Enantioselective Organocatalytic Desymmetrization of Cyclopentene-1

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Enantioselective Organocatalytic Desymmetrization of Cyclopentene-1,3-diones through Formal C(sp2)−H Amidation Hao Liang, Xiaotong Zhou, Liyao Zheng, and Jun Wang* Key Laboratory of Bioinorganic and Synthetic Chemistry of Ministry of Education, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, People’s Republic of China

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S Supporting Information *

ABSTRACT: An enantioselective organocatalytic desymmetrization of 2,2-disubstituted cyclopentene-1,3-diones via a formal C(sp2)−H amidation is reported. The reaction was carried out with N-methoxy amide as the nitrogen source and commercially available cinchonidine as the catalyst under mild reaction conditions, releasing methanol as the only byproduct. It provides an efficient way to synthesize enantioenriched chiral cyclopentenyl amines bearing an all-carbon quaternary stereogenic carbon center. hiral five-membered carbocyclic skeletons are ubiquitous in natural products and biologically active molecules.1 Their stereoselective construction has attracted great attention from the synthetic community.1a−d,f,2 Among various synthetic strategies, catalytic enantioselective desymmetrization3 of an achiral 2,2-disubstituted cyclopentene-1,3-dione substrate has proved highly efficient, which features remote chirality control of a quaternary carbon center. To date, there are mainly three types of reactions developed for such asymmetric desymmetrization, including the cycloaddition reaction of the CC bond (e.g., 1,3-dipolar addition,4 Diels−Alder reaction,5 [3+2] cycloaddition6), nucleophilic addition to the CC bond,7 and (formal) C(sp2)−H bond functionalization8 (Scheme 1A). Despite great success having been achieved in this area, however, the reported desymmetrization approaches are merely limited to C−C bond formations. There is no report on the construction of chiral cyclopentenyl amines. Herein, we describe an organocatalytic enantioselective synthesis of chiral cyclopentenyl amines by a formal C(sp2)−H amidation of 2,2disubstituted cyclopentene-1,3-diones with N-methoxy amides (Scheme 1B), which may complement the corresponding organocatalytic enantioselective formal C(sp2)−H alkylation with nitroalkanes by Mukherjee et al.8e and the palladiumcatalyzed enantioselective C(sp2)−H arylation through the oxidative Heck reaction by Lee et al.8a,d (Scheme 1A). This presented reaction was discovered from our preliminary studies of the reaction of the amide 1a and the enedione 2a in the presence of a rhodium catalyst and base with the purpose of forming a C−H activation product (Scheme 1C). However, only product 3aa was obtained. Further studies indicated that the reaction could smoothly occur in the presence of either inorganic or organic bases such as K2CO3 and Et3N at room temperature. No reaction occurred in the presence of weak

C

© XXXX American Chemical Society

bases (e.g., pyridine) or in the absence of a base at room temperature. Literature surveys indicated two similar reactions were reported. As early as 1970, Smith et al.9 reported that 1,1dimethylhydrazine could react with 2,2-dimethyl cyclopentene1,3-dione smoothly in dry ethanol to give enamine (80% yield) together with the side product, dimethylamine. In 2016, Chou et al.10 revealed that hydroxamic acid could react with naphthoquinones to afford various amidoquinones promoted by 2 equiv of i-Pr2NEt (Scheme 1C). Considering that either no catalyst or a stoichiometric amount of base was required, respectively, in the reactions reported by Smith9 and Chou,10 it is likely a challenging task to realize the asymmetric catalytic reaction of the amide 1a and the enedione 2a. Nevertheless, inspired by the reasons stated above, we were highly interested in developing the first catalytic asymmetric variant of this formal C(sp2)−H bond amidation of 2,2-disubstituted cyclopentene-1,3-dione with remote control of an all-carbon quaternary stereogenic carbon center. To commence our research, the reaction of 1a and 2a was chosen as the model reaction. A series of basic organocatalysts were then examined, and it turned out that the cinchona alkaloids were promising catalysts (for details, see Supporting Information). Notably, among those four cinchona alkaloids, cinchonidine (Cat-2) gave the best result (62% yield, 66% ee, Table 1, entries 1−4). Interestingly, the hydroxy group of cinchonidine proved essential to the reaction reactivity and enantioselectivity. When it was protected by a methanesulfonyl group (Ms), the corresponding catalyst could hardly promote the reaction (entry 5). To our delight, the reaction outcomes remain unchanged when the catalyst loading was reduced from Received: June 28, 2019

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DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

acid was employed as the amidation reagent, only a poor result was obtained (28% yield and 4% ee) (entry 9). Under the optimized reaction conditions (Table 1, entry 6), the substrate scope of N-methoxy amide was examined (Table 2). First, the amide substrates with different para-substituted benzoyl groups were evaluated. While comparable enantioselectivities were observed (3aa−3ia), slightly lower yields were given by the amides with strongly electron-withdrawing groups (e.g., 3ha and 3ia), which was probably due to their lower nucleophilicity. meta-Substituted benzoyl amides were also tested, affording comparable results to the corresponding parasubstituted ones. However, ortho-substituted amides showed decreased reactivity (3la−ma). Large steric hindrance near the nucleophilic nitrogen atom also caused a drastic decrease of enantioselectivity (3la). Some disubstituted benzoyl amides were studied as well, affording the products in good results (3na−pa). The condensed aromatic and heteroaromatic substrates were also suitable substrates for this reaction (3qa−sa). When the α,β-unsaturated amide 1t was employed, the product was obtained in 48% yield and 47% ee (3ta). Finally, alkyl amides were also applicable, providing moderate yields and ee values (3ua−wa). Subsequently, different 2,2-disubstituted cyclopentene-1,3diones were investigated. As shown in Table 3, the benzyl group bearing a methyl or bromo group was well tolerated, giving the products in 45−60% yields and 58−69% ee (3ab− af). The substitution pattern had a little effect on the reaction outcomes. The substrates with an α- or β-naphthyl methyl group were then tried, delivering the products 3ag and 3ah in moderate yields and enantioselectivities. We also attempted the substrate substituted by phenylpropynyl, phenyl, allyl, or methoxycarbonylmethyl, but decreased enantioselectivities were observed (3ai−al). When the norbornenoquinone 2m was employed, the corresponding product 3am was obtained in 58% yield albeit with 12% ee. To examine the practicability of this enantioselective formal C(sp2)−H amidation reaction, it was performed on a gram scale (Scheme 2). Under the standard reaction conditions, the reaction proceeded smoothly, giving the product 3aa in 63% yield and 66% ee. The optical purity of the product could be improved to 90% ee after a single recrystallization from ethyl acetate/petroleum ether (1:5, v/v) in 68% recovery yield. Further recrystallization with the same solvent gave the product with a better optical purity of 96% ee, with which single-crystal growth from diethyl ether was attempted and finally succeeded. The absolute configuration of the chiral quaternary carbon center was determined to be S by singlecrystal X-ray diffraction. As shown in Scheme 3, the potential utilities of this methodology were demonstrated by some transformations starting from product 3aa. In the presence of K2CO3, formal C(sp2)−H bond methylation of product 3aa can be facilely achieved with nitromethane,8e giving the desired product (4) in 82% yield with 91% ee. The C−C double bond of 3aa could be reduced by using zinc powder in AcOH, generating product 5 in a 9:1 dr. The major diastereomer could be isolated by silica gel column chromatography in 63% yield with 89% ee. Interestingly, under Luche reduction conditions, one of the carbonyl groups of 3aa was selectively reduced, producing the α-amino alcohol 6 in a high diastereoselectivity (16:1 dr). After silica gel column chromatography, the major diastereomer was isolated in 71% yield with 90% ee. The relative configurations of 5 and 6 were determined by 2D NMR

Scheme 1. Background for This Research

Table 1. Optimization of the Reaction Conditionsa

entry 1 2 3 4 5 6 7 8 9

catalyst (mol %) Cat-1 Cat-2 Cat-3 Cat-4 Cat-5 Cat-2 Cat-2 Cat-2 Cat-2

(20) (20) (20) (20) (20) (10) (20) (10) (20)

t (h)

T (°C)

yield (%)

ee (%)

24 24 24 24 24 24 24 48 24

rt rt rt rt rt rt 0 rt rt

56 62 60 27 trace 62 44 63 28

44 66 −42 −62 nd 66 55 66 4

a

Reaction conditions: 1a (0.05 mmol), 2a (1.0 equiv), catalyst, PhCl (0.5 mL). Yields were determined by 1H NMR analysis of the crude reaction mixture. bHydroxamic acid was used instead of 1a.

20 mol % to 10 mol % (entry 6). To further improve the yield and enantioselectivity of the reaction, various reaction parameters have been screened, but unfortunately, no improvement has been achieved. For example, when the reaction was carried out at 0 °C, both the yield and the ee value decreased (entry 7). Extending the reaction time to 48 h also failed to give a better yield (entry 8). When hydroxamic B

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 2. Substrate Scope of N-Methoxy Amidesa

a

Reaction conditions: 1 (0.05 mmol), 2a (1.0 equiv), cinchonidine (10 mol %), PhCl (0.5 mL) at room temperature for 24 h. Yields of isolated products are reported. bFor 48 h.

to the small difference in energy between the complexes I and I′. In other words, the pro-chiral quaternary carbon center is remote from the catalytic center, causing difficulties in discriminating the two pro-chiral faces of 2a by the catalyst. Second, elimination of a molecule of methanol assisted by the tertiary amine of cinchonidine gives intermediate III, which spontaneously tautomerizes to afford the observed product 3aa. Simultaneously, the catalyst was recovered to close the catalytic cycle. In conclusion, an organocatalytic enantioselective desymmetrization of 2,2-disubstituted cyclopentene-1,3-diones via a formal C(sp2)−H amidation was developed. It provides an efficient way to synthesize enantioenriched chiral cyclopentenyl amines bearing an all-carbon quaternary stereogenic carbon center using N-methoxy amide as the nitrogen source and commercially available cinchonidine as the catalyst under mild reaction conditions. Though only moderate enantioselectivities have been achieved in this study, this methodology is still synthetic useful as highly enantiopure products could be facilely obtained by recrystallization. This reaction can be performed on a gram scale, and the products can be readily converted to potentially useful chiral five-membered carbocyclic amines. Finally, a plausible reaction mechanism is proposed.

spectra (see Supporting Information). Finally, the removal of the benzoyl group of 3aa was attempted, but it failed when performing the hydrolysis in the refluxing 20% NaOH aqueous solution. Delightedly, the benzoyl amide was successfully hydrolyzed to the cyclopentenyl amine product 7 in 53% yield with 90% ee under the mild conditions of hydrogen peroxide and Na2CO3 at room temperature, which might be attributed to the better nucleophilicity of the hydroperoxide anion. To shed some light on the reaction mechanism, some NMR experiments were carried out in order to detect interactions between substrates and catalyst (see Supporting Information). Interestingly, noticeable variations of chemical shifts were observed when mixing either 1a or 2a with cinchonidine in CDCl3, which were probably attributed to interactions between reactants and the catalyst. According to the previous studies,9,10 and taking into account the above observations together with the aforementioned importance of the hydroxy group of cinchonidine, a plausible reaction mechanism is proposed (Scheme 4). First, 1a and 2a interact with cinchonidine to generate the activated complex I (favored) or I′ (disfavored), which facilely undergo the enantioselective Michael addition to form the chiral intermediate II. Notably, this step is enantioselectivity-determining to the reaction. The modest enantioselectivities observed in this study might be due C

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 3. Substrate Scope of Cyclopentene-1,3-dionesa

a

Reaction conditions: 1a (0.05 mmol), 2 (1.0 equiv), cinchonidine (10 mol %), PhCl (0.5 mL) at room temperature for 24 h. Yields of isolated products are reported.

Scheme 2. Large-Scale Reaction

a

Recrystallization from ethyl acetate/petroleum ether (1:5, v/v). The single crystal was grown from diethyl ether by using the sample with 96% ee.

■

stationary phase in comparison with an authentic racemate. All of the chiral stationary phases including Chiralpak AS-H, Chiralpak OD-H, and Chiralpak IA used in this study were purchased from Daicel Chiral Technologies. HRMS was recorded on an ESI-TOF mass spectrometer. Preparation of Substrate. Amides 1a−w were prepared following literature procedures.11 Cyclopantene-1,3-diones 2a−l were prepared following literature procedures.8e,12 Norbornenoquinone 2m was prepared according to literature procedures.13 2-Methyl-2-(3-phenylprop-2-yn-1-yl)cyclopent-4-ene-1,3dione (2i). Yellow solid, 40.6 mg, 44% yield. 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 2H), 7.30−7.20 (m, 5H), 2.76 (s, 2H), 1.22 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 206.1, 148.8, 131.7, 128.3,

EXPERIMENTAL SECTION

General Information. Unless specified otherwise, all reactions were carried out under an air atmosphere using dried glassware. Solvents were dried and distilled according to the standard procedures before use. Analytical thin-layer chromatography (TLC) was performed on precoated silica gel 60 F254 plates. Compounds were visualized by exposure to UV light or by exposure to iodine vapor or by dipping into the solution of KMnO4 or Co(SCN)2. Flash column chromatography was performed using silica gel (300−400 meshes). NMR spectra were recorded on a 400 MHz spectrometer at an ambient temperature. The chemical shifts were given in dimensionless δ values and were frequency referenced relative to TMS in 1H and 13C NMR spectroscopy. Enantiomeric excesses (ee’s) were determined by high-performance liquid chromatography (HPLC) with a chiral D

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Elaboration of Product 3aa

Scheme 4. Plausible Reaction Mechanism

J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.5, 165.0, 149.5, 135.5, 133.4, 132.0, 129.6, 129.1, 128.4, 127.5, 127.2, 124.4, 51.3, 40.7, 19.9. HRMS (ESI): [M + H]+ calcd for C20H18NO3+, 320.1281; found, 320.1285. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-methylbenzamide (3ba). Pale yellow solid, 9.0 mg, 54% yield, 70% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 13.9 min, tR (major) = 16.4 min. 1 H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.77−7.70 (m, 2H), 7.33−7.29 (m, 2H), 7.27 (s, 1H), 7.18−7.10 (m, 3H), 6.97−6.94 (m, 2H), 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 2.43 (s, 3H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.6, 164.9, 149.5, 144.4, 135.5, 129.8, 129.6, 129.2, 128.4, 127.6, 127.1, 124.2, 51.3, 40.7, 21.7, 19.9. HRMS (ESI): [M + H]+ calcd for C21H20NO3+, 334.1438; found, 334.1435. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-methoxybenzamide (3ca). Pale yellow solid, 11.3 mg, 65% yield, 68% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 19.8 min, tR (major) = 22.2 min. 1 H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.86−7.76 (m, 2H), 7.25 (s, 1H), 7.18−7.10 (m, 3H), 7.00−6.96 (m, 4H), 3.88 (s, 3H), 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13 C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.7, 164.4, 163.7,

122.8, 84.0, 83.9, 49.9, 24.7, 18.3. HRMS (ESI): [M + H]+ calcd for C15H13NO2+, 225.0910; found, 225.0905. Preparation of Racemic Products. To a 5 mL test tube charged with 1a (10.0 mg, 0.05 mmol, 1.0 equiv) and 2a (7.5 mg, 0.05 mmol, 1.0 equiv) were added K2CO3 (0.025 mmol, 0.5 equiv) and MeCN (0.5 mL). After stirring at room temperature for 18 h, the reaction mixture was purified by preparative TLC plates using EtOAc/ petroleum ether as a developing solvent. Procedures for Catalytic Reactions. To a 5 mL test tube charged with 1 (7.6 mg, 0.05 mmol, 1.0 equiv) and 2 (10.0 mg, 0.05 mmol, 1.0 equiv) were added cinchonidine (1.5 mg, 0.005 mmol, 10 mol %) and PhCl (0.5 mL). After stirring for 24 or 48 h at room temperature, the crude mixture was directly subjected to silica gel column chromatography with EtOAc/petroleum ether as an eluent. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzamide (3aa). Pale yellow solid, 9.9 mg, 62% yield, 66% ee. The optical purity of the product could be improved to 90% ee after a single recrystallization from ethyl acetate/petroleum ether (1:5) in 68% recovery yield. [α]25 D +30.1 (90% ee, c = 0.200 in CHCl3). Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 14.4 min, tR (major) = 16.6 min. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 7.83−7.80 (m, 2H), 7.62−7.58 (m, 1H), 7.51−7.47 (m, 2H), 7.27 (s, 1H), 7.16− 7.09 (m, 3H), 6.96−6.94 (m, 2H), 3.10 (d, J = 13.4 Hz, 1H), 3.00 (d, E

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

mL/min, λ = 254 nm), tR (minor) = 16.5 min, tR (major) = 19.6 min. 1 H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.98−7.92 (m, 2H), 7.87−7.71 (m, 2H), 7.29 (s, 1H), 7.19−7.10 (m, 3H), 6.99−6.91 (m, 2H), 3.11 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 13.3 Hz, 1H), 1.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.1, 203.3, 163.4, 149.0, 135.7, 135.4, 132.9, 129.6, 128.4, 128.2, 127.2, 125.2, 117.4, 117.0, 51.4, 40.7, 19.9. HRMS (ESI): [M + H]+ calcd for C21H17N2O3+, 345.1234; found, 345.1239. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-3-fluorobenzamide (3ja). Pale yellow solid, 8.5 mg, 50% yield, 61% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 8.9 min, tR (major) = 10.4 min. 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.62−7.58 (m, 1H), 7.58−7.54 (m, 1H), 7.51 (ddd, J = 8.0, 7.8, 5.4 Hz, 1H), 7.32 (tdd, J = 8.2, 2.6, 1.0 Hz, 1H), 7.27 (s, 1H), 7.20−7.10 (m, 3H), 6.99−6.91 (m, 2H), 3.10 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 13.3 Hz, 1H), 1.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.3, 163.8 (d, J = 2.4 Hz), 162.9 (d, J = 249.0 Hz), 149.2, 135.4, 134.1 (d, J = 7.0 Hz), 130.9 (d, J = 7.9 Hz), 129.6, 128.4, 127.2, 124.8, 122.9 (d, J = 3.1 Hz), 120.6 (d, J = 21.2 Hz), 115.0 (d, J = 23.1 Hz), 51.4, 40.70, 19.8. 19F NMR (376 MHz, CDCl3): δ −110.1. HRMS (ESI): [M + H]+ calcd for C20H17FNO3+, 338.1187; found, 338.1185. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-3-chlorobenzamide (3ka). White solid, 10.3 mg, 58% yield, 66% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 8.6 min, tR (major) = 10.4 min. 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.82 (t, J = 1.9 Hz, 1H), 7.70 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.59 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.19−7.11 (m, 3H), 6.97 (m, 1.5 Hz, 2H), 3.11 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 13.3 Hz, 1H), 1.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.4, 163.8, 149.2, 135.5, 135.4, 133.7, 133.5, 130.4, 129.6, 128.4, 127.9, 127.2, 125.4, 124.8, 51.4, 40.7, 19.8. HRMS (ESI): [M + H]+ calcd for C20H1735ClNO3+, 354.0891; found, 354.0893. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-2-methylbenzamide (3la). Pale yellow solid, 7.6 mg, 46% yield, 28% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 8.5 min, tR (major) = 9.6 min. 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.50−7.38 (m, 2H), 7.31− 7.26 (m, 2H), 7.24 (s, 1H) 7.18−7.13 (m, 3H), 7.01−6.93 (m, 2H), 3.09 (d, J = 13.2 Hz, 1H), 2.98 (d, J = 13.2 Hz, 1H), 2.42 (s, 3H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.6, 167.4, 149.6, 137.8, 135.6, 133.2, 132.0, 131.9, 129.7, 128.5, 127.2, 127.2, 126.3, 124.3, 51.4, 41.0, 20.2, 19.7. HRMS (ESI): [M + H]+ calcd for C21H20NO3+, 334.1438; found, 334.1433. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-2-fluorobenzamide (3ma). Pale yellow solid, 6.1 mg, 36% yield, 66% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 85:15, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 7.2 min, tR (major) = 8.4 min. 1H NMR (400 MHz, CDCl3): δ 9.03 (d, J = 15.2 Hz, 1H), 8.06 (td, J = 7.8, 1.9 Hz, 1H), 7.60 (dddd, J = 8.3, 7.3, 5.3, 1.9 Hz, 1H), 7.32 (ddd, J = 7.9, 7.4, 1.0 Hz, 1H), 7.27 (s, 1H), 7.22 (ddd, J = 12.2, 8.4, 1.0 Hz, 1H), 7.18−7.09 (m, 3H), 6.99−6.95 (m, 2H), 3.09 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.7, 203.1, 161.8 (d, J = 3.0 Hz), 160.9 (d, J = 249.2 Hz), 149.7, 135.6, 135.6 (d, J = 7.4 Hz), 132.4, 129.7, 128.5, 127.2, 125.5 (d, J = 2.0 Hz), 125.1 (d, J = 1.0 Hz), 119.1 (d, J = 10.9 Hz), 116.7 (d, J = 24.8 Hz), 51.5, 40.8, 19.9. 19F NMR (376 MHz, CDCl3): δ −111.0. HRMS (ESI): [M + H]+ calcd for C20H17FNO3+, 338.1187; found, 338.1197. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-3,5-dimethoxybenzamide (3na). Pale yellow solid, 11.5 mg, 61% yield, 63% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 93:7, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 13.6 min, tR (major) = 15.3 min.

149.6, 135.5, 129.7, 128.4, 127.1, 124.2, 124.0, 114.3, 55.6, 51.3, 40.7, 19.9. HRMS (ESI): [M + H]+ calcd for C21H20NO4+, 350.1387; found, 350.1388. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-(tertbutyl)benzamide (3da). White solid, 7.3 mg, 39% yield, 50% ee. Eluent: EtOAc/petroleum ether = 5:95. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 7.1 min, tR (major) = 8.1 min. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.79−7.75 (m, 2H), 7.55− 7.46 (m, 2H), 7.27 (s, 1H), 7.19−7.09 (m, 3H), 7.00−6.93 (m, 2H), 3.10 (d, J = 13.1 Hz, 1H), 3.00 (d, J = 13.7 Hz, 1H), 1.35 (s, 9H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.7, 165.0, 157.5, 149.6, 135.6, 129.7, 129.2, 128.5, 127.5, 127.2, 126.2, 124.3, 51.4, 40.8, 35.3, 31.1, 19.9. HRMS (ESI): [M + H]+ calcd for C24H26NO3+, 376.1907; found, 376.1901. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-fluorobenzamide (3ea). Pale yellow solid, 9.2 mg, 55% yield, 65% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 14.6 min, tR (major) = 15.9 min. 1 H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.86 (ddd, J = 10.1, 5.1, 2.6 Hz, 2H), 7.27 (s, 1H), 7.23−7.10 (m, 5H), 7.00−6.94 (m, 2H), 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13 C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.5, 165.8 (d, J = 265.2 Hz), 163.9, 149.4, 135.4, 130.1 (d, J = 9.6 Hz), 129.6, 128.4, 128.2 (d, J = 3.2 Hz), 127.2, 124.5, 116.4 (d, J = 22.2 Hz), 51.3, 40.7, 19.9. 19F NMR (376 MHz, CDCl3): δ −103.9. HRMS (ESI): [M + H]+ calcd for C20H17FNO3+, 338.1187; found, 338.1193. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-fluorobenzamide (3fa). White solid, 9.1 mg, 51% yield, 63% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 14.3 min, tR (major) = 15.9 min. 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.82−7.76 (m, 2H), 7.52−7.46 (m, 2H), 7.27 (s, 1H), 7.19−7.11 (m, 3H), 6.99− 6.93 (m, 2H), 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.4, 164.0, 149.3, 140.0, 135.4, 130.3, 129.6, 129.5, 128.9, 128.4, 127.2, 124.7, 51.3, 40.7, 19.9. HRMS (ESI): [M + H]+ calcd for C20H1735ClNO3+, 354.0891; found, 354.0885. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-bromobenzamide (3ga). Pale yellow solid, 9.6 mg, 48% yield, 63% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 21.1 min, tR (major) = 23.9 min. 1 H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.73−7.63 (m, 4H), 7.27 (s, 1H), 7.19−7.11 (m, 3H), 6.98−6.94 (m, 2H), 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.4, 164.1, 149.3, 135.4, 132.5, 130.8, 129.6, 129.0, 128.6, 128.4, 127.2, 124.7, 51.3, 40.7, 19.9. HRMS (ESI): [M + H]+ calcd for C20H1779BrNO3+, 398.0386; found, 398.0384. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4(trifluoromethyl)benzamide (3ha). Pale yellow oil, 7.5 mg, 39% yield, 62% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 8.9 min, tR (major) = 10.7 min. 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.95 (d, J = 8.2, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.29 (s, 1H), 7.19− 7.12 (m, 3H), 6.99−6.95 (m, 2H), 3.11 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 13.3 Hz, 1H), 1.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.4, 164.0, 149.3, 135.4, 135.3, 135.0 (q, J = 33.1), 129.7, 128.5, 128.1, 127.5, 126.2 (q, J = 3.5 Hz), 125.1, 123.4 (q, J = 273.0 Hz), 51.5, 40.8, 19.9. 19F NMR (376 MHz, CDCl3): δ −63.1. HRMS (ESI): [M + H]+ calcd for C21H17F3NO3+, 388.1155; found, 388.1156. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-4-cyanobenzamide (3ia). Pale yellow solid, 5.7 mg, 33% yield, 67% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 85:15, flow rate: 1.0 F

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.26 (s, 1H), 7.19−7.09 (m, 3H), 6.99−6.94 (m, 2H), 6.92 (d, J = 2.3 Hz, 2H), 6.67 (t, J = 2.2 Hz, 1H), 3.84 (s, 6H), 3.09 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.4, 165.0, 161.2, 149.4, 135.5, 134.0, 129.7, 128.4, 127.2, 124.5, 105.4, 105.2, 55.7, 51.3, 40.7, 19.8. HRMS (ESI): [M + H]+ calcd for C22H22NO5+, 380.1492; found, 380.1502. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-2,4-dimethylbenzamide (3oa). Pale yellow solid, 6.9 mg, 40% yield, 37% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 93:7, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 10.6 min, tR (major) = 11.9 min. 1 H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 7.20−7.12 (m, 3H), 7.09 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.00−6.92 (m, 2H), 3.08 (d, J = 13.2 Hz, 1H), 2.98 (d, J = 13.2 Hz, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 1.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.5, 167.2, 149.6, 142.5, 138.0, 135.5, 132.8, 130.0, 129.7, 128.3, 127.3, 127.1, 126.8, 124.0, 51.3, 40.9, 21.4, 20.2, 19.6. HRMS (ESI): [M + H]+ calcd for C22H22NO3+, 348.1594; found, 380.1595. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzo[d][1,3]dioxole-5-carboxamide (3pa). Pale yellow solid, 10.9 mg, 60% yield, 71% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 93:7, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 20.2 min, tR (major) = 27.1 min. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.38 (dd, J = 8.2, 1.8 Hz, 1H), 7.31 (m, 1H), 7.24 (s, 1H), 7.19−7.09 (m, 3H), 6.99−6.93 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.08 (s, 2H), 3.09 (d, J = 13.3 Hz, 1H), 2.99 (d, J = 13.3 Hz, 1H), 1.32 (s, 3H). 13 C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.7, 164.2, 152.2, 149.6, 148.7, 135.6, 129.7, 128.5, 127.2, 126.2, 124.2, 123.0, 108.5, 108.0, 102.3, 51.4, 40.8, 20.0. HRMS (ESI): [M + H]+ calcd for C21H18NO5+, 364.1179; found, 364.1189. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-2-naphthamide (3qa). Pale yellow solid, 9.1 mg, 49% yield, 67% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 11.7 min, tR (major) = 13.2 min. 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 8.36 (d, J = 1.4 Hz, 1H), 8.00−7.94 (m, 2H), 7.94−7.89 (m, 1H), 7.87 (dd, J = 8.6, 1.9 Hz, 1H), 7.68−7.58 (m, 2H), 7.34 (s, 1H), 7.20−7.10 (m, 3H), 7.01−6.97 (m, 2H), 3.12 (d, J = 13.3 Hz, 1H), 3.03 (d, J = 13.3 Hz, 1H), 1.36 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.7, 165.2, 149.6, 135.6, 132.5, 129.8, 129.4, 129.3, 129.2, 129.0, 128.8, 128.7, 128.5, 128.0, 127.5, 127.3, 124.5, 123.3, 51.4, 40.8, 20.0. HRMS (ESI): [M + H]+ calcd for C24H20NO3+, 370.1438; found, 370.1439. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)furan-2-carboxamide (3ra). Pale yellow solid, 10.1 mg, 65% yield, 60% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (OD-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 11.2 min, tR (major) = 13.2 min. 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 7.58 (dd, J = 1.8, 0.8 Hz, 1H), 7.29 (dd, J = 3.6, 0.8 Hz, 1H), 7.23 (s, 1H), 7.18−7.09 (m, 3H), 6.99−6.94 (m, 2H), 6.59 (dd, J = 3.6, 1.8 Hz, 1H), 3.09 (d, J = 13.2 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 1.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.1, 155.6, 149.1, 146.1, 145.9, 135.5, 129.7, 128.5, 127.2, 124.4, 118.0, 113.3, 51.4, 40.8, 19.9. HRMS (ESI): [M + H]+ calcd for C18H16NO4+, 310.1074; found, 310.1066. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)thiophene2-carboxamide (3sa). Pale yellow solid, 9.7 mg, 60% yield, 61% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 16.6 min, tR (major) = 20.2 min. 1 H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.71−7.61 (m, 2H), 7.22 (s, 1H), 7.19−7.05 (m, 4H), 6.99−6.90 (m, 2H), δ 3.10 (d, J = 13.3 Hz, 1H), 3.00 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.3, 203.4, 159.4, 149.3, 136.6, 135.5, 133.6, 1

130.5, 129.7, 128.5, 128.4, 127.3, 124.5, 51.4, 40.8, 20.0. HRMS (ESI): [M + H]+ calcd for C18H16NO3S+, 326.0845; found, 326.0842. N-(4-Benzyl-4-methyl-3,5-diox ocyclopent-1-en-1 -yl)cinnamamide (3ta). White solid, 8.3 mg, 48% yield, 47% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 17.1 min, tR (major) = 26.4 min. 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.53 (m, 2H), 7.48−7.36 (m, 3H), 7.24 (s, 1H), 7.21−7.07 (m, 3H), 7.00−6.85 (m, 2H), 6.52 (d, J = 15.6 Hz, 1H), 3.09 (d, J = 13.3 Hz, 1H), 2.98 (d, J = 13.3 Hz, 1H), 1.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 203.3, 202.5, 162.8, 148.5, 144.9, 134.5, 132.7, 130.0, 128.6, 128.1, 127.4, 126.1, 123.5, 117.1, 50.3, 39.8, 18.8. HRMS (ESI): [M + H]+ calcd for C22H20NO3+, 346.1438; found, 346.1440. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)-3-phenylpropanamide (3ua). Pale yellow oil, 4.6 mg, 27% yield, 35% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 16.3 min, tR (major) = 19.9 min. 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.30−7.25 (m, 2H), 7.21−7.19 (m, 1H), 7.15−7.11 (m, 6H), 6.94−6.87 (m, 2H), 3.03 (d, J = 13.7 Hz, 1H), 3.97−2.90 (m, 3H), 2.72−2.65 (m, 2H), 1.25 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.4, 170.9, 149.1, 139.7, 135.6, 129.7, 128.8, 128.4, 128.3, 127.2, 126.8, 124.5, 51.3, 40.7, 38.8, 30.7, 19.9. HRMS (ESI): [M + H]+ calcd for C22H22NO3+, 348.1594; found, 348.1602. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)butyramide (3va). Pale yellow oil, 4.7 mg, 33% yield, 49% ee. Eluent: EtOAc/ petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 10.5 min, tR (major) = 12.5 min. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.18−7.10 (m, 4H), 6.96−6.91 (m, 2H), 3.06 (d, J = 13.2 Hz, 1H), 2.95 (d, J = 13.3 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 1.67 (h, J = 7.4 Hz, 2H), 1.29 (s, 3H), 0.94 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.6, 171.7, 149.2, 135.6, 129.7, 128.4, 127.2, 124.4, 51.3, 40.8, 39.0, 19.8, 18.3, 13.6. HRMS (ESI): [M + H]+ calcd for C17H20NO3+, 286.1438; found, 286.1446. N-(4-Benzyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)acetamide (3wa). Pale yellow oil, 3.3 mg, 26% yield, 45% ee. Eluent: EtOAc/ petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 87:13, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 12.2 min, tR (major) = 16.2 min. 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.18−7.13 (m, 3H), 7.12 (s, 1H), 6.96−6.91 (m, 2H), 3.06 (d, J = 13.2 Hz, 1H), 2.95 (d, J = 13.3 Hz, 1H), 2.18 (s, 3H), 1.29 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.4, 203.4, 168.5, 149.1, 135.5, 129.6, 128.4, 127.1, 124.4, 51.2, 40.7, 24.1, 19.8. HRMS (ESI): [M + H]+ calcd for C15H16NO3+, 258.1125; found, 258.1121. N-(4-Methyl-4-(4-methylbenzyl)-3,5-dioxocyclopent-1-en-1-yl)benzamide (3ab). Pale yellow solid, 10.0 mg, 60% yield, 67% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 17.2 min, tR (major) = 19.1 min. 1 H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.90−7.81 (m, 2H), 7.67−7.59 (m, 1H), 7.56−7.49 (m, 2H), 7.29 (s, 1H), 6.95 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 3.06 (d, J = 13.4 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H), 2.22 (s, 3H), 1.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.6, 165.1, 149.5, 136.7, 133.4, 132.3, 132.0, 129.5, 129.1, 129.1, 127.5, 124.5, 51.3, 40.3, 21.0, 19.9. HRMS (ESI): [M + H]+ calcd for C21H20NO3+, 334.1438; found, 334.1442. N-(4-Methyl-4-(2-methylbenzyl)-3,5-dioxocyclopent-1-en-1-yl)benzamide (3ac). Pale yellow solid, 9.2 mg, 55% yield, 69% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 12.3 min, tR (major) = 13.7 min. 1 H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.88−7.80 (m, 2H), 7.66−7.59 (m, 1H), 7.56−7.49 (m, 2H), 7.35 (s, 1H), 7.08−6.95 (m, 3H), 6.92−6.87 (m, 1H), 3.14 (d, J = 13.8 Hz, 1H), 3.08 (d, J = 13.8 G

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Hz, 1H), 2.28 (s, 3H), 1.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.6, 203.7, 165.1, 149.6, 136.6, 134.1, 133.4, 132.1, 130.9, 130.1, 129.1, 127.5, 127.2, 125.8, 124.5, 51.1, 37.0, 20.0, 19.7. HRMS (ESI): [M + H]+ calcd for C21H20NO3+, 334.1438; found, 334.1437. N-(4-(4-Bromobenzyl)-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzamide (3ad). Pale yellow solid, 9.8 mg, 49% yield, 65% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 16.7 min, tR (major) = 19.7 min. 1 H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.90−7.83 (m, 2H), 7.66−7.60 (m, 1H), 7.57−7.49 (m, 2H), 7.33 (s, 1H), 7.31−7.27 (m, 2H), 6.88−6.84 (m, 2H), 3.05 (d, J = 13.4 Hz, 1H), 2.95 (d, J = 13.4 Hz, 1H), 1.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.2, 203.3, 165.1, 149.6, 134.5, 133.6, 132.0, 131.6, 131.5, 129.2, 127.6, 124.4, 121.3, 51.1, 39.7, 20.3. HRMS (ESI): [M + H]+ calcd for C20H1779BrNO3+, 398.0386; found, 398.0383. N-(4-(3-Bromobenzyl)-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzamide (3ae). Pale yellow solid, 11.9 mg, 60% yield, 61% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 16.7 min, tR (major) = 18.9 min. 1 H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 7.90−7.83 (m, 2H), 7.66−7.60 (m, 1H), 7.55−7.50 (m, 2H), 7.32 (s, 1H), 7.29−7.26 (m, 1H), 7.14 (t, J = 1.8 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.93−6.91 (m, 1H), 3.05 (d, J = 13.3 Hz, 1H), 2.95 (d, J = 13.3 Hz, 1H), 1.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 202.9, 202.1, 164.1, 148.5, 136.8, 132.5, 131.6, 131.0, 129.4, 129.0, 128.1, 127.4, 126.5, 123.3, 121.3, 50.1, 38.9, 19.0. HRMS (ESI): [M + H]+ calcd for C20H1779BrNO3+, 398.0386; found, 398.0385. N-(4-(2-Bromobenzyl)-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzamide (3af). Pale yellow solid, 8.9 mg, 45% yield, 58% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 20.7 min, tR (major) = 22.6 min. 1 H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 7.87 (m, 2H), 7.66− 7.60 (m, 1H), 7.57−7.46 (m, 3H), 7.42 (s, 1H), 7.19 (td, J = 7.5, 1.3 Hz, 1H), 7.13 (dd, J = 7.7, 1.9 Hz, 1H), 7.05 (ddd, J = 8.0, 7.2, 1.9 Hz, 1H), δ 3.27 (d, J = 13.9 Hz, 1H), 3.22 (d, J = 13.9 Hz, 1H), 1.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.0, 202.3, 165.3, 149.4, 135.3, 133.6, 133.3, 132.1, 131.9, 129.2, 129.0, 127.7, 127.4, 125.5, 123.7, 50.1, 40.0, 18.9. HRMS (ESI): [M + H]+ calcd for C20H1779BrNO3+, 398.0386; found, 398.0381. N-(4-Methyl-4-(naphthalen-1-ylmethyl)-3,5-dioxocyclopent-1en-1-yl)benzamide (3ag). Pale yellow solid, 6.8 mg, 37% yield, 64% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 19.8 min, tR (major) = 23.1 min. 1 H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.77−7.69 (m, 3H), 7.65 (d, J = 8.2 Hz, 1H), 7.62−7.55 (m, 1H), 7.54−7.44 (m, 3H), 7.41 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.31− 7.26 (m, 1H), 7.20−7.17 (m, 2H), 3.58 (s, 2H), 1.44 (s, 3H). 13 C{1H} NMR (101 MHz, CDCl3): δ 203.4, 202.5, 164.0, 148.4, 132.9, 132.3, 131.0, 130.7, 128.0, 127.6, 127.6, 127.0, 126.4, 124.9, 124.6, 124.1, 123.6, 123.3, 50.3, 35.8, 18.8. HRMS (ESI): [M + H]+ calcd for C24H20NO3+, 370.1438; found, 370.1441 N-(4-Methyl-4-(naphthalen-2-ylmethyl)-3,5-dioxocyclopent-1en-1-yl)benzamide (3ah). Pale yellow solid, 9.9 mg, 54% yield, 63% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (OD-H, n-hexane/i-PrOH = 93:7, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 19.6 min, tR (major) = 24.2 min. 1 H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 7.80−7.68 (m, 4H), 7.64 (d, J = 8.5 Hz, 1H), 7.61−7.56 (m, 1H), 7.52−7.44 (m, 3H), 7.44−7.35 (m, 2H), 7.27 (s, 1H), 7.09 (dd, J = 8.4, 1.8 Hz, 1H), 3.28 (d, J = 13.4 Hz, 1H), 3.17 (d, J = 13.3 Hz, 1H), 1.39 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.5, 165.1, 149.5, 133.5, 133.3, 133.2, 132.5, 132.1, 129.1, 128.7, 128.1, 127.8, 127.7, 127.6, 126.1, 125.8, 124.5, 51.5, 40.7, 20.3. HRMS (ESI): [M + H]+ calcd for C24H20NO3+, 370.1438; found, 370.1439.

N-(4-Methyl-3,5-dioxo-4-(3-phenylprop-2-yn-1-yl)cyclopent-1en-1-yl)benzamide (3ai). Pale yellow solid, 10.3 mg, 60% yield, 30% ee. Eluent: EtOAc/petroleum ether = 1:10. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 19.7 min, tR (major) = 22.6 min. 1 H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 7.94−7.88 (m, 2H), 7.67−7.61 (m, 2H), 7.58−7.51 (m, 2H), 7.26−7.17 (m, 5H), 2.85 (d, J = 16.6 Hz, 1H), 2.79 (d, J = 16.7 Hz, 1H), 1.31 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 203.3, 202.5, 165.3, 149.6, 133.5, 132.0, 131.5, 129.2, 128.2, 128.1, 127.6, 124.3, 122.7, 84.2, 83.7, 48.8, 24.9, 18.4. HRMS (ESI): [M + H]+ calcd for C22H18NO3+, 344.1280; found, 344.1281. N-(4-Methyl-3,5-dioxo-4-phenylcyclopent-1-en-1-yl)benzamide (3aj). Pale yellow oil, 6.0 mg, 39% yield, 28% ee. Eluent: EtOAc/ petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 97:3, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 26.7 min, tR (major) = 31.0 min. 1H NMR (400 MHz, CDCl3): δ 7.95−7.89 (m, 2H), 7.68−7.62 (m, 2H), 7.58−7.52 (m, 2H), 7.37−7.27 (m, 5H), 1.66 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 202.7, 201.6, 165.4, 149.2, 136.9, 133.7, 132.1, 129.3, 129.0, 128.0, 127.6, 126.6, 124.3, 53.2, 19.9. HRMS (ESI): [M + H]+ calcd for C19H16NO3+, 306.1125; found, 306.1124. N-(4-Allyl-4-methyl-3,5-dioxocyclopent-1-en-1-yl)benzamide (3ak). Pale yellow oil, 5.4 mg, 40% yield, 29% ee. Eluent: EtOAc/ petroleum ether = 1:10. The enantioselectivity was determined by HPLC (IA, n-hexane/i-PrOH = 99:1, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 34.4 min, tR (major) = 39.1 min. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 7.94−7.90 (m, 2H), 7.68−7.63 (m, 1H), 7.59−7.52 (m, 2H), 7.50 (s, 1H), 5.55 (dddd, J = 17.1, 10.1, 7.9, 7.1 Hz, 1H), 5.10−4.99 (m, 2H), 2.49 (dd, J = 13.6, 7.0 Hz, 1H), 2.42 (dd, J = 13.6, 8.0 Hz, 1H), 1.24 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 204.5, 203.6, 165.4, 149.2, 133.6, 132.2, 131.5, 129.3, 127.6, 124.0, 119.8, 49.5, 39.0, 19.0. HRMS (ESI): [M + H]+ calcd for C16H16NO3+, 270.1125; found, 270.1126. Methyl 2-(3-Benzamido-1-methyl-2,5-dioxocyclopent-3-en-1-yl)acetate (3al). Pale yellow oil, 3.5 mg, 23% yield, 32% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 90:10, flow rate: 1.0 mL/min, λ = 254 nm), tR (minor) = 19.2 min, tR (major) = 23.3 min. 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.95−7.90 (m, 2H), 7.67−7.61 (m, 1H), 7.59−7.52 (m, 3H), 3.58 (s, 3H), 3.00 (d, J = 17.7 Hz, 1H), 2.87 (d, J = 17.7 Hz, 1H), 1.25 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 203.4, 202.3, 170.9, 165.4, 149.1, 133.5, 132.3, 129.2, 127.6, 123.0, 52.2, 46.6, 37.7, 20.9. HRMS (ESI): [M + H]+ calcd for C16H16NO5+, 302.1023; found, 302.1029. N-(5,8-Dioxo-1,4,5,8-tetrahydro-1,4-methanonaphthalen-6-yl)benzamide (3am). Orange solid, 8.4 mg, 58% yield, 12% ee. Eluent: EtOAc/petroleum ether = 1:5. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 95:5, flow rate: 1.0 mL/min, λ = 254 nm), tR (major) = 18.3 min, tR (minor) = 19.6 min. 1H NMR (400 MHz, CDCl3): δ 8.89 (s, 1H), 7.90−7.87 (m, 2H), 7.63−7.58 (m, 1H), 7.56 (s, 1H), 7.54−7.50 (m, 2H), 6.92−6.82 (m, 2H), 4.15 (ddd, J = 3.0, 1.4 Hz, 2H), 2.36 (dt, J = 7.1, 1.4 Hz, 1H), 2.32 (dt, J = 7.1, 1.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 185.1, 179.3, 165.7, 164.0, 156.8, 142.6, 142.5, 138.3, 133.5, 132.9, 129.1, 127.3, 113.4, 73.9, 48.9, 48.4. HRMS (ESI): [M + H]+ calcd for C18H14NO3+, 292.0968; found, 292.0971. Procedures for the Large-Scale Reaction. To a 100 mL roundbottom flask charged with 1a (0.76 g, 5.0 mmol, 1.0 equiv) and 2a (1.0 g, 5.0 mmol, 1.0 equiv) were added cinchonidine (147 mg, 0.5 mmol, 10 mol %) and PhCl (50 mL). After stirring for 60 h at room temperature, the reaction mixture was directly subjected to silica gel column chromatography with EtOAc/petroleum ether (1:10, v/v) as the eluent to give 3aa (1.0 g, 63% yield, 66% ee). The product was then recrystallized with EtOAc/petroleum ether (1:5, v/v). The precipitate was filtered out and washed with PE to give the product 3aa with a low enantiopurity (0.32 g, 32% recovery yield, 42% ee). The mother liquid was concentrated to give the product 3aa with a high enantiopurity (0.68 g, 68% recovery yield, 90% ee). [α]25 D +30.1 (c 0.200 in CHCl3, 90% ee). H

DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

stirred at room temperature for 10 min, H2O2 (40 μL, 30% in water, 3.0 equiv) was added. The reaction mixture was further stirred at room temperature for 20 h. Then it was diluted with DCM (5 mL) and distilled water (5 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (3 × 5 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:3, v/v) as the eluent to afford compound 7. Pale yellow solid, 11.5 mg, 0.053 mmol, 53% yield, 90% ee. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm), tR (major) = 10.9 min, tR (minor) = 9.4 min. [α]25 D = +9.6 (c = 0.124 in CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.18−7.11 (m, 3H), 7.01−6.92 (m, 2H), 5.70 (s, 1H), 4.95 (br, 2H), 3.02 (d, J = 13.0 Hz, 1H), 2.92 (d, J = 13.1 Hz, 1H), 1.27 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 203.8, 202.3, 157.4, 136.2, 129.8, 128.2, 126.9, 112.5, 52.2, 41.0, 20.0. HRMS (ESI): [M + H]+ calcd for C13H14NO2+, 216.1019; found, 216.1020.

Synthesis of N-(4-Benzyl-2,4-dimethyl-3,5-dioxocyclopent1-en-1-yl)benzamide (4). To a clean pressure tube charged with 3aa (15.2 mg, 0.05 mmol, 1.0 equiv, 90% ee) and K2CO3 (13.8 mg, 0.1 mmol, 2.0 equiv) was added 0.5 mL of CH3NO2. After stirring at 80 °C in an oil bath for 24 h, the mixture turned red. The reaction vial was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:10, v/ v) as the eluent to afford 4. Pale yellow solid, 13.7 mg, 0.041 mmol, 82% yield, 91% ee. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 98:2, flow rate: 1.0 mL/min, λ = 254 nm), tR (major) = 12.1 min, tR (minor) = 11.1 min. [α]25 D −6.9 (c 0.224 in CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.89−7.81 (m, 2H), 7.66−7.58 (m, 1H), 7.52 (m, 2H), 7.15 (s, 3H), 6.97−6.89 (m, 2H), 3.07 (d, J = 13.1 Hz, 1H), 2.98 (d, J = 13.3 Hz, 1H), 2.08 (s, 3H), 1.32 (s, 3H).13C{1H} NMR (101 MHz, CDCl3): δ 204.6, 202.6, 164.4, 146.3, 138.9, 135.7, 133.2, 132.7, 129.6, 129.1, 128.4, 127.9, 127.2, 50.8, 41.4, 19.6, 11.5. HRMS (ESI): [M + H]+ calcd for C21H20NO3+, 334.1438; found, 334.1434. Synthesis of N-(3-Benzyl-3-methyl-2,4-dioxocyclopentyl)benzamide (5). To a clean pressure tube charged with 3aa (30.4 mg, 0.1 mmol, 1.0 equiv, 90% ee) and Zn powder (26.2 mg, 0.6 mmol, 6.0 equiv) was added 0.3 mL of AcOH. After stirring under a nitrogen atmosphere at 80 °C in an oil bath for 24 h, the reaction vial was cooled to room temperature. The solvent was then removed under a vacuum. The dr ratio (9:1) was determined by 1H NMR analysis of the crude reaction mixture. The residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:3, v/v) as the eluent to afford the major diastereomer of product 5. White solid, 20.3 mg, 0.063 mmol, 63% yield, 89% ee. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm), tR (major) = 10.4 min, 1 tR (minor) = 12.7 min. [α]25 D +103.3 (c 0.290 in CHCl3). H NMR (400 MHz, CDCl3): δ 7.73−7.68 (m, 2H), 7.49 (m, 1H), 7.43−7.36 (m, 2H), 7.29−7.23 (m, 3H), 7.07−7.03 (m, 2H), 6.94 (d, J = 6.0 Hz, 1H), 3.34 (ddd, J = 10.6, 8.2, 6.2 Hz, 1H), 3.06 (d, J = 12.7 Hz, 1H), 2.93 (d, J = 12.8 Hz, 1H), 2.65 (dd, J = 18.5, 7.6 Hz, 1H), 2.58 (dd, J = 18.5, 10.0 Hz, 1H), 1.45 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 214.7, 214.6, 167.0, 135.5, 132.5, 132.3, 129.6, 128.9, 128.8, 127.7, 127.2, 59.3, 56.4, 44.7, 43.3, 19.8. HRMS (ESI): [M + H]+ calcd for C20H20NO3+, 322.1438; found, 322.1439. Synthesis of N-(4-Benzyl-5-hydroxy-4-methyl-3-oxocyclopent-1-en-1-yl)benzamide (6). Under N2, to a clean vial charged with 3aa (30.4 mg, 0.1 mmol, 1.0 equiv, 90% ee) and CeCl3 (73.9 mg, 0.3 mmol, 3.0 equiv) was added absolute MeOH (1 mL). After the mixture was stirred at 0 °C for 10 min, NaBH4 (3.8 mg, 0.1 mmol, 1.0 equiv) was added and the reaction mixture was further stirred for 10 min. Then, the reaction was quenched with water (1 mL), and methanol was removed under a vacuum. The aqueous phase was extracted with EtOAc (3 × 3 mL). All of the organic phase was combined, dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:1, v/v) to afford product 6 with a 16:1 dr as determined by 1 H NMR analysis. Further purification by column chromatography on silica gel with EtOAc/petroleum ether (1:3, v/v) as an eluent afforded the major diastereomer of product 6. White solid, 22.8 mg, 0.071 mmol, 71% yield, 90% ee. The enantioselectivity was determined by HPLC (AS-H, n-hexane/i-PrOH = 80:20, flow rate: 1.0 mL/min, λ = 254 nm), tR (major) = 22.7 min, tR (minor) = 15.9 min. [α]25 D −7.5 (c 0.302 in CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 1H), 7.94−7.79 (m, 2H), 7.65−7.58 (m, 1H), 7.57−7.46 (m, 2H), 7.24− 7.11 (m, 5H), 6.40 (s, 1H), 4.70 (s, 1H), 3.24 (br, 1H), 3.05 (d, J = 13.8 Hz, 1H), 2.90 (d, J = 13.7 Hz), 1.22 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 208.9, 166.0, 164.7, 137.6, 133.3, 132.7, 130.8, 129.1, 128.1, 127.7, 126.6, 111.6, 78.5, 52.5, 40.0, 21.5. HRMS (ESI): [M + H]+ calcd for C20H20NO3+, 322.1438; found, 322.1436. Synthesis of N-(3-Benzyl-2,4-dihydroxy-3methylcyclopentyl)benzamide (7). To a clean vial charged with 3aa (30.4 mg, 0.1 mmol, 1.0 equiv, 90% ee) and Na2CO3(100 mg) was added acetone/water (2 mL, v/v = 3:1). After the mixture was

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01678. Catalyst preparation, optimization of reaction conditions, copies of HPLC chromatograms, and copies of NMR spectra (PDF) X-ray crystallographic data for 3aa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Liyao Zheng: 0000-0002-1996-7727 Jun Wang: 0000-0002-4035-2786 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21402244). REFERENCES

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DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.9b01678 J. Org. Chem. XXXX, XXX, XXX−XXX