Rigidified Bis(sulfonyl)ethylenes as Effective Michael Acceptors for Asymmetric Catalysis: Application to the Enantioselective Synthesis of Quaternary Hydantoins

Rigidified Bis(sulfonyl)ethylenes as Effective Michael Acceptors for Asymmetric Catalysis: Application to the Enantioselective Synthesis of Quaternary Hydantoins Leire Villaescusa, Iker Hernández, Laura Azcune, Ainhoa Rudi, JoséM. Mercero, Aitor Landa,* Mikel Oiarbide,*and Claudio Palomo* Cite This: J. Org. Chem. 2023, 88, 972−987 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: The catalytic, enantioand diastereoselective addition of hydantoin surrogates II to “rigidified” vinylidene bis(sulfone) reagents is developed, thus overcoming the inability of commonly employed βsubstituted vinylic sulfones to react. Adducts are transformed in enantioenriched 5,5-disubstituted hydantoins through hydrolysis and reductive desulfonylation processes providing new structures for eventual bioassays. Density functional theory studies that rationalize the observed reactivity and stereoselectivity trends are also provided. ■INTRODUCTION Hydantoins are widespread heterocyclic scaffolds within biologically active compounds, 1 and consequently, their chemical synthesis has raised considerable current interest. 2 In particular, 5,5-disubstituted (quaternary) hydantoin structural subunits are found in marketed drugs 3 and promising clinical candidates for the treatment of psoriasis 4 as well as selective androgen receptor modulators. 5 Compounds possessing α-quaternary hydantoin units also include new potent inhibitors of aggrecanase ADAMTS-5 (involved in cartilage degradation during osteoarthritis 6 ) and inhibitors of the decaprenylphospho-β-D-ribofuranose 2-oxidase (DprE1), useful as antimycobacterial inhibitors. 7 However, the number of stereoselective synthetic approaches to quaternary hydantoins, and more specifically methods involving direct and selective Cfunctionalization of preformed hydantoins, is still scarce. 8 Recently, our laboratory has introduced sulfur-substituted dihydroimidazol-4-ones of general structures Iand II as useful hydantoin surrogates amenable for base-promoted C−H functionalization (Figure 1a). More specifically, in the presence of a chiral Brønsted base/H-bonding (BB/HB) bifunctional catalyst, they can react smoothly with active electrophiles, for example, nitroolefins, enones, and aldehydes, affording the αaddition adducts in high yields and very high enantioselectivity for most cases. The resulting adducts may deliver the corresponding 5,5-disubstituted hydantoins or related αmodified α-amino acid derivatives with preserved configuration via hydrolytic protocols. 9 In order to expand this technology onto a broader range of α,α-disubstituted hydantoins and α-amino acid derivatives, we envisioned vinyl sulfones as an attractive category of Received: October 6, 2022 Published: January 11, 2023 Figure 1. Enantioselective synthesis of quaternary hydantoins from templates I/II and the new extension using sulfonyl electrophiles. Articlepubs.acs.org/joc © 2023 American Chemical Society 972 https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 Downloaded via UNIV DEL PAIS VASCO on July 17, 2023 at 07:55:19 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. electrophilic reaction partners. Sulfones are recognized as versatile intermediates in synthesis. 10,11 For instance, they may be transformed into the parent alkanes through reductive desulfonylation or be further elaborated via well-established αcarbanion chemistry. However, preliminary experiments using simple sulfonyl (A) and β-substituted bis(sulfonyl)ethylene (B) reagents (Figure 1b) in conjunction with surrogates I/II and suitable BB/HB catalysts led to the recovery of unreacted materials mainly. This observation is ascribable to the relatively low reactivity of α,β-unsaturated sulfonyl systems, particularly the β-substituted ones (vide infra). Here, we present bis(sulfonyl)ethylenes C(Figure 2) as competent Michael acceptors in catalytic enantioselective reactions for which common acyclic congeners Bare not. More specifically, the addition reaction of N-acyl surrogates II to Cin the presence of suitable BB/HB catalysts proceeded smoothly at room temperature, affording the Michael reaction adducts as essentially single diastereomers in generally good yields and very high enantioselectivity (Figure 1c). This finding allows us to significantly broaden the range of 5,5-disubstituted hydantoin structures available in optically pure form for eventual biological activity screening programs. Our selection of Cas a potentially more reactive Michael acceptor sulfonyl system was routed on previous inspirational observations from the literature. On the one hand, lower reactivity of acyclic versus cyclic bis-sulfonyl alkanes as nucleophiles in iminium-mediated catalytic addition reactions has been reported by our group and others (Figure 2a). 12 Similarly, the lower Michael acceptor reactivity of (acyclic) alkyliden malonates versus (cyclic) alkyliden Meldrum’s acids, which correlates with the lower carbon acidity of malonic esters versus Meldrum’s acid, is well recognized in the literature. 13 In addition, Mayr has reported 14 that, based on kinetic data, aryl-substituted cyclic bis(sulfones) are approximately 1 order of magnitude more electrophilic than their acyclic counterparts. Several attempts to rationalize theoretically these acidity and reactivity trends when comparing acrylic versus cyclic (rigidified) systems are known. 15 With these precedents in mind, we hypothesized that given the fluxional nature of the four C−S bonds in the acyclic bissulfonyl system B, its low reactivity may be ascribed to the unfavorable relative orientation of the S�O dipoles of one SO2Ph group relative to the other and the two aryl rings relative to one another as a result of steric repulsions. In sharp contrast, the rigid structure of C would keep the S�O groups well aligned for catalyst coordination while the πaryl and olefin systems would stand perfectly coplanar, ultimately leading to highly ordered and compact transition structures. ■RESULTS AND DISCUSSION Assessment of Pronucleophile Reactivity Trends Using β-Unsubstituted Ethylene Bis(sulfone) 1a. Since the first organocatalytic conjugate addition to vinyl bis- (sulfone) 1a reported by Mosseand Alexakis in 2005, 16 the implementation of enantioselective catalytic C−C bondforming methods involving vinylic sulfones, and vinylidene bis(sulfones) in particular, has progressed unevenly. Reagent 1a exhibits high reactivity (E=−7.50 on the Mayr scale) 14 and has been often employed as an electrophilic reaction partner under various catalytic activation approaches. However, the sterically more congested β-substituted congeners, for example, 1b, have been used less often 17 because of their relatively lower electrophilicity (≈1 unit lower Evalues were reported) 14 and the appearance of retro-Knoevenagel side reaction. 16c In this study, both bis(sulfonyl)olefins 1a and 1b along with related reagent 2displaying a rigidified skeleton were tested in catalytic additions of hydantoin surrogates I/II. The study was initiated by evaluating the addition reaction of various dihydroimidazol-4-ones 3and 4to bis(sulfonyl)- ethylene 1a using representative bifunctional BB/HB catalysts such as squaramide C1,Scheme 2. To our delight, the reaction of N-benzoyl dihydroimidazol-4-one 3a in the presence of 10 mol % C1 in dichloromethane as the solvent at 0 °C proceeded to almost completion within 24 h to afford product 10a in 88% ee. Surprisingly, the N-acetyl analogue 4a resulted completely unreactive under the same conditions. Differences in carbon acidity may be invoked to rationalize this huge difference in the reactivity of N-phenyl versus N-acetyl analogue. In a first estimate, the pKavalues according to Grzybowski’s prediction tool 18 for 3a and 4a in DMSO are 15 and 16, respectively. In its turn, the “tautomeric” 8reacted to a significant 80% conversion but produced essentially a racemic material. These results indicated that the present catalytic reaction system is quite sensitive in terms of both reactivity and selectivity to Figure 2. Tunning Nuc/Elec reactivity by substrate rigidification. Scheme 1. Vinylidene Bis(sulfones) and Pronucleophilic Heterocycles Employed in This Study The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 973 tinny structural variations on the substrate heterocycle. For comparative purposes, the reaction using azlactone 9 was also carried out, which led to full conversion with the formation of adduct 13 in 58% ee. Thus, the relatively higher reactivity of azlactones in this type of catalytic additions 19 was corroborated. After this brief substrate screening, several other catalysts C2−C6 with varying structure and functionality were evaluated for the model reaction between 1a and 3a. As the results in Table 1 show, catalyst C2, which has been developed in our group and presents an additional amide NH available for engaging in H-bonding interactions, 9,20 afforded an increased 98% ee (entry 2 vs 1). Takemoto’s catalyst C6 21 (entry 6) and the related urea and thiourea catalysts C3 22 and C4 23 (entries 3 and 4) did also promote the reaction, although neither yields nor enantioselectivities were improved. Finally, the ureidoaminal C5, which also has an additional NH group and demonstrated highly active and selective catalysts for various reactions, 24 failed to promote this reaction effectively (entry 5). With C2 selected as an optimal catalyst, the scope of the reaction was briefly explored. As the results in Scheme 3a show, the reaction of 1a with 3bearing simple alkyl or allyl substituents at C5 proceeded satisfactorily giving rise to products 10b−ein ee’s in between 93 and 98% and generally high yields (adduct 10b was an exception). The reactions leading to adducts 10f and 10g also worked well, affording the respective product in 91%/98% yield and 92%/96% ee, thus showing that substrates bearing thioether and ester functions are well tolerated. However, as data in Scheme 3b show, phenyl-substituted bis(sulfonyl)ethene 1b was not reactive enough, and only marginal conversion was attained after prolonged time at room temperature. Catalytic Addition Reactions Using Rigidified βSubstituted Ethylene Bis(sulfone) 2. Prompted by this result, our attention turned to the rigidified reagents C. Preparation of 2-benzylidene-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxides 2a and 2b in one step from benzodithiole tetroxide was reported by Mayr in 75 and 77% yields, respectively. Following a slightly modified three-step sequence from commercially available o-benzenedithiol (Scheme 1), the remaining compounds 2c−fwere obtained in an overall 31− 53% yield. 25 With reagent 2a at hand, its behavior as a Michael acceptor in the above catalytic reactions was investigated (Scheme 4). Gratifyingly, the reaction of 2a with 3a in the presence of 10 mol % C1 proceeded to almost completion after Scheme 2. Evaluation as Several Pronucleophiles against the Catalytic Addition Reaction to Bis(sulfone) 1a Table 1. Catalyst Screening for the Addition of 1a to 3a Entry Catalyst Time (h) a Conv. (%) b ee (%) c 1C1 24 95 88 2C2 24 75 98 4C3 48 82 75 5C4 48 68 67 6C5 24 63 29 7C6 24 88 18 a Reaction conditions: 3a (0.1 mmol), 1a (0.12 mmol), and catalyst (10 mol %) in CH2Cl2(1.0 mL). b Conversion determined by 1H NMR. c ee determined by HPLC. Scheme 3. (a) Scope of Heterocycles 3 Suitable for the Catalytic Addition to 1a and (b) the Attenuated Reactivity of Acceptor 1b The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 974 24 h at 0 °C, from which 60% of adduct 15aa of 91% ee could be isolated. Once again, catalyst C2 imparted almost perfect stereoinduction providing a single enantiomer of 15aa in 79% yield after 48 h at the same temperature. The N-acyl analogues 4−6and the “tautomeric” dihydroimidazol-4-one 8 were less efficient pronucleophiles against the new reagent 2a (Scheme 4). Not surprisingly, the N-benzyl analogue 7a was also totally unreactive under the present catalytic conditions. Encouraged by the good reactivity profile showed by reagent 2a, the remaining analogues 2b−2f were also evaluated in combination with a variety of pronucleophiles 3(Table 2). In the first set of reactions in the presence of C2,2a was submitted to the reaction with alkyland allyl-substituted dihydroimidazolones 3c,3d, and 3e which led to the corresponding adducts 15ca,15da, and 15ea as single diastereomer in high yields and enantioselectivities of 96, 92, and 95%, respectively. The thioetherand methyl ester-bearing substrates 3f and 3g also led to the addition of adducts 15fa and 15ga in high yield and diastereoselectivity, although the latter was obtained with slightly diminished enantioselectivity unless reaction temperature was decreased to −20 °C. The reaction of unsaturated ester-bearing 3h to afford 15ha proceeded exceedingly (91% ee), demonstrating that the present catalytic conjugate addition reactions may proceed chemoselectively in the presence of additional Michael acceptor units in the substrate. Then, several aryl-substituted acceptors 2were screened. p-Methoxyphenyl-substituted acceptor 2b was equally competent to give rise to 15ab in a highly selective manner. Similarly, the p-chlorophenyl-substituted analogue 2c reacted to completion within 2 days regardless of the temperature with the dihydroimidazolones 3a, 3b, and 3e, affording products 15ac,15bc, and 15ec in good yields and excellent enantiocontrol. The reactions with 1naphthyl and 2-naphthyl-bearing vinyl sulfones 2g and 2h did also work satisfactorily to produce compounds 15ge and 15ah in good yields and high stereoselectivity. Interestingly, 15ah presented split signals in 1H NMR, which were assigned to the existence of rotameric isomers. That is why this compound was characterized as the corresponding hydantoin derivative after hydrolytically removing both the N-benzoyl and benzylthio groups (see the Supporting Information for details). On the other hand, bis(sulfones) 2d−f, bearing a heteroaryl βsubstituent, were also tolerated. The furyl and pyridyl derivatives 15ad and 15af were obtained in good yields and very high stereoselectivity. The thiophenyl-substituted adducts 15ae and 15ge were isolated with somewhat reduced yields and, in the latter case, diminished selectivity too. Finally, the method is applicable at a larger scale without any significant variation in yields or selectivities. For instance, in reactions carried out at a 4 mmol scale, 2.18 g (77%) and 2.43 g (82%) of adducts 15aa and 15ac, respectively, were obtained in both cases with almost perfect enantioselectivity of 99% ee (see the Supporting Information for details). Scheme 4. Initial Assessment of Reagent 2a as a Michael Acceptor in Catalysis Table 2. Scope of the Reaction between Hydantoin Surrogate 3 and Acceptor 2 in the Presence of Catalyst C2 a a Reactions conducted on a 0.1 mmol scale in 1 mL of CH2Cl2; mol ratio of 3/2/C2 1:1.2:0.1. Yield of isolated product after column chromatography. ee’s determined by HPLC analysis using a chiral stationary phase. b Reaction run at a 4 mmol scale using 5 mol % C2 as a catalyst. c Obtained as a mixture of rotamers. The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 975 Having established 2as a competent Michael acceptor reagent for the enantioconvergent transformations involving chiral racemic pronucleophiles 3, the likelihood of the parent unsubstituted dihydroimidazolone 21 participating in such enantioselective transformations was assessed next (Scheme 5). It could be anticipated that a major difficulty would be associated with the configurational integrity of the Cα stereocenter in the product 22 in the presence of the basic catalyst. Accordingly, reactions were carried out in cryogenic conditions. As the results in Scheme 5 show, it was delighting to observe that even at −25 °C, the reaction of 21 with bis(sulfone) 2a in the presence of 10 mol % C2 proceeded to afford product 22a as a single diastereomer in reasonably good yield (61, 70% conv.) and 95% ee. Similarly, the reaction with p-chlorophenyl derivative 2b afforded product 22b in 74% yield and 88% ee. At this point, it is important to note that product 22 did not epimerize during column chromatography purifications on silica gel. Then, some possibilities of further chemical elaboration of enantioenriched adducts were explored, particularly the hydrolysis of the heterocyclic ring and the reductive elimination of the sulfonyl moiety (Scheme 6). For example, treatment of 10a with 6 M HCl in 1,4-dioxane at 65 °C led to hydantoin 23 in 73% yield. Desulfonylation 26 of 23 with Mg/ TMSCl/1,2-dibromoethane in methanol at room temperature afforded, unexpectedly and selectively, the monodesulfonylation product 24 in 51% yield. This case of selective monodesulfonylation of a bis-sulfonylated adduct is relevant because the alternative and direct route to the monosulfonyl derivative through catalytic addition of the dihydroimidazolone 3a to phenylsulfonylethene did not work even at 70 °C overnight. Acidic hydrolysis at 80 °C (bath temperature) of adducts 15aa and 15ac gave rise to N-benzoyl hydantoins 25a and 25b in good yields. 27 An X-ray crystal structure analysis of 25b allowed us to establish its absolute and relative configurations. 28 The configuration of the remaining adducts was assigned assuming a uniform reaction mechanism. Double desulfonylation of 25a under the above conditions yielded the 5,5-disubstituted hydantoin 26 in 67% yield over the two steps from 15aa. On the other hand, removing the N-benzoyl group from 15aa could be carried out by treatment with TFA at 40 Scheme 5. Enantioand Diastereoselective Addition of 5Unsubstituted Dihydroimidazol-4-One 21 to Acceptors 2 Scheme 6. Chemical Elaboration of Adducts into Hydantoins and Derivatives Thereof The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 976 °C, leading to 27 in essentially quantitative yield. With the NH derivative 27 in hand, hydrolysis led to hydantoin 32a; alternatively, various alkyl and allyl groups could be installed at nitrogen via standard N-alkylation protocols leading to 28−31 and thus overcoming the inability of N-alkyl dihydroimidazol4-ones (e.g., 7a,Scheme 4) to participate in the above catalytic addition reaction. Submission of the N-alkyl derivatives 28−30 to acid hydrolysis led to N-alkyl hydantoins 32b−d. Surprisingly, hydrolysis of adduct 31 followed a divergent pathway and afforded bicyclic isothiourea 33, probably through a chloride anion-promoted S-debenzylation/intramolecular Salkylation cascade. Determination of the enantiomeric purity of product 32c (98% ee) served to prove that the full sequence, including N-deprotection, N-alkylation, and final hydrolysis, proceeded with preserved stereochemistry. Theoretical Rationalization of the Observed Reactivity Trends and Stereoselectivity. A theoretical analysis was undertaken in order to understand (a) the huge differences in reactivity between the N-benzoyl heterocycle 3and the Nacetyl analogue 4observed experimentally and (b) the stereoselectivity and sense of chiral induction in the above catalytic reactions. To ascertain whether the higher reactivity of 3a versus 4a was attributable, as hypothesized above, to differences in the carbon acidities among these two pronucleophiles, we first calculated the pKavalues for 3a and 4a using the Jaguar pKamodule 29 as implemented in the Schrodinger 2021-01 30 program suite. In both water and DMSO as a solvent, the calculated pKaof 3a is smaller than that of 4a, 11.56 versus 12.51 in water and 19.71 versus 21.15 in DMSO, respectively. These differences are in agreement with our initial gross estimates (vide supra) and correlate well with the observed reactivity trend. Subsequently, the energy barrier was calculated for the deprotonation step of both 3a and 4a by the action of catalyst C2. In this step, a proton from the α-position of either substrate is transferred to the catalyst quinuclidine nitrogen via TS1 leading to complexes C2−H· 3aenolate and C2−H·4aenolate, with energy barriers of 13.03 and 16.95 kcal/mol, respectively (Figure 3). The difference Figure 3. Catalyst−reactant complex, reaction TS1 for the reactant deprotonation, and protonated catalyst−enolate complex corresponding to the proton transfer step for both 3a and 4a. Energies in kcal/mol. Figure 4. Structures participating in steps 2 and 3 of the reaction. In the first row, the transition state TS2 of the C−C formation step, with the corresponding intermediates, and in the third row, TS3 for the third step corresponding to the proton transfer from protonated C2 to the final product 15aa. The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 977 between both energy barriers (3.92 kcal/mol) is appreciable and may justify the significant reactivity difference observed experimentally for both substrates. In an attempt to understand the stereoselectivity of the reaction, we have analyzed the C−C formation step, which will dictate both the product relative and absolute configuration. Four different transition states were located (see Supporting Information for calculations details) that correspond to different orientations of reactants, out of which TS2 was the lowest in energy (Figure 4). In this transition state, each squaramide NH group of the catalyst interacts with the enolate from 3a in accordance with the so-called Papai model. In comparison, transition state TS2-B (see Supporting Information), which would lead to the corresponding enantiomeric product, is 4.40 kcal/mol higher in energy. The energy difference could be attributed to the additional H-bond formed between the protonated quinuclidine moiety of the catalyst and the enolate oxygen in TS2. The remaining two transition states TS2-C and TS2-D are 5.9 and 9.3 kcal/mol higher in energy than TS2 and present a single H-bond interaction between the enolate oxygen and the catalyst (see Supporting Information for details). In the last step of the catalytic cycle, the proton will be transferred back from the protonated catalyst to the formed Michael adduct delivering product 15aa via TS3. In TS3, the product−catalyst interaction involving the dihydroimidazolinone and the squaramide moieties, respectively, changes, and now the squaramide two NH groups interact with one of the dihydroimidazolinone carbonyls only. This new arrangement of the H-bonds causes this transition state to be around 15 kcal/mol higher in energy. Note though that the final proton transfer to the anionic reaction adduct might also occur via other alternative mechanisms. Figure 5 shows collectively the various reaction elementary steps for the lowest in the energy pathway from reactants 3a and 2a in the presence of catalyst C2. ■CONCLUSIONS In conclusion, the catalytic asymmetric conjugate addition of hydantoin surrogates to vinyl sulfones has been developed using a secondary amide-bearing tertiary amine/squaramide bifunctional catalyst. N-Benzoyl 2-(benzylthio)-1,5-dihydro4H-imidazole-4-ones, for example, 3, are able to act as hydantoin surrogates and react with vinyl bis(sulfone) 1a smoothly to provide the corresponding adducts in good yield and stereoselectivity. In contrast, the β-substituted vinyl bis(sulfones), such as 1b, proved to be completely unreactive under the above catalytic conditions. This problem could be circumvented by employing the “rigidified” β-substituted vinyl sulfones 2instead. Ulterior acid hydrolysis of the heterocycle system in adducts combined with a desulfonylation process allowed to access a variety of 5-substituted hydantoins, including the 5,5-disubstituted quaternary ones, in essentially optically pure form for eventual applications in medicinal chemistry. The suitability of “rigidified” β-substituted vinyl sulfones 2as Michael acceptors in other unrelated catalytic addition reactions may be foreseen. ■EXPERIMENTAL SECTION General Information. All nonaqueous reactions were performed under an inert atmosphere using oven-dried glassware and were magnetically stirred. For reactions that require heating, an oil bath was used. Yields refer to chromatographically purified samples unless otherwise stated. Wet organic layers were dried over MgSO4, and solvents were evaporated under reduced pressure. For trace solvent removal, a vacuum pump (≈0.5 mmHg) was applied. Column chromatography was performed on ROCC 60 silica gel 40−63 μm as the stationary phase and a suitable mixture of solvents (typically hexane: ethyl acetate) as the eluent. Optical rotations were recorded using a Jasco P-2000 polarimeter. Melting points were determined in open capillaries in a Stuart SHP3 melting point apparatus. 1H NMR and 13C NMR spectra were recorded at 300 or 500 MHz and 75 or 126 MHz, respectively. The chemical shifts are reported in ppm relative to CDCl3(δ= 7.26) and CD2Cl2(δ= 5.32) for 1H NMR and relative to the central resonances of CDCl3(δ= 77.2) and CD2Cl2(δ = 53.8) for 13C NMR. Peaks are labeled as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), double doublet (dd), double triplet (dt), double of doublet of triplets (ddt), quartets of doublets (qd), or multiplet (m). Coupling constants (J) are reported in Hertz (Hz). Mass spectra were recorded on an ESI-ion trap mass spectrometer (Agilent 1100 series LC/MSD, SL model) and a UPLC−DAD−QTOF, ultra-high-performance liquid chromatography−mass spectrometer. Enantiomeric (ee) values were determined by HPLC performed on Waters 600-E (equipped with a 2998 photodiode array UV detector) employing Daicel Chiralpack columns (IA, IB, IC, and IF). Infrared spectra were measured employing a Bruker ALPHA-P compact FT-IR spectrometer. The X-ray diffraction analysis was conducted by the General Research Service (SGIker) of UPV/EHU. All reagents were purchased from commercial suppliers and used without further purification, unless otherwise stated. Substrates 1a,1b, 3a,3b,3c,3d,3f,4a,5a,6a,7a,8, and 9were synthesized according to the reported procedures (see the Supporting Information for details). Triethylamine was purified by distillation. Dichloromethane and acetonitrile were dried over CaH2, and DMF was dried over molecular sieves. Analytical reagent-grade MeOH and toluene were used without further drying. General Procedure for the Catalytic Addition of Hydantoin Surrogates 3 to 1a. In a 5 mL test tube, the corresponding pronucleophile (0.1 mmol, 1 equiv) was dissolved in CH2Cl2(1 mL) at room temperature, and after cooling the solution down to 0 °C, the corresponding vinylic sulfone (37 mg, 0.12 mmol, 1.2 equiv) and catalyst C2 (8 mg, 0.01 mmol, 10 mol %) were added. The mixture was stirred at 0 °C until the reaction was finished as monitored by 1H NMR. The crude product was directly submitted to silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). (S)-1-Benzoyl-5-benzyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)- ethyl)-1,5-dihydro-4H-imidazole-4-one (10a). The title compound was prepared from 1-benzoyl-5-benzyl-2-(benzylthio)-1,5-dihydro4H-imidazole-4-one (40 mg, 0.1 mmol) according to the general Figure 5. Reaction profile. Relative Gibbs free energy values in kcal mol−1calculated with Orca 5 (see Supporting Information for more details). The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 978 procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White foam. Yield: 67 mg, 95%. [α]D 20 + 47.0 (c= 1, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.15−6.94 (m, 25H), 5.67 (dd, J= 6.1, 3.0 Hz, 1H), 4.20 (d, J= 13.3 Hz, 1H), 4.04 (d, J= 13.3 Hz, 1H), 3.54 (d, J= 13.6 Hz, 1H), 3.33 (dd, J= 16.6, 3.0 Hz, 1H), 3.22 (d, J= 13.8 Hz, 1H), 3.19−3.11 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ186.2, 185.0, 168.2, 138.0, 137.0, 134.9, 134.7, 134.4, 134.0, 133.1, 132.1, 130.3, 130.2, 130.0, 129.8, 129.3, 129.1, 128.9, 128.78, 128.76, 128.6, 128.0, 127.7, 77.9, 73.2, 41.2, 39.7, 31.6. HRMS (ESI) m/z: [M + H]+calcd for C38H33N2O6S3, 709.1501; found, 709.1506. IR (cm−1): 3062, 3056, 2940, 1725, 1600. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/ min, retention times: 43.8 min (major) and 52.0 min (minor). (S)-1-Benzoyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)ethyl)-5methyl-1,5-dihydro-4H-imidazole-4-one (10b). The title compound was prepared from 1-benzoyl-2-(benzylthio)-5-methyl-1,5-dihydro4H-imidazole-4-one (32 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). Yellow foam. Yield: 23 mg, 36%. (conv. 55%). [α]D 20 −3.3 (c= 1, 97% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.14−8.05 (m, 2H), 8.02−7.93 (m, 2H), 7.75−7.36 (m, 12H), 7.24 (m, 4H), 5.56 (dd, J= 5.8, 3.1 Hz, 1H), 4.47−4.34 (m, 2H), 3.19 (dd, J= 16.5, 3.1 Hz, 1H), 2.99 (dd, J= 16.5, 5.8 Hz, 1H), 1.57 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.9, 183.9, 168.0, 138.2, 136.8, 134.9, 134.61, 134.56, 133.3, 133.2, 130.4, 130.0, 129.29, 129.26, 129.1, 128.9, 128.8, 128.1, 77.3, 68.1, 39.6, 31.5, 22.4. HRMS (ESI) m/z: [M + H]+calcd for C32H29N2O6S3, 633.1182; found, 633.1192. IR (cm−1): 3062, 2931, 1728, 1681. The ee value was determined by HPLC analysis (Daicel Chiralpak IA, hexane/ isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 32.8 min (major) and 39.7 min (minor). (S)-1-Benzoyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)ethyl)-5ethyl-1,5-dihydro-4H-imidazole-4-one (10c). The title compound was prepared from 1-benzoyl-2-(benzylthio)-5-ethyl-1,5-dihydro-4Himidazole-4-one (34 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White foam. Yield: 62 mg, 96%. [α]D 20 + 19.7 (c= 1, 93% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.11−8.03 (m, 2H), 7.98−7.92 (m, 2H), 7.74−7.63 (m, 2H), 7.62− 7.52 (m, 8H), 7.48−7.35 (m, 2H), 7.23 (m, 4H), 5.56 (dd, J= 6.0, 2.9 Hz, 1H), 4.39 (s, 2H), 3.13 (dd, J= 16.6, 3.0 Hz, 1H), 3.00 (dd, J = 16.6, 6.0 Hz, 1H), 2.27 (dq, J= 14.5, 7.3 Hz, 1H), 1.82 (dq, J= 14.4, 7.3 Hz, 1H), 0.72 (t, J= 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.3, 184.8, 167.9, 138.2, 136.9, 134.8, 134.7, 134.6, 133.3, 133.2, 130.3, 130.1, 129.29, 129.26, 129.1, 128.92, 128.85, 128.1, 77.4, 72.8, 39.7, 31.4, 28.9, 8.2. HRMS (ESI) m/z: [M + H]+ calcd for C33H31N2O6S3, 647.1344; found, 647.1340. IR (cm−1): 3062, 2971, 2934, 1726, 1682. The ee value was determined by HPLC analysis (Daicel Chiralpak IF, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 44.9 min (major) and 97.4 min (minor). (S)-1-Benzoyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)ethyl)-5isobutyl-1,5-dihydro-4H-imidazole-4-one (10d). The title compound was prepared from 1-benzoyl-2-(benzylthio)-5-isobutyl-1,5dihydro-4H-imidazole-4-one (37 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White foam. Yield: 56 mg, 83%. [α]D 20 + 11.5 (c= 1, 97% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.16−8.04 (m, 2H), 8.04−7.93 (m, 2H), 7.75−7.39 (m, 12H), 7.23 (s, 4H), 5.51 (dd, J= 5.9, 2.9 Hz, 1H), 4.39 (s, 2H), 3.14 (dd, J= 16.6, 2.9 Hz, 1H), 2.95 (dd, J= 16.6, 5.9 Hz, 1H), 2.10 (dd, J = 14.2, 4.9 Hz, 1H), 1.53 (dd, J= 14.1, 7.8 Hz, 1H), 1.39 (dq, J= 19.4, 6.5 Hz, 1H), 0.75 (dd, J= 7.3, 6.6 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3): δ186.5, 184.4, 167.9, 138.3, 137.2, 134.8, 134.7, 134.6, 133.3, 133.1, 130.2, 130.1, 129.3, 129.2, 129.1, 128.81, 128.76, 128.7, 128.0, 77.5, 71.5, 43.0, 39.6, 32.8, 24.9, 23.8, 22.8. HRMS (ESI) m/z: [M + H]+calcd For C35H35N2O6S3, 675.1657; found, 675.1650. IR (cm−1): 3062, 2958, 2916, 1728, 1682. The ee value was determined by HPLC analysis (Daicel Chiralpak IF, hexane/ isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 44.2 min (major) and 86.0 min (minor). (S)-5-Allyl-1-benzoyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)- ethyl)-1,5-dihydro-4H-imidazole-4-one (10e). The title compound was prepared from 5-allyl-1-benzoyl-2-(benzylthio)-1,5-dihydro-4Himidazole-4-one (35 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White foam. Yield: 56 mg, 85%. [α]D 20 + 27.3 (c= 1, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.12−7.15 (m, 20H), 5.56 (dd, J= 6.0, 3.0 Hz, 1H), 5.44 (m, 1H), 5.19−5.04 (m, 2H), 4.36 (s, 2H), 3.21 (dd, J= 16.6, 3.1 Hz, 1H), 3.05 (dd, J= 10.8, 5.8 Hz, 1H), 3.02−2.95 (m, 1H), 2.57 (ddt, J= 13.9, 5.4, 1.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ186.1, 184.9, 168.2, 138.3, 137.1, 135.1, 134.9, 133.5, 133.3, 130.6, 130.3, 130.2, 129.5, 129.3, 129.2, 129.0, 129.0, 128.8, 128.3, 121.9, 77.7, 71.8, 39.9, 39.6, 31.3. HRMS (ESI) m/z: [M + H]+calcd for C34H31N2O6S3, 659.1344; found, 659.1346. IR (cm−1): 3061, 2923, 1728, 1683. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 34.6 min (major) and 42.5 min (minor). (S)-1-Benzoyl-2-(benzylthio)-5-(2,2-bis(phenylsulfonyl)ethyl)-5- (2-(methylthio)ethyl)-1,5-dihydro-4H-imidazole-4-one (10f). The title compound was prepared from 1-benzoyl-2-(benzylthio)-5-(2- (methylthio)ethyl)-1,5-dihydro-4H-imidazole-4-one (38 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White foam. Yield: 63 mg, 91%. [α]D 20 + 19.7 (c= 1, 92% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.18−8.06 (m, 2H), 8.05−7.95 (m, 2H), 7.85−7.38 (m, 12H), 7.25 (m, 4H), 5.57 (dd, J= 5.9, 3.0 Hz, 1H), 4.41 (s, 2H), 3.16 (dd, J= 16.6, 3.0 Hz, 1H), 3.00 (dd, J= 16.6, 5.9 Hz, 1H), 2.51 (ddd, J= 14.0, 9.2, 5.4 Hz, 1H), 2.30−2.14 (m, 2H), 2.07 (ddd, J= 8.0, 5.6, 2.4 Hz, 1H), 2.02 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ185.7, 184.7, 168.0, 138.1, 136.9, 135.0, 134.7, 134.6, 133.3, 133.1, 130.3, 130.1, 129.4, 129.3, 129.2, 129.0, 128.90, 128.86, 128.2, 77.3, 71.4, 39.7, 34.3, 31.7, 28.4, 15.6. HRMS (ESI) m/ z: [M + H]+calcd for C34H33N2O6S4, 693.1221; found, 693.1227. IR (cm−1): 3060, 2928, 2849, 1727, 1681. The ee value was determined by HPLC analysis (Daicel Chiralpak IF, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 58.9 min (major) and 114.1 min (minor). Methyl (S)-2-(1-Benzoyl-2-(benzylthio)-5-(2,2bis(phenylsulfonyl)ethyl)-4-oxo-4,5-dihydro-1H-imidazole-5-yl)acetate (10g). The title compound was prepared from methyl 2-(1-benzoyl-2-(benzylthio)-4-oxo-4,5-dihydro-1H-imidazole-5-yl)acetate (38 mg, 0.1 mmol) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). Yellow foam. Yield: 68 mg, 98%. [α]D 20 −17.9 (c= 1, 96% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.12−7.98 (m, 4H), 7.96− 7.88 (m, 1H), 7.77−7.37 (m, 12H), 7.24−7.22 (m, 3H), 5.50 (dd, J= 4.8, 3.3 Hz, 1H), 4.53 (d, J= 13.3 Hz, 1H), 4.34 (d, J= 13.3 Hz, 1H), 3.64 (s, 3H), 3.39 (d, J= 17.9 Hz, 1H), 3.31 (dd, J= 16.6, 3.3 Hz, 1H), 3.11 (d, J= 17.8 Hz, 1H), 2.88 (dd, J= 16.6, 4.8 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ185.4, 184.7, 169.8, 168.2, 137.9, 136.6, 135.1, 135.0, 134.71, 134.65, 133.22, 133.16, 130.6, 130.1, 129.9, 129.4, 129.3, 129.2, 129.1, 128.9, 128.8, 128.1, 77.1, 68.3, 52.3, 39.8, 36.6, 31.6. HRMS (ESI) m/z: [M + H]+calcd for C34H31N2O8S3, 691.1237; found, 691.1240. IR (cm−1): 3063, 2951, 1731, 1680. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 47.5 min (minor) and 67.6 min (major). General Procedure for the Catalytic Addition of Surrogates 3 to 2. In a 5 mL test tube, the corresponding dihydroimidazole-5one (0.1 mmol) was dissolved in 1 mL of CH2Cl2at room temperature. Then, the reaction was cooled down to 0 °C, and the vinyl sulfone (1.2 equiv, 0.12 mmol) and 10 mol % of C2 (8 mg, 0.01 mmol) were added. Once the addition was completed, the mixture was stirred at 0 °C until the reaction was finished as monitored by NMR. The crude was purified directly by silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 979 (S)-1-Benzoyl-5-benzyl-2-(benzylthio)-5-((R)-phenyl(1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-1,5-dihydro-4H-imidazole-4-one (15aa). The title compound was prepared from 1benzoyl-5-benzyl-2-(benzylthio)-1,5-dihydro-4H-imidazole-4-one (40 mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]dithiole 1,1,3,3tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White foam. Yield: 56 mg, 79%. [α]D 20 + 35.1 (c= 1, 99% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.19−7.77 (m, 6H), 7.65−7.29 (m, 8H), 7.25−7.15 (m, 8H), 6.95− 6.89 (m, 2H), 6.32 (d, J= 9.7 Hz, 1H), 5.21 (d, J= 9.8 Hz, 1H), 4.30 (d, J= 13.2 Hz, 1H), 4.08 (d, J= 13.2 Hz, 1H), 3.92 (d, J= 12.9 Hz, 1H), 3.77 (d, J= 12.9 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 186.7, 185.2, 167.3, 137.9, 136.5, 135.2, 135.0, 134.4, 133.8, 133.1, 132.8, 132.62, 132.55, 130.9, 130.0, 129.5, 129.2, 128.7, 128.64, 128.56, 128.4, 128.23, 128.18, 128.0, 127.6, 123.0, 122.2, 77.7, 73.9, 46.6, 41.9, 40.0. HRMS (ESI) m/z: [M + H]+calcd for C38H31N2O6S3, 707.1344; found, 707.1339. IR (cm−1): 3060, 3025, 2968, 1697, 1652. The ee value was determined by HPLC analysis (Daicel Chiralpak IA, hexane/isopropanol 30:70), flow rate: 0.5 mL/ min, retention times: 37.0 min (minor) and 55.5 min (major). (S)-1-Benzoyl-2-(benzylthio)-5-ethyl-5-((R)-phenyl(1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-1,5-dihydro-4H-imidazole-4-one (15ca). The title compound was prepared from 1benzoyl-2-(benzylthio)-5-ethyl-1,5-dihydro-4H-imidazole-4-one (34 mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]dithiole 1,1,3,3tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White solid, mp: 115−120 °C. Yield: 50 mg, 78%. [α]D 20 + 24.1 (c= 1, 96% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.16−8.02 (m, 1H), 8.00−7.69 (m, 4H), 7.51−7.04 (m, 14H), 6.15 (d, J= 9.4 Hz, 1H), 4.95 (d, J= 9.4 Hz, 1H), 4.27 (d, J= 13.4 Hz, 1H), 4.11 (d, J= 13.4 Hz, 1H), 2.95−2.77 (m, 2H), 0.76 (t, J= 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.9, 184.8, 166.9, 138.0, 136.7, 135.2, 135.0, 134.6, 133.12, 133.07, 132.6, 131.3, 129.5, 129.3, 128.92, 128.86, 128.7, 128.5, 128.4, 128.1, 127.9, 123.0, 122.2, 77.8, 73.9, 46.4, 39.7, 30.0, 8.7. HRMS (ESI) m/z: [M + H]+ calcd for C33H29N2O6S3, 645.1182; found, 645.1192. IR (cm−1): 3083, 3022, 2850, 1724, 1681. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 38.1 min (minor) and 55.8 min (major). (S)-1-Benzoyl-2-(benzylthio)-5-isobutyl-5-((R)-phenyl-(1,1,3,3tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-1,5-dihydro-4Himidazole-4-one (15da). The title compound was prepared from 1benzoyl-2-(benzylthio)-5-isobutyl-1,5-dihydro-4H-imidazole-4-one (37 mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White solid, mp 213−217 °C. Yield: 65 mg, 97%. [α]D 20 + 14.3 (c= 1, 92% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.19−8.06 (m, 1H), 7.97−7.73 (m, 3H), 7.52−7.21 (m, 13H), 7.13 (m, 2H), 6.13 (d, J= 9.0 Hz, 1H), 5.00 (d, J= 9.0 Hz, 1H), 4.28 (d, J= 13.3 Hz, 1H), 4.09 (d, J= 13.4 Hz, 1H), 2.85 (dd, J= 13.9, 4.7 Hz, 1H), 2.76 (dd, J= 13.9, 7.2 Hz, 1H), 1.42 (dt, J= 11.5, 6.7 Hz, 1H), 0.95 (d, J= 6.6 Hz, 3H), 0.88 (d, J= 6.6 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ187.2, 184.7, 167.0, 138.2, 136.8, 135.1, 135.0, 134.6, 133.3, 133.0, 132.9, 130.7, 129.6, 129.4, 128.78, 128.75, 128.6, 128.5, 128.3, 128.1, 123.0, 122.3, 76.3, 73.9, 47.7, 44.3, 39.8, 25.8, 24.4, 23.2. HRMS (ESI) m/z: [M + H]+ calcd for C35H33N2O6S3, 673.1501; found, 673.1492. IR (cm−1): 2982, 2868, 1720, 1683. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 29.4 min (minor) and 75.1 min (major). (S)-5-Allyl-1-benzoyl-2-(benzylthio)-5-((R)-phenyl(1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-1,5-dihydro-4H-imidazole-4-one (15ea). The title compound was prepared from 5-allyl1-benzoyl-2-(benzylthio)-1,5-dihydro-4H-imidazole-4-one (35 mg, 0.1 mmol) and 2-benzylidene-2H-benzo[d][1,3]dithiole 1,1,3,3tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ ethyl acetate, from 3:1 to 1:1). White solid, mp 225−228 °C. Yield: 52.5 mg, 80%. [α]D 20 + 54.9 (c= 1, 95% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.21−6.99 (m, 19H), 6.18 (d, J= 9.7 Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H), 5.12−4.95 (m, 2H), 4.26 (d, J= 13.4 Hz, 1H), 4.06 (d, J= 13.4 Hz, 1H), 3.68−3.49 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ186.3, 184.8, 166.9, 142.7, 137.9, 136.5, 135.3, 135.22, 135.17, 135.1, 134.6, 133.8, 132.9, 132.8, 132.7, 132.6, 130.9, 130.0, 129.5, 129.3, 128.7, 128.6, 128.3, 128.0, 122.9, 122.4, 122.2, 122.1, 121.5, 76.3, 73.7, 46.0, 40.4, 39.5. HRMS (ESI) m/z: [M + H]+ calcd for C34H29N2O6S3, 657.1188; found, 657.1179. IR (cm−1): 2978, 1714, 1694. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/ min, retention times: 49.0 min (minor) and 57.9 min (major). (S)-1-Benzoyl-2-(benzylthio)-5-(2-(methylthio)ethyl)-5-((R)- phenyl(1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-1,5dihydro-4H-imidazole-4-one (15fa). The title compound was prepared from 1-benzoyl-2 (benzylthio)-5-(2-(methylthio)ethyl)-1,5dihydro-4H-imidazole-4-one (38 mg, 0.1 mmol) and 2-benzylidene2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White foam. Yield: 64 mg, 93%. [α]D 20 + 30.6 (c= 1, 96% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.16−8.07 (m, 1H), 8.03−7.77 (m, 4H), 7.51−7.10 (m, 14H), 6.14 (d, J= 9.4 Hz, 1H), 4.99 (d, J= 9.5 Hz, 1H), 4.28 (d, J= 13.3 Hz, 1H), 4.12 (d, J= 13.4 Hz, 1H), 3.27− 3.09 (m, 2H), 2.37−2.14 (m, 2H), 2.12 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ186.3, 184.8, 167.0, 138.1, 136.7, 135.2, 135.0, 134.5, 133.3, 133.2, 132.5, 130.6, 129.7, 129.4, 129.0, 128.9, 128.8, 128.4, 128.2, 128.1, 123.1, 122.3, 76.2, 73.9, 46.7, 39.8, 35.5, 28.6, 15.4. HRMS (ESI) m/z: [M + H]+calcd for C34H31N2O6S4, 691.1065; found, 691.1061. IR (cm−1): 3060, 3029, 2915, 1723, 1682. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 40.6 min (minor) and 74.2 min (major). Methyl 2-((S)-1-benzoyl-2-(benzylthio)-4-oxo-5-((R)-phenyl- (1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-4,5-dihydro-1H-imidazole-5-yl)acetate (15ga). The title compound was prepared from methyl 2-(1-benzoyl-2-(benzylthio)-4-oxo-4,5-dihydro1H-imidazole-5-yl)acetate (38 mg, 0.1 mmol) and 2-benzylidene-2Hbenzo[d][1,3]dithiole 1,1,3,3-tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White foam. Yield: 62 mg, 91%. [α]D 20 −6.5 (c= 1, 84% ee, CH2Cl2) (−20 °C). 1H NMR (300 MHz, CDCl3): δ8.16−8.08 (m, 1H), 7.98−7.78 (m, 3H), 7.54−7.26 (m, 9H), 7.25−7.04 (m, 6H), 5.94 (d, J= 10.1 Hz, 1H), 5.11 (d, J= 10.1 Hz, 1H), 4.25−4.16 (m, 2H), 4.07 (d, J= 13.1 Hz, 1H), 3.89 (d, J= 16.6 Hz, 1H), 3.65 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ185.6, 185.2, 169.7, 167.1, 138.1, 136.2, 135.4, 135.1, 134.2, 133.0, 132.91, 132.87, 129.8, 129.5, 129.3, 129.0, 128.8, 128.7, 128.6, 128.4, 128.1, 127.6, 123.0, 122.4, 73.5, 72.4, 52.3, 47.1, 40.1, 38.7. HRMS (ESI) m/z: [M + H]+calcd for C34H29N2O8S3, 689.1086; found, 689.1092. IR (cm−1): 2952, 2936, 1725, 1679. The ee value was determined by HPLC analysis (Daicel Chiralpak IC, hexane/isopropanol 30:70), flow rate: 0.5 mL/min, retention times: 63.9 min (minor) and 80.6 min (major). Methyl 2-(((S)-1-benzoyl-2-(benzylthio)-4-oxo-5-((R)-phenyl- (1,1,3,3-tetraoxido-2H-benzo[d][1,3]dithiol-2-yl)methyl)-4,5-dihydro-1H-imidazole-5-yl)methyl)acrylate (15ha). The title compound was prepared from a sample of 3h containing its dialkylated analogue 3h′(mol ratio of 3h/3h′2:1; 41 mg, 0.1 mmol) and 2-benzylidene2H-benzo[d][1,3]dithiole 1,1,3,3-tetraoxide (37 mg, 0.12 mmol, 1.2 equiv) according to the general procedure. Silica gel flash column chromatography (eluent: hexane/ethyl acetate, from 3:1 to 1:1). White foam. Yield: 47 mg, 98%. [α]D 20 + 20.1 (c= 1, 91% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ8.17−8.08 (m, 1H), 7.95−7.78 (m, 3H), 7.64−7.19 (m, 13H), 7.15−7.06 (m, 2H), 6.35 (d, J= 9.7 Hz, 1H), 6.25 (d, J= 1.4 Hz, 1H), 5.80 (d, J= 1.3 Hz, 1H), 5.14 (d, J= 9.7 Hz, 1H), 4.13 (q, J= 13.1 Hz, 2H), 4.04−3.90 (m, 2H), 3.65 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ185.6, 184.8, 167.0, 166.9, The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 980 Nitroalkenes: Inversion of Configuration at C9 Dramatically Improves Catalyst Performance. Angew. Chem., Int. Ed. 2005,44, 6367−6370. (23) (a) Ye, J.; Dixon, D. J.; Hynes, P. S. Enantioselective Organocatalytic Michael Addition of Malonate Esters to Nitro Olefins Using Bifunctional Cinchonine Derivatives. Chem. Commun. 2005, 4481−4483. (b) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly Enantioselective Conjugate Addition of Nitromethane to Chalcones Using Bifunctional Cinchona Organocatalysts. Org. Lett. 2005,7, 1967−1969. (c) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Asymmetric Michael Addition of Arylthiols to α,βUnsaturated Carbonyl Compounds Catalyzed by Bifunctional Organocatalysts. Synlett 2005, 603−606. (24) (a) Diosdado, S.; Etxabe, J.; Izquierdo, J.; Landa, A.; Mielgo, I.; Olaizola, A.; López, R.; Palomo, C. Catalytic Enantioselective Synthesis of Tertiary Thiols From 5H-Thiazol-4-ones and Nitroolefins: Bifunctional Ureidopeptide-Based Brønsted Base Catalysis. Angew. Chem., Int. Ed. 2013,52, 11846−11851. (b) Diosdado, S.; López, R.; Palomo, C. Ureidopeptide-Based Brønsted Bases: Design, Synthesis and Application to the Catalytic Enantioselective Synthesis of β-Amino Nitriles from (Arylsulfonyl)acetonitriles. Chem.�Eur. J. 2014,20, 6526−6531. (25) See the Supporting Information for details. (26) Brown, A. C.; Carpino, L. A. Magnesium in Methanol: Substitute for Sodium Amalgam in Desulfonylation Reactions. J. Org. Chem. 1985,50, 1749−1750. (27) Yield of 25b, 78%; 25a was not isolated and the crude material was submitted to ulterior desulfonylation to afford 26 in 67% yield over two steps. It should be noted that hydrolysis of adducts 15 under basic conditions (11 equiv of NaOH 6 M, 20 °C, 2 h, 1,4-dioxane) was unpractical because the occurrence of retro-Michael reaction to a variable extent. (28) Single crystal X-ray crystallographic data have been deposited at the Cambridge Crystallographic Data Centre under deposition number CCDC-2183172. (29) (a) Bochevarov, A. D.; Watson, M. A.; Greenwood, J. R.; Philipp, D. M. Multiconformation, Density Functional Theory-Based pKa Prediction in Application to Large, Flexible Organic Molecules with Diverse Functional Groups. J. Chem. Theory Comput. 2016,12, 6001−6019. (b) Yu, H. S.; Watson, M. A.; Bochevarov, A. D. Weighted Averaging Scheme and Local Atomic Descriptor for pKa Prediction Based on Density Functional Theory. J. Chem. Inf. Model. 2018,58, 271−286. (c) Klicic, J. J.; Friesner, R. A.; Liu, S.-Y.; Guida, W. C. Accurate Prediction of Acidity Constants in Aqueous Solution via Density Functional Theory and Self-Consistent Reaction Field Methods. J. Phys. Chem. A 2002,106, 1327−1335. (30) Schrodinger Release 2021-1: Jaguar pKa; Schrodinger, LLC: New York, NY, 2020. The Journal of Organic Chemistry pubs.acs.org/joc Article https://doi.org/10.1021/acs.joc.2c02403 J. Org. Chem. 2023, 88, 972−987 987 Recommended by ACS Enantioselective Sulfonium–Claisen Rearrangement with Cinnamyl Thioethers Jiwon Jang, Seunghoon Shin, et al. 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