Metal-Controlled Switching of Enantioselectivity in the Mukaiyama

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Metal-Controlled Switching of Enantioselectivity in Mukaiyama-Michael Reaction of #,#-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Metal-Pybox Complexes Subhrajit Rout, Arko Das, and Vinod K. Singh J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00399 • Publication Date (Web): 16 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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The Journal of Organic Chemistry

Metal-Controlled Switching of Enantioselectivity in MukaiyamaMichael 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 - 208 016, UP, India Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal - 462 066, MP, India

‡

GRAPHICAL ABSTRACT

ABSTRACT Metal directed switching of enantioselectivity in Mukaiyama-Michael reaction of silyl enol ethers to α,β- unsaturated 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 δketo acid and ester, and 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

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 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 metal-catalyzed reactions can be achieved by using the same enantiomer of a chiral ligand with different metals,2a-e and by changing reaction conditions such as solvent,2f temperature,2g pressure,2h counteranion,2i,j and additive.2k In 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 were found to induce a switch in the enantioselectivity of a metal-catalyzed reaction.3 Further, enantioswitching in organocatalytic reactions have also received attention in asymmetric catalysis.4 Asymmetric Mukaiyama-Michael reaction is one of the potential chemical tools for the synthesis of enantioenriched 1,5-dicarbonyls. Considerable attention has been devoted in the

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development of asymmetric Mukaiyama-Michael reaction.5,6 However, access to both enantiomeric 1,5-dicarbonyls via 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 Mukaiyama-Michael reaction of 2-carbomethoxy cyclopentenone promoted by chiral bisoxazoline-Cu(II) complexes.2i The aforementioned methodology is limited to few examples in moderate yields with enantioselectivities up to 66% ee. Nakada and co-workers have also studied one example of counteranion directed enantioswitching with the same chiral bisoxazoline ligand in their recent report on enantioselective MukaiyamaMichael addition of cyclic α-alkylidene β-keto phosphonate and phosphine oxide.5k Consequently, 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 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, 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,βunsaturated 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-3butenoate to 2-enoyl imidazoles.5i Recently, we have described a pybox-diph-Zn(II) complex catalyzed enantioselective Mukaiyama-Michael addition of 2-enoyl pyridine N-oxides.5j Herein, we report an enantioselective Mukaiyama-Michael reaction of silyl enol ethers to α,β-unsaturated 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.

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 % of a 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 Intensive study of various bisoxazoline ligands with Sc(OTf)3 resulted 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, 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 enantioselectivity of opposite enantiomer decreased in the absence of HFIP, and also confirmed that there was no effect of HFIP on the reversal of enantioselectivity (Table 1, entry 12). With the hope to secure better enantioselectivity, the effects of solvent and catalyst loading on the formation of both the enantiomeric products were investigated (Table 2). Screening of various solvents disclosed that chloroform was the best combination with 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 4aa with slight loss in enantioselectivity, and needed longer reaction time (Table 2, entry 6). To improve the enantioselectivity, the effect of reaction temperature


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was investigated. The reaction at 0 °C did not bring any improvement to the enantioselectivity, but decreased the yield of product 4aa with 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 % of Sc(OTf)3-1a complex in chloroform at room temperature (Table 2, entry 1). Further, testing of different solvents with In(OTf)3-1a system was unfruitful in terms of enantioselectivity of opposite enantiomer (Table 2, entries 9-11). We next screened 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 % of catalyst loading (Table 2, entry 13). Table 1. Screening of Ligands and Lewis acidsa

H O

O H

N N

O

H

N

H 1a

entry

ligand

Ph

time (h)

i

Ph

1c: R = Pr 1d: R = Me 1e: R = Bn b

yield (%)

R

O

O

Ph

N

R

1b

Lewis acid

O

N N

Ph

N

Ph

O

Ph

O

N

N

N

N

Ph

Ph 1f

erc

1d Sc(OTf)3 4 81 90:10 1a 2 Sc(OTf)3 1 90 91:9 1a 3 Sc(OTf)3 24 15 58.5:41:5 1b 4 Sc(OTf)3 24 16 70.5:29.5 1c 5 Sc(OTf)3 24 15 57:43 1d 6 Sc(OTf)3 24 13 53:47 1e 7 Sc(OTf)3 24 15 50:50 1f 8 Zn(OTf)2 24 30 51:49 1a 9 Mg(OTf)2 24 15 54:46 1a 10 Yb(OTf)3 24 18 58:42 1a 11 In(OTf)3 1 92 26:74 1a d 12 In(OTf)3 24 63 30:70 1a 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 chiral IA-3 column. d Reaction was carried out without HFIP. With optimized reaction conditions, the substrate scope for 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 2-acyl imidazoles with phenyl group containing electron-withdrawing 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 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 –donating substituents 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.



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Table 2. Optimization Studiesa

solvent

Lewis acid

time (h)

yieldb (%)

erc

1

CHCl3

Sc(OTf)3

1

90

91:9

2

CH2Cl2

Sc(OTf)3

1

91

90:10

3

DCE

Sc(OTf)3

1

91

89:11

4

THF

Sc(OTf)3

24

20

87:13

5

toluene

Sc(OTf)3

24

Trace

-

CHCl3 CHCl3 CHCl3 DCE CH3CN

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

2 8 1 1.5 1

90 81 92 71 91

90:10 90.5:9.5 26:74 27:73 27:73

entry

d

6 7e 8 9 10 11

EtOAc

In(OTf)3

24

31

50:50

f

CHCl3

In(OTf)3

2.5

91

27:73

e

13 14g

CHCl3 CHCl3

In(OTf)3 In(OTf)3

3.5 8

90 80

23:77 23:77

15e,h

CHCl3

In(OTf)3

3.5

90

23:77

12

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 chiral IA-3 column. dReaction was carried out using 6 mol % of 1a and 5 mol % of Sc(OTf)3. eReaction at 0 °C. f Reaction was carried out using 6 mol % of 1a and 5 mol % of In(OTf)3. gReaction at -20 °C. hUse of 4Å molecular sieves (10 mg).

Next, we devoted our efforts to evaluate the substrate scope for the Mukaiyama-Michael reaction with the optimized reaction conditions of 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 rich phenyl groups were 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 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 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 moderate enantioselectivity (71.5:28.5 er), when silyl enol ether 2d bearing a heteroaryl group was charged with α,β-unsaturated 2-acyl imidazole 3j. Further, we realized to show the potential and the practicality of the metalcontrolled enantioswitching of Mukaiyama-Michael reaction. Toward this, a reaction of 0.5 gram 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 same yield and without loss of


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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 2-enoyl imidazoles catalyzed by 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 Si face is hindered by the 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. Scheme 1. Substrate Scope Promoted by Chiral Sc(OTf)3-1a Complex



Scheme 2. Substrate Scope Promoted by Chiral In(OTf)3-1a Complex

Re -f a ce

Figure. 1 Proposed transition state.


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We next turned our attention to highlight the synthetic utility of our approach by elaborating 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 3,4- dihydropyran-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 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). Furtherer, the product 9 was transformed into a diester 10 via methylation followed by reaction of MeOH and DBU.5i Th absolute stereochemistry of the product was found to be (R) by comparing the optical rotation of the compound 10 with literature (Scheme 4).20 Importantly, structural framework comprising a gem-dimethyl group connected to a tertiary sterecenter is found in many biologically active natural products.21 Further, the importance of gem-dimethyl group has also been recognized in drug development.21 Scheme 3. Scale-Up of Reaction and Synthetic Elaboration



Scheme 4. Scope of a Silyl Ketene Acetal

CONCLUSION In conclusion, we have reported the metal-controlled enantioswitching in MukaiyamaMichael reaction of α,β- unsaturated 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, and 3,4dihydropyran-2-one. Moreover, the strategy enabled us to install a tertiary stereocenter adjacent to a gem-dimethyl group with reversal of enantioselectivity. The enantioswitching was explained by proposed transition states. Further, active investigations along these directions are currently underway in our laboratory.

EXPERIMENTAL SECTION Materials and Methods Ligands 1a-b and 1f are commercially available. Ligands 1c-e were synthesized according to procedure known in literature.22 α,β-Unsaturated 2-acyl imidazoles 3a-d, f, g-k were prepared according to 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 reported method.24 HFIP (1, 1, 1, 3, 3, 3-Hexafluoro-2-propanol) and all 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 MHz and 400 MHz) spectrometers in CDCl3. Chemical shifts are reported in delta (δ) units, in parts per million (ppm). Tetramethylsilane and CDCl3 were used as internal standard for 1H and 13C{1H} NMR respectively. Coupling constants were reported in 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, p for pentet. IR spectra were measured with PerkinElmer FT-IR Spectrum Two spectrometer. Mass spectrometric analysis was done on waters Q Tof Premier Micromass (ESI). Routine monitoring of reactions were performed using precoated silicagel TLC plates from E-Merck. All the 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 iso-propanol and n-hexane as eluent at 25º 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-1-methylimidazole (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


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added to it. The resulting mixture was extracted with CH2Cl2 (3 x 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-1-one (3e): The compound was isolated as grey solid in 71% (3.601 g) yield. Rf = 0.3 (40% EtOAc in hexane). Mp: 138−140 °C. 1H NMR (500 MHz, CDCl3): δ 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-2-en-1-one (3h): The compound was isolated as light yellow solid, 3.30 g, 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; m/z [M + H]+ calcd for C13H11 80.9163 Br2N2O 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 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 hours under nitrogen atmosphere. α,β-Unsaturated 2acyl imidazole 3 (0.20 mmol) was added and the whole mixture was stirred for an additional 15 minute at rt. HFIP (21 µL, 0.20 mmol) was then added to the mixture and the resulting reaction mixture was again stirred for 15 minute at rt. Then silyl enol ether 2 (0.40 mmol) was added and the reaction mixture was allowed for stirring 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. For scale-up of reaction: A solution of a 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 hours under nitrogen atmosphere. α,β-Unsaturated 2-acyl imidazole 3j (500 mg, 2.06 mmol) were added and the whole mixture was stirred for an additional 15 minute at rt. HFIP (216 µL, 2.06 mmol) was then added to the mixture and the resulting reaction mixture was again stirred for 15 minute at rt. Then silyl enol ether 2b (1.12 g, 4.12 mmol) was added and the reaction mixture was allowed for stirring 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 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 hour under nitrogen atmosphere. α,βUnsaturated 2-acyl imidazole 3 (0.20 mmol) was added and the whole mixture was stirred for an additional 15 minute at rt. The mixture was cooled to 0 °C and HFIP (21 µL, 0.20 mmol) was added



and the resulting mixture was again allowed to stir for additional 15 minute at 0 °C. The silyl enol ether 2 (0.40 mmol) was added and the reaction mixture was allowed for stirring 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. For 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 hour under 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 minute at rt. The mixture was cooled to 0 °C and HFIP (216 µL, 2.06 mmol) was added and the resulting mixture was again allowed to stir for additional 15 minute at 0 °C. The silyl enol ether 2b (1.12 g, 4.12 mmol) was added and the reaction mixture was allowed for stirring 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)-1-(1-methyl-1H-imidazol-2-yl)-3,5-diphenylpentane-1,5-dione (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: The compound 4aa was isolated as white solid in 90% (59.9 mg)

yield with 91:9 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 100-102 °C. [α]D25 = +12.1 (c 0.44, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IA-3 column, n-hexane/2-propanol (90:10) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 19.4 min, tR (minor) = 22.5 min. For In(OTf)3-1a: The compound ent-4aa was isolated as white solid in 92% (61.3 mg) yield with 77:23 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 100-102 °C. [α]D25 = –9.3 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IA-3 column, n-hexane/2-propanol (90:10) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 19.5 min, tR (major) = 22.4 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,


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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; m/z [M + H]+ calcd for C21H2080.9163BrN2O2 413.0688, found 413.0698. For Sc(OTf)3-1a:

The compound 4ab was isolated as white solid in 92% (75.5 mg) yield with 85:15 er. Rf = 0.25 (40% EtOAc in hexane). Mp: 124-126 °C. [α]D25 = +14.2 (c 0.44, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 14.8 min, tR (minor) = 53.8 min. For In(OTf)3-1a: The compound ent-4ab was isolated as 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 Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 14.8 min, tR (major) = 53.0 min.

(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; m/z [M + H]+ calcd for C21H2036.9659ClN2O2 369.1184, found 369.1199. For Sc(OTf)3-1a: The compound 4ac was isolated as 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]D25 = + 30.0 (c 0.41, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 15.0 min, tR (minor) = 56.9 min. For In(OTf)3-1a: The compound ent-4ac was isolated as white solid in 92% (67.3 mg) yield with 85:15 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 126-128 °C. [α]D25 = –22.5 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 15.0 min, tR (major) = 54.4 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: The compound 4ad

was isolated as white solid in 93% (65.3 mg) yield with 90:10 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 98-100 °C. [α]D25 = +16.4 (c 0.45, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 18.2 min, tR (minor) = 58.2 min. For In(OTf)3-1a: The compound ent-4ad was isolated as 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 Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 18.5 min, tR (major) = 58.1 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, 986 cm-1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20IN2O2 459.0569, found 459.0569. For Sc(OTf)3-1a: The compound 4ae was isolated as 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]D25 = +18.5 (c 0.40, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 15.0 min, tR (minor) = 50.5 min. For In(OTf)3-1a: The compound ent-4ae was isolated as 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]D25 = –10.6 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 15.0 min, tR (major) = 49.2 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 =


Page 12 of 26

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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. 19 F 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: The compound 4af was isolated as white semisolid in 92% (64.6

mg) yield with 89:11 er. Rf = 0.22 (40% EtOAc in hexane). [α]D25 = +5.4 (c 0.39, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 10.5 min, tR (minor) = 24.2 min. For In(OTf)3-1a: The compound ent-4af was isolated as white semisolid in 92% (64.3 mg) yield with 68.5:31.5 er. Rf = 0.22 (40% EtOAc in hexane). [α]D25 = –11.7 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 10.7 min, tR (major) = 25.2 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; m/z [M + H]+ calcd for C21H2080.9163BrN2O2 413.0688, found 413.0687. For Sc(OTf)3-1a: The compound 4ag

was isolated as white semisolid in 92% (75.5 mg) yield with 90:10 er. Rf = 0.24 (40% EtOAc in hexane). [α]D25 = +11.4 (c 0.53, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 11.4 min, tR (minor) = 19.5 min. For In(OTf)3-1a: The compound ent-4ag was isolated as white semisolid in 90% (74.2 mg) yield with 59:41er. Rf = 0.24 (40% EtOAc in hexane). [α]D25 = –2.8 (c 0.66, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as 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). 13 C{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; m/z [M + H]+ calcd for C21H1980.9163Br2N2O2 490.9793, found 490.9819. For Sc(OTf)3-1a: The compound 4ah was isolated as white solid in

81% (79.6 mg) yield with 85:15 er. Rf = 0.2 (40% EtOAc in hexane).Mp: 103-105 °C. [α]D25 = +4.8 (c 0.72, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak OJ-H column, n-hexane/2-propanol (90:10) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 33.0 min, tR (major) = 41.9 min. For In(OTf)3-1a: The compound ent-4ah was isolated as white solid in 76% (74.7 mg) yield with 85:15 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 103-105 °C. [α]D25 = –18.5 (c 0.26, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak OJ-H column, n-hexane/2-propanol (90:10) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 32.5 min, tR (minor) = 43.0 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 (ESI-TOF): m/z [M + H]+ calcd for C21H1934.9689Cl2N2O2 401.0824, found 401.0822; m/z [M + H]+ calcd for C21H1936.9659Cl2N2O2 403.0794, found 403.0809. For Sc(OTf)3-1a: The compound 4ai

was isolated as white solid in 90% (72.5 mg) yield with 86:14 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 120-122 °C. [α]D25 = +6.4 (c 1.24, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak OD column, n-hexane/2-propanol (98:2) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 38.3 min, tR (minor) = 51.1 min. For In(OTf)3-1a: The compound ent-4ai was isolated as white solid in 80% (64.4 mg) yield with 91:9 er. Rf = 0.2 (40% EtOAc in hexane). Mp: 120-122 °C. [α]D25 = –9.1 (c 0.84, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak OD column, n-hexane/2-propanol (98:2) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 40.8 min, tR (major) = 52.0 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,


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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:The compound 4aj was isolated as white solid in 78% (56.3 mg) yield with 90:10 er. Rf = 0.23 (40% EtOAc in hexane). Mp: 131-133 °C. [α]D25 = +32.2 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 28.0 min, tR (minor) = 63.4 min. For In(OTf)3-1a: The compound ent-4aj was isolated as 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]D25 = –31.0 (c 0.39, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 29.5 min, tR (major) = 64.9 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: The compound 4ak was isolated as

white solid in 85% (61.8 mg) yield with 89:11 er. Rf = 0.22 (40% EtOAc in hexane). Mp: 121-123 °C. [α]D25 = +13.6 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 24.2 min, tR (minor) = 65.2 min. For In(OTf)3-1a: The compound ent-4ak was isolated as 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 Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 24.7 min, tR (major) = 64.7 min.

(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, 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). 13C{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:

The compound 4al was isolated as white semisolid in 79% (60.2 mg) yield with 89.5:10.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = +12.1 (c 0.48, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 16.8 min, tR (minor) = 40.1 min. For In(OTf)3-1a: The compound ent-4al was isolated as white semisolid in 81% (61.8 mg) yield with 69.5:30.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = –18.7 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 17.2 min, tR (major) = 41.4 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). 13C{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; m/z [M + H]+ calcd for C21H2080.9163BrN2O2 413.0688, found 413.0686. For Sc(OTf)3-1a: The compound 4ba was isolated as white semisolid in 92%

(75.8 mg) yield with 92:8 er. Rf = 0.24 (40% EtOAc in hexane). [α]D25 = + 8.4 (c 0.38, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 20.6 min, tR (minor) = 53.3 min. For In(OTf)3-1a: The compound ent-4ba was isolated as 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 Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 20.5 min, tR (major) = 52.3 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 =


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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; m/z [M + H]+ calcd for C22H2280.9163BrN2O3 443.0793, found 443.0801. For Sc(OTf)3-1a:

The compound 4bj was isolated as white semisolid in 82% (72.5 mg) yield with 91:9 er. Rf = 0.21 (40% EtOAc in hexane). [α]D25 = +14.3 (c 0.41, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 29.6 min, tR (minor) = 78.8 min. For In(OTf)3-1a: The compound ent-4bj was isolated as white semisolid in 92% (81.4 mg) yield with 97:3 er. Rf = 0.21 (40% EtOAc in hexane). [α]D25 = – 24.4 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as 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-1,5-dione (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 (ESI-TOF): m/z [M + H]+ calcd for C22H23N2O2 347.1760, found 347.1765. For Sc(OTf)3-1a: The compound

4ca was isolated as white semisolid in 92% (63.6 mg) yield with 90:10 er. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = +10.4 (c 0.36, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 26.4 min, tR (minor) = 56.5 min. For In(OTf)31a: The compound ent-4ca was isolated as white semisolid in 92% (63.5 mg) yield with 71.5:28.5 er. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = –6.0 (c 0.25, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, nhexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 27.4 min, tR (major) = 57.3 min.

MeO

O N O

N

S



(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: The compound 4dj was isolated as 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]D25 = +24.6 (c 0.42, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 39.1 min, tR (minor) = 57.7 min. For In(OTf)3-1a: The compound ent-4dj was isolated as 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]D25 = –15.0 (c 0.40, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (70:30) as 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 ent4bj (88.3 mg, 0.2 mmol) in dry CH3CN (2 mL) at 35 °C, was added 4Å molecular sieve (60 mg) and MeOTf (27 µL, 0.25 mmol) under N2 atmosphere. After stirring for 4.5 hours 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 x 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.

(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; m/z [M + H]+ calcd for C18H1880.9163BrO4 379.0368, found 379.0362. For Sc(OTf)3-1a: The compound 5 was isolated as white semisolid in 80% (60.5

mg) yield. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = -2.6 (c 0.7, CHCl3). For In(OTf)3-1a: The compound ent-5 was isolated as white semisolid in 81% (61.3 mg) yield. Rf = 0.2 (40% EtOAc in hexane). [α]D25 = +2.7 (c 0.6, CHCl3).


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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 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 one hour, 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)-6-(4-bromophenyl)-4-(2-methoxyphenyl)-3,4-dihydro-2H-pyran-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). 13C{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; m/z [M + H]+ calcd for C18H1680.9163BrO3 361.0262, found 361.0272. For Sc(OTf)3-1a: The compound 6 was isolated

as white semisolid in 80% (43.3 mg) yield with 89.5:10.5 er. Rf = 0.55 (40% ether in hexane). [α]D25 = -39.2 (c 0.25, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (90:10) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 13.8 min, tR (minor) = 17.2 min. For In(OTf)3-1a: The compound ent-6 was isolated as white semisolid in 82% (44.2 mg) yield with 96:4 er. Rf = 0.55 (40% ether in hexane). [α]D25 = +62.4 (c 0.26, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (90:10) as 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, was added 4Å molecular sieve (60 mg) and MeOTf (27 µL, 0.25 mmol) under N2 atmosphere. After stirring for 4.5 hours at 35 °C, MeOH (500 µL) and DBU (37 µL,0.25 mmol) was added. The resulting mixture was allowed to stir for 30 min at 35 °C and the reaction mixture was purified purified over silica gel by column chromatography (2040% ethyl acetate in hexane) to afford the products.

(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). 13 C{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; m/z [M + H]+ for C19H2080.9163BrO4 393.0525, found 393.0533. For Sc(OTf)3-1a: The

compound 7 was isolated as white semisolid in 83% (65 mg) yield with 90.5:9.5 er. Rf = 0.5 (20% EtOAc in hexane). [α]D25 = +4.2 (c 1.49, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (minor) = 17.8 min, tR (major) = 27.7 min. For In(OTf)3-1a: The compound ent-7 was isolated as white semisolid in 81% (63.5 mg) yield with 96:4 er. Rf = 0.5 (20% EtOAc in hexane). [α]D25 = – 6.2 (c 1.46, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, nhexane/2-propanol (80:20) as 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 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 hours under 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 minute at rt. HFIP (21 µL, 0.20 mmol) was then added to the mixture and the resulting reaction mixture was again stirred for 15 minute at rt. Then silyl ketene acetal 8 (102 µL, 0.5 mmol) was added and the reaction mixture was allowed for stirring at room temperature until the completion of the reaction (monitored by TLC). 1M HCl (2 mL) was added to it and stirred for 1 h. Then, water (2 mL) was added and the resulting reaction mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers was concentrated in vacuo and purified over silica gel by column chromatography (10-40% ethyl acetate in hexane) to afford the product 9. General procedure for the reaction of silyl ketene acetal 8 with α,β-unsaturated 2-acyl imidazole 3a catalyzed by 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 hour under 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 minute at rt. The mixture was cooled to 0 °C and HFIP (21 µL, 0.20 mmol) was added and the resulting mixture was again allowed to stir for additional 15 minute at 0 °C. The silyl ketene acetal 8 (102 µL, 0.5 mmol) was added and the reaction mixture was allowed for stirring at 0 °C until the completion of the reaction (monitored by TLC). 1M HCl (2 mL) was added to it and stirred for 1 h. Then, water (2 mL) was added and the resulting reaction mixture was extracted with dichloromethane (10 mL x 3). The combined organic layers was concentrated in vacuo and purified over silica gel by column chromatography (10-40% ethyl acetate in hexane) to afford the product ent-9.

(R)-methyl 2,2-dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-phenylpentanoate (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),


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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: The compound 9 was isolated

as white semisolid in 91% (57.3 mg) yield with 96:4 er. Rf = 0.3 (40% EtOAc in hexane). [α]D25 = +18.4 (c 0.69, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 13.9 min, tR (minor) = 52.6 min. For In(OTf)3-1a: The compound ent-9 was isolated as white semisolid in 77% (48.6 mg) yield with 90:10 er. Rf = 0.3 (40% EtOAc in hexane). [α]D25 = –51.3 (c 0.68, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, n-hexane/2-propanol (80:20) as 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, was added 4Å molecular sieve (50 mg) and MeOTf (27µL, 0.25 mmol) under N2 atmosphere. After stirring for 4.5 hours at 35 °C, MeOH (500 µL) and DBU (37 µL, 0.25 mmol) was added. The resulting mixture was then allowed to stir for 30 min at 35 °C and the reaction mixture was purified purified over silica gel by column chromatography (5-20% ethyl acetate in hexane) to afford the product 10.

(R)-methyl 2,2-dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-phenylpentanoate (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. The compound 10 was isolated as colorless liquid in 70% (37.1

mg) yield with 96:4 er. Rf = 0.3 (20% EtOAc in hexane). [α]D25 = +10.4 (c 0.95, CHCl3). The enantiomeric ratio was determined by chiral HPLC using Daicel Chiralpak IC-3 column, nhexane/2-propanol (80:20) as eluent, flow rate = 1.0 mL/min, 254 nm. tR (major) = 6.9 min, tR (minor) = 18.7 min.

ASSOCIATED CONTENT Supporting Information This material is available free of charge on the ACS Publications website at http://pubs.acs.org. 1H NMR and 13C{1H} NMR spectra for all compounds and HPLC chromatograms AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes



The authors declare no competing financial interest. ACKNOWLEDGMENT V.K.S. thanks SERB, DST (EMR/2014/001165) for a research grant and Department of Science and Technology, India for J. C. Bose fellowship. A. D. is grateful to IIT Kanpur for a doctoral fellowship. 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, 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-C3-Symmetric 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. 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 2-Carbomethoxy 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.


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Metal-Controlled Switching of Enantioselectivity in the Mukaiyama

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