Metal-Controlled Switching of Enantioselectivity in ... - ACS Publications

Article Cite This: J. Org. Chem. 2018, 83, 5058−5071

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Metal-Controlled Switching of Enantioselectivity in the Mukaiyama− Michael Reaction of α,β-Unsaturated 2‑Acyl Imidazoles Catalyzed by Chiral Metal−Pybox Complexes Subhrajit Rout,† Arko Das,† and Vinod K. Singh*,†,‡ †

Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208016, India Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, India

‡

S Supporting Information *

ABSTRACT: Metal-directed switching of enantioselectivity in the Mukaiyama−Michael reaction of silyl enol ethers to α,βunsaturated 2-acyl imidazoles using the same chiral indapybox ligand has been reported. The utility of this approach has been portrayed in the synthesis of both enantiomers of optically active δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of the tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

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tion.5,6 However, access to both enantiomeric 1,5-dicarbonyls via the Mukaiyama−Michael reaction using the same chiral ligand or organocatalyst is a noble approach, but remains a formidable challenge. In this context, Bernardi described the counterion induced reversal of enantioselectivity in the Mukaiyama−Michael reaction of 2-carbomethoxy cyclopentenone promoted by chiral bisoxazoline-Cu(II) complexes.2i The aforementioned methodology is limited to a few examples in moderate yields with enantioselectivities up to 66% ee. Nakada and co-workers have also studied one example of counteraniondirected enantioswitching with the same chiral bisoxazoline ligand in their recent report on the enantioselective Mukaiyama−Michael addition of cyclic α-alkylidene β-keto phosphonate and phosphine oxide.5k Consequently, the development of an enantiodivergent Mukaiyama−Michael strategy using the same chiral ligand to afford a variety of synthetically useful enantiomeric 1,5-dicarbonyls will be of great importance in contemporary chemistry. Further, chiral 3,4-dihydropyran-2-one is an important structural framework, which occurs in various natural products.7 Besides, it is a privileged intermediate in organic synthesis.8 Although a number of elegant asymmetric approaches to this target have appeared in the literature, access to both enantiomeric 3,4-dihydropyran-2-ones using the same chiral source would be desirable in asymmetric synthesis.9 On the other hand, the importance of imidazoles is evident from their various fascinating pharmacological activity.10 Needless to say,

INTRODUCTION The development of a synthetic method that offers an expeditious entry to both enantiomers of a chiral molecule is important to organic synthesis, bioorganic chemistry, and the pharmaceutical industry.1 The utilization of chiral ligands with opposite configurations in metal-catalyzed transformations is the established approach to synthesize both enantiomeric products. However, enantiomers of the ligands are not always straightforwardly available, or they require expensive and lengthy experimental methods to be synthesized. Alternatively, efforts have also been directed to develop enantiodivergent approaches wherein the reversal of enantioselectivity of metalcatalyzed reactions can be achieved by using the same enantiomer of a chiral ligand with different metals2a−e and by changing reaction conditions such as the solvent,2f temperature,2g pressure,2h counteranion,2i,j and additive.2k In the case of metal-directed enantiodivergent approaches, the unique features of metals, such as atomic radius and electronic properties, control their coordination pattern with the same chiral ligand, allowing the formation of different catalytic active species, which lead to inversion in chirality. The use of ligands synthesized from a single chiral source, but possessing modified subunits, was found to induce a switch in the enantioselectivity of a metal-catalyzed reaction.3 Further, enantioswitching in organocatalytic reactions has also received attention in asymmetric catalysis.4 An asymmetric Mukaiyama−Michael reaction is one of the potential chemical tools for the synthesis of enantioenriched 1,5-dicarbonyls. Considerable attention has been devoted to the development of an asymmetric Mukaiyama−Michael reac© 2018 American Chemical Society

Received: February 10, 2018 Published: April 16, 2018 5058

DOI: 10.1021/acs.joc.8b00399 J. Org. Chem. 2018, 83, 5058−5071

Article

The Journal of Organic Chemistry Table 1. Screening of Ligands and Lewis Acidsa

entry

ligand

Lewis acid

time (h)

yieldb (%)

erc

1d 2 3 4 5 6 7 8 9 10 11 12d

1a 1a 1b 1c 1d 1e 1f 1a 1a 1a 1a 1a

Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Zn(OTf)2 Mg(OTf)2 Yb(OTf)3 In(OTf)3 In(OTf)3

4 1 24 24 24 24 24 24 24 24 1 24

81 90 15 16 15 13 15 30 15 18 92 63

90:10 91:9 58.5:41:5 70.5:29.5 57:43 53:47 50:50 51:49 54:46 58:42 26:74 30:70

a Reaction conditions: 2a (0.2 mmol), 3a (0.1 mmol), 1 (0.012 mmol), Lewis acid (0.01 mmol), HFIP (0.1 mmol), CHCl3 (1.0 mL), rt. bIsolated yield. cDetermined by HPLC using a chiral IA-3 column. dReaction was carried out without HFIP.

Table 2. Optimization Studiesa

an imidazole ring is also found in various natural products,11a chiral ligands,11b and organocatalysts.11c Furthermore, the derivatives of imidazole have been utilized as the precursors of ionic liquids12a and N-heterocyclic carbenes.12b In this respect, α,β-unsaturated 2-acyl imidazole has emerged as a privileged substrate for several novel enantioselective transformations.13 Doyle and co-workers beautifully developed a [CuII{(S,S)-tBu-box}] (SbF6)2 promoted enantioselective Mukaiyama−Michael addition of 3-(tert-butyldimethylsilyloxy)-2-diazo-3-butenoate to 2-enoyl imidazoles.5i Recently, we have described a pybox-diph-Zn(II) complex-catalyzed enantioselective Mukaiyama−Michael addition of 2-enoylpyridine N-oxides.5j Herein, we report an enantioselective Mukaiyama−Michael reaction of silyl enol ethers to α,βunsaturated 2-acyl imidazoles using the same chiral indapybox ligand with either Sc(OTf)3 or In(OTf)3 to achieve a switch in the enantioselectivity.

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RESULTS AND DISCUSSION Initially, the model reaction was investigated using silyl enol ether 2a and β-phenyl-substituted 2-enoyl imidazole 3a in the presence of 10 mol % Sc(OTf)3-1a complex in chloroform at room temperature.14 Product 4aa was isolated in 81% yield with 90:10 er (Table 1, entry 1). The yield and enantioselectivity of 4aa could be increased to 90% and 91:9 er, respectively, using HFIP as an additive (Table 1, entry 2).15 An intensive study of various bisoxazoline ligands with Sc(OTf)3 resulted in no improvement to the enantioselectivity (Table 1, entries 3−7). We next turned our attention to screen different metal centers (Table 1, entries 8−11). To our delight, the In(OTf)3-1a system furnished the opposite enantiomer in 92% yield with 26:74 er. It was noteworthy to mention that the yield as well as the enantioselectivity of the opposite enantiomer decreased in the absence of HFIP and also

entry

solvent

Lewis acid

time (h)

yieldb (%)

erc

1 2 3 4 5 6d 7e 8 9 10 11 12f 13e 14g 15e,h

CHCl3 CH2Cl2 DCE THF toluene CHCl3 CHCl3 CHCl3 DCE CH3CN EtOAc CHCl3 CHCl3 CHCl3 CHCl3

Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3 In(OTf)3

1 1 1 24 24 2 8 1 1.5 1 24 2.5 3.5 8 3.5

90 91 91 20 trace 90 81 92 71 91 31 91 90 80 90

91:9 90:10 89:11 87:13 90:10 90.5:9.5 26:74 27:73 27:73 50:50 27:73 23:77 23:77 23:77

a

Reaction conditions: 2a (0.2 mmol), 3a (0.1 mmol), 1a (0.012 mmol), Lewis acid (0.01 mmol), HFIP (0.1 mmol), CHCl3 (1.0 mL), rt. bIsolated yield. cDetermined by HPLC using a chiral IA-3 column. d Reaction was carried out using 6 mol % 1a and 5 mol % Sc(OTf)3. e Reaction at 0 °C. fReaction was carried out using 6 mol % 1a and 5 mol % In(OTf)3. gReaction at −20 °C. hUse of 4 Å molecular sieves (10 mg).

confirmed that there was no effect of HFIP on the reversal of enantioselectivity (Table 1, entry 12). With the hope to secure a better enantioselectivity, the effects of solvent and catalyst loading on the formation of both the enantiomeric products were investigated (Table 2). 5059


Article

The Journal of Organic Chemistry Scheme 1. Substrate Scope Promoted by the Chiral Sc(OTf)3-1a Complex

drawing substituents were evaluated, and the products (4aa− ai) were afforded in high yields with good enantioselectivities (up to 91:9 er). α,β-Unsaturated 2-acyl imidazoles with a methoxy-substituted phenyl group reacted efficiently to produce the products (4aj−ak) in good yields and enantioselectivities (up to 90:10 er). A naphthyl-substituted α,β-unsaturated 2-acyl imidazole (3l) also responded to this protocol to deliver the product 4al in 79% yield and 89.5:10.5 er. Further, silyl enol ethers bearing aryl groups embracing either electron-withdrawing or electron-donating substituents were observed to be suitable for the protocol and furnished the products (4ba, 4bj, and 4ca) in high yields with good enantioselectivities. A thienyl-substituted silyl enol ether (2d) reacted with a α,β-unsaturated 2-acyl imidazole 3j to provide the product 4dj in 84% yield with 90.5:9.5 er. Next, we devoted our efforts to evaluate the substrate scope for the Mukaiyama−Michael reaction with the optimized reaction conditions of the In(OTf)3-1a complex. The opposite enantiomers (ent-4) were afforded in high yields with moderate to high enantioselectivities (Scheme 2). Toward this, a series of α,β-unsaturated 2-acyl imidazoles having electron-deficient and electron-rich phenyl groups was charged with silyl enol ether 2a to access the products (ent-4aa−ak) in high yields (up to 92%) with moderate to high enantioselectivities (up to 95.5:4.5 er). α,β-Unsaturated 2-acyl imidazole with a naphthyl group (3l) on

Screening of various solvents disclosed that chloroform was the best combination with the Sc(OTf)3-1a system to furnish the product 4aa in 90% yield with 91:9 er (Table 2, entry 1). Further, lowering the catalyst loading of Sc(OTf)3-1a from 10 to 5 mol % resulted in 4aa with a slight loss in enantioselectivity and a longer reaction time (Table 2, entry 6). To improve the enantioselectivity, the effect of the reaction temperature was investigated. The reaction at 0 °C did not bring any improvement to the enantioselectivity, but the reaction decreased the yield of product 4aa with a longer reaction time (Table 2, entry 7). Eventually, the optimization studies revealed that the best result for the formation of 4aa could be achieved using 10 mol % Sc(OTf)3-1a complex in chloroform at room temperature (Table 2, entry 1). Further, testing of different solvents with the In(OTf)3-1a system was unfruitful in terms of enantioselectivity of an opposite enantiomer (Table 2, entries 9−11). We next screened the In(OTf)3-1a system with different reaction conditions (Table 2, entries 12−15), and the best outcome was encountered at 0 °C with 10 mol % catalyst loading (Table 2, entry 13). With optimized reaction conditions, the substrate scope for the Mukaiyama−Michael reaction of different silyl enol ethers to a variety of α,β-unsaturated 2-acyl imidazoles catalyzed by Sc(OTf)3-1a was studied (Scheme 1). The α,β-unsaturated 2acyl imidazoles with phenyl group-containing electron-with5060


Article

The Journal of Organic Chemistry Scheme 2. Substrate Scope Promoted by the Chiral In(OTf)3-1a Complex

the si face is hindered by the aryl group of the ligand, furnishing the (R)-isomer of the product. Indium(III) has a larger ionic radius than scandium(III).17 We propose that 2g/In(OTf)3 forms a pentagonal bipyramidal complex with 2-enoyl imidazole (TS-2, Figure 1).18 The silyl enol ether attacks from the less hindered si face to furnish the (S)-isomer of the product. We next turned our attention to highlight the synthetic utility of our approach by elaborating the Mukaiyama−Michael enantiomeric products to various synthetically important intermediates (Scheme 3). Products 4bj and ent-4bj on methylation followed by treatment of DBU and H2O afforded enantioenriched δ-keto acids 5 and ent-5, respectively.13b Further, δ-keto acids 5 and ent-5 were treated with oxalyl chloride and DMF to obtain synthetically important 3,4dihydropyran-2-ones 6 (89.5:10.5 er) and ent-6 (96:4 er), respectively, in high yields.19 We again transformed products 4bj and ent-4bj into δ-keto esters 7 (90.5:9.5 er) and ent-7 (96:4), respectively, in synthetically viable yields, utilizing a methylation condition followed by reaction with MeOH and DBU.5i Gratifyingly, the reaction of the alkyl group-substituted silyl ketene acetal 8 with the model substrate 3a under the optimized reaction conditions furnished both enantiomeric products (9 and ent-9), bearing a tertiary stereocenter adjacent to a gem-dimethyl group in good yields and enantioselectivities (Scheme 4). Further, product 9 was transformed into diester 10 via methylation followed by reaction of MeOH and DBU.5i The

treatment with silyl enol ether 2a yielded ent-4al in 81% yield with 69.5:30.5 er. Further, a variety of silyl enol ethers containing either electron-deficient or electron-rich phenyl groups reacted smoothly to afford ent-4ba, ent-4bj, and ent-4ca in excellent yields with moderate to high enantioselectivities. Product ent-4dj was produced in 88% yield with a moderate enantioselectivity (71.5:28.5 er), when silyl enol ether 2d bearing a heteroaryl group was charged with α,β-unsaturated 2acyl imidazole 3j. Further, we realized the potential and the practicality of the metal-controlled enantioswitching of the Mukaiyama−Michael reaction. Toward this, a reaction of a 0.5 g scale of 3j with silyl enol ether 2b under the optimized reaction conditions of either Sc(OTf)3-1a or In(OTf)3-1a system yielded 4bj and ent-4bj in almost the same yield and without a loss of enantioselectivity (Scheme 3). We then set out to determine the absolute stereochemistry of the products. Recently, Kang and co-workers reported a highly enantioselective decarboxylative Michael reaction of β-keto acids with 2enoyl imidazoles catalyzed by a chiral-at-metal Rh(III) complex.13c The comparison of the optical rotation of 4aa with Kang’s report established the absolute stereochemistry to be (R).13c Moreover, the enantioswitching observed in this approach could be explained by proposed transition states (Figure 1). In the case of TS-1, it is proposed that the 2-enoyl imidazole with two-point binding sites form an octahedral complex with the catalyst 2g/Sc(OTf)3.16 The attack of silyl enol ether occurs from the sterically less demanding re face as 5061


Article

The Journal of Organic Chemistry Scheme 3. Scale-Up of Reaction and Synthetic Elaboration

Figure 1. Proposed transition state.

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absolute stereochemistry of the product was found to be (R) by

In conclusion, we have reported the metal-controlled enantioswitching in the Mukaiyama−Michael reaction of α,βunsaturated 2-acyl imidazoles using the same chiral indapybox ligand. Enantiomeric 1,5-diketones were afforded in up to 93% yield and 97:3 er. The significance of this methodology was highlighted in the synthesis of both enantiomers of δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, the strategy enabled us to install a tertiary stereocenter adjacent to

comparing the optical rotation of compound 10 with the literature (Scheme 4).

20

CONCLUSION

Importantly, structural framework

comprising a gem-dimethyl group connected to a tertiary stereocenter is found in many biologically active natural products.21 Further, the importance of a gem-dimethyl group has also been recognized in drug development.21 5062


Article

The Journal of Organic Chemistry Scheme 4. Scope of a Silyl Ketene Acetal

3.30 g, in 69% (3.885 g) yield. Rf = 0.25 (30% EtOAc in hexane). Mp: 113−115 °C. 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 16.3 Hz, 1H), 7.79 (d, J = 16.3 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 7.10 (s, 1H), 7.02 (t, J = 8.0 Hz, 1H), 4.12 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 179.9, 143.9, 140.8, 136.4, 132.6, 131.2, 130.4, 129.9, 127.6, 124.2, 36.4. IR (film): νmax 3106, 2956, 1663, 1615, 1545, 1404, 1281, 1157, 1016 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H1178.9183Br2N2O, 368.9238; found, 368.9230. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H11 80.9163Br2N2O, 370.9218; found, 370.9202. General Procedure for the Reaction of Silyl Enol Ethers 2 with α,β-Unsaturated 2-Acyl Imidazoles 3 Catalyzed by the Sc(OTf)3-1a Complex. A solution of ligand 1a (9.44 mg, 0.024 mmol) and Sc(OTf)3 (9.84 mg, 0.02 mmol) in dry chloroform (2 mL) was stirred at room temperature for 3.5 h under a nitrogen atmosphere. α,βUnsaturated 2-acyl imidazole 3 (0.20 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. HFIP (21 μL, 0.20 mmol) was then added to the mixture, and the resulting reaction mixture was again stirred for 15 min at rt. Then silyl enol ether 2 (0.40 mmol) was added, and the reaction mixture was allowed to stir at room temperature until the completion of the reaction (monitored by TLC). The mixture was concentrated in vacuo and purified over silica gel by column chromatography (10−40% ethyl acetate in hexane) to afford the products 4. Scale-Up of Reaction. A solution of ligand 1a (97.18 mg, 0.247 mmol) and Sc(OTf)3 (101.38 mg, 0.206 mmol) in dry chloroform (12 mL) was stirred at room temperature for 3.5 h under a nitrogen atmosphere. α,β-Unsaturated 2-acyl imidazole 3j (500 mg, 2.06 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. HFIP (216 μL, 2.06 mmol) was then added to the mixture, and the resulting reaction mixture was again stirred for 15 min at rt. Then silyl enol ether 2b (1.12 g, 4.12 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 5 h. The mixture was concentrated in vacuo and purified over silica gel by column chromatography (10−40% ethyl acetate in hexane) to afford the product 4bj in 81% yield with 91:9 er. General Procedure for the Reaction of Silyl Enol Ethers 2 with α,β-Unsaturated 2-Acyl Imidazoles 3 Catalyzed by the In(OTf)3-1a Complex. A solution of ligand 1a (9.44 mg, 0.024 mmol) and In(OTf)3 (11.24 mg, 0.02 mmol) in dry chloroform (2 mL) was stirred at room temperature for 3.5 h under a nitrogen atmosphere. α,β-Unsaturated 2-acyl imidazole 3 (0.20 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. The mixture was cooled to 0 °C, and HFIP (21 μL, 0.20 mmol) was added; the resulting mixture was again allowed to stir for an additional 15 min at 0 °C. The silyl enol ether 2 (0.40 mmol) was added, and the reaction mixture was allowed to stir at 0 °C until the completion of the reaction (monitored by TLC). The mixture was concentrated in vacuo and purified over silica gel by column chromatography (10−40% ethyl acetate in hexane) to afford the products ent-4. Scale-Up of Reaction. A solution of ligand 1a (97.18 mg, 0.247 mmol) and In(OTf)3 (115. 77 mg, 0.206 mmol) in dry chloroform (12 mL) was stirred at room temperature for 3.5 h under a nitrogen atmosphere. α,β-Unsaturated 2-acyl imidazole 3j (500 mg, 2.06 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. The mixture was cooled to 0 °C, and HFIP (216 μL, 2.06 mmol) was added; the resulting mixture was again allowed to stir for an

a gem-dimethyl group with a reversal of enantioselectivity. The enantioswitching was explained by proposed transition states. Further, active investigations along these directions are currently underway in our laboratory.

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EXPERIMENTAL SECTION

Materials and Methods. Ligands 1a,b and 1f are commercially available. Ligands 1c−e were synthesized according to the procedure known in the literature.22 α,β-Unsaturated 2-acyl imidazoles 3a−d,f,g− k were prepared according to the literature known procedure.13a,23 Silyl enol ether 2a and silyl ketene acetal 8 are commercially available, and silyl enol ethers 2b−d were prepared according to the reported method.24 HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) and all of the metal triflates are commercially available. All reactions were carried out under an atmosphere of nitrogen in oven-dried glassware with magnetic stirring. 1H and 13C{1H} NMR spectra were recorded on Jeol (500 and 400 MHz) spectrometers in CDCl3. Chemical shifts (δ) are reported in parts per million (ppm). Tetramethylsilane and CDCl3 were used as internal standards for 1H and 13C{1H} NMR, respectively. Coupling constants (J) were reported in hertz (Hz). Splitting patterns are designated as s for singlet, d for doublet, t for triplet, q for quartet, dd for doublet of doublet, m for multiplet, and p for pentet. IR spectra were measured with a PerkinElmer FT-IR Spectrum Two spectrometer. Mass spectrometric analysis was done on a Waters QTof Premier Micromass (ESI) unit. Routine monitoring of reactions was performed using precoated silica gel TLC plates from EMerck. All chromatographic separations were carried out by using silica gel (Acme’s, 100−200 mesh). Enantiomeric excess was determined by HPLC analysis on Daicel chiral columns using isopropanol and n-hexane as eluents at 25 °C. Optical rotations were measured on a commercially available automatic polarimeter. Melting points were recorded on a digital melting point apparatus. General Procedure and Characterization Data of α,β-Unsaturated 2-Acyl Imidazoles 3e and 3h. To a solution of 2-acetyl-1methylimidazole (15 mmol, 1 equiv) in EtOH (50 mL) were added the desired aromatic aldehydes (15 mmol, 1 equiv) and KOH (2 pallets). The solution was allowed to stir for 12 h at room temperature. Then, EtOH was evaporated, and H2O (25 mL) and saturated NaCl (35 mL) were added to it. The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then dried over Na2SO4 and filtered. The solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (hexane/EtOAc) to afford products 3e and 3h. (E)-3-(2-Iodophenyl)-1-(1-methyl-1H-imidazol-2-yl)prop-2-en-1one (3e). The compound was isolated as a gray solid in 71% (3.601 g) yield. Rf = 0.3 (40% EtOAc in hexane). Mp: 138−140 °C. 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 15.8 Hz, 1H), 7.97 (d, J = 15.8 Hz, 1H), 7.91 (dd, J = 7.9, 0.9 Hz, 1H), 7.82 (dd, J = 7.8, 1.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 7.06 (td, J = 7.8, 1.5 Hz, 1H), 4.11 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 179.9, 146.4, 144.0, 140.1, 138.1, 131.4, 129.6, 128.5, 127.8, 127.5, 125.6, 102.3, 36.5. IR (film): νmax 3125, 3098, 2921, 1656, 1599, 1460, 1406, 1262, 1159, 1022 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H12IN2O, 338.9994; found, 338.9990. (E)-3-(2,6-Dibromophenyl)-1-(1-methyl-1H-imidazol-2-yl)prop-2en-1-one (3h). The compound was isolated as a light yellow solid, 5063


Article

The Journal of Organic Chemistry additional 15 min at 0 °C. The silyl enol ether 2b (1.12 g, 4.12 mmol) was added, and the reaction mixture was allowed to stir at 0 °C for 5.5 h. The mixture was concentrated in vacuo and purified over silica gel by column chromatography (10−40% ethyl acetate in hexane) to afford the product ent-4bj in 90% yield with 97:3 er.

(R)-3-(2-Chlorophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ac). 1H NMR (400 MHz, CDCl3): δ 7.80−7.77 (m, 2H), 7.41−7.36 (m, 1H), 7.30−7.26 (m, 2H), 7.24−7.19 (m, 2H), 7.06−7.01 (m, 1H), 6.98 (dd, J = 7.8, 1.7 Hz, 1H), 6.95 (d, J = 0.8 Hz, 1H), 6.84 (s, 1H), 4.46−4.39 (m, 1H), 3.78 (s, 3H), 3.60−3.46 (m, 2H), 3.35−3.23 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.1, 190.6, 143.1, 141.2, 136.9, 133.8, 133.1, 130.0, 129.0, 128.6, 128.2, 128.1, 127.7, 127.0, 127.0, 43.6, 43.4, 36.1, 33.2. IR (film): νmax 3061, 2923, 1678, 1596, 1579, 1475, 1447, 1409, 1363, 1289, 1220, 1154, 1035, 986 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2034.9689ClN2O2, 367.1213; found, 367.1212. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2036.9659ClN2O2, 369.1184; found, 369.1199. For Sc(OTf)3-1a, compound 4ac was isolated as a white solid in 91% (66.6 mg) yield with 86.5:13.5 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 126−128 °C. [α]25 D = +30.0 (c 0.41, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 15.0 min, tR (minor) = 56.9 min. For In(OTf)3-1a, compound ent-4ac was isolated as a white solid in 92% (67.3 mg) yield with 85:15 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 126−128 °C. [α]25 D = −22.5 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 15.0 min, tR (major) = 54.4 min.

(R)-1-(1-Methyl-1H-imidazol-2-yl)-3,5-diphenylpentane-1,5dione (4aa). 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 7.35−7.32 (m, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.20−7.16 (m, 2H), 7.09−7.06 (m, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 4.02 (p, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.59 (dd, J = 17.0, 7.8 Hz, 1H), 3.48−3.42 (m, 1H), 3.38−3.32 (m, 1H), 3.29−3.23 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.5, 191.0, 144.2, 143.2, 137.1, 133.0, 129.0, 128.6, 128.1, 127.7, 126.9, 126.6, 45.3, 45.1, 36.6, 36.2. IR (film): νmax 2917, 1677, 1581, 1537, 1447, 1407, 1263, 1153, 985 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H21N2O2, 333.1603, found 333.1603. For Sc(OTf)3-1a, compound 4aa was isolated as a white solid in 90% (59.9 mg) yield with 91:9 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 100−102 °C. [α]25 D = +12.1 (c 0.44, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IA-3 column, n-hexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 19.4 min, tR (minor) = 22.5 min. For In(OTf)3-1a, compound ent-4aa was isolated as a white solid in 92% (61.3 mg) yield with 77:23 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 100−102 °C. [α]25 D = −9.3 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IA-3 column, n-hexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 19.5 min, tR (major) = 22.4 min.

(R)-3-(2-Fluorophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ad). 1H NMR (400 MHz, CDCl3): δ 7.79−7.77 (m, 2H), 7.41−7.37 (m, 1H), 7.31−7.27 (m, 2H), 7.21 (td, J = 7.6, 1.6 Hz, 1H), 7.04−6.98 (m, 1H), 6.96 (s, 1H), 6.92−6.83 (m, 3H), 4.20− 4.13 (m, 1H), 3.79 (s, 3H), 3.57 (dd, J = 17.4, 7.6 Hz, 1H), 3.48 (dd, J = 17.4, 6.9 Hz, 1H), 3.37−3.28 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.3, 190.8, 161.1 (d, JC−F = 247 Hz), 143.1, 137.0, 133.1, 130.7 (d, JC−F = 13 Hz), 129.8 (d, JC−F = 5 Hz), 129.1, 128.6, 128.2, 128.1, 127.0, 124.1 (d, JC−F = 3 Hz), 115.8 (d, JC−F = 23 Hz), 43.6, 43.5, 36.1, 31.5. 19F NMR (373 MHz, CDCl3): δ −117.15. IR (film): νmax 3061, 2918, 1679, 1596, 1580, 1491, 1448, 1409, 1365, 1289, 1217, 1154, 1078, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20FN2O2, 351.1509; found, 351.1500. For Sc(OTf)3-1a, compound 4ad was isolated as a white solid in 93% (65.3 mg) yield with 90:10 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 98−100 °C. [α]25 D = +16.4 (c 0.45, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 18.2 min, tR (minor) = 58.2 min. For In(OTf)3-1a, compound ent-4ad was isolated as a white solid in 88% (61.8 mg) yield with 86.5:13.5 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 98−100 °C. [α]D25 = −13.4 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 18.5 min, tR (major) = 58.1 min.

(R)-3-(2-Bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ab). 1H NMR (400 MHz, CDCl3): δ 7.80−7.78 (m, 2H), 7.41−7.37 (m, 2H), 7.30−7.26 (m, 2H), 7.22 (dd, J = 7.9, 1.6 Hz, 1H), 7.10−7.06 (m, 1H), 6.95 (d, J = 0. 7, 1H), 6.91−6.87 (m, 1H), 6.84 (s, 1H), 4.45−4.38 (m, 1H), 3.78 (s, 3H), 3.58−3.46 (m, 2H), 3.33−3.21 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 190.5, 143.1, 142.9, 136.9, 133.3, 133.1, 129.0, 128.6, 128.1, 128.0, 127.7, 127.0, 124.6, 43.8, 43.5, 36.1, 35.6. IR (film): νmax 2920, 2852, 1677, 1536, 1469, 1408, 1364, 1289, 1155, 1022, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2078.9183BrN2O2, 411.0708; found, 411.0710. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2080.9163BrN2O2, 413.0688; found, 413.0698. For Sc(OTf)3-1a, compound 4ab was isolated as a white solid in 92% (75.5 mg) yield with 85:15 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 124−126 °C. [α]25 D = +14.2 (c 0.44, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 14.8 min, tR (minor) = 53.8 min. For In(OTf)3-1a, compound ent-4ab was isolated as a white solid in 90% (74.2 mg) yield with 91:9 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 124−126 °C. [α]D25 = −17.4 (c 0.43, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 14.8 min, tR (major) = 53.0 min.

(R)-3-(2-Iodophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ae). 1H NMR (400 MHz, CDCl3): δ 7.87−7.85 (m, 2H), 7.78−7.75 (m, 1H), 7.48−7.44 (m, 1H), 7.37−7.33 (m, 2H), 7.24−7.16 (m, 2H), 7.02 (d, J = 0.8 Hz, 1H), 6.91 (s, 1H), 6.81−6.77 (m, 1H), 4.36−4.29 (m, 1H), 3.86 (s, 3H), 3.55 (d, J = 7.3 Hz, 2H), 3.37−3.23 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 190.5, 146.0, 143.1, 140.1, 136.9, 133.1, 129.1, 128.6, 128.3, 128.2, 127.1, 127.0, 101.6, 44.2, 43.9, 40.6, 36.2. IR (film): νmax 3057, 2918, 1677, 1596, 1579, 1466, 1447, 1409, 1363, 1288, 1220, 1154, 1008, 5064


Article

The Journal of Organic Chemistry 986 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20IN2O2, 459.0569; found, 459.0569. For Sc(OTf)3-1a, compound 4ae was isolated as a white solid in 87% (79.6 mg) yield with 86.5:13.5 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 97−99 °C. [α]25 D = +18.5 (c 0.40, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 15.0 min, tR (minor) = 50.5 min. For In(OTf)3-1a, compound ent-4ae was isolated as a white solid in 88% (80.8 mg) yield with 80.5:19.5 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 97−99 °C. [α]25 D = −10.6 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 15.0 min, tR (major) = 49.2 min.

isolated as a white semisolid in 90% (74.2 mg) yield with 59:41er. Rf = 0.24 (40% EtOAc in hexane). [α]25 D = −2.8 (c 0.66, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 11.5 min, tR (major) = 19.6 min.

(R)-3-(2,6-Dibromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ah). 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 7.4 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.43−7.40 (m, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.88 (t, J = 8.0 Hz, 1H), 5.08−5.03 (m, 1H), 4.00−3.94 (m, 4H), 3.82 (dd, J = 17.3, 6.6 Hz, 1H), 3.77 (d, J = 7.1 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 198.1, 190.3, 141.1, 137.0, 134.4, 133.1, 132.9, 129.0, 128.6, 128.3, 128.2, 126.9, 123.3, 42.4, 41.6, 37.2, 36.4. IR (film): νmax 3061, 2922, 1677, 1596, 1578, 1549, 1447, 1409, 1369, 1287, 1215, 1155, 1077, 988 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H1978.9183Br2N2O2, 488.9813; found, 488.9811. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H1980.9163Br2N2O2, 490.9793; found, 490.9819. For Sc(OTf)3-1a, compound 4ah was isolated as a white solid in 81% (79.6 mg) yield with 85:15 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 103−105 °C. [α]25 D = +4.8 (c 0.72, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak OJ-H column, n-hexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 33.0 min, tR (major) = 41.9 min. For In(OTf)3-1a, compound ent-4ah was isolated as a white solid in 76% (74.7 mg) yield with 85:15 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 103−105 °C. [α]25 D = −18.5 (c 0.26, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak OJ-H column, n-hexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 32.5 min, tR (minor) = 43.0 min.

(R)-3-(4-Fluorophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4af). 1H NMR (400 MHz, CDCl3): δ 7.76−7.74 (m, 2H), 7.41−7.37 (m, 1H), 7.30−7.26 (m, 2H), 7.18−7.13 (m, 2H), 6.96 (s, 1H), 6.84 (s, 1H), 6.82−6.76 (m, 2H), 3.96 (p, J = 7.2 Hz, 1H), 3.78 (s, 3H), 3.50 (dd, J = 17.0, 7.8 Hz, 1H), 3.36 (dd, J = 17.0, 6.9 Hz, 1H), 3.27 (dd, J = 17.0, 6.7 Hz, 1H), 3.17 (dd, J = 17.0, 7.5 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.2, 190.7, 161.5 (d, JC−F = 246 Hz), 143.1, 139.7, 137.0, 133.1, 129.1, 129.1, 128.6, 128.1, 127.0, 115.3 (d, JC−F = 21 Hz), 45.3, 45.1, 36.1, 35.9. 19F NMR (373 MHz, CDCl3): δ −117.31. IR (film): νmax 2923, 1677, 1597, 1509, 1447, 1407, 1363, 1289, 1220, 1157, 985 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20FN2O2, 351.1509; found, 351.1505. For Sc(OTf)3-1a, compound 4af was isolated as a white semisolid in 92% (64.6 mg) yield with 89:11 er. Rf = 0.22 (40% EtOAc in hexane). [α]25 D = +5.4 (c 0.39, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 10.5 min, tR (minor) = 24.2 min. For In(OTf)3-1a, compound ent-4af was isolated as a white semisolid in 92% (64.3 mg) yield with 68.5:31.5 er. Rf = 0.22 (40% EtOAc in hexane). [α]25 D = −11.7 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 10.7 min, tR (major) = 25.2 min.

(R)-3-(2,6-Dichlorophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ai). 1H NMR (400 MHz, CDCl3): δ 7.81− 7.79 (m, 2H), 7.41−7.37 (m, 1H), 7.31−7.27 (m, 2H), 7.19−7.07 (m, 2H), 6.97 (s, 1H), 6.93−6.89 (m, 1H), 6.86 (s, 1H), 4.90 (p, J = 7.2 Hz, 1H), 3.83−3.77 (m, 4H), 3.67 (dd, J = 17.5, 6.9 Hz, 1H), 3.61− 3.59 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.2, 190.7, 142.9, 138.6, 136.9, 134.8, 133.1, 129.9, 129.1, 128.8, 128.6, 128.2, 127.0, 42.0, 41.4, 36.2, 32.8. IR (film): νmax 2919, 1678, 1596, 1579, 1559, 1447, 1434, 1408, 1287, 1154, 1082, 987 cm−1. HRMS (ESITOF): m/z [M + H]+ calcd for C21H1934.9689Cl2N2O2, 401.0824; found, 401.0822. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H1936.9659Cl2N2O2, 403.0794; found, 403.0809. For Sc(OTf)3-1a, compound 4ai was isolated as a white solid in 90% (72.5 mg) yield with 86:14 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 120−122 °C. [α]25 D = +6.4 (c 1.24, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak OD column, n-hexane/2propanol (98:2) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 38.3 min, tR (minor) = 51.1 min. For In(OTf)3-1a, compound ent-4ai was isolated as a white solid in 80% (64.4 mg) yield with 91:9 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 120−122 °C. [α]25 D = −9.1 (c 0.84, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak OD column, n-hexane/2propanol (98:2) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 40.8 min, tR (major) = 52.0 min.

(R)-3-(3-Bromophenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ag). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.39 (s, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.23−7.16 (m, 2H), 7.04 (t, J = 7.8 Hz, 2H), 6.91 (s, 1H), 4.00−3.93 (m, 1H), 3.85 (s, 3H), 3.58 (dd, J = 17.0, 7.6 Hz, 1H), 3.49−3.43 (m, 1H), 3.38−3.32 (m, 1H), 3.26−3.20 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 190.0, 146.5, 142.3, 136.8, 133.2, 130.7, 130.2, 129.8, 128.7, 128.1, 127.0, 126.6, 122.6, 45.1, 44.9, 36.4, 36.2. IR (film): νmax 3059, 2924, 1680, 1595, 1580, 1566, 1475, 1448, 1410, 1362, 1288, 1219, 1155, 1075, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2078.9183BrN2O2, 411.0708; found, 411.0707. HRMS (ESI-TOF): m/z [M + H] + calcd for C21H2080.9163BrN2O2, 413.0688; found, 413.0687. For Sc(OTf)3-1a, compound 4ag was isolated as a white semisolid in 92% (75.5 mg) yield with 90:10 er. Rf = 0.24 (40% EtOAc in hexane). [α]25 D = +11.4 (c 0.53, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 11.4 min, tR (minor) = 19.5 min. For In(OTf)3-1a, compound ent-4ag was 5065


Article

The Journal of Organic Chemistry

3H), 3.65 (dd, J = 17.0, 7.8 Hz, 1H), 3.47 (dd, J = 17.0, 6.8 Hz, 1H), 3.37 (dd, J = 17.1, 7.0 Hz, 1H), 3.29 (dd, J = 17.1, 7.0 Hz, 1H). 13 C{1H} NMR (100 MHz, CDCl3): δ 198.3, 190.8, 143.1, 141.7, 137.0, 133.5, 133.05, 132.4, 129.0, 128.5, 128.2, 128.1, 127.8, 127.6, 127.0, 126.2, 126.0, 125.9, 125.4, 45.3, 45.0, 36.6, 36.1. IR (film): νmax 3054, 2956, 1679, 1597, 1579, 1507, 1447, 1408, 1356, 1269, 1214, 1154, 1078, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H23N2O2, 383.1760; found, 383.1766. For Sc(OTf)3-1a, compound 4al was isolated as a white semisolid in 79% (60.2 mg) yield with 89.5:10.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = +12.1 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 16.8 min, tR (minor) = 40.1 min. For In(OTf)3-1a, compound ent-4al was isolated as a white semisolid in 81% (61.8 mg) yield with 69.5:30.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = −18.7 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 17.2 min, tR (major) = 41.4 min.

(R)-3-(2-Methoxyphenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4aj). 1H NMR (400 MHz, CDCl3): δ 7.87− 7.84 (m, 2H), 7.45−7.41 (m, 1H), 7.36−7.31 (m, 2H), 7.20−7.18 (m, 1H), 7.09−7.05 (m, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 6.79−6.72 (m, 2H), 4.26 (p, J = 7.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.65 (dd, J = 17.4, 7.3 Hz, 1H), 3.52 (dd, J = 17.4, 6.9 Hz, 1H), 3.33 (d, J = 7.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 191.6, 157.3, 143.3, 137.3, 132.8, 131.8, 128.9, 128.7, 128.5, 128.2, 127.6, 126.7, 120.6, 110.8, 55.4, 43.7, 43.1, 36.2, 32.2. IR (film): νmax 2937, 2835, 1676, 1597, 1580, 1492, 1462, 1448, 1407, 1289, 1242, 1154, 1027, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2O3, 363.1709; found, 363.1708. For Sc(OTf)3-1a, compound 4aj was isolated as a white solid in 78% (56.3 mg) yield with 90:10 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 131−133 °C. [α]25 D = +32.2 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 28.0 min, tR (minor) = 63.4 min. For In(OTf)3-1a, compound ent-4aj was isolated as a white solid in 84% (61 mg) yield with 95.5:4.5 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 131−133 °C. [α]25 D = −31.0 (c 0.39, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 29.5 min, tR (major) = 64.9 min.

(R)-1-(4-Bromophenyl)-5-(1-methyl-1H-imidazol-2-yl)-3-phenylpentane-1,5-dione (4ba). 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.24−7.16 (m, 4H), 7.10− 7.06 (m, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 4.01−3.96 (m, 1H), 3.83 (s, 3H), 3.56 (dd, J = 16.9, 7.4 Hz, 1H), 3.46 (dd, J = 17.0, 7.1 Hz, 1H), 3.31 (dd, J = 16.8, 6.9 Hz, 1H), 3.20 (dd, J = 16.8, 6.9 Hz, 1H). 13 C{1H} NMR (100 MHz, CDCl3): δ 197.5, 190.9, 143.9, 143.1, 135.8, 131.9, 129.7, 129.1, 128.6, 128.2, 127.6, 127.0, 126.7, 45.3, 45.0, 36.7, 36.2. IR (film): νmax 3027, 2921, 1677, 1584, 1494, 1453, 1408, 1289, 1263, 1154, 1070, 987 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2078.9183BrN2O2, 411.0708; found, 411.0704. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H2080.9163BrN2O2, 413.0688; found, 413.0686. For Sc(OTf)3-1a, compound 4ba was isolated as a white semisolid in 92% (75.8 mg) yield with 92:8 er. Rf = 0.24 (40% EtOAc in hexane). [α]25 D = +8.4 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 20.6 min, tR (minor) = 53.3 min. For In(OTf)3-1a, compound ent-4ba was isolated as a white semisolid in 92% (75.5 mg) yield with 80:20 er. Rf = 0.24 (40% EtOAc in hexane). [α]D25 = −14.2 (c 0.43, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 20.5 min, tR (major) = 52.3 min.

(R)-3-(4-Methoxyphenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-phenylpentane-1,5-dione (4ak). 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 6.9 Hz, 1H), 7.35−7.32 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.01 (s, 1H), 6.89 (s, 1H), 6.71 (d, J = 8.1 Hz, 2H), 3.99−3.96 (m, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 3.58−3.52 (m, 1H), 3.42 (dd, J = 16.9, 6.6 Hz, 1H), 3.34−3.28 (m, 1H), 3.24−3.18 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.6, 191.1, 158.2, 143.3, 137.1, 136.2, 133.0, 129.0, 128.6, 128.1, 126.9, 113.9, 55.3, 45.6, 45.3, 36.2, 35.9. IR (film): νmax 2918, 2853, 1676, 1577, 1511, 1447, 1406, 1246, 1177, 1032, 985 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2O3, 363.1709; found, 363.1704. For Sc(OTf)3-1a, compound 4ak was isolated as a white solid in 85% (61.8 mg) yield with 89:11 er. Rf = 0.22 (40% EtOAc in hexane). Mp: 121−123 °C. [α]25 D = +13.6 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 24.2 min, tR (minor) = 65.2 min. For In(OTf)3-1a, compound ent-4ak was isolated as a white solid in 90% (65.4 mg) yield with 76.5:23.5 er. Rf = 0.22 (40% EtOAc in hexane). Mp: 121−123 °C. [α]D25 = −11.4 (c 0.42, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 24.7 min, tR (major) = 64.7 min.

(R)-1-(4-Bromophenyl)-3-(2-methoxyphenyl)-5-(1-methyl-1H-imidazol-2-yl)pentane-1,5-dione (4bj). 1H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.23 (p, J = 7.0 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.62 (dd, J = 17.3, 7.0 Hz, 1H), 3.53 (dd, J = 17.3, 7.2 Hz, 1H), 3.31−3.24 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.3, 191.5, 157.2, 143.3, 136.0, 131.8, 131.5, 129.8, 129.0, 128.6, 127.9, 127.7, 126.8, 120.7, 110.8, 55.3, 43.8, 43.1, 36.2, 32.2. IR (film): νmax 2923, 1678, 1584, 1493, 1463, 1438, 1408, 1362, 1289, 1243, 1154, 1070, 988 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H2278.9183BrN2O3, 441.0814; found, 441.0816. HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H2280.9163BrN2O3, 443.0793; found,

(R)-1-(1-Methyl-1H-imidazol-2-yl)-3-(naphthalen-2-yl)-5-phenylpentane-1,5-dione (4al). 1H NMR (400 MHz, CDCl3): δ 7.77−7.74 (m, 2H), 7.63−7.60 (m, 4H), 7.39−7.34 (m, 2H), 7.29−7.22 (m, 4H), 6.94 (d, J = 0.9 Hz, 1H), 6.78 (s, 1H), 4.19−4.12 (m, 1H), 3.72 (s, 5066


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column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 39.3 min, tR (major) = 57.0 min. General Procedure and Characterization of 5 and ent-5. To the solution of compound 4bj or ent-4bj (88.3 mg, 0.2 mmol) in dry CH3CN (2 mL) at 35 °C, was added 4 Å molecular sieve (60 mg) and MeOTf (27 μL, 0.25 mmol) under N2 atmosphere. After stirring for 4.5 h at 35 °C, deionized water (0.4 mL) and DBU (37 μL, 0.25 mmol) were added. The resulting mixture was allowed to stir for 30 min at 35 °C. The reaction mixture was acidified with 0.5 N citric acid (2 mL) and CH3CN (3 mL) was added to it, and the aqueous layer was separated. Further, aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic layers (both CH3CN+EtOAc) was concentrated in vacuo and purified over silica gel by column chromatography (20−40% ethyl acetate in hexane) to afford the enantiomeric products.

443.0801. For Sc(OTf)3-1a, compound 4bj was isolated as a white semisolid in 82% (72.5 mg) yield with 91:9 er. Rf = 0.21 (40% EtOAc in hexane). [α]25 D = +14.3 (c 0.41, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 29.6 min, tR (minor) = 78.8 min. For In(OTf)3-1a, compound ent-4bj was isolated as a white semisolid in 92% (81.4 mg) yield with 97:3 er. Rf = 0.21 (40% EtOAc in hexane). [α]25 D = −24.4 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 30.0 min, tR (major) = 76.6 min.

(R)-1-(1-Methyl-1H-imidazol-2-yl)-3-phenyl-5-p-tolylpentane-1,5dione (4ca). 1H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 7.4 Hz, 2H), 7.26−7.23 (m, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 4.12−4.06 (m, 1H), 3.90 (s, 3H), 3.68−3.63 (m, 1H), 3.51 (dd, J = 17.0, 6.8 Hz, 1H), 3.38 (dd, J = 16.8, 7.1 Hz, 1H), 3.30 (dd, J = 16.8, 6.9 Hz, 1H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 198.1, 191.0, 144.3, 143.8, 143.2, 134.7, 129.3, 129.0, 128.6, 128.3, 127.7, 126.9, 126.5, 45.2, 45.1, 36.6, 36.2, 21.7. IR (film): νmax 2921, 2851, 1677, 1606, 1494, 1453, 1408, 1289, 1264, 1180, 1154, 985 cm−1. HRMS (ESITOF): m/z [M + H]+ calcd for C22H23N2O2, 347.1760; found, 347.1765. For Sc(OTf)3-1a, compound 4ca was isolated as a white semisolid in 92% (63.6 mg) yield with 90:10 er. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = +10.4 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 26.4 min, tR (minor) = 56.5 min. For In(OTf)3-1a, compound ent-4ca was isolated as a white semisolid in 92% (63.5 mg) yield with 71.5:28.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = −6.0 (c 0.25, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 27.4 min, tR (major) = 57.3 min.

(R)-5-(4-Bromophenyl)-3-(2-methoxyphenyl)-5-oxopentanoic Acid (5). 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.20−7.16 (m, 2H), 6.88−6.82 (m, 2H), 4.08−4.03 (m, 1H), 3.78 (s, 3H), 3.39−3.30 (m, 2H), 2.90−2.79 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 198.1, 177.7, 157.1, 135.8, 131.9, 130.5, 129.8, 128.7, 128.2, 128.1, 120.8, 110.9, 55.3, 42.9, 38.2, 33.2. IR (film): νmax 2937, 2838, 1707, 1687, 1585, 1567, 1493, 1463, 1439, 1397, 1362, 1289, 1245, 1177, 1118, 1071, 1054, 1027, 1008 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H1878.9183BrO4, 377.0388; found, 377.0380. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H1880.9163BrO4, 379.0368; found, 379.0362. For Sc(OTf)3-1a, compound 5 was isolated as a white semisolid in 80% (60.5 mg) yield. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = −2.6 (c 0.7, CHCl3). For In(OTf)3-1a, compound ent-5 was isolated as a white semisolid in 81% (61.3 mg) yield. Rf = 0.2 (40% EtOAc in hexane). [α]25 D = +2.7 (c 0.6, CHCl3). General Procedure and Characterization of 6 and ent-6. The compound 5 or ent-5 (56.6 mg, 0.15 mmol) was suspended in dry dichloromethane (1.5 mL), and the mixture was allowed to stir at room temperate for 15 min. Then oxalyl chloride (26 μL, 0.3 mmol) was added to the reaction mixture slowly followed by 1−2 drops of DMF. After 1 h, the reaction was diluted with water and dichloromethane, and the organic layer was washed with brine and dried over anhydrous Na2SO4. The mixture was concentrated in value and purified over silica gel by column chromatography (25%−40% ether in hexane) to afford the enantiomeric products.

(S)-3-(2-Methoxyphenyl)-1-(1-methyl-1H-imidazol-2-yl)-5-(thiophen-2-yl)pentane-1,5-dione (4dj). 1H NMR (500 MHz, CDCl3): δ 7.65 (dd, J = 3.8, 1.1 Hz, 1H), 7.49 (dd, J = 4.9, 1.1 Hz, 1H), 7.20− 7.18 (m, 1H), 7.09−7.06 (m, 1H), 7.01−6.99 (m, 2H), 6.89 (s, 1H), 6.79−6.76 (m, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.26 (p, J = 7.1 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 3.65 (dd, J = 17.2, 7.3 Hz, 1H), 3.53 (dd, J = 17.3, 7.0 Hz, 1H), 3.28−3.20 (m, 2H). 13C{1H}NMR (100 MHz, CDCl3): δ 192.1, 191.4, 157.2, 144.8, 143.3, 133.3, 131.9, 131.5, 128.9, 128.6, 128.0, 127.7, 126.8, 120.6, 110.8, 55.4, 44.5, 43.0, 36.1, 32.6. IR (film): νmax 3105, 2924, 2852, 1670, 1493, 1463, 1438, 1413, 1355, 1289, 1243, 1154, 1116, 1054, 988 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21N2O3S, 369.1273; found, 369.1271. For Sc(OTf)3-1a, compound 4dj was isolated as a white solid in 84% (61.7 mg) yield with 90.5:9.5 er. Rf = 0.22 (40% EtOAc in hexane). Mp: 116−118 °C. [α]25 D = +24.6 (c 0.42, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 39.1 min, tR (minor) = 57.7 min. For In(OTf)3-1a, compound ent-4dj was isolated as a white solid in 88% (64.7 mg) yield with 71.5:28.5 er. Rf = 0.22 (40% EtOAc in hexane). Mp: 116−118 °C. [α]25 D = −15.0 (c 0.40, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3

(S)-6-(4-Bromophenyl)-4-(2-methoxyphenyl)-3,4-dihydro-2Hpyran-2-one (6). 1H NMR (500 MHz, CDCl3): δ 7.47−7.42 (m, 4H), 7.19−7.17 (m, 1H), 7.09 (dd, J = 7.4, 1.3 Hz, 1H), 6.87−6.81 (m, 2H), 5.81 (d, J = 5.0 Hz, 1H), 4.16 (dd, J = 12.6, 6.1 Hz, 1H), 3.76 (s, 3H), 2.92 (dd, J = 16.1, 7.6 Hz, 1H), 2.75 (dd, J = 16.1, 6.2 Hz, 1H). 13 C{1H} NMR (125 MHz, CDCl3) δ 167.9, 157.0, 149.7, 131.8, 131.6, 129.1, 128.9, 127.7, 126.3, 123.2, 121.0, 110.9, 104.1, 55.2, 34.7, 32.2. IR (film): νmax 2923, 2852, 1737, 1686, 1585, 1493, 1462, 1438, 1397, 1366, 1243, 1172, 1071, 1026 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H1678.9183BrO3, 359.0283; found, 359.0288. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H1680.9163BrO3, 361.0262; found, 361.0272. For Sc(OTf)3-1a, compound 6 was isolated as a white semisolid in 80% (43.3 mg) yield with 89.5:10.5 er. Rf = 0.55 (40% ether in hexane). [α]25 D = −39.2 (c 0.25, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 13.8 min, tR (minor) = 5067


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the reaction mixture was allowed to stir at 0 °C until the completion of the reaction (monitored by TLC). HCl (2 mL, 1 M) was added to it, and the mixture was stirred for 1 h. Then, water (2 mL) was added, and the resulting reaction mixture was extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated in vacuo and purified over silica gel by column chromatography (10− 40% ethyl acetate in hexane) to afford product ent-9.

17.2 min. For In(OTf)3-1a, compound ent-6 was isolated as a white semisolid in 82% (44.2 mg) yield with 96:4 er. Rf = 0.55 (40% ether in hexane). [α]25 D = +62.4 (c 0.26, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, nhexane/2-propanol (90:10) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 13.8 min, tR (major) = 17.1 min. General Procedure and Characterization of 7 and ent-7. To a solution of compound 4bj or ent-4bj (88.3 mg, 0.2 mmol) in dry CH3CN (2 mL) at 35 °C were added 4 Å molecular sieves (60 mg) and MeOTf (27 μL, 0.25 mmol) under a N2 atmosphere. After stirring the mixture for 4.5 h at 35 °C, MeOH (500 μL) and DBU (37 μL,0.25 mmol) were added. The resulting mixture was allowed to stir for 30 min at 35 °C, and the reaction mixture was purified over silica gel by column chromatography (20−40% ethyl acetate in hexane) to afford the products.

(R)-Methyl 2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3phenylpentanoate (9). 1H NMR (500 MHz, CDCl3): δ 7.26−7.20 (m, 4H), 7.17−7.14 (m, 1H), 7.11 (d, J = 0.7 Hz, 1H), 6.93 (s, 1H), 4.01 (dd, J = 17.3, 11.0 Hz, 1H), 3.82−3.79 (m, 4H), 3.63 (s, 3H), 3.20 (dd, J = 17.3, 3.6 Hz, 1H), 1.23 (s, 3H), 1.11 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 191.0, 177.7, 143.3, 140.3, 129.6, 129.0, 127.9, 126.9, 126.8, 51.9, 47.4, 46.4, 39.8, 36.1, 24.1, 21.9. IR (film): νmax 2924, 2854, 1728, 1680, 1463, 1454, 1409, 1289, 1255, 1190, 1128, 1086, 1015 cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H23N2O3, 315.1709; found, 315.1704. For Sc(OTf)3-1a, compound 9 was isolated as a white semisolid in 91% (57.3 mg) yield with 96:4 er. Rf = 0.3 (40% EtOAc in hexane). [α]25 D = +18.4 (c 0.69, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 13.9 min, tR (minor) = 52.6 min. For In(OTf)3-1a, compound ent-9 was isolated as a white semisolid in 77% (48.6 mg) yield with 90:10 er. Rf = 0.3 (40% EtOAc in hexane). [α]25 D = −51.3 (c 0.68, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, nhexane/2-propanol (80:20) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 13.9 min, tR (major) = 50.8 min. General Procedure and Characterization of 10. To a solution of compound 9 (62.9 mg, 0.2 mmol) in dry CH3CN (2 mL) at 35 °C were added 4 Å molecular sieves (50 mg) and MeOTf (27 μL, 0.25 mmol) under a N2 atmosphere. After stirring the mixture for 4.5 h at 35 °C, MeOH (500 μL) and DBU (37 μL, 0.25 mmol) were added. The resulting mixture was then allowed to stir for 30 min at 35 °C, and the reaction mixture was purified over silica gel by column chromatography (5−20% ethyl acetate in hexane) to afford the product 10.

(R)-Methyl 5-(4-Bromophenyl)-3-(2-methoxyphenyl)-5-oxopentanoate (7). 1H NMR (500 MHz, CDCl3): δ 7.80 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.20−7.16 (m, 2H), 6.89−6.82 (m, 2H), 4.09 (p, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.58 (s, 3H), 3.35 (d, J = 7.0 Hz, 2H), 2.86−2.75 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 198.0, 172.9, 157.1, 135.8, 131.9, 130.7, 129.8, 128.6, 128.1, 128.0, 120.7, 110.9, 55.3, 51.6, 43.0, 38.4, 33.4. IR (film): νmax 2922, 2852, 1737, 1684, 1585, 1493, 1462, 1243, 1009 cm−1. HRMS (ESI-TOF): m/z [M + H]+ for C19H2078.9183BrO4, 391.0545; found, 391.0547. HRMS (ESI-TOF): m/z [M + H]+ for C19H2080.9163BrO4, 393.0525; found, 393.0533. For Sc(OTf)3-1a, compound 7 was isolated as a white semisolid in 83% (65 mg) yield with 90.5:9.5 er. Rf = 0.5 (20% EtOAc in hexane). [α]25 D = +4.2 (c 1.49, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 17.8 min, tR (major) = 27.7 min. For In(OTf)3-1a, compound ent-7 was isolated as a white semisolid in 81% (63.5 mg) yield with 96:4 er. Rf = 0.5 (20% EtOAc in hexane). [α]25 D = −6.2 (c 1.46, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2propanol (80:20) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 17.9 min, tR (minor) = 28.1 min. General Procedure for the Reaction of Silyl Ketene Acetal 8 with α,β-Unsaturated 2-Acyl Imidazole 3a Catalyzed by the Sc(OTf)3-1a Complex. A solution of ligand 1a (9.44 mg, 0.024 mmol) and Sc(OTf)3 (9.84 mg, 0.02 mmol) in dry chloroform (2 mL) was stirred at room temperature for 4 h under a nitrogen atmosphere. α,βUnsaturated 2-acyl imidazole 3a (42.4 mg, 0.20 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. HFIP (21 μL, 0.20 mmol) was then added to the mixture, and the resulting reaction mixture was again stirred for 15 min at rt. Then silyl ketene acetal 8 (102 μL, 0.5 mmol) was added, and the reaction mixture was allowed to stir at room temperature until the completion of the reaction (monitored by TLC). HCl (2 mL, 1 M) was added to it, and the mixture was stirred for 1 h. Then, water (2 mL) was added, and the resulting reaction mixture was extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated in vacuo and purified over silica gel by column chromatography (10−40% ethyl acetate in hexane) to afford product 9. General Procedure for the Reaction of Silyl Ketene Acetal 8 with α,β-Unsaturated 2-Acyl Imidazole 3a Catalyzed by the In(OTf)3-1a Complex. A solution of a ligand 1a (9.44 mg, 0.024 mmol) and In(OTf)3 (11.24 mg, 0.02 mmol) in dry chloroform (2 mL) was stirred at room temperature for 3.5 h under a nitrogen atmosphere. α,β-Unsaturated 2-acyl imidazole 3a (42.4 mg, 0.20 mmol) was added, and the whole mixture was stirred for an additional 15 min at rt. The mixture was cooled to 0 °C; HFIP (21 μL, 0.20 mmol) was added, and the resulting mixture was again allowed to stir for an additional 15 min at 0 °C. The silyl ketene acetal 8 (102 μL, 0.5 mmol) was added, and

(R)-Methyl 2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3phenylpentanoate (10). 1H NMR (400 MHz, CDCl3): δ 7.24−7.11 (m, 3H), 7.11−7.05 (m, 2H), 3.58 (s, 3H), 3.46 (dd, J = 11.3, 4.2 Hz, 1H), 3.41 (s, 3H), 2.79 (dd, J = 15.7, 11.3 Hz, 1H), 2.60 (dd, J = 15.7, 4.2 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 177.5, 172.6, 139.4, 129.3, 128.0, 127.1, 52.0, 51.7, 48.9, 46.1, 35.8, 24.3, 21.6. IR (film): νmax 3030, 2981, 2951, 1737, 1732, 1454, 1435, 1303, 1256, 1128, 1086, 1018 cm−1. Compound 10 was isolated as a colorless liquid in 70% (37.1 mg) yield with 96:4 er. Rf = 0.3 (20% EtOAc in hexane). [α]25 D = +10.4 (c 0.95, CHCl3). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as an eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 6.9 min, tR (minor) = 18.7 min.

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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.8b00399. 5068


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The Journal of Organic Chemistry 1

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H and 13C{1H} NMR spectra for all compounds and HPLC chromatograms (PDF)

Optically Active Iridium Imidazol-2-ylidene-oxazoline Complexes: Preparation and Use in Asymmetric Hydrogenation of Arylalkenes. J. Am. Chem. Soc. 2003, 125, 113. (i) Bernardi, A.; Colombo, G.; Scolastico, C. Enantioselective Mukaiyama−Michael Reactions of 2Carbomethoxy Cyclopentenone Catalyzed by Chiral Bis(oxazoline)Cu(II) Complexes. Tetrahedron Lett. 1996, 37, 8921. (j) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of Catalytic Enantioselective Aldol Additions of Enolsilanes to (Benzyloxy)acetaldehyde. J. Am. Chem. Soc. 1999, 121, 669. (k) Kobayashi, S.; Ishitani, H. Lanthanide(III)Catalyzed Enantioselective Diels-Alder Reactions. Stereoselective Synthesis of Both Enantiomers by Using a Single Chiral Source and a Choice of Achiral Ligands. J. Am. Chem. Soc. 1994, 116, 4083. (3) (a) Wu, W.-Q.; Peng, Q.; Dong, D.-X.; Hou, X.-L.; Wu, Y.-D. A Dramatic Switch of Enantioselectivity in Asymmetric Heck Reaction by Benzylic Substituents of Ligands. J. Am. Chem. Soc. 2008, 130, 9717. (b) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. Hydrogen-Bonding Directed Reversal of Enantioselectivity. J. Am. Chem. Soc. 2007, 129, 750. (4) For selected examples, see: (a) Berkessel, A.; Mukherjee, S.; Lex, J. Reversal of Enantioselectivity by Catalyst Protonation: Asymmetric Hydrocyanation of Imines with Oxazaborolidines. Synlett 2006, 41. (b) Sohtome, Y.; Tanaka, S.; Takada, K.; Yamaguchi, T.; Nagasawa, K. Solvent-Dependent Enantiodivergent Mannich-Type Reaction: Utilizing a Conformationally Flexible Guanidine/Bisthiourea Organocatalyst. Angew. Chem., Int. Ed. 2010, 49, 9254. (c) Hua, M.-Q.; Cui, H.-F.; Wang, L.; Nie, J.; Ma, J.-A. Reversal of Enantioselectivity by Tuning the Conformational Flexibility of Phase-Transfer Catalysts. Angew. Chem., Int. Ed. 2010, 49, 2772. (d) Alix, A.; Lalli, C.; Retailleau, P.; Masson, G. Highly Enantioselective Electrophilic α-Bromination of Enecarbamates: Chiral Phosphoric Acid and Calcium Phosphate Salt Catalysts. J. Am. Chem. Soc. 2012, 134, 10389. (e) Abermil, N.; Masson, G.; Zhu, J. Invertible Enantioselectivity in 6′-Deoxy-6′acylamino-β-isocupreidine-Catalyzed Asymmetric Aza-Morita−Baylis−Hillman Reaction: Key Role of Achiral Additive. Org. Lett. 2009, 11, 4648. (f) Nakayama, K.; Maruoka, K. Complete Switch of Product Selectivity in Asymmetric Direct Aldol Reaction with Two Different Chiral Organocatalysts from a Common Chiral Source. J. Am. Chem. Soc. 2008, 130, 17666. (g) Wang, J.; Feringa, B. L. Dynamic Control of Chiral Space in a Catalytic Asymmetric Reaction Using a Molecular Motor. Science 2011, 331, 1429. (5) For enantioselective metal-catalyzed approaches, see: (a) Yura, T.; Iwasawa, N.; Narasaka, K.; Mukaiyama, T. The Catalytic Asymmetric Michael Reaction of Tin(II) Enethiolates. Chem. Lett. 1988, 17, 1025. (b) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. A Catalytic Asymmetric Michael Reaction of Silyl Enol Ethers with α,β-Unsaturated Ketones Using a Chiral Titanium Oxide. Chem. Lett. 1994, 23, 97. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti, S.; Scolastico, C. Enantioselective Conjugate Additions of Silylketene Acetals to 2-Carboxycyclopentenones Promoted by Chiral Ti Complexes. Tetrahedron 1997, 53, 13009. (d) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. C2-Symmetric Cu(II) Complexes as Chiral Lewis Acids. Catalytic Enantioselective Michael Addition of Silylketene Acetals to Alkylidene Malonates. J. Am. Chem. Soc. 1999, 121, 1994. (e) Evans, D. A.; Willis, M. C.; Johnston, J. N. Catalytic Enantioselective Michael Additions to Unsaturated Ester Derivatives Using Chiral Copper(II) Lewis Acid Complexes. Org. Lett. 1999, 1, 865. (f) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. Enantioselective Lewis Acid Catalyzed Michael Reactions of Alkylidene Malonates. Catalysis by C2-Symmetric Bis(oxazoline) Copper(II) Complexes in the Synthesis of Chiral, Differentiated Glutarate Esters. J. Am. Chem. Soc. 2000, 122, 9134. (g) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. Enantioselective and Diastereoselective Mukaiyama−Michael Reactions Catalyzed by Bis(oxazoline) Copper(II) Complexes. J. Am. Chem. Soc. 2001, 123, 4480. (h) Ishihara, K.; Fushimi, M. Design of a Small-Molecule Catalyst Using Intramolecular Cation-π Interactions for Enantioselective DielsAlder and Mukaiyama−Michael Reactions: L-DOPA-Derived Monop-

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Vinod K. Singh: 0000-0003-0928-5543 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS V.K.S. thanks SERB, DST (EMR/2014/001165) for a research grant and the Department of Science and Technology, India for the J. C. Bose fellowship. A.D. is grateful to IIT Kanpur for a doctoral fellowship.

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DEDICATION This work is dedicated to Professor V. Chandrasekhar on the occasion of his 60th birthday. REFERENCES

(1) For reviews, see: (a) Kim, Y. H. Dual Enantioselective Control in Asymmetric Synthesis. Acc. Chem. Res. 2001, 34, 955. (b) Sibi, M. P.; Liu, M. Reversal of Stereochemistry in Enantioselective Transformations. Can They Be Planned or Are They Just Accidental? Curr. Org. Chem. 2001, 5, 719. (c) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Toggling Enantioselective Catalysis-A Promising Paradigm in the Development of More Efficient and Versatile Enantioselective Synthetic Methodologies. Chem. Soc. Rev. 2003, 32, 115. (d) Tanaka, T.; Hayashi, M. New Approach for Complete Reversal of Enantioselectivity Using a Single Chiral Source. Synthesis 2008, 2008, 3361. (e) Bartók, M. Unexpected Inversions in Asymmetric Reactions: Reactions with Chiral Metal Complexes, Chiral Organocatalysts, and Heterogeneous Chiral Catalysts. Chem. Rev. 2010, 110, 1663. (f) Escorihuela, J.; Burguete, M. I.; Luis, S. V. New Advances in Dual Stereocontrol for Asymmetric Reactions. Chem. Soc. Rev. 2013, 42, 5595. (g) Blanco, V.; Leigh, D. A.; Marcos, V. Artificial Switchable Catalysts. Chem. Soc. Rev. 2015, 44, 5341. (2) For selected examples, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Conformationally Constrained Bis(oxazoline) Derived Chiral Catalyst: A Highly Effective Enantioselective Diels-Alder Reaction. Tetrahedron Lett. 1996, 37, 3815. (b) Sibi, M. P.; Chen, J. Enantioselective Tandem Radical Reactions: Vicinal Difunctionalization in Acyclic Systems with Control over Relative and Absolute Stereochemistry. J. Am. Chem. Soc. 2001, 123, 9472. (c) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. Switching Enantiofacial Selectivities Using One Chiral Source: Catalytic Enantioselective Synthesis of the Key Intermediate for (20S)-Camptothecin Family by (S)-Selective Cyanosilylation of Ketones. J. Am. Chem. Soc. 2001, 123, 9908. (d) Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Reversal of Enantioselectivity Between the Copper(I)- and Silver(I)-Catalyzed 1,3-Dipolar Cycloaddition Reactions Using a Brucine-Derived Amino Alcohol Ligand. Angew. Chem., Int. Ed. 2009, 48, 7420. (e) Wang, Z.; Yang, Z.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Highly Enantioselective Michael Addition of Pyrazolin-5-ones Catalyzed by Chiral Metal/ N,N′-Dioxide Complexes: Metal-Directed Switch in Enantioselectivity. Angew. Chem., Int. Ed. 2011, 50, 4928. (f) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. Controllable Enantioselective Friedel−Crafts Reaction Between Indoles and Alkylidene Malonates Catalyzed by Pseudo-C3Symmetric Trisoxazoline Copper(II) Complexes. J. Org. Chem. 2004, 69, 1309. (g) Storch, G.; Trapp, O. Temperature-Controlled Bidirectional Enantioselectivity in a Dynamic Catalyst for Asymmetric Hydrogenation. Angew. Chem., Int. Ed. 2015, 54, 3580. (h) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.; Burgess, K. 5069


Article


Equivalents from α,β-Unsaturated Aldehydes for Enantioselective Diels−Alder Reactions. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20661. (10) Shalini, K.; Sharma, P. K.; Kumar, N. Imidazole and Its Biological Activities: A Review. Chem. Sin. 2010, 1, 36. (11) (a) Weinreb, S. M. Some Recent Advances in the Synthesis of Polycyclic Imidazole-Containing Marine Natural Products. Nat. Prod. Rep. 2007, 24, 931. (b) Sívek, R.; Bureš, F.; Pytela, O.; Kulhánek, J. Imidazole-Based Potential Bi- and Tridentate Nitrogen Ligands: Synthesis, Characterization and Application in Asymmetric Catalysis. Molecules 2008, 13, 2326. (c) Miller, S. J. In Search of Peptide-Based Catalysts for Asymmetric Organic Synthesis. Acc. Chem. Res. 2004, 37, 601. (12) (a) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Ionic Liquid (Molten Salt) Phase Organometallic Catalysis. Chem. Rev. 2002, 102, 3667. (b) Crudden, C. M.; Allen, D. P. Stability and Reactivity of NHeterocyclic Carbene Complexes. Coord. Chem. Rev. 2004, 248, 2247. (13) (a) Evans, D. A.; Fandrick, K. R.; Song, H.-J. Enantioselective Friedel−Crafts Alkylations of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Bis(oxazolinyl)pyridine−Scandium(III) Triflate Complexes. J. Am. Chem. Soc. 2005, 127, 8942. (b) Evans, D. A.; Fandrick, K. R. Catalytic Enantioselective Pyrrole Alkylations of α,β-Unsaturated 2-Acyl Imidazoles. Org. Lett. 2006, 8, 2249. (c) Li, S.-W.; Gong, J.; Kang, Q. Chiral-at-Metal Rh(III) Complex-Catalyzed Decarboxylative Michael Addition of β-Keto Acids with α,β-Unsaturated 2-Acyl Imidazoles or Pyridine. Org. Lett. 2017, 19, 1350. (d) Rout, S.; Das, A.; Singh, V. K. An Asymmetric Vinylogous Mukaiyama−Michael Reaction of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Sc(III)− or Er(III)−Pybox Complexes. Chem. Commun. 2017, 53, 5143. (e) Li, K.; Wan, Q.; Kang, Q. Chiral-at-Metal Rh(III) Complex Catalyzed Asymmetric Conjugate Addition of Unactivated Alkenes with α,β-Unsaturated 2-Acyl Imidazoles. Org. Lett. 2017, 19, 3299. (14) (a) Chen, D.; Chen, Z.; Xiao, X.; Yang, Y.; Lin, L.; Liu, X.; Feng, X. Highly Enantioselective Michael Addition of Malonate Derivatives to Enones Catalyzed by an N,N′-Dioxide−Scandium(III) Complex. Chem. - Eur. J. 2009, 15, 6807. (b) Zhang, Q.; Xiao, X.; Lin, L.; Liu, X.; Feng, X. Highly Enantioselective Synthesis of γ-Substituted Butenolides via the Vinylogous Mukaiyama−Michael Reaction Catalyzed by a Chiral Scandium(III)−N,N′-Dioxide Complex. Org. Biomol. Chem. 2011, 9, 5748. (c) Wang, Z.; Yao, Q.; Kang, T.; Feng, J.; Liu, X.; Lin, L.; Feng, X. Highly Diastereo- and Enantioselective Michael Addition of 3-Substituted Benzofuran-2(3H)-ones to 4-Oxoenoates Catalyzed by Lanthanide(III) Complexes. Chem. Commun. 2014, 50, 4918. (15) Kitajima, H.; Katsuki, T. Chiral Lewis Acid Promoted Asymmetric Michael Addition Reaction of 2-(Trimethylsilyloxy)furans. Synlett 1997, 1997, 568. (16) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Asymmetric Friedel−Crafts Alkylation of Indoles with Methyl (E)-2Oxo-4-aryl-3-butenoates Catalyzed by Sc(OTf)3/Pybox. Chem. - Eur. J. 2008, 14, 3630. (17) Shannon, R. D. Revised Effective Ionic Radii and Systematic Studies of Interatomic Distances in Halides and Chaleogenides. Acta Crystallogr., Sect. A: Cryst. Phys., Diffr., Theor. Gen. Crystallogr. 1976, 32, 751. (18) (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K. Catalytic Asymmetric Synthesis of Substituted 3-Hydroxy2-Oxindoles. Angew. Chem., Int. Ed. 2010, 49, 744. (b) Gutierrez, E. G.; Wong, C. J.; Sahin, A. H.; Franz, A. K. Enantioselective and Regioselective Indium(III)-Catalyzed Addition of Pyrroles to Isatins. Org. Lett. 2011, 13, 5754. (19) Zhang, F.-Y.; Corey, E. J. Highly Enantioselective Michael Reactions Catalyzed by a Chiral Quaternary Ammonium Salt. Illustration by Asymmetric Syntheses of (S)-Ornithine and Chiral 2Cyclohexenones. Org. Lett. 2000, 2, 1097. (20) Gatzenmeier, T.; Kaib, P. S. J.; Lingnau, J. B.; Goddard, R.; List, B. The Catalytic Asymmetric Mukaiyama−Michael Reaction of Silyl Ketene Acetals with α,β-Unsaturated Methyl Esters. Angew. Chem., Int. Ed. 2018, 57, 2464.

eptide·Cu(II) Complex. Org. Lett. 2006, 8, 1921. (i) Xu, X.; Hu, W.H.; Doyle, M. P. Highly Enantioselective Catalytic Synthesis of Functionalized Chiral Diazoacetoacetates. Angew. Chem., Int. Ed. 2011, 50, 6392. (j) Rout, S.; Ray, S. K.; Singh, V. K. Enantioselective Mukaiyama−Michael with 2-Enoyl pyridine N-Oxides Catalyzed by PYBOX-DIPH-Zn(II)-Complexes at Ambient Temperature. Org. Biomol. Chem. 2013, 11, 4537. (k) Nagatani, K.; Minami, A.; Tezuka, H.; Hoshino, Y.; Nakada, M. Enantioselective Mukaiyama− Michael Reaction of Cyclic α-Alkylidene β-Keto Phosphine Oxide and Phosphonate and Asymmetric Synthesis of (R)-Homosarkomycin. Org. Lett. 2017, 19, 810. (6) For enantioselective organocatalytic approaches, see: (a) Zhang, F.-Y.; Corey, E. J. Enantio- and Diastereoselective Michael Reactions of Silyl Enol Ethers and Chalcones by Catalysis Using a Chiral Quaternary Ammonium Salt. Org. Lett. 2001, 3, 639. (b) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A. Asymmetric Mukaiyama−Michael Addition of Acyclic Enones Catalyzed by alloThreonine-Derived B-Aryloxazaborolidinones. Org. Lett. 2001, 3, 2101. (c) Harada, T.; Adachi, S.; Wang, X. Dimethylsilyl Ketene Acetal as a Nucleophile in Asymmetric Michael Reaction: Enhanced Enantioselectivity in Oxazaborolidinone-Catalyzed Reaction. Org. Lett. 2004, 6, 4877. (d) Wang, W.; Li, H.; Wang, J. Enantioselective Organocatalytic Mukaiyama−Michael Addition of Silyl Enol Ethers to α,β-Unsaturated Aldehydes. Org. Lett. 2005, 7, 1637. (e) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. Enantioselective Lewis Acid-Catalyzed Mukaiyama−Michael Reactions of Acyclic Enones. Catalysis by allo-Threonine-Derived Oxazaborolidinones. J. Org. Chem. 2003, 68, 10046. (f) Wang, X.; Harada, T.; Iwai, H.; Oku, A. Practical Asymmetric Mukaiyama−Michael Reaction of Benzalacetone Derivatives Catalyzed by allo-Threonine-Derived Oxazaborolidinone. Chirality 2003, 15, 28. (g) Claraz, A.; Sahoo, G.; Berta, D.; Madarász, Á .; Pápai, I.; Pihko, P. M. A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters. Angew. Chem., Int. Ed. 2016, 55, 669. (7) (a) Liblikas, I.; Santangelo, E. M.; Sandell, J.; Baeckström, P.; Svensson, M.; Jacobsson, U.; Unelius, C. R. Simplified Isolation Procedure and Interconversion of the Diastereomers of Nepetalactone and Nepetalactol. J. Nat. Prod. 2005, 68, 886. (b) Cui, C.-M.; Li, X.M.; Meng, L.; Li, C.-S.; Huang, C.-G.; Wang, B.-G. 7-Norergosterolide, a Pentalactone-Containing Norsteroid and Related Steroids from the Marine-Derived Endophytic Aspergillus ochraceus EN-31. J. Nat. Prod. 2010, 73, 1780. (8) (a) Willot, M.; Radtke, L.; Könning, D.; Fröhlich, R.; Gessner, V. H.; Strohmann, C.; Christmann, M. Total Synthesis and Absolute Configuration of the Guaiane Sesquiterpene Englerin A. Angew. Chem., Int. Ed. 2009, 48, 9105. (b) Yao, W.; Dou, X.; Lu, Y. Highly Enantioselective Synthesis of 3,4-Dihydropyrans through a PhosphineCatalyzed [4 + 2] Annulation of Allenones and β,γ-Unsaturated αKeto Esters. J. Am. Chem. Soc. 2015, 137, 54. (9) For selected examples, see: (a) Juhl, K.; Jørgensen, K. A. The First Organocatalytic Enantioselective Inverse-Electron-Demand Hetero-Diels−Alder Reaction. Angew. Chem., Int. Ed. 2003, 42, 1498. (b) Evans, D. A.; Thomson, R. J.; Franco, F. Ni(II) Tol-BINAPCatalyzed Enantioselective Michael Reactions of β-Ketoesters and Unsaturated N-Acylthiazolidinethiones. J. Am. Chem. Soc. 2005, 127, 10816. (c) He, M.; Uc, G. J.; Bode, J. W. Chiral N-Heterocyclic Carbene Catalyzed, Enantioselective Oxodiene Diels−Alder Reactions with Low Catalyst Loadings. J. Am. Chem. Soc. 2006, 128, 15088. (d) Tozawa, T.; Yamane, Y.; Mukaiyama, T. Enantioselective Synthesis of 3,4-Dihydropyran-2-ones by Chiral Quaternary Ammonium Phenoxide-Catalyzed Tandem Michael Addition and Lactonization. Chem. Lett. 2006, 35, 56. (e) Samanta, S.; Krause, J.; Mandal, T.; Zhao, C.-G. Inverse-Electron-Demand Hetero-Diels−Alder Reaction of β,γUnsaturated α-Ketophosphonates Catalyzed by Prolinal Dithioacetals. Org. Lett. 2007, 9, 2745. (f) Li, G.-Q.; Dai, L.-X.; You, S.-L. NHeterocyclic Carbene Catalyzed Ring Expansion of Formylcyclopropanes: Synthesis of 3,4-Dihydro-α-pyrone Derivatives. Org. Lett. 2009, 11, 1623. (g) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Chiral N-Heterocyclic Carbene-catalyzed Generation of Ester Enolate 5070


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The Journal of Organic Chemistry (21) Talele, T. T. Natural-Products-Inspired Use of the gemDimethyl Group in Medicinal Chemistry. J. Med. Chem. 2018, 61, 2166. (22) (a) Sekar, G.; DattaGupta, A.; Singh, V. K. Asymmetric Kharasch Reaction: Catalytic Enantioselective Allylic Oxidation of Olefins Using Chiral Pyridine Bis(diphenyloxazoline)−Copper Complexes and tert-Butyl Perbenzoate. J. Org. Chem. 1998, 63, 2961. (b) Ginotra, S. K.; Singh, V. K. Enantioselective Oxidation of Olefins Catalyzed by Chiral Copper Bis(oxazolinyl) Pyridine Complexes: a Reassessment. Tetrahedron 2006, 62, 3573. (c) Ginotra, S. K.; Singh, V. K. Studies on Enantioselective Allylic Oxidation of Olefins Using Peresters Catalyzed by Cu(I)-Complexes of Chiral Pybox Ligands. Org. Biomol. Chem. 2006, 4, 4370. (23) (a) Myers, M. C.; Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A. Catalytic Conjugate Additions of Carbonyl Anions under Neutral Aqueous Conditions. J. Am. Chem. Soc. 2005, 127, 14675. (b) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Enantioselective Nitrone Cycloadditions of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Bis(oxazolinyl)pyridine−Cerium(IV) Triflate Complexes. Org. Lett. 2006, 8, 3351. (c) Drissi-Amraoui, S.; Morin, M. S. T.; Crévisy, C.; Baslé, O.; de Figueiredo, R. M.; Mauduit, M.; Campagne, J.-M. Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl-N-methylimidazole Michael Acceptors: A Powerful Synthetic Platform. Angew. Chem., Int. Ed. 2015, 54, 11830. (24) (a) Shen, H.; Li, J.; Liu, Q.; Pan, J.; Huang, R.; Xiong, Y. Umpolung Strategy for Synthesis of β-Ketonitriles through Hypervalent Iodine-Promoted Cyanation of Silyl Enol Ethers. J. Org. Chem. 2015, 80, 7212. (b) Wei, S.; Du, H. A Highly Enantioselective Hydrogenation of Silyl Enol Ethers Catalyzed by Chiral Frustrated Lewis Pairs. J. Am. Chem. Soc. 2014, 136, 12261.

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