TBHP as oxidizing agent, hexane as solvent, and room temperature). The observed outcomes were withdrawing group (Ar = 4-NO -C H catalyst 2, entry 2) on the aromatic moiety dramatically reduce compared with the simplest2 6α,α4,-diphenyl prolinol 1 (Table 1). The presence of an electron the enantioselectivitywithdrawing group as well (Ar = as 4-NO the2 efficiency-C6H4, catalyst in terms2, entry of 2) time on the and aromatic yield, moiety even though dramatically the diastereomeric reduce ratio wasthe quite enantioselectivity favourable to as the well epoxide as thetrans efficiency-12. Conversely, in terms of thetime introduction and yield, even of an though electron the donating moiety (Ardiastereomeric = 4-OMe-C ratio6H was4, catalyst quite favourable3, entry 3),to the dramatically epoxide trans reduced-12. Conversely, the diastereoselectivity, the introduction of an while the enantiomericelectron ratio donating was almostmoiety comparable(Ar = 4-OMe-C to the6H4, referencecatalyst 3,catalyst. entry 3), Additionally, dramatically reduced the more the hindered diastereoselectivity, while the enantiomeric ratio was almost comparable to the reference catalyst. catalyst 4 (entry 4) slightly favoured the formation of the cis isomer (25:75) without any significant Additionally, the more hindered catalyst 4 (entry 4) slightly favoured the formation of the cis isomer enhancement(25:75) inwithout the enantioselectivity, any significant enhancement which was completelyin the enantioselectivity, smoothed over which when was a secondcompletely stereogenic centre wassmoothed introduced over when on thea second five-membered stereogenic centre ring (entrywas introduced 5). on the five-membered ring (entry The5). tetrazolic catalyst 6 (entry 6), featured with an NH function instead of the free hydroxyl moiety, furnishedThe tetrazolic an interesting catalyst 6 high (entry diastereo- 6), featured (79:21) with an and NH enantioselectivity function instead of (92:8), the free but hydroxyl a pronounced decreasemoiety, of reactivity furnished was an observed interesting in termshigh diastereo- of reaction (79:21) time and (240 en h)antioselectivity and yield (4%). (92:8), The but use a of other pronounced decrease of reactivity was observed in terms of reaction time (240 h) and yield (4%). The amidic catalysts was subsequently evaluated: pyrrolidine derivative 7 and 8 (Figure1), in which the use of other amidic catalysts was subsequently evaluated: pyrrolidine derivative 7 and 8 (Figure 1), OH functionin which is sustainedthe OH function by a is second sustained NH by function, a second NH and function, thioureas and9 thioureasand 10 (Figure 9 and 101 ),(Figure in which 1), in the OH functionwhich is substituted the OH function by an is NHsubstituted moiety. by Unfortunately,an NH moiety. Unfort no substantialunately, no substantial improvement improvement was observed and onlywas lower observed enantioselectivity and only lower enantioselectivity was detected(entries was detected7–9). (entries A distinctive 7–9). A distinctive issue has issue to behas addressed to when compoundbe addressed10 whenwas compound employed. 10 was Indeed, employed. although Indeed, the alth Sooughós thioureathe Soós thiourea (10) furnished (10) furnished the desired the desired products with an optical purity comparable to the model reaction, the low overall yield products with an optical purity comparable to the model reaction, the low overall yield (36%) and (36%) and a reaction time that was too long (144 h) made catalyst 10 unsuitable for further a reactioninvestigations. time thatwas too long (144 h) made catalyst 10 unsuitable for further investigations.

Table 1.TableEffect 1. ofEffect selected of selected organocatalyst organocatalyst (1 (–1–1010,, FigureFigure 1)1) on on the the asymmetric asymmetric epoxidation epoxidation of various of various N-methylN-methylα-ylidene α-ylidene oxindoles oxindoles (11a (11a–g–)g bearing) bearing aa carboxylatecarboxylate (CO (CO2Et)2 Et)as electron-withdrawing as electron-withdrawing group group (EWG) on(EWG) the on exocyclic the exocyclic double double bond bonda,b a,b. .

1 2 c d e e EntryEntry Sub Sub R R1 RR2 CatCat * *Time Time (h) (h)Yield (%) Yield c (%)dr d drtrans-12trans er e -12 ciser -13 ercis e -13 er 11 aa H H H H 1 1 72 72 92 92 64:36 64:36 91:9 91:9 60:40 60:40 22 aa H H H H 2 2 168 168 56 56 85:15 85:15 56:44 56:44 67:33 67:33 33 aa H H H H 3 3 48 48 44 44 55:45 55:45 81:19 81:19 72:28 72:28 4 a H H 4 48 30 25:75 69:31 80:20 4 a H H 4 48 30 25:75 69:31 80:20 5 a H H 5 144 36 33:67 43:57 47:53 65 aa H H H H 5 6 144 240 36 4 33:67 79:21 43:57 92:8 47:53 39:61 7 a H H 7 72 20 60:40 49:51 56:44 8 a H H 8 72 33 78:22 53:47 51:49 Molecules 2018, 23, x 3 of 18

2. Results and Discussion

2.1. Evaluation of the Catalyst Modification Initially, considering the efficiency of the α, α-diarylprolinol 1, the catalyst scope was enlarged to various compounds in which: (i) either the aromatic rings or the pyrrolidine framework were decorated with substituents different in terms of hindrance- and electron demand (2–5, Figure 1); (ii) the Brønsted basic site was preserved, whereas the Lewis acidic site was changed to a tetrazolic ring (6, Figure 1); (iii) the Brønsted basic site was preserved, while two hydrogen bond donors were introduced (7 and 8, e.g., an hydroxyl group and an amide moiety, Figure 1); (iv) the Brønsted basic site was preserved, and linked to a thiourea through a methylene (9, Figure 1); (v) the chiral skeleton was changed to an epi-quinine, in which the basic site is a tertiary amine and the Lewis acid group is a thiourea (Soós catalyst 10, Figure 1). The nucleophilic epoxidation reaction was initially performed using the alkyliden oxindole 11a as model substrate, testing catalysts 2–10 and employing previously optimized conditions [25] (i.e., TBHP as oxidizing agent, hexane as solvent, and room temperature). The observed outcomes were compared with the simplest α,α-diphenyl prolinol 1 (Table 1). The presence of an electron withdrawing group (Ar = 4-NO2-C6H4, catalyst 2, entry 2) on the aromatic moiety dramatically reduce the enantioselectivity as well as the efficiency in terms of time and yield, even though the diastereomeric ratio was quite favourable to the epoxide trans-12. Conversely, the introduction of an electron donating moiety (Ar = 4-OMe-C6H4, catalyst 3, entry 3), dramatically reduced the diastereoselectivity, while the enantiomeric ratio was almost comparable to the reference catalyst. Additionally, the more hindered catalyst 4 (entry 4) slightly favoured the formation of the cis isomer (25:75) without any significant enhancement in the enantioselectivity, which was completely smoothed over when a second stereogenic centre was introduced on the five-membered ring (entry 5). The tetrazolic catalyst 6 (entry 6), featured with an NH function instead of the free hydroxyl moiety, furnished an interesting high diastereo- (79:21) and enantioselectivity (92:8), but a pronounced decrease of reactivity was observed in terms of reaction time (240 h) and yield (4%). The use of other amidic catalysts was subsequently evaluated: pyrrolidine derivative 7 and 8 (Figure 1), in which the OH function is sustained by a second NH function, and thioureas 9 and 10 (Figure 1), in which the OH function is substituted by an NH moiety. Unfortunately, no substantial improvement was observed and only lower enantioselectivity was detected (entries 7–9). A distinctive issue has to be addressed when compound 10 was employed. Indeed, although the Soós thiourea (10) furnished the desired products with an optical purity comparable to the model reaction, the low overall yield (36%) and a reaction time that was too long (144 h) made catalyst 10 unsuitable for further investigations. Molecules 2018, 23, 438 4 of 18 Table 1. Effect of selected organocatalyst (1–10, Figure 1) on the asymmetric epoxidation of various N-methyl α-ylidene oxindoles (11a–g) bearing a carboxylate (CO2Et) as electron-withdrawing group (EWG) on the exocyclic double bond a,b. Table 1. Cont.

Molecules 2018, 23, x 4 of 18

6 a H H 6 240 4 79:21 92:8 39:61 7 a H H 7 72 20 60:40 49:51 56:44 1 2 c d e e EntryEntry8 Sub Suba R HR1 R HR 2 8Cat Cat * *Time 72 Time (h) (h) 33Yield (%) Yield 78:22 c (%) dr d 53:47drtrans -12trans er 51:49 e -12 ciser -13 ercis e -13 er 91 9 aaa H H H H H 9 1 9 72 72 72 10 92 65:35 10 64:36 67:33 65:35 91:9 71:29 67:33 60:40 71:29 1010 aa H H H 10 10 144 144 36 40:60 36 90:10 40:60 58:42 90:10 58:42 2 a f H H 2 168 56 85:15 56:44 67:33 11 11b f b II H H 1 1 24 24 97 33:67 97 80:20 33:67 66:34 80:20 66:34 3 a g i H H 3 48 44 55:45 81:19 72:28 1212 c g c iPrPr H 1 1 96 96 90 42:58 90 89:11 42:58 64:36 89:11 64:36 4 a g H H 4 48 30 25:75 69:31 80:20 1313 d g d ClCl Cl 1 1 33 33 79 37:63 79 93:7 37:63 77:23 93:7 77:23 514 h ae h OCH H 3 H H 1 5 48 144 98 36 51:49 33:67 90:10 43:57 62:38 47:53 14 e OCH3 H 1 48 98 51:49 90:10 62:38 15 h e h NO2 H 1 48 72 27:73 85:15 62:38 15 e NO2 H 1 48 72 27:73 85:15 62:38 EtO2C

1616 g g g g O 1 124 24 98 51:49 98 91:9 51:49 55:45 91:9 55:45 N

CH3

a Reactiona Reaction conditions: conditions:N-Methyl N-Methylα-ylideneoxindole α-ylideneoxindole 1111 (0.5(0.5 mmol), mmol), catalyst catalyst 1 (0.151 mmol),(0.15 mmol),THBP (0.6 THBP (0.6 mmol), and high-performancemmol), and high-performance liquid chromatography liquid chromatography (HPLC) (HPLC) grade hexanegrade hexane (2.7 (2.7 mL) mL) at at rt. rt.b b The given given stereochemical assignmentsstereochemical are based onassignments the previously are based reported on the previously data for reported spiroepoxides data for transspiroepoxides-12a and transcis--13a12a [25]. c The yields of the isolatedand cis products-13a [25]. arec The expressed yields of the as isolated the sum products of the are diastereomers. expressed as thed sumDetermined of the diastereomers. by proton d nuclear magnetic resonanceDetermined (1H-NMR) by of theproton crude nuclear reaction magnetic mixture. resonancee Determined (1H-NMR) by of chiral-phasethe crude reaction HPLC mixture. analysis. e f For the already known α-ylideneoxyndoleDetermined by chiral-phase11b see referenceHPLC analysis. [28]. gf ForThe the novel alreadyα-ylideneoxyndoles known α-ylideneoxyndole11c, 11d 11b, and see11g were prepared and fully characterizedreference [28]. asg The reported novel inα-ylideneoxyndoles the supporting material.11c, 11d, andh For 11g the were already prepared known andα -ylideneoxyndolesfully 11e i and 11f, seecharacterized reference [as29 reported]. isopropyl. in the supporting material. h For the already known α-ylideneoxyndoles 11e and 11f, see reference [29]. i isopropyl. Since the Since the just disclosed results are quite difﬁcult to rationalize and clearly highlight that Since the Since the just disclosed results are quite difficult to rationalize and clearly highlight the overallthat domino the overall reaction domino reaction is not is positively not positively affected affected by either either the thesubstitution substitution of the hydroxyl of the hydroxyl with other functions,with other or functions, a change or a of change the catalyst’s of the catalyst’s scaffold, scaffold, or or the the introductionintroduction of an of additional an additional H- H-bonding site, we decidedbonding site, to pursuewe decided our to investigationspursue our investigations employing employing diarylprolinol diarylprolinol 11, ,the the best best catalyst catalyst so far. so far. Speciﬁcally,Specifically, the nucleophilicthe nucleophilic epoxidationepoxidation was wasperformed performed on the N on-methyl the carboxylateN-methyl carboxylate ylideneoxindolesylideneoxindoles11b– g11b(entries–g (entries 11–16) 11–16) that that always always furnished furnished the easily the separable easily diastereomers separable diastereomers trans-12b–transg and-12bcis–g and-13b cis–-g13b, in–g, good in good to to excellent excellent yields yields and and with withnotable notable enantioselectivity enantioselectivity (up to 93:7 (up to 93:7 er) er) in favour of the enantiomers 0(2R′, 03R′) and (2S′0, 3R′),0 respectively. Noteworthy, the epoxidation in favourof of compounds the enantiomers endowed with (2R two,3R chlorine) and atoms (2S (entry,3R 13),),respectively. led to the highest Noteworthy,enantioselectivities the for epoxidation of compoundsthe trans endowed product (93:7 with er two) together chlorine with the atoms highest (entryoptical purity 13), ledfor the to cis the isomer highest too (77:23 enantioselectivities er). In for the trans addition,product in (93:7few caseser) (entries together 11–13, with 15), an the inversion highest of the optical diastereomeric purity ratio for was the observed,cis isomer in too (77:23 er). favour of the products cis-13. Such an effect could be mainly ascribable to some supplementary In addition,interactions in few between cases the (entries substituent 11–13, and the 15), catalyst an inversion able to stabilize of the the transition diastereomeric state that precedes ratio was observed, in favourthe of cis the isomer products formation.cis- Furthermore,13. Such anthe effectsteric hindra couldnce beas well mainly as the ascribableelectronic demand to some on the supplementary interactionsaromatic between ring due the to substituent either a methoxy and group the (entry catalyst 14) or able to a naphthyl-derivative to stabilize the transition(entry 16) do statenot that precedes strongly affect the overall reactivity. the cis isomer formation. Furthermore, the steric hindrance as well as the electronic demand on the aromatic2.2. ring Evaluation due to of either the Substrate a methoxy Scope group (entry 14) or to a naphthyl-derivative (entry 16) do not strongly affectIn theorder overall to explore reactivity. the effect of the EWG on the developed catalytic system, the reaction was subsequently performed on α-ylidenoxindole where the carboxylate had been replaced by the more 2.2. Evaluationhindered of thephosphonic Substrate moiety, Scope which should contribute mostly to an inductive effect (-I) When phosphonate α-ylidenoxindoles 11h–l (Table 2) were employed as substrates in the optimised In orderorganocatalytic to explore epoxidation, the effect a moderate of the to EWGgood enantioselectivity on the developed was observed catalytic for the system, trans the reaction was subsequentlyisomers (12h– performedl, up to 80:20 er); on meanwhile,α-ylidenoxindole the steric hindrance where due to the the larger carboxylate electronwithdrawing had been replaced by group [PO(OEt)2] enhanced the formation of the cis isomers (13h–l), which, as already observed with the morecarboxylic hindered derivatives, phosphonic became the moiety, major diastereomer which should when a contributehalide (11l) was mostly introduced to in an position inductive effect (-I) When phosphonate5 on the aromaticα-ylidenoxindoles ring. 11h–l (Table2) were employed as substrates in the optimised organocatalytic epoxidation, a moderate to good enantioselectivity was observed for the trans isomers (12h–l, up to 80:20 er); meanwhile, the steric hindrance due to the larger electronwithdrawing group [PO(OEt)2] enhanced the formation of the cis isomers (13h–l), which, as already observed with carboxylic derivatives, became the major diastereomer when a halide (11l) was introduced in position 5 on the aromatic ring. Molecules 2018, 23, 438 5 of 18 Molecules 2018, 23, x 5 of 18 Molecules 2018,Molecules 23, x 2018, 23, x 5 5of of 18 18 Table 2.TableSubstrate 2. Substrate scope scope of theof the organocatalytic organocatalytic epoxidation epoxidation on α on-ylideneoxindolesα-ylideneoxindoles 11h–l bearing11h– la bearing Table 2. Substrate scope of the organocatalytic epoxidation on α-ylideneoxindoles 11h–l bearing a TablePO(OEt) 2. Substrate2 moiety as scope the EWG of the group organocatalytic of the exocyclic epoxidation double bond on α -ylideneoxindolesa. a 11h–l bearing a a PO(OEt)2 moiety as the EWG group of the exocyclic double bonda . PO(OEt)2 moietyPO(OEt) as 2the moiety EWG as groupthe EWG of groupthe exocyclic of the exocyclic double double bond bonda. .

1 1 2 b c c d d d d SubSub R1Sub R R R 2 R Yield (%)YieldYield b (%) dr c dr dr transtrans-12 -12ertrans d er -12 erciscis-13-13 er ciser d -13 er e e 1 111h H 2 CH3 b 80 c 56:44 80:20d 61:39d 1 1 Sub11h11h e RH HCHR 3 CH3 Yield80 (%) 8056:44dr 56:44trans80:20-12 er 80:20cis-1361:39 er 61:39 e 2 11i e H Ph 95 60:40 79:21 62:38 2 11iee H3 Ph 95 60:40 79:21 62:38 12 11h11i HH e CHPh 80 95 56:4460:40 80:2079:21 61:39 62:38 e 3 11j H Bn 80 56:44 74:26 55:45 3 11je H Bn 80 56:44 74:26 55:45 23 11i11j e HH PhBn 95 80 60:4056:44 79:2174:26 62:38 55:45 3 11j e H Bn 80 56:44 74:26 55:45 4 11k e 4 11k e H H 83 65:35 65:35 72:28 72:28 55:45 55:45 4 11k e H 83 65:35 72:28 55:45 e f 4 11k H f 83 65:35 72:28 55:45 5 11l 5 11l ClCl CH3 65 40:60 40:60 77:23 77:2357:43 57:43 a a Reaction conditions:5 11l Reactionf α-ylideneoxindoleCl conditions:CH α3-ylideneoxindole 11, (0.5 mmol)65 11 catalyst, (0.5 mmol)140:60, (0.15 catalyst mmol). 1, (0.1577:23 THBP mmol). (0.6 THBP mmol) (0.657:43 mmol) and HPLC-grade and HPLC-gradef b hexane (2.7 mL) at rt. b The yields of the isolated products are expressed as the sum of hexane (2.7a Reaction5 mL)11l atconditions: rt. ClThe α yields-ylideneoxindoleCH of3 the isolated 11, (0.565products mmol) catalyst40:60 are expressed 1, (0.15 77:23mmol). as the THBP sum (0.6 of57:43 mmol) the diastereomers. and c 1 c 1 d d e Determineda by H-NMRthe diastereomers. of the crude Determined reaction by mixture. H-NMR ofDetermined the crude reaction by chiral-phase mixture. Determined HPLC analysis. by chiral- For the HPLC-gradeReaction conditions: hexane (2.7α-ylideneoxindole mL) at rt. b The 11 yields, (0.5 mmol)of the isolatedcatalyst 1products, (0.15 mmol). are expressed THBP (0.6 as mmol) the sum and of α e f α f already known -ylideneoxyndolephase HPLC analysis.11h –Fork b seethe already reference known [26 ].α-ylideneoxyndoleThe novel -ylideneoxyndole 11h–k see reference 11l[26].was The preparednovel and HPLC-grade hexanec (2.7 mL) at rt. The1 yields of the isolated products are expressedd as the sum of fully characterizedthe diastereomers. asα-ylideneoxyndole reported Determined in the 11l Supporting was by preparedH-NMR Material. and of thefully crude characterized reaction as mixture. reported in Determined the Supporting by Material. chiral- thephase diastereomers. HPLC analysis. c Determined e For the already by 1H-NMR known of α -ylideneoxyndolethe crude reaction 11h mixture.–k see referenced Determined [26]. fby The chiral- novel phase HPLC analysis. e For the already known α-ylideneoxyndole 11h–k see reference [26]. f The novel The givenα-ylideneoxyndole stereochemicalThe given 11l stereochemical was outcomes prepared andoutcomes are fully assigned characterizedare assigned upon uponas reported a thorougha thorough in the comparison Supporting comparison ofMaterial. the ofreported the reported α-ylideneoxyndoleexperiments, 11l analytical was prepared data, and and a fullyquantum characterized mechanical as ab reported initio calculation in the Supporting of chiroptical Material. properties. experiments, analytical data, and a quantum mechanical ab initio calculation of chiroptical properties. The givenSpecifically, stereochemical the major outcomes diastereomers are assigned were identified upon a asthorough the trans comparison products by of comparing the reported the Specifically,experiments,The the givenspectroscopic major analytical stereochemical diastereomers analysesdata, and outcomes of a each quantum wereisolated are assignedmechanical identifiedcompound upon abwith asinitio a thethorough the calculationcorrespondingtrans comparisonproducts of datachiroptical already of bythe properties. reported reported comparing in the spectroscopicexperiments,Specifically, analysesliterature analyticalthe major of[26], eachdata, whilediastere and isolated the omersa (2 quantum′S, 3′ S compoundwere) configuration mechanical identified with was ab as initioassigned thethe calculation correspondingtrans to the products major of chiroptical enantiomer by data comparing properties. alreadyof trans -12hthe reported (see the stereochemistry analysis section below). Specifically,spectroscopic the analyses major ofdiastere 0each0 isolatedomers werecompound identified with theas thecorresponding trans products data byalready comparing reported the in in literature [26], whileThe theforehead (2 S results,3 S) configurationclearly suggest that was the tested assigned substituents to the on majorthe exocyclic enantiomer double bond of dotrans -12h spectroscopicliterature [26], analyses while the of (2each′S, 3isolated′S) configuration compound was with assigned the corresponding to the major data enantiomer already reportedof trans-12h in (see the stereochemistrynot dramatically analysis influence section the reagent below). approach to the electrophilic center (Cβ) which is preferentially literature [26], while the (2′S, 3′S) configuration was assigned to the major enantiomer of trans-12h (see the stereochemistrydriven toward theanalysis less-hindered section Re below).-face of the double bond, although the steric hindrance noticeably The(see forehead the stereochemistry results clearly analysis suggest sectionthat below). the tested substituents on the exocyclic double bond do The foreheadaffects the results stereoinduction. clearly suggest that the tested substituents on the exocyclic double bond do not dramatically influence the reagent approach to the electrophilic center (C ) which is preferentially not dramaticallyThe foreheadSubsequently, influence results clearly the the reagent suggestsubstrate approach that scop thee totestedwas the enlarged electrophilic substituents by evaluating center on the (C exocyclic βα) -ylidenoxindoleswhichβ double is preferentially bond 11m do–u drivennot towarddriven dramatically toward thevariously less-hindered the influence less-hindered decorated the onreagentRe the-faceRe -facearomatic approach of of the the ring doubledouble to and the featured electrophilicbond, bond, aalthough N although-unprotected center the (Csteric the βamide,) which steric hindrance which is hindrance preferentially should noticeably install noticeably affects thedrivenaffects stereoinduction. towardthe stereoinduction.a further the less-hindered H-bond between Re -facethe substrate of the double and the bond, catalyst-oxidant although complexthe steric (Table hindrance 3). noticeably affectsSubsequently, the stereoinduction. the substrate scope was enlarged by evaluating α-ylidenoxindoles 11m–u Subsequently, theTable substrate 3. Substrate scope scope of was the enlargedorganocatalytic by epoxidation evaluating of α-ylideneoxindolesα-ylidenoxindoles 11m–u featured11m– u variously variouslySubsequently, decorated the on thesubstrate aromatic scop ringe wasand featuredenlarged a Nby-unprotected evaluating amide,α-ylidenoxindoles which should 11m install–u decorated on the aromaticwith N-unprotected ring and amide featured a. a N-unprotected amide, which should install a further variouslya further H-bonddecorated between on the thearomatic substrate ring and and the featured catalyst-oxidant a N-unprotected complex amide, (Table which 3). should install H-bonda betweenfurther H-bond the substrate between the and substrate the catalyst-oxidant and the catalyst-oxidant complex complex (Table (Table3). 3). Table 3. Substrate scope of the organocatalytic epoxidation of α-ylideneoxindoles 11m–u featured Table 3.TablewithSubstrate N 3.-unprotected Substrate scope scopeof amide the of organocatalytic a.the organocatalytic epoxidation epoxidation of ofα α-ylideneoxindoles-ylideneoxindoles 11m11m–u –featuredu featured with a N-unprotectedwith N-unprotected amide a. amide .

Sub R1 R2 Time (h) Yield (%) b dr c trans-12 er d cis-13 er d 1 11me H H 144 96 65:35 75:25 61:39 2 11ne F H 43 97 34:66 93:7 61:39 e 3 11o Cl H 140 83 40:60 73:27 59:41 e 4 11p I H 170 91 78:22 68:32 59:41 5 11qe OCF3 H 96 76 38:62 87:13 66:34 Sub R1 R2 Time (h) Yield (%) b dr c trans-12 er d cis-13 er d 1 6 11re 2 H F 66 93 b 23:77 c 92:8 70:30d d Sub Sub Re R1 RR2 TimeTime (h) (h)YieldYield (%) b (%) dr c transdr -12 er dtrans cis-12-13er er d cis-13 er 1 11m 7 H11s e H H 144Cl 48 96 99 65:35 36:64 75:25 88:12 61:39 62:38 1 11me12 11m11nee H HF HH 144 43 144 96 97 96 65:35 34:66 65:35 75:25 93:7 75:25 61:39 61:39 61:39 e 2 11n 2 11ne eFF H H 43 43 97 97 34:66 34:66 93:7 93:7 61:39 61:39 e 3 11o Cl H 140 83 40:60 73:27 59:41 3 11o e Cl H 140 83 40:60 73:27 59:41 34 11o11p e ClI HH 140 170 83 91 40:60 78:22 73:27 68:32 59:41 59:41 4 11pe I H 170 91 78:22 68:32 59:41 4 11pe e I H 170 91 78:22 68:32 59:41 5 11qe 5 11qOCF OCF3 H 96 96 76 76 38:62 38:62 87:13 87:13 66:34 66:34 e 3 6 11re56 11q11re HOCFH 3 HF 96 66 66 76 93 93 38:62 23:77 23:77 87:13 92:8 92:8 66:34 70:30 70:30 7 11se67 11r11se e HHH FCl 66 48 48 93 99 99 23:77 36:64 36:64 92:888:12 88:12 70:30 62:38 62:38 e 8 11t 7 11se HH Cl Br 48 86 99 87 36:64 56:44 88:12 92:8 62:38 65:35 9 11ue Cl Cl 78 42 35:65 83:17 86:14 a Reaction conditions: α-ylideneoxindole 11. (0.5 mmol), catalyst 1 (0.15 mmol). THBP (0.6 mmol) and HPLC-grade hexane (2.7 mL) at rt. b The yields of the isolated products are expressed as the sum of the diastereomers. c Determined by 1H-NMR of the crude reaction mixture. d Determined by chiral-phase HPLC analysis. e For the already known α-ylideneoxyndole 11m–u, see reference [30]. Molecules 2018, 23, x 6 of 18

8 11te H Br 86 87 56:44 92:8 65:35 9 11ue Cl Cl 78 42 35:65 83:17 86:14 a Reaction conditions: α-ylideneoxindole 11. (0.5 mmol), catalyst 1 (0.15 mmol). THBP (0.6 mmol) and HPLC-grade hexane (2.7 mL) at rt. b The yields of the isolated products are expressed as the sum of Molecules 2018, 23, 438 6 of 18 the diastereomers. c Determined by 1H-NMR of the crude reaction mixture. d Determined by chiralphase HPLC analysis. e For the already known α-ylideneoxyndole 11m–u, see reference [30]. Comparing the data depicted in Table3 with the outcomes previously observed [ 25], it is Comparing the data depicted in Table 3 with the outcomes previously observed [25], it is undeniable that the reaction was successfully in term of overall yields (up to 99%) without any undeniable that the reaction was successfully in term of overall yields (up to 99%) without any loss lossconcerning concerning the the diastereomeric diastereomeric ratios ratios (up (up to to78:22 78:22 dr), dr), whereas whereas only only a slight a slight decrease decrease in the in the enantioselectivityenantioselectivity was was detected. detected. Nevertheless,Nevertheless, a quite quite surprising surprising result result was was the the outgrowth outgrowth deriving deriving fromfrom the the iodine iodine derivative derivative11p 11p(entry (entry 4,4, TableTable3 3),), whichwhich furnishedfurnished an an inverted inverted diastereomeric diastereomeric ratio ratio (78:22(78:22 in favourin favour of of the thetrans transisomer), isomer), lower lower reactivity reactivity (170h (170h vs. vs. 24h), 24h), and and lowerlower opticaloptical puritypurity (68:32 vs. 80:20)vs. 80:20) compared compared to the to corresponding the corresponding methylated methylated molecule molecule (entry (entry 11, 11, Table Table1). 1). SuchSuch observations, observations, taking taking into accountinto account the stereoselectivity the stereoselectivity previously previously detected withdetected phosphonate with derivativesphosphonate11i– kderivatives, which were 11i– decoratedk, which were with decorated different Nwith-substituents different N (entries-substituents 2–4, Table (entries2), suggest 2–4, a specialTable role2), suggest of the free a special NH function role of inthe the free H-bond NH function network in existing the H-bond among network substrate/catalyst/oxidant, existing among a hypothesissubstrate/catalyst/oxidant, which was validated a hypoth (i)esis by analysingwhich was thevalidated configuration (i) by analysing of the newly the configuration formed stereogenic of the centres;newly as formed well as stereogenic (ii) by introducing centres; as the welltert -butylas (ii) by carbonyl introducing moiety the as tert nitrogen-protecting-butyl carbonyl moiety group as that shouldnitrogen-protecting furnish a further group coordination that should site furnish in the a epoxidation further coordination transition site state. in the epoxidation transition state.In order to understand how the nucleophilic attack of the oxidizing agent toward the electrophilic In order to understand how the nucleophilic attack of the oxidizing agent toward the centre (Cβ) on the electron poor oleﬁns 11m–u is stereochemically driven, the experiment depicted in electrophilic centre (Cβ) on the electron poor olefins 11m–u is stereochemically driven, the experiment Scheme1a was performed. Speciﬁcally, the N-methylation of the major diastereomer trans–12m led depicted in Scheme 1a was performed. Specifically, the N-methylation of the major diastereomer to a clean product that, upon spectroscopic and chiral HPLC analysis, resulted to be the enantiomer 0 trans–0 12m led to a clean product that, upon spectroscopic and chiral HPLC analysis, resulted to be (2 Sthe,3 Senantiomer)-12a, i.e., the(2′S minor, 3′S)-12a enantiomer, i.e., the minor obtained enantiomer during theobtained direct du organocatalyticring the direct epoxidationorganocatalytic of the modelepoxidation substrate of 11athe (entrymodel substrate 1, Table1 ).11a (entry 1, Table 1).

SchemeScheme 1. 1.Comparison Comparison betweenbetween NN-methyl-methyl spiroepoxyoxindoles spiroepoxyoxindoles furnished furnished (a) by (a )the by methylation the methylation of the major diastereomer trans-12m; and (b) by the organocatalytic epoxidation of the N-methyl α- of the major diastereomer trans-12m; and (b) by the organocatalytic epoxidation of the N-methyl ylidenoxindole 11a. α-ylidenoxindole 11a.

Therefore,Therefore, the the ﬁrst first attack attack on on11m 11m occursoccurs at the top face face of of the the double double bond, bond, i.e., i.e., oppositely oppositely to to what was observed when N-methyl α-ylideneoxindoles 11a–l were employed. what was observed when N-methyl α-ylideneoxindoles 11a–l were employed. Additionally, to our delight, the epoxidation reaction carried on the N-Boc protected α- Additionally, to our delight, the epoxidation reaction carried on the N-Boc protected ylideneoxindole 11v successfully provided the desired spiroepoxide trans-12v and cis-13v not only α-ylideneoxindole 11v successfully provided the desired spiroepoxide trans-12v and cis-13v not only with good diastereomeric excess (66:34 dr), as previously detected, but especially with excellent with good diastereomeric excess (66:34 dr), as previously detected, but especially with excellent enantioselectivity (97:3 er) in the case of the major isomer trans-12v. Actually, in the ﬁrst trial complete conversion was accomplished only after 144 h with a quite poor yield of 36%, an outcome that was remarkably improved (70% of total yield, 24h of reaction time) by using a higher excess of the oxidizing agent (2.0 equiv. instead of 1.2 equiv.) without any loss in stereoselectivity (66:34 dr, 96:4 er for the major diastereomer trans-12v) (Scheme2). Molecules 2018, 23, x 7 of 18

enantioselectivity (97:3 er) in the case of the major isomer trans-12v. Actually, in the first trial complete conversion was accomplished only after 144 h with a quite poor yield of 36%, an outcome that was remarkably improved (70% of total yield, 24h of reaction time) by using a higher excess of the Moleculesoxidizing2018, 23agent, 438 (2.0 equiv. instead of 1.2 equiv.) without any loss in stereoselectivity (66:34 dr, 96:47 er of 18 for the major diastereomer trans-12v) (Scheme 2).

Scheme 2. Organocatalytic epoxidation reaction carried on N-Boc protected α-ylidenoxindole 11v [30] Scheme 2. Organocatalytic epoxidation reaction carried on N-Boc protected α-ylidenoxindole 11v [30] using 2.0 equivalent of oxidating agent (TBHP). using 2.0 equivalent of oxidating agent (TBHP). 2.3. Stereochemistry Analysis 2.3. Stereochemistry Analysis To better investigate the stereochemistry of compounds trans-12h and cis-13h, we employed chiropticalTo better spectroscopies. investigate the In stereochemistryparticular, we perfor of compoundsmed electronictrans and- 12hvibrationaland cis circular-13h, we dichroism employed chiroptical(ECD and spectroscopies. VCD) and optical In particular,rotatory dispersion we performed (ORD) electronicmeasurements and vibrationalwith subsequent circular analysis dichroism by (ECDdensity and functional VCD) and theory optical (DFT) rotatory and time-dep dispersionendent (ORD) DFT measurements (TDDFT) calculations with subsequent [31–37]. analysis by densityECD functional measurement theory (DFT) was andperformed time-dependent in acetonitri DFTle (TDDFT) solution calculations(see experimental [31–37 ].details in supportingECD measurement material) in was the performed range of 400–180 in acetonitrile nm. The solutionECD spectrum (see experimental exhibits a weak details negative in supporting band material)at ca. 310 in nm, the rangea splitted of 400–180 negative nm. band The at ca. ECD 273 spectrum nm, and a exhibits sequence a weakof intense negative positive, band negative at ca. 310 and nm, a splittedpositive negativebands at band250, 224 at ca.and 273 about nm, 190 and nm, a sequencerespectively. of intenseThe negative positive, band negative at 273 nm and and positive the bandspositive at 250, at 250 224 nm and are about both 190allied nm, to respectively.the ultraviolet The (UV) negative band centered band at at 273 260 nm nm and which the shows positive at 250multiple nm arefeatures both (Figure allied to2). EC theD/UV ultraviolet calculation (UV) was band performed centered at TDDFT/CAM-B3LYP/TZVP at 260 nm which shows multiple level on the previously optimized most populated conformers at DFT/B3LYP/TZVP level with polarizable features (Figure2). ECD/UV calculation was performed at TDDFT/CAM-B3LYP/TZVP level on continuum model (PCM) [38] approximation (see Figure SM-2 for details) of both the (2′S,3′S) and the previously optimized most populated conformers at DFT/B3LYP/TZVP level with polarizable the (2′S,3′R) diastereomers. In Figure 2 a comparison between experimental ECD and UV spectra with continuum model (PCM) [38] approximation (see Figure SM-2 for details) of both the (20S,30S) and the (2′S,3′S) and (2′S,3′R) calculated ones is presented. (20S,30R) diastereomers. In Figure2 a comparison between experimental ECD and UV spectra with 0 0 Despite 0small0 differences on relative intensities of the negative and the positive bands at 224 and (2 S190,3 S nm) and respectively, (2 S,3 R) calculated the calculated ones spectra is presented. of both diastereomers do not clearly discriminate about 3′ carbonDespite AC. small On the differences other hand, on relativeunambiguous intensities assignment of the negativeis provided and for the 2 positive′ carbon bandsas S. Safe at 224 andassignment 190 nm respectively, is also supported the calculatedby considering spectra that a ofll single both diastereomersconformers ECD do spectra not clearly do not differ discriminate each 0 0 aboutother 3 (Figurecarbon AC.SM-3) On showing the other that hand, the calculation unambiguous is also assignment quite insensitive is provided to populations for 2 carbon and energy as S. Safe assignmentcalculation is accuracy. also supported All conformers by considering differ by that rela alltive single orientation conformers of phosphate ECD spectra and ethoxy do not moieties differ each other(see (Figure Figure SM-3)SM-1) showingwhile oxindole that the chromophore calculation ha iss also quite quite a rigid insensitive structure to leading populations to similar and ECD energy calculationprofiles which accuracy. are driven All conformers by the S configuration differ by relative of 2′ carbon. orientation of phosphate and ethoxy moieties (see FigureInterestingly, SM-1) while the calculations oxindole chromophore of ORD spectra has are quite sensitive a rigid to structurethe 3′ carbon leading configuration. to similar The ECD profilesexperimental which are ORD driven curve by was the definedS configuration by measuring of 20 carbon.OR at four wavelengths 589, 546, 435 and 405 nmInterestingly, in chloroform the solvent. calculations The experimental of ORD spectraORD trend are is sensitive negative to in thesign 3 0withcarbon specific configuration. rotation Thevalues experimental from −20 ORDto −110. curve The calculation was defined was by performed measuring at ORCAM-B3LYP/6-311++G(d,p)/PCM(CHCl at four wavelengths 589, 546, 4353 and) 405level nm inat chloroformthe measured solvent. wavelengths. The experimental In Figure 3 we ORD report trend a comparison is negative inbetween sign with experimental specific rotation and calculated ORD curves. values from −20 to −110. The calculation was performed at CAM-B3LYP/6-311++G(d,p)/PCM(CHCl3) level at the measured wavelengths. In Figure3 we report a comparison between experimental and calculated ORD curves.

Molecules 2018, 23, 438 8 of 18 Molecules 2018, 23, x 8 of 18 Molecules 2018, 23, x 8 of 18

Figure 2. Comparison of experimental and computed electronic circular dichroism (ECD) (left) and Figure 2. Comparison of experimental and computed electronic circular dichroism (ECD) (left) and ultravioletFigure 2. Comparison (UV) (right of) spectra experimental for the and different computed ACs electronicfor compounds circular trans dichroism-12h (experimental (ECD) (left) and ultraviolet (UV) (right) spectra for the different ACs for compounds trans-12h (experimental and calculated)ultraviolet (UV)and cis (right-13h )(calculated). spectra for the different ACs for compounds trans-12h (experimental and calculated)calculated) and andcis cis-13h-13h(calculated). (calculated).

Figure 3. Comparison of experimental and computed optical rotatory dispersion (ORD) spectra for Figure 3. Comparison of experimental and computed optical rotatory dispersion (ORD) spectra for Figurethe different 3. Comparison ACs for of compounds experimental trans and-12h computed (experimental optical and rotatory calculated) dispersion and cis- (ORD)13h (calculated). spectra for the the different ACs for compounds trans-12h (experimental and calculated) and cis-13h (calculated). different ACs for compounds trans-12h (experimental and calculated) and cis-13h (calculated).

Molecules 2018, 23, 438 9 of 18

MoleculesThe experimental2018, 23, x ORD curve compares better to the one calculated for (20S,30S) with a9 specificof 18 rotation values from −54 to −186, while the (20S,30R) calculation provides a positive ORD trend The experimental ORD curve compares better to the one calculated for (2′S,3′S) with a specific androtation calculated values rotation from −54 values to −186, from while +103 the (2 to′S +236.,3′R) calculation It is worth provides noting a that,positive like ORD in the trend ECD and case, thecalculated trend in rotation sign of values each separatedfrom +103 to conformer +236. It is worth is consistent noting that, within like eachin the diastereomer ECD case, the calculation:trend in 0 0 0 0 thesign (2 Sof,3 eachS) conformer’s separated conformer distribution is consistent presents negativewithin each specific diastereomer rotation calculation: values, while the the(2′S (2,3′S),3 R) diastereomerconformer’s distribution presents positive presents values negative for allspecific conformers rotation (seevalues, supporting while the material(2′S,3′R) diastereomer Figure SM-3 for 0 0 details).presents These positive results values strongly for all suggestconformers (2 S ,3(seeS) supporting is the AC ofmaterial the experimentally Figure SM-3 for analyzed details). compound These transresults-12h .strongly Figure4 suggest shows the(2′S comparison,3′S) is the AC of experimentalof the experimentally and calculated analyzed VCD/infrared compound trans (IR)-12h spectra. (900–1500Figure 4 shows cm−1 therange) comparison for the of two experimental possible configurations and calculated VCD/infrared considered for (IR) compounds spectra (900–1500trans- 12h andcmcis−1 range)-13h. for the two possible configurations considered for compounds trans-12h and cis-13h.

Figure 4. Comparison of experimental and computed vibrational circular dichroism (VCD) (left) and Figure 4. Comparison of experimental and computed vibrational circular dichroism (VCD) (left) and infrared (IR) (right) spectra for the different ACs for compound trans-12h (experimental and infrared (IR) (right) spectra for the different ACs for compound trans-12h (experimental and calculated) calculated) and cis-13h (calculated). Scaling factor = 0.98 (see Supplementary Materials for details). and cis-13h (calculated). Scaling factor = 0.98 (see Supplementary Materials for details).

Experimental VCD/IR spectra were measured in CCl4 solution while calculations were Experimental VCD/IR spectra were measured in CCl4 solution while calculations were performed performed at the B3LYP/TZVP/PCM(CCl4) level. The VCD/IR case is similar to the ECD/UV: also, at the B3LYP/TZVP/PCM(CCl ) level. The VCD/IR case is similar to the ECD/UV: also, from this from this technique there is no doubt4 that configuration at 2′ is S, while it is difficult to establish the technique there is no doubt that configuration at 20 is S, while it is difficult to establish the configuration configuration0 at 3′. In fact, there is not a clear discrimination between the two calculated VCD spectra. atIndeed, 3 . In fact, some there of the is experimental not a clear discriminationfeatures suggest between a co-presence the two of the calculated two diastereomers. VCD spectra. In detail, Indeed, someit is possible of the experimental to note the experimental features suggest peaks 7 a an co-presenced 8 which are of well the twopredicted diastereomers. in both IR spectra In detail, and it is possiblethey are to present note the (even experimental if very weak) peaks in the 7 and (2′S 8,3 which′S) VCD are spectrum. well predicted Narrow in feature both IR2 seems spectra to andarise they 0 0 arefrom present the (even(2′S,3′ ifR) very diastereomer, weak) in the while (2 S ,3experimentalS) VCD spectrum. band 3a Narrow is predicted feature only 2 seems in to(2′S arise,3′S). from An the 0 0 0 0 (2additionalS,3 R) diastereomer, analysis is whilepossible experimental on the basis bandof the 3a similarity is predicted indices only S.I. in and (2 S Sim_NN,3 S). An of additional experimental analysis isand possible calculated on the VCD basis spectra. of the The similarity first index indices [39] varies S.I. and between Sim_NN −1 (reversed of experimental AC assignment and calculated has been VCD spectra.made) and The +1 first (right index assignment [39] varies has betweenbeen made)−1 with (reversedout intensity AC assignment sensitivity; hasthe second been made) index [32] and +1 (rightis also assignment sensitive hasto intensity. been made) Empirically, without intensityit is possible sensitivity; to confirm the secondthat a good index AC [32 assignment] is also sensitive is toreached intensity. when Empirically, S.I. ≥ 0.5. itThe is possiblelargest S.I. to and confirm Sim_NN that avalues good are AC found assignment for (2′S is,3 reached′S) with a when S.I. = S.I.+0.44≥ 0.5. Theand largest Sim_NN S.I. = and +0.16; Sim_NN similarity values indices are for found (2′S,3 for′R) (2 are0S,3 positive0S) with but a S.I. quite = +0.44 smaller and (S.I. Sim_NN = +0.34 =and +0.16; similaritySim_NN indices= +0.09). forThe (2 (20S′S,3,30R′S)) areAC positiveis slightly but favored quite by smaller vibrational (S.I. analysis = +0.34 and and this Sim_NN agrees =with +0.09). TheORD (20 Sresults,30S) AC for isthe slightly AC assignment favored of by compound vibrational trans analysis-12h. and this agrees with ORD results for the In conclusion, the ECD/UV experimental and computational analysis confirms that the AC of AC assignment of compound trans-12h. carbon 2′ is no doubt S but is unable to discriminate the AC of the second chiral center on carbon 3′ In conclusion, the ECD/UV experimental and computational analysis confirms that the AC of since the relevant electronic transitions are farther from 3′. ORD analysis suggests (2′S,3′S) to be the carbon 20 is no doubt S but is unable to discriminate the AC of the second chiral center on carbon 30 AC with a well predicted ORD curve in sign and order of magnitude with respect to the experimental

Molecules 2018, 23, 438 10 of 18 since the relevant electronic transitions are farther from 30. ORD analysis suggests (20S,30S) to be the AC with a well predicted ORD curve in sign and order of magnitude with respect to the experimental one. VCD/IR analysis conﬁrms the ECD/UV conclusion for center 20, but it does not give a clear answer for center 30. A co-presence of both (20S,30S) and (20S,30R) diastereomers of trans-12h and cis-13h cannot be excluded, with a prevalence of (20S,30S) as suggested by similarity indices.

3. Materials and Methods Solvents and common reagents were purchased from a commercial source and used without further puriﬁcation. All the known α-ylideneoxindoles (11a–b, 11e–f, 11h–k, and 11m–v) were synthesised according the literature [26,28–30], whereas the unknown substrates (11c, 11d, 11g, 11l) were analogously prepared and fully characterised as reported in the Supplementary Materials. All reactions were monitored by thin-layer chromatography (TLC) carried out on Merck F-254 silica glass plates and visualized with UV light or by 5% phosphomolibdic acid/ethanol test. Flash chromatography was performed on Sigma-Aldrich silica gel (60, particle size: 0.040–0.063 1 13 mm). H-NMR and C-NMR were recorded in CDCl3 (99.8% in deuterium) using a Varian Gemini 300 spectrometer (300 MHz, Varian inc., Palo Alto, CA, USA). All chemical shifts are expressed in parts per million (δ scale) and are referenced to the residual protons of the NMR solvent (CDCl3, δ 7.24 ppm). Optical rotations were made with the enantioenriched samples on a Jasco DIP-370 digital polimeter using a Na-lamp. The diastereomeric ratio of the epoxides was determined by 1H-NMR analysis of the crude reaction mixtures. The enantioselectivities were determined by HPLC analysis on chiral stationary phase [TSP Spectra Series P200, UV detector at λ = 254 nm, using a Daicel Chiralpack IC column and Daicel Chiralpack IA column]. Infrared spectra (FT-IR) were obtained using a Bruker Vector 22 spectrometer (Bruker, Billerica, MA, USA); data are presented as the frequency of absorption (cm−1). Melting points were determined with a Mel-Temp. High-resolution mass spectrometry (HRMS) spectra were recorded with Micromass Q-TOF micro mass spectrometer (Waters Corporations, Milford, MA, USA) and Micromass LCT (ESI, Waters Corporations, Milford, MA, USA) with Lock-Spray-Injector (Injection Loop-Modus in a HPLC system, Waters, Alliance 2695). ORD spectra of trans-12h were recorded with Jasco DIP370 digital polarimeter at four different wavelengths (589, 546, 435, 405 nm) at a concentration of 0.35 g/100 mL in chloroform solution. Experimental ECD/UV spectra were obtained by a JASCO 815SE apparatus from 400 nm to 180 nm under the following experimental conditions: integration time 1 s, scan speed 200 nm/min, bandpass 1 nm, 10 accumulations. Concentration used was 0.00354 M in acetonitrile solution in a 0.1 mm pathlength quartz cuvette. IR and VCD spectra were collected on a JASCO FVS6000 FTIR (JASCO Corporation, Easton, ML, USA) equipped with a liquid N2-cooled MCT detector, 5000 accumulations −1 −1 were averaged in the 850–1500 cm region at 4 cm resolution. The spectra were obtained in CCl4 solutions, in 200 mm pathlength BaF2 cells for a concentration of 0.046 M.

Synthesis and Characterization of Epoxides Trans-12a–v The synthetic procedures and analytical characterization of the diastereoisomers cis-13a–v are listed in the Supplementary Materials.

Typical Experimental Procedure for the Synthesis of Epoxides To a solution of the catalyst 1 (38 mg, 0.15 mmol) and trans-α-ylideneoxindoles 11 (0.5 mmol) in nHexane for HPLC grade (2.7 mL) was added TBHP (5.5 M in decane solution, 0.6 mmol, 0.11 mL). The resultant heterogeneous mixture was maintained under stirring at room temperature (25 ◦C) until reaction completion (TLC nHexane/EtOAc). Afterwards, the crude reaction mixture was puriﬁed by ﬂash chromatography on silica gel (nHexane/EtOAc) to furnish the expected epoxy oxindoles trans-12 and cis-13. Molecules 2018, 23, 438 11 of 18

(20R,30R)-ethyl 1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12a. Following the above general procedure, trans diastereoisomer 12a was obtained as a whitish solid in 61% yield after purification by ◦ flash chromatography on silica gel (nHexane/EtOAc = 7/3), m.p. 132–134 C. IR (CHCl3): νe = 3033, −1 1 ◦ 3010, 2984, 1736, 1709, 1618, 1495, 1473, 1376, 1347 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.26 (t, J = 7.2 Hz, 3H, CH3CH2O), 3.25 (s, 3H, CH3N), 4.18 (s, 1H, OCH), 4.24 (dq, J = 10.9 Hz, 7.2 Hz, 1H, CH3CHHO), 4.29 (dq, J = 10.9 Hz, 7.2 Hz, 1H, CH3CHHO), 6.89 (ddd, J = 7.9 Hz, 0.9 Hz, 0.6 Hz, 1H, CHarom), 7.04 (dt, J = 7.7 Hz, 0.9 Hz,1H, CHarom), 7.39 (dt, J = 7.9 Hz, 1.3 Hz, 1H, CHarom), 7.45 (ddd, J = 7.7 Hz, 1.3 Hz, 0.6 Hz, 1H, CHarom). 13C-NMR (CDCl3, 75 MHz, 25 ◦C): δ (ppm) 14.3, 27.0, 60.0, 60.3, 62.4, 109.1, 119.5, 123.3, 125.0, 131.3, 145.9, 165.9, 170.1. HRMS: exact mass calculated for (C13H13NNaO4) requires m/z 270.0742, found m/z 270.0741. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 7/3, flow rate 1.0 mL/min]: Tmajor = 11.91 min, Tminor = 14.97 min er = 91:9. [α]D = −93 (c = 1.6 g/cm3 inCH2Cl2). (20R,30R)-ethyl 5-iodo-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12b. Following the above general procedure, trans diastereoisomer 12b was obtained as a pale yellow solid in 32% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3), m.p. 143–145 ◦C. −1 1 IR (CHCl3): νe = 3028, 3017, 3008, 1736, 1727, 1611, 1535, 1486, 1358, 1340 cm . H-NMR (CDCl3, ◦ 300 MHz, 25 C): δ (ppm) 1.33 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.24 (s, 3H, NCH3); 3.94–4.41 (m, 13 3H, CH3CH2O, OCH); 6.69 (t, J = 8.2 Hz, 1H, CHarom); 6.68–6.78 (m, 2H, CHarom). C-NMR ◦ (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 27.0, 59.6, 60.0, 62.6, 85.6, 111.0, 121.7, 133.6, 140.0, 145.4, 165.5, 169.3. HRMS: exact mass calculated for (C13H12INNaO4) requires m/z 395.9709, found m/z 395.9712. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 3 1.0 mL/min]: Tmajor = 13.04 min, Tminor = 10.19 min er = 80:20. [α]D = −9 (c = 0.0140 g/cm in CHCl3). (20R,30R)-ethyl 5,7-dichloro-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12c. Following the above general procedure, trans diastereoisomer 12c was obtained as a pale yellow solid in 38% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 98–100 ◦C. −1 1 IR (CHCl3): νe = 3025, 3011, 2959, 1739, 1727, 1625, 1494, 1471, 1369, 1346 cm . H-NMR (CDCl3, ◦ 300 MHz, 25 C): δ (ppm) 1.20 (d, J = 6.8 Hz, 6H, (CH3)2CHCarom); 1.29 (t, J = 7.1 Hz, 3H, CH3CH2O); 2.80–2.95 (m, 1H, (CH3)2CHCarom); 3.26 (s, 3H, NCH3); 4.18–4.41 (m, 3H, CH3CH2O, OCH); 6.84 (d, 13 J = 7.9 Hz, 1H, CHarom); 7.24 (d, J = 7.9 Hz, 1H, CHarom); 7.33 (m, 2H, CHarom). C-NMR (CDCl3, 75 MHz, 25 ◦C): δ (ppm) 14.3, 24.2 (2 × C), 26.9, 34.0, 59.9, 60.3, 62.3, 108.9, 119.3, 123.0, 129.0, 143.6, 144.3, 165.9, 170.0. HRMS: exact mass calculated for (C16H19NNaO4) requires m/z 312.1212, found m/z 312.1215. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, 3 flow rate 1.0 mL/min]: Tmajor = 14.85 min, Tminor = 8.42 min er = 89:11. [α]D = −79 (c = 0.0220 g/cm in CHCl3). (20R,30R)-ethyl 5,7-dichloro-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30- carboxylate 12d. Following the above general procedure, trans diastereoisomer 12d was obtained as a pale red solid in 29% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 124–126 ◦C. −1 1 IR (CHCl3): νe = 3031, 3006, 1740, 1729, 1578, 1463, 1337, 1309 cm . H-NMR (CDCl3, 300 MHz, ◦ 25 C): δ (ppm) 1.31 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.62 (s, 3H, NCH3); 4.18–4.40 (m, 3H, CH3CH2O, 13 ◦ OCH); 7.34 (s, 1H, CHarom); 7.40 (s, 1H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 30.5, 59.4, 60.6, 62.8, 117.0, 123.6, 124.0, 129.0, 132.9, 140.2, 165.1, 170.1. HRMS: exact mass calculated for (C13H11Cl2NNaO4) requires m/z 337.9963, found m/z 337.9961. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH=70/30, flow rate 1.0 mL/min]: Tmajor = 11.74 min, 3 Tminor = 9.48 min er = 93:7. [α]D = −96 (c = 0.0160 g/cm in CHCl3). (20R,30R)-ethyl 5-methoxy-1-methyl-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12e. Following the above general procedure, trans diastereoisomer 12e was obtained as a pale yellow solid in 50% yield after purification by flash chromatography on silica gel (nHexane /EtOAc = 8/2), m.p. 105–107 ◦C. −1 1 ◦ IR (CHCl3): νe = 1735, 1734, 1614, 1492, 1467, 1358, 1260 cm . H-NMR (CDCl3, 300 MHz, 25 C): Molecules 2018, 23, 438 12 of 18

δ (ppm) 1.28 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.23 (s, 3H, NCH3); 3.75 (s, 3H, OCH3); 4.18 (s, 1H, OCH); 4.22–4.25 (m, 2H, CH3CH2O); 6.80 (d, J = 8.5 Hz, 1H, CHarom); 6.92 (d, J = 8.5 Hz, 1H, CHarom); 13 ◦ 7.09 (s, 1H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 26.9, 56.0, 59.9, 62.3, 66.1, 109.5, 112.3, 115.9, 120.5, 139.1, 156.3, 165.8, 169.8 ppm. HRMS: exact mass calculated for (C14H15NNaO4) requires m/z 300.0848, found m/z 300.0844. HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHeptane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 16.33 min, Tminor = 11.45 min er = 90:10. 3 [α]D = −10 (c = 0.0451 g/cm in CHCl3). (20R,30R)-ethyl 1-methyl-5-nitro-2-oxospiro[indoline-3,20-oxirane]-30- carboxylate 12f. Following the above general procedure, trans diastereoisomer 12f was obtained as a pale yellow solid in 19% yield after ◦ purification by flash chromatography on silica gel (DCM 100%), m.p. 170–172 C. IR (CHCl3): νe = 3031, −1 1 ◦ 3017, 3009, 1754, 1743, 1617, 1533, 1494, 1340 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.34 (t, J = 7.1 Hz, 3H, CH3CH2O); 3.35 (s, 3H, NCH3); 4.23–4.42 (m, 3H, CH3CH2O, OCH); 7.03 (d, J = 8.9 Hz, 13 ◦ 1H, CHarom); 8.37 (d, J = 7.4 Hz, 2H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.2, 27.4, 59.4, 60.1, 62.9, 108.9, 120.4, 121.1, 128.0, 143.8, 150.9, 165.1, 170.1. HRMS: exact mass calculated for (C13H12N2NaO6) requires m/z 315.0593, found m/z 315.0596. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 23.13 min, 3 Tminor = 22.02 min er = 85:15. [α]D = −29 (c = 0.0180 g/cm in CDCl3). (20R,30R)-ethyl 1-methyl-2-oxo-1,2-dihydrospiro[benzo[g]indole-3,20-oxirane]-30-carboxylate 12g. Following the above general procedure, trans diastereoisomer 12g was obtained as a pale red solid in 50% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2), m.p. 185–187 ◦C. 1 ◦ H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.26–1.30 (m, 3H, CH3CH2O); 3.88 (s, 3H, NCH3); 4.21–4.31 (m, 3H, OCH, CH3CH2O), 7.50–7.55 (m, 4H, CHarom); 7.86–7.88 (m, 1H, CHarom), 8.40–8.43 (m, 1H, 13 ◦ CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 28.3, 59.2, 62.5, 63.6, 109.2, 118.5, 122.2, 123.7, 124.7, 126.6, 128.1, 129.2, 142.3, 149.3, 168.6, 170.1. HRMS: exact mass calculated for (C17H15NNaO4) requires m/z 320.0899, found m/z 320.0896. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 1.0 mL/min]: Tmajor = 18.48 min, Tminor = 13.56 min 3 er = 91:9. [α]D = −20.15 (c = 0.0059 g/cm in CHCl3). (20S,30S)-diethyl 1-methyl-2-oxospiro[indoline-3,20-oxiran]-30-yl)phosphonate 12h. Following the above general procedure, trans diastereoisomer 12h was obtained as a pale yellow solid in 45% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 4/6), m.p. 166–168 ◦C. −1 1 ◦ IR (CHCl3): νe = 1725, 1236 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.21 [t, J = 7.0 Hz, 3H, (CH3CH2O)2P], 1.41 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 3.26 (s, 3H, NCH3), 3.73 (d, JHP = 27.6 Hz, 1H, OCH), 3.95–4.14 [m, 2H, (CH3CH2O)2P], 4.20–4.37 [m, 2H, (CH3CH2O)2P], 6.90 (d, J = 7.9 Hz, 1H, CHarom), 7.1 (dt, J = 7.7, 1.0 Hz, 1H, CHarom), 7.39 (dt, J = 7.9, 1.3 Hz, 1H, CHarom), 7.99 (d, 13 ◦ J = 7.7 Hz, 1H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 15.9 (d, JCCOP = 5.8 Hz), 16.0 (d, JCCOP = 5.7 Hz), 26.3, 55.5 (d, JCP = 203.5 Hz), 59.7, 62.7 (d, JCOP = 6.3 Hz), 63.1 (d, JCOP = 6.1 Hz), 108.4, 118.9, 122.6, 126.5, 130.6, 145.3, 170.2. HRMS: exact mass calculated for (C14H18NNaO5P) requires m/z 334.0820, found m/z 334.0824. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 42.20 min, Tminor = 23.60 min er = 80:20. 3 [α]D = −2 (c = 0.0101 g/cm in CHCl3). (20S,30S)-diethyl 1-phenyl-2-oxospiro[indoline-3,20-oxiran]-30-yl phosphonate 12i. Following the above general procedure, trans diastereoisomer 12i was obtained as a pale yellow solid in 57% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 197–199 ◦C. −1 1 ◦ IR (CHCl3): νe = 1716, 1265 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.18 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 1.34 [t, J =7.1 Hz, 3H, (CH3CH2O)2P], 3.76 (d, JHP = 27.6 Hz, 1H, OCH), 4.00–4.08 [m, 2H, (CH3CH2O)2P], 4.18–4.33 [m, 2H, (CH3CH2O)2P], 6.77 (d, J = 7.6 Hz, 1H, CHarom), 7.05 (t, J = 7.6 Hz, 1H, CHarom), 7.22 (t, J = 7.6 Hz, 1H, CHarom), 7.35–7.46 (m, 5H, CHarom), 7.96 (d, J = 7.6 Hz, 1H, CHarom). 13 ◦ C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 16.0 (d, JCCOP = 5.7 Hz), 16.2 (d, JCCOP = 5.8 Hz), 58.1 (d, Molecules 2018, 23, 438 13 of 18

JCP = 203.7 Hz), 60.1, 62.9 (d, JCOP = 6.2 Hz), 63.4 (d, JCOP = 6.1 Hz), 109.8, 118.8, 123.3, 126.1, 126.9, 128.3, 129.5, 130.6, 133.5, 145.5, 169.8 ppm. HRMS: exact mass calculated for (C19H20NNaO5P) requires m/z 396.0977, found m/z 396.0975. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 39.90 min, Tminor = 17.50 min er = 79:21. 3 [α]D = −6.7 (c = 0.0122 g/cm in CHCl3). (20S,30S)-diethyl 1-benzyl-2-oxospiro[indoline-3,20-oxiran]-30-yl phosphonate 12j. Following the above general procedure, trans diastereoisomer 12j was obtained as a yellow solid in 45% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 205–207 ◦C. −1 1 ◦ IR (CHCl3): νe = 1731, 1262 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.22 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 1.43 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 3.81 (d, JHP = 27.4 Hz, 1H, OCH), 4.02–4.14 [m, 2H, (CH3CH2O)2P], 4.24–4.39 [m, 2H, (CH3CH2O)2P], 4.96 (s, 2H, CH2N), 6.81 (d, J = 7.6 Hz, 1H, CHarom), 7.07 (t, J = 7.6 Hz, 1H, CHarom), 7.24–7.36 (m, 6H, CHarom), 8.00 (d, J = 7.6 Hz, 1H, CHarom). 13 ◦ C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 16.2 (d, JCCOP = 5.7 Hz), 16.4 (d, JCCOP = 5.8 Hz), 44.4, 58.1 (d, JCP = 203.1 Hz), 60.2 (d, JCCP = 1.1 Hz), 62.9 (d, JCOP = 6.0 Hz), 63.3 (d, JCOP = 6.0 Hz), 109.3, 119.2, 122.1, 127.3, 127.5, 127.7, 128.7, 131.7, 135.2, 145.5, 170.7 ppm. HRMS: exact mass calculated for (C20H22NNaO5P) requires m/z 410.1133, found m/z 410.1130. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow rate 1.0 mL/min]: Tmajor = 39.90 min, 3 Tminor = 17.50 min er = 74:26. [α]D = −6.7 (c = 0.0122 g/cm in CHCl3). (20S,30S)-diethyl 1-(2,4-dichlorobenzyl)-2-oxospiro[indoline-3,20-oxiran]-30-yl)phosphonate 12k. Following the above general procedure, trans diastereoisomer 12k was obtained as a pale yellow solid in 54% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 235–237 ◦C. −1 1 ◦ IR (CHCl3): νe = 1733, 1253 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.23 [t, J = 7.1 Hz, 3H, (CH3CH2O)2P], 1.42 [t, J =7.1 Hz, 3H, (CH3CH2O)2P], 3.81 (d, JHP = 27.4 Hz, 1H, OCH), 3.97–4.19 [m, 2H, (CH3CH2O)2P], 4.22–4.39 [m, 2H, (CH3CH2O)2P], 5.03 (s, 2H, CH2N), 6.73 (d, J = 7.9 Hz, 1H, CHarom), 7.05–7.20 (m, 3H, CHarom), 7.30–7.34 (m, 3H, CHarom), 7.43 (d, J = 1.9 Hz, 1H, CHarom), 8.00 (d, 13 ◦ J = 7.6 Hz, 1H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 15.9 (d, JCCOP = 5.6 Hz), 16.0 (d, JCCOP = 5.5 Hz), 41.1, 57.9 (d, JCP = 203.0 Hz), 59.7 (d, JCCP = 1.1 Hz), 62.6 (d, JCOP = 6.2 Hz), 63.1 (d, JCOP = 6.2 Hz), 109.2, 118.9, 123.0, 126.8, 127.2, 128.8, 129.2, 130.6, 130.8, 133.2, 133.8, 144.0, 170.6 ppm. HRMS: exact mass calculated for (C20H20Cl2NNaO5P) requires m/z 478.0354, found m/z 478.0356. Chiral-phase HPLC analysis: [Daicel Chiralpack IB 5µ, λ = 254 nm, nHexane/iPrOH = 9/1, flow 3 rate 1.0 mL/min]: Tmajor = 26.20 min, Tminor = 16.80 min er = 72:28. [α]D = −20.4 (c = 0.0091 g/cm in CHCl3). (20S,30S)-diethyl 5-chloro-1-methyl-2-oxospiro[indoline-3,20-oxiran]-30-yl)phosphonate 12l. Following the above general procedure, trans diastereoisomer 12l was obtained as a white solid in 38% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1), m.p. 211–215 ◦C. −1 1 ◦ IR (CHCl3): νe = 1734, 1260 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.26 [t, J = 7.0 Hz, 3H, (CH3CH2O)2P], 1.42 [t, J =7.0 Hz, 3H, (CH3CH2O)2P], 3.26 (s, 3H, NCH3); 3.73 (d, JHP = 26.6 Hz, 1H, OCH), 4.05–4.18 [m, 2H, (CH3CH2O)2P], 4.25–4.34 [m, 2H, (CH3CH2O)2P], 6.83 (d, J = 8.3 Hz, 1H, 13 ◦ CHarom), 7.38 (d, J = 8.3 Hz, 1H, CHarom), 8.02 (s, 2H, CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 16.4 (d, JCP = 5.9 Hz), 16.6 (d, JCP = 5.6 Hz), 27.1, 58.1 (d, JCP = 203.4 Hz), 59.9, 63.3 (d, JCP = 6.3 Hz), 63.8 (d, JCP = 6.1 Hz), 109.8, 121.2, 127.5, 128.8, 131.0, 144.3, 170.4. HRMS: exact mass calculated for (C14H17ClNNaO5P) requires m/z 368.0431, found m/z 368.0433. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 9/1, flow rate 1.0 mL/min]: 3 Tmajor = 18.92 min, Tminor = 17.56 min er = 77:23. [α]D = +4 (c = 0.0170 g/cm in CHCl3). (20S,30S)-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12m. Following the above general procedure, trans diastereoisomer 12m was obtained as a white solid in 62% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3433, 3035, 3009, 1751, −1 1 ◦ 1726, 1622, 1474, 1340, 1318 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.29 (t, J = 7.1 Hz, Molecules 2018, 23, 438 14 of 18

3H, CH3CH2O); 4.17–4.47 (m, 3H, CH3CH2O, OCH); 6.87–7.17 (m, 2H, CHarom); 7.27–7.51 (m, 2H, 13 ◦ CHarom); 9.38 (s, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 59.9, 60.5, 62.5, 111.4, 119.6, 123.3, 125.2, 131.3, 143.0, 165.7, 172.6. HRMS: exact mass calculated for (C12H11NNaO4) requires m/z 256.0586, found m/z 256.0582. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 90/10, flow rate 1.0 mL/min]: Tmajor = 6.28 min, Tminor = 5.51 min er = 75:25. 3 [α]D = −84.22 (c = 0.0155 g/cm in CHCl3). (20S,30S)-ethyl 5-fluoro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12n. Following the above general procedure, trans diastereoisomer 12n was obtained as a white solid in 32% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3429, 3207, 3031, −1 1 ◦ 2979, 1715, 1767, 1752, 1630, 1481, 1319, 1231, 1204 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.32 (t, 3H, J = 7.1 Hz, CH3CH2O); 4.19 (s, 1H, OCH); 4.26–4.36 (m, 2H, CH3CH2O); 6.88 (m, 1H, 13 CHarom); 7.06 (t, 1H, J = 8.4 Hz, CHarom); 7.24 (m, 1H, CHarom); 8.66 (s, 1H, NH). C-NMR (CDCl3, ◦ 75 MHz, 25 C): δ (ppm) 14.3, 60.0, 60.5, 62.7, 111.9 (d, JCF = 7.9 Hz), 113.5 (d, JCF = 26.7 Hz), 117.9 (d, JCF = 23.9 Hz), 121.3 (d, JCF = 9.1 Hz), 138.8, 159.3 (d, JCF = 242.2 Hz), 165.4, 172.3. HRMS: exact mass calculated for (C12H10FNNaO4) requires m/z 274.0492, found m/z 274.0497. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 90/10, flow rate 1.0 mL/min]: 3 Tmajor = 10.44 min, Tminor = 9.05 min er = 93:7. [α]D = −132 (c = 0.0155 g/cm in CHCl3). (20S,30S)-ethyl 5-chloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12o. Following the above general procedure, trans diastereoisomer 12o was obtained as a white solid in 33% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1). IR (CHCl3): νe = 3433, 3213, 3021, −1 1 ◦ 1764, 1755, 1602, 1441, 1240, 1228, 1213 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.32 (t, 3H, J = 7.1 Hz, CH3CH2O); 4.19 (s, 1H, OCH); 4.26–4.36 (m, 2H, CH3CH2O); 6.88 (m, 1H, CHarom); 13 7.06 (t, 1H, J = 8.4 Hz, CHarom); 7.24 (m, 1H, CHarom); 8.66 (s, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 ◦C): δ (ppm) 14.3, 60.0, 60.5, 62.7, 112.1, 123.3, 125.9, 129.0, 131.3, 140.3, 165.4, 171.8. HRMS: exact mass calculated for (C12H10ClNNaO4) requires m/z 290.0196, found m/z 290.0198. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 70/30, flow rate 1.0mL/min]: 3 Tmajor = 5.15 min, Tminor = 4.66 min er = 73:27. [α]D = −43 (c = 0.0108 g/cm in CHCl3). (20S,30S)-ethyl 5-iodo-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12p. Following the above general procedure, trans diastereoisomer 12p was obtained as a white solid in 71% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 1/1). IR (CHCl3): νe = 1765, 1760, 1602, −1 1 ◦ 1441, 1240, 1228 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.34 (t, 3H, J = 7.0 Hz, CH3CH2O); 4.17–4.40 (m, 3H, CHO, CH3CH2O); 6.76 (d, 1H, J = 8.3 Hz, CHarom); 7.67 (d, 1H, J = 8.3 Hz, CHarom); 13 ◦ 7.76 (s, 1H, CHarom), 8.73 (bs, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.4, 59.8, 60.1, 62.7, 85.6, 113.0, 122.0, 134.2, 140.1, 142.4, 165.4, 171.2. HRMS: exact mass calculated for (C12H10INNaO4) requires m/z 381.9552, found m/z 381.9555. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 90/10, flow rate 1.0 mL/min]: Tmajor = 11.56 min, Tminor = 9.81 min 3 ee = 68:32. [α]D = −23 (c = 0.0120 g/cm in CHCl3). (20S,30S)-ethyl 2-oxo-5-(trifluoromethoxy)spiro[indoline-3,20-oxirane]-30-carboxylate 12q. Following the above general procedure, trans diastereoisomer 12q was obtained as a white solid in 29% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3433, 3210, −1 1 ◦ 3028, 1764, 1724, 1630, 1478, 1371, 1234, 1197 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.31 (t, 3H, J = 7.0 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.31 (q, 2H, J = 7.0 Hz, CH3CH2O); 6.97 (d, 1H, J = 8.4 Hz, 13 CHarom); 7.22–7.26 (m, 1H, CHarom); 7.41 (s, 1H, CHarom); 8.41 (bs, 1H, NH). C-NMR (CDCl3, 75 MHz, ◦ 25 C): δ (ppm) 14.2, 60.1, 60.0, 62.7, 111.6, 119.6, 120.6 (q, JCF = 256.0 Hz), 121.3, 124.6, 141.3, 145.1, 165.3, 171.7. HRMS: exact mass calculated for (C13H10F3NNaO5) requires m/z 340.0409, found m/z 340.0410. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 95/5, 3 flow rate 1.0mL/min]: Tmajor = 12.04 min, Tminor = 9.15 min er = 87:13. [α]D = −56.53 (c = 0.0168 g/cm in CHCl3). Molecules 2018, 23, 438 15 of 18

(20S,30S)-ethyl 7-fluoro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12r. Following the above general procedure, trans diastereoisomer 12r was obtained as a white solid in 21% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 8/2). IR (CHCl3): νe = 3433, 3031, 2976, −1 1 ◦ 2930, 1752, 1737, 1639, 1493, 1234, 1228 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.30 (t, 3H, J = 7.0 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.25–4.30 (m, 2H, CH3CH2O); 7.01–7.05 (m, 1H, CHarom); 13 7.14 (t, 1H, J = 9.2 Hz, CHarom); 7.28 (d, 1H, J = 9.2 Hz, CHarom); 7.84 (s, 1H, NH). C-NMR (CDCl3, ◦ 75 MHz, 25 C): δ (ppm) 14.3, 60.0, 60.1, 62.5, 118.4 (d, JCF = 17 Hz), 121.1 (d, JCF = 3.6 Hz), 122.2, 124.0 (d, JCF = 5.9 Hz), 129.9, 147.4 (d, JCF = 244.7 Hz), 165.3, 170.5. HRMS: exact mass calculated for (C12H10FNNaO4) requires m/z 274.0492, found m/z 274.0493. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 8/2, flow rate 1.0 mL/min]: Tmajor = 7.88 min, 3 Tminor = 8.60 min er = 92:8. [α]D = −63.2 (c = 0.0150 g/cm in CHCl3). (20S,30S)-ethyl 7-chloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12s. Following the above general procedure, trans diastereoisomer 12s was obtained as a white solid in 35% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3420, 3177, 3009, −1 1 ◦ 1764, 1749, 1624, 1478, 1316, 1234, 1189 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.29 (t, 3H, J = 6.8 Hz, CH3CH2O); 4.20–4.31 (m, 2H, CH3CH2O, OCH); 7.01 (t, 1H, J = 8.1 Hz, CHarom); 7.36 (t, 2H, 13 ◦ J = 8.1 Hz, CHarom); 8.14 (s, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.2, 60.1, 60.7, 62.5, 116.3, 121.3, 123.6, 124.1, 131.1, 140.4, 165.3, 171.2. HRMS: exact mass calculated for (C12H10ClNNaO4) requires m/z 290.0196, found m/z 290.0197. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 8/2, flow rate 1.0 mL/min]: Tmajor = 7.72 min, Tminor = 10.00 min 3 er = 88:12. [α]D = −186.6 (c = 0.0220 g/cm in CHCl3). (20S,30S)-ethyl 7-bromo-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12t. Following the above general procedure, trans diastereoisomer 12t was obtained as a white solid in 49% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3414, 3210, 3006, −1 1 ◦ 1742, 1730, 1621, 1444, 1316, 1234 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.29 (t, 3H, J = 7.1 Hz, CH3CH2O); 4.20 (s, 1H, OCH); 4.23–4.37 (m, 2H, CH3CH2O); 6.96 (t, 1H, J = 7.9 Hz, CHarom); 13 7.42 (d, 1H, J = 7.9 Hz, CHarom); 7.48 (d, 1H, J = 7.9 Hz, CHarom); 8.06 (s, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 ◦C): δ (ppm) 14.3, 60.1, 61.0, 62.6, 104.1, 121.4, 124.3, 124.5, 133.9, 141.9, 165.3, 170.5. HRMS: exact mass calculated for (C12H10BrNNaO4) requires m/z 333.9691, found m/z 333.9693. Chiralphase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 7/3, flow rate 1.0mL/min]: 3 Tmajor = 6.14 min, Tminor = 7.18 min er = 92:8. [α]D = −15.85 (c = 0.0132 g/cm in CHCl3). (20S,30S)-ethyl 5,7-dichloro-2-oxospiro[indoline-3,20-oxirane]-30-carboxylate 12u. Following the above general procedure, trans diastereoisomer 12u was obtained as a white solid in 27% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3423, −1 1 ◦ 3031, 3009, 1757, 1743, 1463, 1323, 1290 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.32 (t, J = 7.0 Hz, 3H, CH3CH2O); 4.18–4.36 (m, 3H, CH3CH2O, OCH); 7.38 (s, 1H, CHarom); 7.42 (s, 1H, 13 ◦ CHarom); 8.09 (s, 1H, NH). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.3, 60.1, 60.4, 62.9, 116.6, 122.4, 124.4, 129.3, 130.8, 138.9, 165.1, 170.1. HRMS: exact mass calculated for (C12H9Cl2NNaO4) requires m/z 323.9806, found m/z 323.9808. Chiral-phase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 7/3, flow rate 1.0 mL/min]: Tmajor = 5.52 min, Tminor = 6.34 min 3 er = 83:17. [α]D = +137 (c = 0.0090 g/cm in CHCl3). (2R,30R)-1-(tert-butyl) 30-ethyl-2-oxospiro[indoline-3,20-oxirane]-1,30-dicarboxylate 12v. Following the above general procedure, trans diastereoisomer 12v was obtained as a white solid in 60% yield after purification by flash chromatography on silica gel (nHexane/EtOAc = 7/3). IR (CHCl3): νe = 3035, −1 1 ◦ 307, 2984, 1736, 1618, 1603, 1495, 1473, 1376, 1347 cm . H-NMR (CDCl3, 300 MHz, 25 C): δ (ppm) 1.23 (t,J = 5.9 Hz, 3H, CH3CH2O), 1.48 (s, 9H), 4.22 (s, 2H, CH3CH2O), 4.59–4.45 (m, 1H), 7.22 (dtd, J = 26.3, 7.4, 2.0 Hz, 1H, CHarom), 7.38 (dd, J = 7.3, 2.2 Hz, 2H, CHarom), 7.89 (dd, J = 7.4, 2.1 Hz, 1H, 13 ◦ CHarom). C-NMR (CDCl3, 75 MHz, 25 C): δ (ppm) 14.0, 27.8, 60.5, 61.1, 69.2, 83.4, 114.4, 115.3, 125.2, Molecules 2018, 23, 438 16 of 18

125.8, 129.3, 131.3, 150.5, 166.4, 170.8. HRMS: exact mass calculated for (C17H19NNaO6) requires m/z 356,1110, found m/z 356,1112. Chiralphase HPLC analysis: [Daicel Chiralpack IC 5µ, λ = 254 nm, nHexane/EtOH = 9/1, ﬂow rate 1.0 mL/min]: Tmajor = 6.80 min, Tminor = 5.75 min er = 96:4. [α]D = +27 3 (c = 0.0103 g/cm in CHCl3).

4. Conclusions In summary, we have investigated the organocatalytic epoxidation of α-ylidene oxindoles in depth, highlighting the strong and weak features of the overall procedure. The above depicted findings clearly underline the importance of installing a robust H-bond network that mainly involves the catalyst and the substrate. Specifically, although a few organocatalysts having manifold scaffolds and diverse substituents have been tested, the simplest α,α-diphenylprolinol 1 results in being the most suitable structure to successfully perform the devised nucleophilic epoxidation in terms of yield, time and enantioselectivity. Additionally, the extension of the substrate scope proves that the nucleophile attack on the electrophilic center (Cβ) only slightly endures the replacement of the EWG on the exocyclic double bond, while it is dramatically affected by the substitution pattern on the amidic moiety: (i) noticeable is the presence of the free NH function that makes the Si-face approach of the oxidizing agent less-hindered, and therefore preferential; (ii) the effect of the tert–butyloxycarbonyl protecting group able to induce excellent levels of stereoselectivity is also remarkable. Such unexpected findings complement our efforts to undertake supplementary mechanistic studies and establish additional improvements to the developed protocol, which not only should lead to a higher value of enantioselectivity, but also could furnish the desired spiroepoxyoxindoles bearing a quaternary stereogenic center with variable stereochemistry by simply modifying the nitrogen-protecting group.

Supplementary Materials: The following are available online. Acknowledgments: Tecla Gasperi, Martina Miceli, Chiara Palumbo, Andrea Mazziotta, Elia Roma, and Eleonora Tosi are deeply thankful to Augusto Gambacorta and Maria A. Loreto for their preciuos advice during every step of their research. Additionally, Tecla Gasperi, Martina Miceli, Elia Roma, and Eleonora Tosi gratefully acknowledge Dipartimento di Scienze and Sezione di Nanoscienze e Nanotecnologie (Università di Roma Tre, Roma, Italy) for the financial support. Author Contributions: Tecla Gasperi, Martina Miceli, Chiara Palumbo, and Andrea Mazziotta conceived, designed and performed the experiments; Giuseppe Mazzeo, Giovanna Longhi, Sergio Abbate performed the calculation and analyzed the data for the configuration assignment; Tecla Gasperi mainly wrote the paper with the help of Elia Roma and Eleonora Tosi; Paolo Lupattelli performed the ORD measurements. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds trans-12a–h, and 12m–u are available from the authors.

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