supplementary materials for -...

www.sciencemag.org/344/6182/392/suppl/DC1

Supplementary Materials for

A Dual-Catalysis Approach to Enantioselective [2 + 2] Photocycloadditions Using Visible Light

Juana Du, Kazimer L. Skubi, Danielle M. Schultz, Tehshik P. Yoon*

*Corresponding author. E-mail: [email protected]

Published 25 April 2014, Science 344, 392 (2014)

DOI: 10.1126/science.1251511

This PDF file includes:

Materials and Methods Supplementary Text Figs. S1 to S3 Tables S1 to S16 Scheme 1 References

Materials and Methods A. General Information B. Synthesis of Ligands 8 and 9 C. 1,2-trans-Selective [2+2] Cycloadditions D. 1,2-cis-Selective [2+2] Cycloadditions E. Derivatization of 2c for X-Ray Analysis F. UV-Vis Spectra G. Influence of Michael Acceptor Stoichiometry H. SFC Chromatograms I. NMR Spectra J. X-Ray Crystallographic Data for S3 and 3c K. References

A. General Information Reagent Preparation Methyl vinyl ketone (3-buten-2-one) and 1-penten-3-one were distilled from K2CO3 immediately prior to use, while 5-methyl-1-hexen-3-one was prepared as previously described (33). i-Pr2NEt was distilled from CaH2 immediately prior to use. Ru(bpy)3Cl2•6H2O, Gd(OTf)3, and Eu(OTf)3 were purchased from Strem Chemicals, EDC and HOBt were purchased from Oakwood Chemical, BINOL ((R)-(+)-1,1′-bi(2-naphthol)) and TADDOL ((4R,5R)-2,2-dimethyl-α,α,α′,α′-tetraphenyldioxolane-4,5-dimethanol) were purchased from Sigma Aldrich, and all were used without further purification. PyBox ligand 6 (34) and dipeptide ligand 7 (25) were synthesized as described previously. Aryl enones were prepared using the general procedure from Cowart (35) and spectral data were consistent with literature values. All other reagents were purchased from commercial suppliers and used without additional purification. All reaction glassware was flame- or oven-dried prior to use. Flash column chromatography was carried out with Sigma Aldrich silica gel (60 Å pore size, 230–400 mesh particle size). Product Characterization NMR data were obtained using a Bruker Avance III 500 spectrometer with DCH or Prodigy cryoprobes. 1H spectra were internally referenced to tetramethyl silane (0.00 ppm). 13C spectra were internally referenced to CDCl3 (77.16 ppm). 19F spectra were absolute referenced to the corresponding 1H spectra as described by Harris (36, 37). Diastereomeric ratios were determined by analysis of crude 1H NMR spectra. The NMR facilities at UW-Madison are supported by the NSF (CHE-1048642, CHE-9208463, S10 RR08389-01), the University of Wisconsin, and a generous gift from Paul J. Bender. Mass spectrometry was performed with a Micromass LCT (electrospray ionization, time-of-flight analyzer). The mass spectrometry facilities are supported by the NSF (CHE-9974839) and the University of Wisconsin. Enantiomeric excesses were determined by chiral SFC of isolated material using a Waters Investigator system with Daicel CHIRALPAK® columns and Chromasolv®-grade i-PrOH. IR spectral data were obtained using a Bruker Vector 22 or Alpha Platinum spectrometer (thin film). Melting points were obtained using a Stanford Research Systems DigiMelt apparatus, and are uncorrected. Optical rotations were measured using an Rudolph Research Autopol III polarimeter at room temperature. UV-vis spectra were acquired on a Varian Cary® 50 UV-visible spectrophotometer with a scan rate of 300 nm/min.

B. Synthesis of Ligands 8 and 9

OH

O

NBoc

n-BuNH2EDC, HOBt

CH2Cl2, rt, 18 hNHn-Bu

O

NBoc

1. 4 M HCl/Dioxanert, 1 h

Boc-Val-OHEDC, HOBt, NEt3CH2Cl2, rt, 18 h

BocHNN

O

Me Me

NHn-BuO

SalicylaldehydeMgSO4, NEt3CH2Cl2, rt, 18 h

NN

O

Me Me

NHn-BuOOH

2.

1. 4 M HCl/Dioxanert, 1 h

2.

S1 S2

8

NaBH4, cat. HClMeOH, 0 °C, 10 min N

H

N

O

Me Me

NHn-BuOOH9

Scheme S1. Synthesis of dipeptide ligands 8 and 9. (S)-N-Butyl-1-((S)-2-((E)-(2-hydroxybenzylidene)amino)-3-methylbutanoyl)pyrrolidine-2-carboxamide (Figure 1C, ligand 8). Prepared using a modification of the procedures reported by Hoveyda (38) and Miller (39). A 250 mL round-bottom flask equipped with a stir bar was charged with Boc-Pro-OH (5.5 g, 25.6 mmol, 1.0 equiv), EDC (5.4 g, 28.2 mmol, 1.1 equiv), and HOBt (3.8 g, 28.2 mmol, 1.1 equiv). The solids were suspended in dry CH2Cl2 (50 mL) and the solution was stirred under N2 while cooling to 0 °C. n-Butylamine (5.3 mL, 53.6 mmol, 2.1 equiv) was added over 5 min via syringe. The solution was then warmed to room temperature and stirred overnight. The reaction was quenched by addition of 10% aqueous citric acid (100 mL). Vigorous stirring over the next 5–20 min produced a white solid, which was removed by vacuum filtration. The filtrate was extracted into CH2Cl2 (3 x 100 mL), and the combined organic layers were washed sequentially with 10% aqueous citric acid, saturated NaHCO3, and brine (100 mL each). The resulting extract was dried over MgSO4 and concentrated in vacuo to give Boc-Pro-NHn-Bu (S1) as a white semisolid which was carried on without further purification. This material was cooled to 0 °C, dissolved in a 4 M solution of HCl in dioxane (38 mL, 153 mmol, 6 equiv), then warmed to room temperature while stirring vigorously. After 1 h, TLC analysis showed completion, and residual HCl gas was removed for 15 min by aspirated vacuum connected to a trap. The crude material was then concentrated in vacuo to afford a yellow semisolid, which was used in the next step without additional purification. In the same flask, Boc-Val-OH (5.4 g, 24.9 mmol, 0.95 equiv), EDC (5.8 g, 30.3 mmol, 1.2 equiv), and HOBt (3.8 g, 28.2 mmol, 1.1 equiv) were added, and the solids were suspended in dry CH2Cl2 (50 mL) under an N2 atmosphere with a vent needle in place. After cooling to 0 °C, Et3N (7.7 mL, 55.3 mmol, 2.2 equiv) was added over a 5 min period. The flask was then warmed to room temperature, the vent needle was removed, and the solution was stirred overnight under N2. Following this, the reaction was poured into 300 mL EtOAc, resulting in a cloudy white emulsion. Aqueous citric acid (0.5 M, 100 mL) was added, and the organic layer was extracted and subsequently washed with 0.5 M citric acid, saturated NaHCO3, and brine (100 mL each). The organic extract was dried over MgSO4 and concentrated to provide Boc-Val-Pro-NHn-Bu (S2) as a foamy off-white oil which was used without further purification. S2 was then subjected to the same HCl Boc deprotection protocol as described above to provide the corresponding amine•HCl salt as a white semisolid, which was subsequently combined with flame-dried MgSO4 (5.0 g) and suspended in dry CH2Cl2 (50 mL). Salicylaldehyde (1.6 mL, 15.0 mmol, 0.6 equiv) was added via syringe, and the heterogeneous solution was allowed to stir for 5 min. Finally, Et3N (6.3 mL, 45.2 mmol, 1.8 equiv) was added over 5 min and the resulting bright yellow solution was stirred overnight under N2. The crude

mixture was passed through a short plug of silica gel and eluted with EtOAc until the majority of yellow material was collected. This crude residue was concentrated in vacuo and purified by flash column chromatography on silica gel (3:1 hexanes:acetone). The isolated product was washed with cold hexanes to remove any residual salicylaldehyde, affording 8 as a yellow crystalline powder (35% yield, 3.3 g, 8.8 mmol). In CDCl3 solution at room temperature, ligand 8 exists as two rotamers in a 7:1 ratio. The stereoisomeric purity of this species was confirmed by subsequent reduction of the imine (vide infra) which quantitatively affords ligand 9 as a single diastereomer. 1H NMR (500 MHz, CDCl3) δ 13.16 (s, 1H), 8.40 (s, 1H), 7.34 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.28 (dd, J = 7.7, 1.6 Hz, 1H), 7.05 (br t, J = 5.0 Hz, 1H), 6.98 (dd, J = 8.5, 1.1 Hz, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 4.62 (dd, J = 8.1, 2.3 Hz, 1H), 3.93 (d, J = 8.1 Hz, 1H), 3.69 (ddd, J = 10.0, 8.4, 3.4 Hz, 1H), 3.54 (td, J = 9.3, 7.1 Hz, 1H), 3.26–3.19 (m, 2H), 2.47–2.35 (m, 2H), 2.24–2.13 (m, 1H), 2.01–1.93 (m, 1H), 1.85–1.74 (m, 1H), 1.50–1.42 (m, 2H), 1.38–1.29 (m, 2H), 1.00 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.8, 170.8, 166.2, 161.3, 133.0, 131.9, 118.8, 118.7, 117.4, 76.3, 60.1, 47.6, 39.4, 31.9, 31.7, 26.8, 25.4, 20.2, 19.8, 18.9, 13.9. IR (thin film) 3314, 2959, 2872, 1627, 1546, 1437, 1279, 757 cm–1. HRMS (ESI+) calculated for [C21H32N3O3]+ requires m/z 374.2439, found m/z 374.2425. mp = 110–112 °C. [α]22

D –94.1° (c1.36, CH2Cl2). (S)-N-Butyl-1-((2-hydroxybenzyl)-L-valyl)pyrrolidine-2-carboxamide (Figure 4A, ligand 9). Prepared using a modification of the procedure reported by Hoveyda (17). A round-bottom flask equipped with a magnetic stir bar was charged with 8 (983 mg, 2.63 mmol, 1.0 equiv) and MeOH (10 mL) before being cooled to 0 °C. NaBH4 (995 mg, 26.3 mmol, 10 equiv) was added to this solution, followed by one drop of 3 M HCl. The reaction was allowed to continue for 10 min before being neutralized to pH 7 with 3 M HCl and extracted into CH2Cl2 (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was dried overnight under high vacuum to afford 9 as a viscous, colorless oil that was used without further purification (96% yield, 941 mg, 2.51 mmol). Ligand 9 was delivered to the reaction mixtures as a 0.22–0.35 M stock solution in acetonitrile. 1H NMR (500 MHz, CDCl3) δ 10.58 (br s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.98 (br t, J = 5.1 Hz, 1H), 6.89 (d, J = 7.4, 1H), 6.86 (d, J = 8.2, 1H), 6.77 (t, J = 7.4, 1H), 4.68 (dd, J = 8.0, 2.4 Hz, 1H), 4.08 (d, J = 13.7 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 3.40 (ddd, J = 9.6, 8.2, 3.5 Hz, 1H), 3.23–3.15 (m, 4H), 2.44 (ddd, J = 12.6, 6.6, 3.2 Hz, 1H), 2.13–2.07 (m, 1H), 1.95–1.89 (m, 2H), 1.88–1.78 (m, 1H), 1.48–1.42 (m, 2H), 1.36–1.29 (m, 2H), 1.00 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.4, 170.5, 157.9, 129.0, 128.3, 122.0, 119.2, 116.4, 63.3, 59.6, 51.0, 47.1, 39.1, 31.5, 31.5, 26.7, 25.1, 20.0, 19.7, 17.9, 13.7. IR (thin film) 3304, 2958, 2930, 2872, 1661, 1626, 1543, 1422, 1254, 753, 729 cm–1. HRMS (ESI+) calculated for [C21H34N3O3]+ requires m/z 376.2595, found 376.2592. [α]22

D –75.3° (c1.95, CH2Cl2).

C. 1,2-trans-Selective [2+2] Cycloadditions (Figure 3) Preparation of Racemic 1,2-trans Cyclobutanes for SFC Analysis Racemic material was prepared using conditions reported previously (20). General Procedure A: Preparation of Enantioenriched 1,2-trans Cyclobutanes A 25 mL Schlenk flask equipped with a magnetic stir bar was flushed with N2, then charged with Eu(OTf)3 (0.1 equiv), Ru(bpy)3Cl2•6H2O (0.05 equiv), and ligand 8 (0.2 equiv). Aryl enone (1.0 equiv) was then added, using dry acetonitrile (0.2 M with respect to enone) to complete the transfer and rinse solids from the sides of the Schlenk flask. Michael acceptor (5.0 equiv) and i-Pr2NEt (2.0 equiv) were subsequently added via syringe, and the solution was degassed by three freeze-pump-thaw cycles in the dark. The reaction was backfilled with N2, cooled to –20 °C, and stirred under visible light irradiation from a 23 W compact fluorescent lightbulb at a distance of 30 cm. After the irradiation period, the reaction vessel was warmed to room temperature, opened to air, and the solution was diluted with 8 mL Et2O. The resulting cloudy orange suspension was passed through a short silica plug with Et2O, and the colorless eluent was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel, affording diastereomerically-pure cycloadducts 2 (1,2-trans) and 3 (1,2-cis). The yields reported in Figure 3 represent the summation of both trans and cis cycloadducts. Characterization data and enantiomeric excesses are reported for the major diastereomer (trans).

1-((1R,2R,3S)-2-Benzoyl-3-methylcyclobutyl)ethan-1-one (Figure 3, entry 2a). Experiment 1: Prepared according to general procedure A using 101 mg (0.69 mmol) (E)-1-phenyl-2-buten-1-one, 42 mg (0.07 mmol) Eu(OTf)3, 26 mg (0.03 mmol) Ru(bpy)3Cl2, 53 mg (0.14 mmol) ligand 8, 280 µL (3.42 mmol) 3-

buten-2-one, 240 µL (1.37 mmol) i-Pr2NEt, 3.4 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 7:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 15:1 toluene:Et2O) to afford the trans cycloadduct as a colorless oil and cis cycloadduct as a white solid. Combined yield: 108 mg (73%, 0.50 mmol); 92% ee (Daicel CHIRALPAK® AD-H, 6% i-PrOH, 6 mL/min, 249 nm; t1 = 1.4 min, t2 = 1.7 min). Experiment 2: 95 mg (0.65 mmol) (E)-1-phenyl-2-buten-1-one, 40 mg (0.07 mmol) Eu(OTf)3, 25 mg (0.03 mmol) Ru(bpy)3Cl2, 50 mg (0.13 mmol) ligand 8, 265 µL (3.26 mmol) 3-buten-2-one, 230 µL (1.32 mmol) i-Pr2NEt, and 3.3 mL acetonitrile. Crude dr: 6:1; Combined isolated yield: 97 mg (69%, 0.45 mmol); 92% ee. [α]22

D –108.1° (c4.35, CH2Cl2). All other spectral data were in accord with reported values (20).

1-((1R,2R,3S)-2-(4-Chlorobenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 2, entry 2b). Experiment 1: Prepared according to general procedure A using 101 mg (0.56 mmol) (E)-1-(4-chlorophenyl)-2-buten-1-one, 34 mg (0.06 mmol) Eu(OTf)3, 23 mg (0.03 mmol) Ru(bpy)3Cl2, 43 mg

(0.12 mmol) ligand 8, 230 µL (2.83 mmol) 3-buten-2-one, 200 µL (1.15 mmol) i-Pr2NEt, 2.8 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 7:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 15:1 toluene:Et2O) to afford the trans cycloadduct as a pale yellow oil and cis cycloadduct as an off-white semisolid. Combined yield: 94 mg (66%, 0.37 mmol); 90% ee (Daicel CHIRALPAK® AD-H, 7% i-PrOH, 3 mL/min, 241 nm; t1 = 3.3 min, t2 = 4.6 min).

O O

Me

Me

O O

Me

MeCl

Experiment 2: 101 mg (0.56 mmol) (E)-1-(4-chlorophenyl)-2-buten-1-one, 34 mg (0.06 mmol) Eu(OTf)3, 22 mg (0.03 mmol) Ru(bpy)3Cl2, 42 mg (0.11 mmol) ligand 8, 230 µL (2.83 mmol) 3-buten-2-one, 200 µL (1.15 mmol) i-Pr2NEt, and 2.8 mL acetonitrile. Crude dr: 7:1; Combined isolated yield: 90 mg (64%, 0.36 mmol); 90% ee. [α]22


1-((1R,2R,3S)-2-(4-Bromobenzoyl)-3-methylcyclobutyl)ethan-1-one

(Figure 3, entry 2c). Experiment 1: Prepared according to general procedure A using 96 mg (0.43 mmol) (E)-1-(4-bromophenyl)but-2-en-1-one, 25 mg (0.04 mmol) Eu(OTf)3, 16 mg (0.02 mmol) Ru(bpy)3Cl2, 32 mg

(0.09 mmol) ligand 8, 170 µL (2.09 mmol) 3-buten-2-one, 150 µL (0.86 mmol) i-Pr2NEt, 2.1 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 5.5:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (4:1 hexanes:EtOAc; trans: 15:1 toluene:Et2O) to afford the trans cycloadduct as a colorless oil and cis cycloadduct as a white solid. Combined yield: 90 mg (71%, 0.30 mmol); 89% ee (Daicel CHIRALPAK® AD-H, 7% i-PrOH, 4 mL/min, 252 nm; t1 = 3.1 min, t2 = 4.1 min). Experiment 2: 104 mg (0.46 mmol) (E)-1-(4-bromophenyl)but-2-en-1-one, 29 mg (0.05 mmol) Eu(OTf)3, 18 mg (0.02 mmol) Ru(bpy)3Cl2, 35 mg (0.09 mmol) ligand 8, 190 µL (2.34 mmol) 3-buten-2-one, 160 µL (0.92 mmol) i-Pr2NEt, and 2.3 mL acetonitrile. Crude dr: 5.5:1; Combined isolated yield: 90 mg (66%, 0.30 mmol); 89% ee. 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 3.88 (t, J = 8.4 Hz, 1H), 3.57 (q, J = 9.1 Hz, 1H), 2.57–2.47 (m, 1H), 2.41 (q, J = 9.9 Hz, 1H), 2.09 (s, 3H), 1.72 (q, J = 9.4 Hz, 1H), 1.17 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.2, 198.6, 135.0, 132.1, 130.3, 128.7, 49.4, 43.7, 30.8, 29.7, 27.7, 21.1. IR (thin film) 1709, 1675, 1585 cm–1. HRMS (ESI+) calculated for [C14H16BrO2]+ requires m/z 295.0329, found m/z 295.0329. [α]22

D –64.0° (c3.25, CH2Cl2).

1-((1R,2R,3S)-2-(4-Methoxybenzoyl)-3-methylcyclobutyl)ethan-1-one

(Figure 3, entry 2d). Experiment 1: Prepared according to general procedure A using 105 mg (0.60 mmol) (E)-1-(4-methoxyphenyl)-2-buten-1-one, 35 mg (0.06 mmol) Eu(OTf)3, 23 mg (0.03 mmol) Ru(bpy)3Cl2, 44

mg (0.12 mmol) ligand 8, 240 µL (2.96 mmol) 3-buten-2-one, 210 µL (1.21 mmol) i-Pr2NEt, 3.0 mL acetonitrile, and an irradiation time of 24 h. The crude product was formed as a 6:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 10:1 toluene:Et2O) to afford the trans cycloadduct as a pale yellow oil and cis cycloadduct as a white solid. Combined yield: 79 mg (54%, 0.32 mmol); 86% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 5 mL/min, 280 nm; t1 = 2.3 min, t2 = 2.7 min). Experiment 2: 91 mg (0.52 mmol) (E)-1-(4-methoxyphenyl)-2-buten-1-one, 31 mg (0.05 mmol) Eu(OTf)3, 19 mg (0.03 mmol) Ru(bpy)3Cl2, 40 mg (0.11 mmol) ligand 8, 210 µL (2.59 mmol) 3-buten-2-one,180 µL (1.03 mmol) i-Pr2NEt, 2.6 mL acetonitrile. Crude dr: 6:1; Combined isolated yield: 67 mg (53%, 0.27 mmol); 86% ee. [α]22


O O

Me

MeBr

O O

Me

MeMeO

1-((1R,2R,3S)-2-(3-Methoxybenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 3, entry 2e). Experiment 1: Prepared according to general procedure A using 94 mg (0.53 mmol) (E)-1-(3-methoxyphenyl)but-2-en-1-one, 33 mg (0.06 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 41 mg

(0.11 mmol) ligand 8, 220 µL (2.71 mmol) 3-buten-2-one, 190 µL (1.09 mmol) i-Pr2NEt, 2.7 mL acetonitrile, and an irradiation time of 24 h. The crude product was formed as a 2.5:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 10:1 toluene:Et2O) to afford the trans cycloadduct as a colorless oil and cis cycloadduct as a white solid. Combined yield: 81 mg (62%, 0.33 mmol); 90% ee (Daicel CHIRALPAK® AD-H, 5% i-PrOH, 6 mL/min, 248 nm; t1 = 1.9 min, t2 = 3.2 min). Experiment 2: 93 mg (0.53 mmol) (E)-1-(3-methoxyphenyl)but-2-en-1-one, 32 mg (0.05 mmol) Eu(OTf)3, 20 mg (0.03 mmol) Ru(bpy)3Cl2, 40 mg (0.11 mmol) ligand 8, 215 µL (2.65 mmol) 3-buten-2-one, 180 µL (1.03 mmol) i-Pr2NEt, and 2.6 mL acetonitrile. Crude dr: 2:1; Combined isolated yield: 90 mg (69%, 0.37 mmol); 91% ee. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.12 (dd, J = 8.2, 2.4 Hz, 1H), 3.89 (t, J = 8.3 Hz, 1H), 3.86 (s, 3H), 3.61 (q, J = 9.1 Hz, 1H), 2.56–2.45 (m, 1H), 2.38 (dt, J = 10.6, 8.7 Hz, 1H), 2.08 (s, 3H), 1.74 (q, J = 9.4 Hz, 1H), 1.18 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.4, 199.3, 160.0, 137.6, 129.8, 121.4, 120.2, 112.7, 55.6, 50.0, 43.7, 31.0, 29.5, 27.8, 21.1. IR (thin film) 1707, 1672, 1261 cm–1. HRMS (ESI+) calculated for [C15H19O3]+ requires m/z 247.1329, found m/z 247.1337. [α]22

D –91.6° (c2.97, CH2Cl2).

1-((1R,2R,3S)-2-(2-Fluorobenzoyl)-3-methylcyclobutyl)ethan-1-one

(Figure 3, entry 2f). Experiment 1: Prepared according to general procedure A using 93 mg (0.57 mmol) (E)-1-(2-fluorophenyl)but-2-en-1-one, 34 mg (0.06 mmol) Eu(OTf)3, 22 mg (0.03 mmol) Ru(bpy)3Cl2, 43 mg (0.12 mmol) ligand 8,

230 µL (2.83 mmol) 3-buten-2-one, 200 µL (1.15 mmol) i-Pr2NEt, 2.8 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 6.5:1 (trans:cis) mixture of diastereomers, which was purified by flash column chromatography on silica gel (6:1 toluene:Et2O) to afford a mixture of cis and trans cycloadducts as a colorless oil. Combined yield (6.5:1 mixture): 89 mg (67%, 0.38 mmol); 93% ee (Daicel CHIRALPAK® AD-H, 6% i-PrOH, 3 mL/min, 233 nm; t1 = 2.4 min, t2 = 3.3 min). Experiment 2: 86 mg (0.52 mmol) (E)-1-(2-fluorophenyl)but-2-en-1-one, 32 mg (0.05 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 39 mg (0.10 mmol) ligand 8, 220 µL (2.71 mmol) 3-buten-2-one, 190 µL (1.09 mmol) i-Pr2NEt, and 2.6 mL acetonitrile. Isolated yield (6.5:1 mixture): 88 mg (72%, 0.38 mmol); 92% ee. Spectroscopic characterization and determination of ee were performed on a diastereomerically-pure sample of 2f, obtained by resubjecting the isolated mixture to flash column chromatography (6:1 hexanes:EtOAc). 1H NMR (500 MHz, CDCl3) δ 7.78 (td, J = 7.6, 1.9 Hz, 1H), 7.51 (dddd, J = 8.2, 7.1, 5.1, 1.9 Hz, 1H), 7.23 (td, J = 7.6, 1.1 Hz, 1H), 7.13 (ddd, J = 11.0, 8.3, 1.1 Hz, 1H), 3.84 (td, J = 8.2, 1.5 Hz, 1H), 3.67–3.57 (m, 1H), 2.46–2.36 (m, 1H), 2.33–2.27 (m, 1H), 2.10 (s, 3H), 1.76 (dt, J = 10.7, 9.3 Hz, 1H), 1.12 (dd, J = 6.7, 1.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.4, 198.6 (d, J = 2.7 Hz), 161.5 (d, J = 254.9 Hz), 134.6 (d, J = 9.0 Hz), 130.9 (d, J = 2.6 Hz), 125.7 (d, J = 12.4 Hz), 124.6 (d, J = 3.5 Hz), 116.8 (d, J = 23.2 Hz), 54.1 (d, J = 5.4 Hz), 43.4, 32.4, 28.8, 27.8, 21.0 (d, J = 1.7 Hz). 19F NMR (471 MHz, CDCl3) δ –110.5. IR (thin film) 1707, 1674, 1608, 1451, 1209 cm–1. HRMS (ESI+) calculated for [C14H16FO2]+ requires m/z 235.1129, found m/z 235.1130. [α]22

D –112.8° (c3.68, CH2Cl2).

O O

Me

Me

MeO

O O

Me

Me

F

1-((1R,2R,3S)-2-(2-Naphthoyl)-3-methylcyclobutyl)ethan-1-one (Figure 3, entry 2g). Experiment 1: Prepared according to general procedure A using 98 mg (0.50 mmol) (E)-1-(naphthalen-2-yl)but-2-en-1-one, 31 mg (0.05 mmol) Eu(OTf)3, 19 mg (0.03 mmol) Ru(bpy)3Cl2, 39 mg (0.10 mmol)

ligand 8, 200 µL (2.46 mmol) 3-buten-2-one, 175 µL (1.00 mmol) i-Pr2NEt, 2.5 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 3:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (4:1 hexanes:EtOAc; trans: 15:1 toluene:Et2O) to afford the trans cycloadduct as a colorless oil and cis cycloadduct as a white solid. Combined yield: 82 mg (62%, 0.31 mmol), 3:1 dr, 88% ee (Daicel CHIRALPAK® AD-H, 10% i-PrOH, 3 mL/min, 247 nm; t1 = 5.2 min, t2 = 5.9 min). Experiment 2: 84 mg (0.43 mmol) (E)-1-(naphthalen-2-yl)but-2-en-1-one, 26 mg (0.04 mmol) Eu(OTf)3, 16 mg (0.02 mmol) Ru(bpy)3Cl2, 33 mg (0.09 mmol) ligand 8, 175 µL (2.16 mmol) 3-buten-2-one, 150 µL (0.86 mmol) i-Pr2NEt, and 2.1 mL acetonitrile. Crude dr: 3:1; Combined isolated yield: 71 mg (62%, 0.27 mmol); 89% ee. 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.04 (dd, J = 8.6, 1.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 4.09 (t, J = 8.4 Hz, 1H), 3.67 (q, J = 9.1 Hz, 1H), 2.62–2.50 (m, 1H), 2.42 (q, J = 9.4 Hz, 1H), 2.10 (s, 3H), 1.79 (q, J = 9.4 Hz, 1H), 1.23 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.5, 199.5, 135.9, 133.5, 132.7, 130.8, 129.8, 128.7, 128.7, 127.9, 126.9, 124.4, 49.9, 43.7, 31.2, 29.6, 27.9, 21.1. IR (thin film) 1706, 1666, 1184 cm–1. HRMS (ESI+) calculated for [C18H19O2]+ requires m/z 267.1380, found m/z 267.1378. [α]22

D –76.4° (c2.68, CH2Cl2).

1-((1R,2R,3S)-2-(Furan-2-carbonyl)-3-methylcyclobutyl)ethan-1-one

(Figure 3, entry 2h). Experiment 1: Prepared according to general procedure A using 95 mg (0.70 mmol) (E)-1-(furan-2-yl)but-2-en-1-one, 43 mg (0.07 mmol) Eu(OTf)3, 27 mg (0.04 mmol) Ru(bpy)3Cl2, 52 mg (0.14 mmol) ligand 8, 280 µL

(3.45 mmol) 3-buten-2-one, 240 µL (1.38 mmol) i-Pr2NEt, 3.5 mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as an 8:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 4:1 toluene:Et2O) to afford the trans cycloadduct as a yellow oil and cis cycloadduct as a pale yellow oil. Combined yield: 101 mg (70%, 0.49 mmol); 94% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 3 mL/min, 268 nm; t1 = 2.2 min, t2 = 2.5 min). Experiment 2: 87 mg (0.64 mmol) (E)-1-(furan-2-yl)but-2-en-1-one, 39 mg (0.07 mmol) Eu(OTf)3, 24 mg (0.03 mmol) Ru(bpy)3Cl2, 48 mg (0.13 mmol) ligand 8, 260 µL (3.20 mmol) 3-buten-2-one, 220 µL (1.26 mmol) i-Pr2NEt, and 3.2 mL acetonitrile. Crude dr: 8:1; Combined isolated yield: 96 mg (73%, 0.47 mmol); 92% ee. [α]22


1-((1R,2R,3S)-2-Benzoyl-3-ethylcyclobutyl)ethan-1-one (Figure 3, entry 2i). Experiment 1: Prepared according to general procedure A using 65 mg (0.41 mmol) (E)-1-phenyl-2-penten-1-one, 24 mg (0.04 mmol) Eu(OTf)3, 15 mg (0.02 mmol) Ru(bpy)3Cl2, 30 mg (0.08 mmol) ligand 8, 165 µL (2.03 mmol) 3-

buten-2-one, 140 µL (0.80 mmol) i-Pr2NEt, 2.0 mL acetonitrile, and an irradiation time of 24 h. The crude product was formed as a 3.9:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 15:1 toluene:Et2O) to afford the trans cycloadduct as a pale yellow oil and cis cycloadduct as an off-white solid. Combined yield: 65 mg (70%, 0.28 mmol); 91% ee (Daicel CHIRALPAK® AD-H, 6%

O O

Me

Me

O O

Me

Me

O

O O

Me

Et

i-PrOH, 4 mL/min, 248 nm; t1 = 2.3 min, t2 = 3.0 min. Experiment 2: 87 mg (0.54 mmol) (E)-1-phenyl-2-penten-1-one, 33 mg (0.06 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 42 mg (0.11 mmol) ligand 8, 220 µL (2.71 mmol) 3-buten-2-one, 190 µL (1.09 mmol) i-Pr2NEt, and 2.7 mL acetonitrile. Crude dr: 3.8:1; Combined isolated yield: 82 mg (66%, 0.36 mmol); 91% ee. [α]22


1-((1R,2R,3R)-2-Benzoyl-3-isopropylcyclobutyl)ethan-1-one (Figure 3, entry 2j). Experiment 1: Prepared according to general procedure A using 109 mg (0.63 mmol) (E)-4-methyl-1-phenylpent-2-en-1-one, 38 mg (0.06 mmol) Eu(OTf)3, 24 mg (0.03 mmol) Ru(bpy)3Cl2, 47 mg (0.13 mmol) ligand 8, 250 µL

(3.08 mmol) 3-buten-2-one, 220 µL (1.26 mmol) i-Pr2NEt, 3.1 mL acetonitrile, and an irradiation time of 24 h. The crude product was formed as a 3:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (6:1 to 4:1 hexanes:EtOAc) to afford the trans cycloadduct as a colorless oil and cis cycloadduct as a white solid. Combined yield: 50 mg (33%, 0.20 mmol); 88% ee (Daicel CHIRALPAK® AD-H, 3% i-PrOH, 4 mL/min, 239 nm; t1 = 3.3, t2 = 4.9 min). Experiment 2: 100 mg (0.57 mmol) (E)-4-methyl-1-phenylpent-2-en-1-one, 35 mg (0.06 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 43 mg (0.12 mmol) ligand 8, 230 µL (2.83 mmol) 3-buten-2-one, 200 µL (1.15 mmol) i-Pr2NEt, and 2.9 mL acetonitrile. Crude dr: 3:1; Combined isolated yield: 49 mg (35%, 0.20 mmol); 88% ee. [α]22


1-((1R,2R,3S)-2-Benzoyl-3-((benzyloxy)methyl)cyclobutyl)ethan-1-one

(Figure 3, entry 2k). Experiment 1: Prepared according to general procedure A using 101 mg (0.40 mmol) (E)-4-(benzyloxy)-1-phenylbut-2-en-1-one, 24 mg (0.04 mmol) Eu(OTf)3, 15 mg (0.02 mmol) Ru(bpy)3Cl2, 30 mg (0.08 mmol) ligand 8, 160 µL (1.97 mmol) 3-buten-2-one, 140 µL (0.80 mmol) i-Pr2NEt, 2.0

mL acetonitrile, and an irradiation time of 15 h. The crude product was formed as a 4:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (3:1 hexanes:EtOAc; trans: 10:1 toluene:Et2O) to afford the trans cycloadduct as a pale yellow oil and cis cycloadduct as an off-white semisolid. Combined yield: 66 mg (51%, 0.20 mmol); 89% ee (Daicel CHIRALPAK® AD-H, 7% i-PrOH, 4 mL/min, 249 nm; t1 = 5.5 min, t2 = 6.4 min. Experiment 2: 112 mg (0.44 mmol) (E)-4-(benzyloxy)-1-phenylbut-2-en-1-one, 27 mg (0.05 mmol) Eu(OTf)3, 17 mg (0.02 mmol) Ru(bpy)3Cl2, 34 mg (0.09 mmol) ligand 8, 180 µL (2.22 mmol) 3-buten-2-one, 160 µL (0.92 mmol) i-Pr2NEt, and 2.2 mL acetonitrile. Crude dr: 4:1; Combined isolated yield: 75 mg (52%, 0.23 mmol); 90% ee. [α]22


1-((1R,2R,3S)-2-Benzoyl-3-methylcyclobutyl)propan-1-one (Figure 3, entry 2l). Experiment 1: Prepared according to general procedure A using 81 mg (0.55 mmol) (E)-1-phenyl-2-buten-1-one, 33 mg (0.06 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 42 mg (0.11 mmol) ligand 8, 280 µL (2.81 mmol) 1-

penten-3-one, 200 µL (1.15 mmol) i-Pr2NEt, 2.8 mL acetonitrile, and an irradiation time of 24 h. The crude product was formed as a 9:1 (trans:cis) mixture of diastereomers, which was separated by flash column chromatography on silica gel (4:1 hexanes:EtOAc; trans: 20:1

O O

Me

i-Pr

O O

Me

OBn

O O

Et

Me

toluene:Et2O) to afford the trans cycloadduct as a pale yellow oil and cis cycloadduct as a white solid. Combined yield: 78 mg (61%, 0.34 mmol); 90% ee (Daicel CHIRALPAK® AD-H, 7% i-PrOH, 3 mL/min, 254 nm; t1 = 2.7 min, t2 = 3.7 min). Experiment 2: 82 mg (0.56 mmol) (E)-1-phenyl-2-buten-1-one, 34 mg (0.06 mmol) Eu(OTf)3, 21 mg (0.03 mmol) Ru(bpy)3Cl2, 42 mg (0.11 mmol) ligand 8, 280 µL (2.81 mmol) 1-penten-3-one, 200 µL (1.15 mmol) i-Pr2NEt, 2.8 mL acetonitrile, and an irradiation time of 24 h. Crude dr: 9:1; Combined isolated yield: 80 mg (62%, 0.35 mmol); 90% ee. [α]22


D. 1,2-cis-Selective [2+2] Cycloadditions (Figure 4) Preparation of Racemic 1,2-cis Cyclobutanes for SFC Analysis A 25 mL Schlenk flask equipped with a magnetic stir bar was charged with aryl enone (1.0 equiv), Ru(bpy)3Cl2•6H2O (0.05 equiv), LiBF4 (0.2 equiv), and acetonitrile (0.2 M with respect to enone) and allowed to stir for 5 min at room temperature. Michael acceptor (5.0 equiv) and i-Pr2NEt (2.0 equiv) were then added, and the solution was degassed by three freeze-pump-thaw cycles in the dark. The reaction was backfilled with N2 and stirred for 14 h at room temperature while being irradiated with a 23 W compact fluorescent lightbulb at a distance of 30 cm. After the irradiation period the solvent was removed in vacuo to yield a residue containing both 1,2-trans- and 1,2-cis-cyclobutanes. The crude reaction mixture was purified by flash column chromatography on silica gel to afford the desired racemic 1,2-cis diastereomer. General Procedure B: Preparation of Enantioenriched 1,2-cis Cyclobutanes A 25 mL Schlenk flask equipped with a magnetic stir bar was charged with aryl enone (1.0 equiv), Ru(bpy)3Cl2•6H2O (0.05 equiv), Eu(OTf)3 (0.1 equiv), ligand 9 (0.3 equiv, delivered to the reaction mixture from a stock solution in acetonitrile), and acetonitrile (0.2 M with respect to enone) and allowed to stir for 5 min at room temperature. Michael acceptor (5.0 equiv) and i-Pr2NEt (2.0 equiv) were then added, and the solution was degassed by three freeze-pump-thaw cycles in the dark. The reaction was backfilled with N2 and stirred at room temperature while being irradiated with a 23 W compact fluorescent lightbulb at a distance of 30 cm. After the irradiation period, the reaction mixture was passed through a short silica plug with Et2O and the eluent was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel, affording diastereomerically-pure cycloadducts 3 (1,2-cis) and 2 (1,2-trans). The yields reported in Figure 4 represent the summation of both cis and trans cycloadducts. Unless otherwise noted, characterization data and enantiomeric excesses are reported for the major diastereomer (cis).

1-((1S,2R,3S)-2-Benzoyl-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3a). Experiment 1: Prepared according to general procedure B using 50 mg (0.34 mmol) (E)-1-phenyl-2-buten-1-one, 13 mg (0.02 mmol) Ru(bpy)3Cl2, 21 mg (0.03 mmol) Eu(OTf)3, 38 mg (0.10 mmol) ligand 9, 143 µL (1.71 mmol) 3-

buten-2-one, 119 µL (0.684 mmol) i-Pr2NEt, 1.7 mL acetonitrile, and an irradiation time of 7 h. The crude product was formed as a 5:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (6:1 to 3:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 56 mg (75%, 0.26 mmol); 95% ee (Daicel CHIRALPAK® AD-H, 5% i-PrOH, 6 mL/min, 236 nm; t1 = 5.1 min, t2 = 6.1 min). Experiment 2: 51 mg (0.35 mmol) (E)-1-phenyl-2-buten-1-one, 11 mg (0.02 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 409 µL of a 0.22 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 4:1; Combined isolated yield: 61 mg (81%, 0.28 mmol); 94% ee. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 3.80 (dd, J = 8.7, 7.0 Hz, 1H), 3.61 (td, J = 9.1, 6.2 Hz, 1H), 2.77 (dt, J = 14.3, 7.0 Hz, 1H), 2.46 (ddd, J = 11.2, 9.1, 5.9 Hz, 1H), 2.02 (s, 3H), 1.88–1.81 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.3, 199.0, 136.2, 132.9, 128.6, 127.9, 52.4, 46.6, 30.8, 28.9, 28.4, 21.1. IR (thin film) 1708, 1679, 1268 cm–1. HRMS (ESI+) calculated for [C14H17O2]+ requires m/z 217.1224, found 217.1230. mp = 55–57 °C. [α]22

D +34.5° (c2.05, CH2Cl2).

O O

Me

Me

1-((1S,2R,3S)-2-(4-Chlorobenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3b). Experiment 1: Prepared according to general procedure B using 62 mg (0.34 mmol) (E)-1-(4-chlorophenyl)but-2-en-1-one, 8 mg (0.01 mmol) Ru(bpy)3Cl2, 20 mg (0.03 mmol) Eu(OTf)3, 38 mg

(0.10 mmol, delivered 293 µL of a 0.35 M stock solution in acetonitrile) ligand 9, 140 µL (1.71 mmol) 3-buten-2-one, 119 µL (0.68 mmol) i-Pr2NEt, 1.7 mL acetonitrile, and an irradiation time of 7 h. The crude product was formed as a 4:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (13:1 to 6:1 hexanes:EtOAc) to afford the cis cycloadduct as a white semisolid and the trans cycloadduct as a colorless oil. Combined yield: 66 mg (77%, 0.26 mmol); 95% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 3 mL/min, 247 nm; t1 = 8.3 min, t2 = 10.8 min). Experiment 2: 54 mg (0.30 mmol) (E)-1-(4-chlorophenyl)but-2-en-1-one, 7 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 3:1; Combined isolated yield: 61 mg (81%, 0.28 mmol); 95% ee. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 3.76–3.60 (m, 2H), 2.84–2.71 (m, 1H), 2.43 (ddd, J = 11.2, 8.9, 5.2 Hz, 1H), 2.03 (s, 3H), 1.90–1.87 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.0, 198.1, 139.1, 134.7, 129.2, 128.9, 52.0, 47.0, 30.6, 29.1, 28.1, 21.1. IR (thin film) 1711, 1680, 1271 cm–1. HRMS (ESI+) calculated for [C14H16ClO2]+ requires m/z 251.0834, found 251.0837. [α]22

D +36.7° (c1.85, CH2Cl2).

1-((1S,2R,3S)-2-(4-Bromobenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3c). Experiment 1: Prepared according to general procedure B using 68 mg (0.30 mmol) (E)-1-(4-bromophenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg

(0.10 mmol, delivered 409 µL of a 0.22 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 7 h. The crude product was formed as a 3:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 4:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 58 mg (65%, 0.20 mmol); 94% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 3 mL/min, 250 nm; t1 = 9.4 min, t2 = 12.7 min). Experiment 2: 69 mg (0.30 mmol) (E)-1-(4-bromophenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 4:1; Combined isolated yield: 59 mg (65%, 0.20 mmol); 94% ee. 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 3.71–3.59 (m, 2H), 2.83–2.73 (m, 1H), 2.42 (ddd, J = 10.9, 8.9, 4.8 Hz, 1H), 2.03 (s, 3H), 1.95–1.84 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 207.9, 198.2, 135.1, 131.9, 129.3, 127.8, 51.9, 47.1, 30.6, 29.2, 28.1, 21.1. IR (thin film) 1708, 1680, 1265 cm–1. HRMS (ESI+) calculated for [C14H16BrO2]+ requires m/z 295.0329, found 295.0332. mp = 79–81 °C. [α]22

D +28.7° (c2.20, CH2Cl2).

O O

Me

MeCl

O O

Me

MeBr

1-((1S,2R,3S)-2-(4-Methoxybenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3d). Experiment 1: Prepared according to general procedure B using 54 mg (0.30 mmol) (E)-1-(4-methoxyphenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg

(0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 36 h. The crude product was formed as a 2.5:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (4:1 to 5:2 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 60 mg (79%, 0.24 mmol); 89% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 4 mL/min, 264 nm; t1 = 7.9 min, t2 = 10.7 min). Experiment 2: 54 mg (0.30 mmol) (E)-1-(4-methoxyphenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 2.5:1; Combined isolated yield: 51 mg (69%, 0.21 mmol); 90% ee. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.82 (dd, J = 9.2, 6.4 Hz, 1H), 3.55 (td, J = 9.0, 6.5 Hz, 1H), 2.74–2.69 (m, 1H), 2.50 (ddd, J = 11.3, 9.1, 6.2 Hz, 1H), 2.02 (s, 3H), 1.83–1.77 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.6, 197.4, 163.4, 130.2, 129.1, 113.8, 55.5, 52.5, 46.2, 30.9, 28.7, 28.5, 21.2. IR (thin film) 1708, 1671, 1606, 1259 cm–1. HRMS (ESI+) calculated for [C15H19O3]+ requires m/z 247.1329, found 247.1324. mp = 72–74 °C. [α]22

D +27.7° (c1.40, CH2Cl2).

1-((1S,2R,3S)-2-(3-Methoxybenzoyl)-3-methylcyclobutyl)ethan-1-one

(Figure 4B, entry 3e). Experiment 1: Prepared according to general procedure B using 53 mg (0.30 mmol) (E)-1-(3-methoxyphenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg

(0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 14 h. The crude product was formed as a 2:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 4:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 59 mg (80%, 0.24 mmol); 89% ee (Daicel CHIRALPAK® AD-H, 6% MeOH, 6 mL/min, 245 nm; t1 = 3.5 min, t2 = 5.7 min). Experiment 2: 53 mg (0.30 mmol) (E)-1-(3-methoxyphenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 2:1; Combined isolated yield: 59 mg (79%, 0.24 mmol); 90% ee. 1H NMR (500 MHz, CDCl3) δ 7.42 (s, 1H), 7.39–7.32 (m, 2H), 7.08 (ddd, J = 7.8, 2.5, 1.0 Hz, 1H), 3.85 (s, 3H), 3.78 (dd, J = 8.7, 7.0 Hz, 1H), 3.61 (td, J = 9.2, 6.0 Hz, 1H), 2.79–2.71 (m, 1H), 2.46 (ddd, J = 11.3, 9.1, 5.8 Hz, 1H), 2.03 (s, 3H), 1.85 (ddd, J = 11.4, 9.4, 6.8 Hz, 1H), 1.28 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.3, 198.8, 159.9, 137.5, 129.5, 120.4, 119.5, 112.2, 55.4, 52.6, 46.6, 30.8, 28.9, 28.4, 21.1. IR (thin film) 1708, 1680, 1265 cm–1. HRMS (ESI+) calc’d for [C15H19O3]+ requires m/z 247.1329, found 247.1324. mp = 47–49 °C. [α]22

D +27.4° (c1.70, CH2Cl2).

O O

Me

MeMeO

O O

Me

Me

MeO

1-((1S,2R,3S)-2-(2-Naphthoyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3g). Experiment 1: Prepared according to general procedure B using 59 mg (0.30 mmol) (E)-1-(naphthalen-2-yl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol,

delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 7 h. The crude product was formed as a 3:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 4:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 51 mg (64%, 0.19 mmol); 83% ee (Daicel CHIRALPAK® AD-H, 8% MeOH, 6 mL/min, 243 nm; t1 = 8.4 min, t2 = 15.3 min). Experiment 2: 61 mg (0.31 mmol) (E)-1-(naphthalen-2-yl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 3:1; Combined isolated yield: 52 mg (63%, 0.20 mmol); 84% ee. 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.96–7.91 (m, 2H), 7.89–7.85 (m, 2H), 7.58 (t, J = 7.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 3.96 (dd, J = 8.5, 7.2 Hz, 1H), 3.68 (td, J = 9.1, 5.9 Hz, 1H), 2.88–2.79 (m, 1H), 2.50 (ddd, J = 11.3, 9.1, 5.8 Hz, 1H), 2.02 (s, 3H), 1.89 (ddd, J = 11.1, 9.5, 7.0 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.3, 199.1, 135.5, 133.6, 132.5, 129.5, 129.3, 128.6, 128.3, 127.8, 126.7, 123.9, 52.5, 46.8, 30.9, 28.9, 28.4, 21.2. IR (thin film) 1708, 1674, 1265 cm–1. HRMS (ESI+) calculated for [C18H19O2]+ requires m/z 267.1380, found 267.1375. mp = 92–94 °C. [α]22

D +37.9° (c1.75, CH2Cl2).

1-((1S,2R,3S)-2-(Furan-2-carbonyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3h). Experiment 1: Prepared according to general procedure B using 47 mg (0.34 mmol) (E)-1-(furan-2-yl)but-2-en-1-one, 13 mg (0.02 mmol) Ru(bpy)3Cl2, 20 mg (0.03 mmol) Eu(OTf)3, 38 mg (0.10 mmol, delivered

293 µL of a 0.35 M stock solution in acetonitrile) ligand 9, 142 µL (1.71 mmol) 3-buten-2-one, 119 µL (0.68 mmol) i-Pr2NEt, 1.7 mL acetonitrile, and an irradiation time of 14 h. The crude product was formed as a 2:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (6:1 to 3:1 hexanes:EtOAc) to afford both the cis and trans cycloadducts as pale yellow oils. Combined yield: 48 mg (68%, 0.23 mmol); 87% ee (Daicel CHIRALPAK® AD-H, 5% i-PrOH, 6 mL/min, 262 nm; t1 = 3.7 min, t2 = 9.4 min). Experiment 2: 47 mg (0.35 mmol) (E)-1-(furan-2-yl)but-2-en-1-one, 13 mg (0.02 mmol) Ru(bpy)3Cl2, 20 mg (0.03 mmol) Eu(OTf)3, 38 mg (0.10 mmol, delivered 409 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 143 µL (1.71 mmol) 3-buten-2-one, 119 µL (0.68 mmol) i-Pr2NEt, and 1.7 mL acetonitrile. Crude dr: 2:1; Combined isolated yield: 50 mg (71%, 0.24 mmol); 86% ee. 1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 1.6, 0.8 Hz, 1H), 7.14 (dd, J = 3.5, 0.8 Hz, 1H), 6.52 (dd, J = 3.5, 1.7 Hz, 1H), 3.63–3.56 (m, 2H), 2.79–2.73 (m, 1H), 2.46 (ddd, J = 11.5, 8.9, 4.4 Hz, 1H), 2.06 (s, 3H), 1.84–1.78 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.3, 188.5, 152.5, 145.9, 116.4, 112.3, 52.1, 46.2, 30.6, 29.1, 28.3, 21.2. IR (thin film) 1708, 1674, 1268 cm–1. HRMS (ESI+) calculated for [C12H15O3]+ requires m/z 207.1016, found 207.1021. [α]22

D +33.3° (c1.20, CH2Cl2).

O O

Me

Me

O O

Me

Me

O

1-((1S,2R,3R)-2-Benzoyl-3-isopropylcyclobutyl)ethan-1-one (Figure 4B, entry 3j). Experiment 1: Prepared according to general procedure B using 52.2 mg (0.300 mmol) (E)-4-methyl-1-phenylpent-2-en-1-one, 11.2 mg (0.015 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered

300 µL of a 0.30 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 36 h. The crude product was formed as a 3:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 6:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 49 mg (67%, 0.20 mmol); 94% ee (Daicel CHIRALPAK® AD-H, 6% i-PrOH, 6 mL/min, 238 nm; t1 = 4.1 min, t2 = 5.7 min). Experiment 2: 54.0 mg (0.310 mmol) (E)-4-methyl-1-phenylpent-2-en-1-one, 11.2 mg (0.015 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 4:1; Combined isolated yield: 50 mg (66%, 0.20 mmol); 94% ee. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 3.86 (t, J = 8.6 Hz, 1H), 3.61 (td, J = 9.5, 4.7 Hz, 1H), 2.59 (p, J = 8.5 Hz, 1H), 2.36–2.31 (m, 1H), 1.99–1.95 (m, 1H), 1.93 (s, 3H), 1.66–1.61 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 207.6, 199.3, 136.6, 132.8, 128.6, 127.9, 48.4, 47.5, 41.6, 33.8, 28.3, 25.9, 19.9, 19.1. IR (thin film) 1711, 1683, 1265 cm–1. HRMS (ESI+) calculated for [C16H21O2]+ requires m/z 245.1537, found 245.1537. mp = 77–79 °C. [α]22

D +79.0° (c1.70, CH2Cl2).

1-((1S,2R,3S)-2-Benzoyl-3-((benzyloxy)methyl)cyclobutyl)ethan-1-one (Figure 4B, entry 3k). Experiment 1: Prepared according to general procedure B using 42 mg (0.17 mmol) (E)-4-(benzyloxy)-1-phenylbut-2-en-1-one, 6 mg (0.01 mmol) Ru(bpy)3Cl2, 10 mg (0.02 mmol) Eu(OTf)3, 18 mg (0.05 mmol, delivered 135 µL of a 0.35 M stock solution in acetonitrile) ligand 9, 66 µL

(0.79 mmol) 3-buten-2-one, 55 µL (0.32 mmol) i-Pr2NEt, 0.8 mL acetonitrile, and an irradiation time of 14 h at 37 °C. The crude product was formed as a 3:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 3:1 hexanes:EtOAc) to afford both the cis and trans cycloadducts as pale yellow oils. Combined yield: 41 mg (77%, 0.13 mmol); 98% ee (Daicel CHIRALPAK® AD-H, 13% i-PrOH, 3 mL/min, 239 nm; t1 = 8.3 min, t2 = 9.3 min). Experiment 2: 75 mg (0.30 mmol) (E)-4-(benzyloxy)-1-phenylbut-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 2:1; Combined isolated yield: 71 mg (74%, 0.22 mmol); 98% ee. 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 7.0 Hz, 2H), 7.51 (t, J = 7.0 Hz, 1H), 7.41–7.35 (m, 6H), 7.34–7.29 (m, 1H), 4.58 (s, 2H), 4.27 (dd, J = 9.0, 6.2 Hz, 1H), 3.67–3.59 (m, 2H), 3.58–3.50 (m, 1H), 2.91–2.89 (m, 1H), 2.43–2.38 (m, 1H), 2.14–2.08 (m, 1H), 2.02 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 208.4, 199.0, 138.3, 135.9, 133.0, 128.6, 128.5, 128.3, 127.7, 127.6, 73.3, 71.7, 47.5, 46.5, 35.3, 28.3, 23.8. IR (thin film) 1711, 1680, 1271 cm–1. HRMS (ESI+) calculated for [C21H23O3]+ requires m/z 323.1642, found 323.1647. [α]22

D +36.8° (c2.70, CH2Cl2).

O O

Me

i-Pr

O O

Me

OBn

1-((1S,2R,3S)-2-Benzoyl-3-methylcyclobutyl)propan-1-one (Figure 4B, entry 3l). Experiment 1: Prepared according to general procedure B using 48 mg (0.33 mmol) (E)-1-phenylbut-2-en-1-one, 11mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M

stock solution in acetonitrile) ligand 9, 147 µL (1.50 mmol) 1-penten-3-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 36 h. The crude product was formed as a 1.5:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (9:1 to 4:1 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 50 mg (67%, 0.22 mmol); 90% ee (Daicel CHIRALPAK® AD-H, 5% i-PrOH, 6 mL/min, 236 nm; t1 = 8.3 min, t2 = 12.7 min). Experiment 2: 49.0 mg (0.335 mmol) (E)-1-phenylbut-2-en-1-one, 11.2 mg (0.015 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 409 µL of a 0.22 M stock solution in acetonitrile) ligand 9, 147 µL (1.50 mmol) 1-penten-3-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 1.5:1; Combined isolated yield: 57 mg (74%, 0.25 mmol); 90% ee. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 3.77 (dd, J = 8.6, 7.2 Hz, 1H), 3.64 (td, J = 9.1, 5.7 Hz, 1H), 2.86–2.77 (m, 1H), 2.44 (td, J = 10.2, 5.6 Hz, 1H), 2.35 (dq, J = 17.5, 7.3 Hz, 1H), 2.25 (dq, J = 17.5, 7.3 Hz, 1H), 1.90–1.80 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 211.0, 199.2, 136.4, 132.8, 128.6, 127.9, 52.4, 45.6, 34.3, 30.9, 29.0, 21.2, 7.7. IR (thin film) 1711, 1680, 1269 cm–1. HRMS (ESI+) calculated for [C15H19O2]+ requires m/z 231.1380, found 231.1370. mp = 97–99 °C. [α]22

D +53.6° (c0.50, CH2Cl2).

1-((1S,2R,3S)-2-Benzoyl-3-methylcyclobutyl)-3-methylbutan-1-one (Figure 4B, entry 3m). Experiment 1: Prepared according to general procedure B using 44 mg (0.30 mmol) (E)-1-phenylbut-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol,

delivered 300 µL of a 0.30 M stock solution in acetonitrile) ligand 9, 168 µL (1.50 mmol) 5-methyl-1-hexen-3-one, 104 µL (0.60 mmol) i-Pr2NEt, 1.5 mL acetonitrile, and an irradiation time of 36 h. The crude product was formed as a 2:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (20:1 to 9:1 hexanes:EtOAc) to afford the cis cycloadduct as a pale yellow semisolid. The trans cycloadduct could not be separated from the crude reaction mixture. Yield of cis isomer: 36 mg (46%, 0.14 mmol); 84% ee (Daicel CHIRALPAK® AD-H, 7% i-PrOH, 4 mL/min, 237 nm; t1 = 5.5 min, t2 = 6.7 min). Experiment 2: 45 mg (0.31 mmol) (E)-1-phenylbut-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 409 µL of a 0.22 M stock solution in acetonitrile) ligand 9, 170 µL (1.50 mmol) 5-methyl-1-hexen-3-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 2:1; Isolated 41 mg of the cis isomer (51%, 0.16 mmol); 83% ee. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 3.69–3.60 (m, 2H), 2.91–2.79 (m, 1H), 2.41–2.31 (m, 1H), 2.18 (dd, J = 16.2, 7.3 Hz, 1H), 2.10 (dd, J = 16.2, 6.4 Hz, 1H), 2.03–1.95 (m, 1H), 1.91–1.83 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 209.8, 199.4, 136.5, 132.7, 128.6, 127.8, 51.9, 49.9, 47.0, 30.4, 29.2, 24.2, 22.5, 22.4, 21.2; IR (thin film) 1708, 1680, 1274, 1259 cm–1. HRMS (ESI+) calculated for [C17H23O2]+ requires m/z 259.1615, found 259.1616. [α]22

D +47.5° (c1.25, CH2Cl2).

O O

Et

Me

O O

Me

1-((1S,2R,3S)-2-(4-Fluorobenzoyl)-3-methylcyclobutyl)ethan-1-one (Figure 4B, entry 3n). Experiment 1: Prepared according to general procedure B using 56 mg (0.34 mmol) (E)-1-(4-fluorophenyl)but-2-en-1-one, 8 mg (0.01 mmol) Ru(bpy)3Cl2, 20 mg (0.03 mmol) Eu(OTf)3, 38 mg (0.10

mmol, delivered 293 µL of a 0.35 M stock solution in acetonitrile) ligand 9, 142 µL (1.71 mmol) 3-buten-2-one, 119 µL (0.68 mmol) i-Pr2NEt, 1.7 mL acetonitrile, and an irradiation time of 7 h. The crude product was formed as a 4:1 (cis:trans) mixture of diastereomers, which was separated by flash column chromatography on silica gel (6:1 to 5:2 hexanes:EtOAc) to afford the cis cycloadduct as a white solid and the trans cycloadduct as a colorless oil. Combined yield: 65 mg (81%, 0.28 mmol); 93% ee (Daicel CHIRALPAK® AD-H, 8% i-PrOH, 3 mL/min, 240 nm; t1 = 4.7 min, t2 = 5.6 min). Experiment 2: 50 mg (0.30 mmol) (E)-1-(4-fluorophenyl)but-2-en-1-one, 11 mg (0.01 mmol) Ru(bpy)3Cl2, 18 mg (0.03 mmol) Eu(OTf)3, 34 mg (0.10 mmol, delivered 359 µL of a 0.25 M stock solution in acetonitrile) ligand 9, 125 µL (1.50 mmol) 3-buten-2-one, 104 µL (0.60 mmol) i-Pr2NEt, and 1.5 mL acetonitrile. Crude dr: 3:1; Combined isolated yield: 56 mg (78%, 0.23 mmol); 93% ee. Major (1,2-cis) Stereoisomer: 1H NMR (500 MHz, CDCl3) δ 7.88–7.84 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 3.73 (dd, J = 8.9, 6.8 Hz, 1H), 3.63 (td, J = 9.1, 5.8 Hz, 1H), 2.79–2.76 (m, 1H), 2.44 (ddd, J = 11.4, 8.9, 5.6 Hz, 1H), 2.03 (s, 3H), 1.88 (ddd, J = 11.1, 9.6, 7.1 Hz, 1H), 1.28 (d, J = 6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.2, 197.6, 165.5 (d, J = 254.8 Hz), 132.7 (d, J = 3.0 Hz), 130.3 (d, J = 9.2 Hz), 115.7 (d, J = 22.1 Hz), 52.1, 46.8, 30.7, 29.0, 28.2, 21.1. 19F NMR (471 MHz, CDCl3) δ –105.6. IR (thin film) 1708, 1680, 1597, 1262 cm–1. HRMS (ESI+) calculated for [C14H16FO2]+ requires m/z 235.1129, found 235.1131. mp = 58–60 °C. [α]22

D +29.9° (c2.10, CH2Cl2). Minor (1,2-trans) Stereoisomer: 1H NMR (500 MHz, CDCl3) δ 8.04–8.00 (m, 2H), 7.14 (t, J = 8.6 Hz, 2H), 3.89 (t, J = 8.4, 1H), 3.58 (q, J = 9.3 Hz, 1H), 2.57–2.48 (m, 1H), 2.45–2.38 (m, 1H), 2.09 (s, 3H), 1.72 (dt, J = 10.6, 9.2 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 208.3, 198.0, 166.1 (d, J = 255.8 Hz), 132.6 (d, J = 2.9 Hz), 131.5 (d, J = 9.3 Hz), 115.9 (d, J = 21.8 Hz), 49.5, 43.8, 30.8, 29.7, 27.7, 21.1. 19F NMR (471 MHz, CDCl3) δ –105.0. IR (thin film) 1707, 1673, 1595, 1221 cm–1. HRMS (ESI+) calculated for [C14H16FO2]+ requires m/z 235.1129, found 235.1128. [α]22

D –54.5° (c0.40, CH2Cl2).

O O

Me

MeF

E. Derivatization of 2c for X-Ray Analysis (Synthesis of S3)

Me

Me

O N

Br

NH

NO2

NO2

Me

Me

O O

Br

H2NNH

NO2

NO2

cat. H2SO4

2c S3

(4-Bromophenyl)((1R,2R,4S)-2-((E)-1-(2-(2,4-dinitrophenyl)hydrazono)ethyl)-4-methylcyclobutyl)methanone (S3). A 25 mL round-bottom flask equipped with a magnetic stir bar was charged with 2c (56 mg, 0.19 mmol, 1.0 equiv), 2,4-dinitrophenylhydrazine (38 mg, 0.19 mmol, 1.0 equiv) and 2 mL ethanol. After stirring at room temperature for 5 min, H2SO4 (5 µL, 0.09 mmol, 0.5 equiv) was added and the reaction mixture was heated to 70 °C for 2.5 h. The resulting solution was concentrated in vacuo to afford a heterogeneous red and yellow oil that was purified by flash column chromatography on silica gel (5:1 hexanes:EtOAc). The major product (S3) was isolated as fine yellow needles (37 mg, 41% yield) that were subsequently recrystallized from CH2Cl2/MeOH to afford X-ray-quality crystals. 1H NMR (500 MHz, CDCl3) δ 11.05 (s, 1H), 9.13 (d, J = 2.6 Hz, 1H), 8.25 (dd, J = 9.5, 2.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 3.87 (t, J = 8.4 Hz, 1H), 3.62 (q, J = 8.9 Hz, 1H), 2.51–2.43 (m, 2H), 2.00 (s, 3H), 1.89–1.82 (m, 1H), 1.26 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 198.6, 157.9, 145.1, 137.8, 135.2, 132.1, 130.0, 130.0, 129.1, 128.7, 123.6, 116.1, 52.2, 39.9, 32.3, 30.4, 21.2, 14.6. IR (thin film) 3945, 3055, 2987, 1619, 1422, 1265 cm–1. HRMS (ESI+) calculated for [C20H20BrN4O5]+ requires m/z 475.0612, found 475.0631. mp = 122–124 °C. [α]22

D –100.5° (c0.35, CH2Cl2).

F. UV-Vis Spectra

Fig. S1. UV-Vis spectra of enones 1a, 1g, and acetonitrile. Both analyte samples are at a concentration of 40 µM in acetonitrile. G. Influence of Michael Acceptor Stoichiometry The effect of the concentration of the alkyl enone coupling partner was evaluated by examining the [2+2] cycloaddition of 1a with 3-buten-2-one. The optimized procedure described in General Procedure A was utilized, except that the amount of the alkyl enone was varied. As revealed in Table S1, higher concentrations of 3-buten-2-one result in a higher overall rate of conversion as well as diminished formation of products arising from homocoupling of 1a (i.e., S6). The ee of the major [2+2] cycloadduct, however, is unaffected. Table S1. Effect of Michael acceptor stoichiometry on product distribution.

Ph

O

Me

Me

O 5 mol% Ru(bpy)3Cl210 mol% Eu(OTf)3

20 mol% 8

O

Me

O

MePh

2 equiv. i-Pr2NEt0.2 M MeCN

visible light, –20 °C, 15 h1a 2a

O

Ph

OHMe

Me

O

Ph

OHPh

MeMe

S4 S5 S6

Ph

O

Me

Me O

entry 3-buten-2-one yielda

1a 2a (ee) S4 S5 S6 1 1 equiv 32% 24% (92%) 6% 13% 7% 2 5 equiv 1% 73% (92%) 4% 9% trace

a Yields determined by 1H NMR spectroscopy using an internal standard.

O

Me

O

Me

1a 1g

1a

1g

acetonitrile

H. SFC Chromatograms

Racemic (Daicel CHIRALPAK® AD-H, 6% i-PrOH, 6 mL/min, 249 nm)

Peak No % Area Area RT (min) Height (mV) 1 49.8284 6915.9851 1.35 1637.3083 2 50.1716 6963.6313 1.9 838.6501 Total: 100 13879.6164 Enantioenriched

Peak No % Area Area RT (min) Height (mV) 1 3.8976 191.9605 1.37 57.9517 2 96.1024 4733.0875 1.66 1013.536 Total: 100 4925.048

I. NMR Spectra

Figure 3, entry 2c 1H NMR, CDCl3 500 MHz

O O

Me

MeBr

Figure 3, entry 2c 13C NMR, CDCl3 126 MHz

O O

Me

MeBr

O O

Me

Me

MeO

Figure 3, entry 2e 1H NMR, CDCl3 500 MHz

O O

Me

Me

MeO

Figure 3, entry 2e 13C NMR, CDCl3 126 MHz

Figure 3, entry 2f 1H NMR, CDCl3 500 MHz

O O

Me

Me

F

Figure 3, entry 2f 13C NMR, CDCl3 126 MHz

O O

Me

Me

F

Figure 3, entry 2f 19F NMR, CDCl3 471 MHz

O O

Me

Me

F

Figure 3, entry 2g 1H NMR, CDCl3 500 MHz

O O

Me

Me

Figure 3, entry 2g 13C NMR, CDCl3 126 MHz

O O

Me

Me

Figure 4B, entry 3a 1H NMR, CDCl3 500 MHz

O O

Me

Me

Figure 4B, entry 3a 13C NMR, CDCl3 126 MHz

O O

Me

Me

Figure 4B, entry 3b 1H NMR, CDCl3 500 MHz

O O

Me

MeCl

Figure 4B, entry 3b 13C NMR, CDCl3 126 MHz

O O

Me

MeCl

Figure 4B, entry 3c 1H NMR, CDCl3 500 MHz

O O

Me

MeBr

Figure 4B, entry 3c 13C NMR, CDCl3 126 MHz

O O

Me

MeBr

Figure 4B, entry 3d 1H NMR, CDCl3 500 MHz

O O

Me

MeMeO

Figure 4B, entry 3d 13C NMR, CDCl3 126 MHz

O O

Me

MeMeO

Figure 4B, entry 3e 1H NMR, CDCl3 500 MHz

O O

Me

Me

MeO

Figure 4B, entry 3e 13C NMR, CDCl3 126 MHz

O O

Me

Me

MeO

Figure 4B, entry 3g 1H NMR, CDCl3 500 MHz

O O

Me

Me

Figure 4B, entry 3g 13C NMR, CDCl3 126 MHz

O O

Me

Me

Figure 4B, entry 3h 1H NMR, CDCl3 500 MHz

O O

Me

Me

O

Figure 4B, entry 3h 13C NMR, CDCl3 126 MHz

O O

Me

Me

O

Figure 4B, entry 3j 1H NMR, CDCl3 500 MHz

O O

Me

i-Pr

Figure 4B, entry 3j 13C NMR, CDCl3 126 MHz

O O

Me

i-Pr

Figure 4B, entry 3k 1H NMR, CDCl3 500 MHz

O O

Me

OBn

Figure 4B, entry 3k 13C NMR, CDCl3 126 MHz

O O

Me

OBn

Figure 4B, entry 3l 1H NMR, CDCl3 500 MHz

O O

Et

Me

Figure 4B, entry 3l 13C NMR, CDCl3 126 MHz

O O

Et

Me

Figure 4B, entry 3m 1H NMR, CDCl3 500 MHz

O O

Me

Figure 4B, entry 3m 13C NMR, CDCl3 126 MHz

O O

Me

Figure 4B, entry 3n 1H NMR, CDCl3 500 MHz

O O

Me

MeF

Figure 4B, entry 3n 13C NMR, CDCl3 126 MHz

O O

Me

MeF

Figure 4B, entry 3n 19F NMR, CDCl3 471 MHz

O O

Me

MeF

Figure 4B, entry 2n (minor diastereomer)

1H NMR, CDCl3 500 MHz

O O

Me

MeF


13C NMR, CDCl3 126 MHz

O O

Me

MeF


19F NMR, CDCl3 471 MHz

O O

Me

MeF

N

O

N

OH ONHn-Bu

Figure 4A, ligand 8 1H NMR, CDCl3 500 MHz

N

O

N

OH ONHn-Bu

Figure 4A, ligand 8 13C NMR, CDCl3 126 MHz

NH

O

N

OH ONHn-Bu

Figure 4A, ligand 9 1H NMR, CDCl3 500 MHz

NH

O

N

OH ONHn-Bu

Figure 4A, ligand 9 13C NMR, CDCl3 126 MHz

Br

O

Me

NNH

NO2

NO2

Me

S3 1H NMR, CDCl3 500 MHz

Br

O

Me

NNH

NO2

NO2

Me

S3 13C NMR, CDCl3 126 MHz

J. X-Ray Crystallographic Data for S3 and 3c

Data Collection for S3 A yellow crystal with approximate dimensions 0.648 x 0.071 x 0.054 mm3 was selected under oil under ambient conditions and attached to the tip of a MiTeGen MicroMount©. The crystal was mounted in a stream of cold nitrogen at 100(1) K and centered in the X-ray beam by using a video camera. The crystal evaluation and data collection were performed on a Bruker Quazar SMART APEXII diffractometer with Mo Kα (λ = 0.71073 Å) radiation and the diffractometer to crystal distance of 4.96 cm. The initial cell constants were obtained from three series of ω scans at different starting angles. Each series consisted of 12

frames collected at intervals of 0.5º in a 6º range about ω with the exposure time of 30 seconds per frame. The reflections were successfully indexed by an automated indexing routine built in the APEXII program suite. The final cell constants were calculated from a set of 7936 strong reflections from the actual data collection. The data were collected by using the full sphere data collection routine to survey the reciprocal space to the extent of a full sphere to a resolution of 0.70 Å. A total of 26774 data were harvested by collecting 3 sets of frames with 0.5º scans in ω and φ with exposure times of 60 sec per frame. These highly redundant datasets were corrected for Lorentz and polarization effects. The absorption correction was based on fitting a function to the empirical transmission surface as sampled by multiple equivalent measurements (40). Structure Solution and Refinement The systematic absences in the diffraction data were uniquely consistent for the space group P212121 that yielded chemically reasonable and computationally stable results of refinement (41-43). A successful solution by the direct methods provided most non-hydrogen atoms from the E-map. The remaining non-hydrogen atoms were located in an alternating series of least-squares cycles and difference Fourier maps. All non-hydrogen atoms were refined with anisotropic displacement coefficients. Hydrazine hydrogen atom H2 was located from the Fourier difference map and refined independently. All other hydrogen atoms were included in the structure factor calculation at idealized positions and were allowed to ride on the neighboring atoms with relative isotropic displacement coefficients. There are three stereocenters in S3 (C8:R, C9:S, C11:R) The absolute configuration was unequivocally established by anomalous dispersion. There is an intramolecular hydrogen bonding interaction between atoms N2 and O4. The final least-squares refinement of 277 parameters against 6023 data resulted in residuals R (based on F2 for I≥2σ) and wR (based on F2 for all data) of 0.0336 and 0.0720, respectively. The final difference Fourier map was featureless. Summary Crystal Data for C20H19N4O5Br (M =475.30): orthorhombic, space group P212121 (no. 19), a = 4.786(3) Å, b = 18.943(8) Å, c = 22.571(9) Å, V = 2046.2(16) Å3, Z = 4, T = 100.0 K, µ(MoKα) = 2.049 mm-1, Dcalc = 1.543 g/mm3, 26774 reflections measured (2.806 ≤ 2Θ ≤ 60.192), 6023 unique (Rint = 0.0388, Rsigma = 0.0337) which were used in all calculations. The final R1 was 0.0336 (I > 2σ(I)) and wR2 was 0.0720 (all data).

Me

Me

O N

Br

NH

NO2

NO2

S3

Fig. S2. A molecular drawing of S3 shown with 50% thermal probability ellipsoids. Table S2. Crystal data and structure refinement for S3. Identification code Yoon33 (CCDC-988978) Empirical formula C20H19N4O5Br Formula weight 475.30 Temperature/K 100.0 Crystal system orthorhombic Space group P212121 a/Å 4.786(3) b/Å 18.943(8) c/Å 22.571(9) α/° 90 β/° 90 γ/° 90 Volume/Å3 2046.2(16) Z 4 ρcalc mg/mm3 1.543 µ/mm-1 2.049 F(000) 968.0 Crystal size/mm3 0.648 × 0.071 × 0.054 Radiation MoKα (λ = 0.71073) 2Θ range for data collection 2.806 to 60.192° Index ranges -6 ≤ h ≤ 6, -25 ≤ k ≤ 26, -31 ≤ l ≤ 30 Reflections collected 26774 Independent reflections 6023 [Rint = 0.0388, Rsigma = 0.0337] Data/restraints/parameters 6023/0/277 Goodness-of-fit on F2 1.035

Final R indexes [I>=2σ (I)] R1 = 0.0336, wR2 = 0.0684 Final R indexes [all data] R1 = 0.0451, wR2 = 0.0720 Largest diff. peak/hole / e Å-3 0.42/-0.52 Flack parameter -0.006(4) Table S3. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for S3. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Br1 7537.2(9) 4101.0(2) 3471.5(2) 38.04(10) O1 13255(5) 3111.2(12) 6112.1(9) 33.2(5) O2 1107(5) 4565.4(11) 10479.8(9) 29.0(5) O3 -1721(4) 3667.8(12) 10487.0(9) 32.3(5) O4 1705(4) 1968.1(10) 8284.3(9) 27.5(5) O5 -1483(4) 1975.3(11) 8962.8(11) 30.6(5) N1 7317(5) 3406.2(10) 7935.9(8) 16.8(4) N2 5222(5) 3007.8(12) 8191.6(10) 18.3(5) N3 236(5) 4005.5(13) 10275.7(10) 23.1(5) N4 613(5) 2225.8(12) 8729.3(11) 23.0(5) C1 8155(5) 4138.0(14) 5300.9(11) 20.6(5) C2 7321(7) 4271.2(13) 4719.5(11) 23.7(5) C3 8649(7) 3912.1(15) 4264.3(12) 25.6(6) C4 10721(7) 3424.0(16) 4373.2(13) 27.3(6) C5 11543(6) 3300.4(15) 4951.0(12) 23.4(6) C6 10273(6) 3660.6(14) 5420.5(11) 18.2(5) C7 11276(6) 3507.5(15) 6035.8(12) 20.8(5) C8 9910(5) 3873.1(13) 6554.9(12) 17.0(5) C9 11268(6) 4595.3(14) 6747.4(12) 20.6(5) C10 11248(6) 4333.5(14) 7396.6(12) 22.7(6) C11 10679(6) 3577.4(14) 7179.3(11) 17.5(5) C12 9712(7) 5272.1(15) 6618.3(15) 31.5(7) C13 8479(6) 3140.8(13) 7474.2(11) 17.4(5) C14 7779(7) 2440.8(13) 7194.4(11) 21.8(5) C15 3977(6) 3240.5(13) 8692.1(11) 16.5(5) C16 4846(6) 3890.5(14) 8953.2(11) 17.8(5) C17 3648(6) 4130.4(14) 9465.8(11) 19.1(5) C18 1542(6) 3738.7(14) 9734.9(11) 18.5(5) C19 590(6) 3112.5(15) 9498.7(12) 19.7(5) C20 1798(5) 2869.1(13) 8977.3(11) 18.3(5)

Table S4. Anisotropic Displacement Parameters (Å2×103) for S3. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Br1 61.8(2) 34.46(15) 17.84(12) 0.57(11) -10.48(17) -8.57(19) O1 35.6(13) 42.5(13) 21.5(10) -1.1(9) 2.8(9) 22.6(10) O2 34.9(12) 25.8(10) 26.2(10) -2.4(9) 5.2(9) 4.1(10) O3 26.8(12) 40.8(12) 29.4(11) 9.5(9) 12.7(9) 1.5(9) O4 38.6(13) 19.0(9) 25.1(9) 1.2(8) -6.6(9) -6.6(9) O5 19.2(10) 22.5(10) 50.1(13) 8.6(10) -3.2(9) -5.4(8) N1 19.4(10) 15.7(9) 15.2(8) 3.3(7) -1.8(10) 1.7(10) N2 25.6(12) 14.9(11) 14.5(10) 1.7(9) -0.6(9) -3.4(9) N3 21.9(12) 27.6(13) 19.8(11) 6.3(10) 3.2(9) 8.2(10) N4 22.0(12) 18.4(11) 28.7(12) 8.3(10) -8.7(10) -2.1(9) C1 22.2(14) 20.9(12) 18.8(11) 0.6(10) -0.4(9) -0.8(11) C2 27.1(14) 21.1(12) 22.8(12) 2.9(9) -4.5(14) -1.4(13) C3 37.3(16) 23.8(14) 15.8(12) -1.2(10) -5.3(11) -11.0(12) C4 37.2(18) 26.0(15) 18.6(13) -5.4(11) 3.4(12) -4.6(13) C5 25.8(15) 22.0(13) 22.4(13) -2.1(10) 3.4(11) -0.8(11) C6 20.6(13) 18.3(12) 15.6(12) -1.4(10) 1.7(10) -2.5(10) C7 21.4(13) 23.1(13) 18.1(12) 0.8(11) 2.4(10) 3.2(11) C8 16.1(12) 19.4(11) 15.5(11) 0.8(10) 1.5(10) 4.3(9) C9 19.3(13) 19.2(12) 23.4(13) 0.3(10) 3.2(11) 1.1(11) C10 24.7(14) 23.0(13) 20.4(13) -1.7(10) -0.6(11) -2.0(11) C11 18.5(13) 18.7(12) 15.3(12) -0.3(9) -1.9(10) 3.6(10) C12 35.5(17) 19.8(13) 39.4(18) 1.2(13) -4.2(14) 3.2(12) C13 21.9(13) 16.0(11) 14.3(11) 1.1(9) -2.4(9) 3.7(10) C14 29.0(15) 16.8(11) 19.7(11) -3.5(9) -2.2(12) 3.0(12) C15 19.7(13) 14.8(11) 15.0(11) 3.6(9) -4.9(10) 0.1(10) C16 17.2(12) 17.8(12) 18.3(12) 2.6(10) 0.6(10) -2.8(10) C17 19.4(12) 19.1(12) 18.8(12) 0.7(10) -3.3(10) 0.1(11) C18 19.0(13) 21.4(12) 15.2(11) 4.8(10) 1.2(9) 4.1(10) C19 14.3(12) 23.2(13) 21.7(13) 10.4(10) -1.1(10) 0.9(10) C20 19.3(14) 16.1(12) 19.4(11) 3.9(9) -5(1) -2.3(9) Table S5. Bond Lengths for S3. Atom Atom Length/Å Atom Atom Length/Å Br1 C3 1.901(3) C5 C6 1.399(4) O1 C7 1.221(3) C6 C7 1.498(4) O2 N3 1.229(3) C7 C8 1.510(4) O3 N3 1.230(3) C8 C9 1.576(4)

O4 N4 1.233(3) C8 C11 1.561(4) O5 N4 1.228(3) C9 C10 1.547(4) N1 N2 1.381(3) C9 C12 1.511(4) N1 C13 1.284(3) C10 C11 1.538(4) N2 C15 1.351(3) C11 C13 1.495(4) N3 C18 1.462(3) C13 C14 1.507(3) N4 C20 1.456(3) C15 C16 1.427(4) C1 C2 1.395(3) C15 C20 1.413(4) C1 C6 1.385(4) C16 C17 1.369(4) C2 C3 1.386(4) C17 C18 1.391(4) C3 C4 1.378(5) C18 C19 1.378(4) C4 C5 1.382(4) C19 C20 1.390(4) Table S6. Bond Angles for S3. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C13 N1 N2 116.1(2) C11 C8 C9 88.0(2) C15 N2 N1 119.4(2) C10 C9 C8 88.87(19) O2 N3 O3 124.2(2) C12 C9 C8 118.7(2) O2 N3 C18 117.8(2) C12 C9 C10 116.9(2) O3 N3 C18 118.0(2) C11 C10 C9 89.9(2) O4 N4 C20 118.6(2) C10 C11 C8 89.7(2) O5 N4 O4 122.9(3) C13 C11 C8 115.8(2) O5 N4 C20 118.5(2) C13 C11 C10 119.9(2) C6 C1 C2 120.7(3) N1 C13 C11 116.7(2) C3 C2 C1 118.5(3) N1 C13 C14 126.1(2) C2 C3 Br1 118.5(2) C11 C13 C14 117.2(2) C4 C3 Br1 119.7(2) N2 C15 C16 119.9(2) C4 C3 C2 121.8(3) N2 C15 C20 122.9(2) C3 C4 C5 119.1(3) C20 C15 C16 117.2(2) C4 C5 C6 120.6(3) C17 C16 C15 120.9(3) C1 C6 C5 119.2(2) C16 C17 C18 119.7(3) C1 C6 C7 122.8(2) C17 C18 N3 119.3(2) C5 C6 C7 117.9(2) C19 C18 N3 118.6(2) O1 C7 C6 119.9(2) C19 C18 C17 122.0(3) O1 C7 C8 120.6(2) C18 C19 C20 118.4(2) C6 C7 C8 119.5(2) C15 C20 N4 121.9(2) C7 C8 C9 115.7(2) C19 C20 N4 116.2(2) C7 C8 C11 115.7(2) C19 C20 C15 121.8(2)

Table S7. Hydrogen Bonds for S3. D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/° N2 H2 O4 0.85(3) 1.98(3) 2.599(3) 129(3) Table S8. Torsion Angles for S3. A B C D Angle/˚ A B C D Angle/˚ Br1 C3 C4 C5 178.9(2) C5 C6 C7 C8 -178.6(3) O1 C7 C8 C9 86.6(3) C6 C1 C2 C3 0.4(4) O1 C7 C8 C11 -14.3(4) C6 C7 C8 C9 -90.5(3) O2 N3 C18 C17 -1.6(4) C6 C7 C8 C11 168.6(2) O2 N3 C18 C19 -179.9(2) C7 C8 C9 C10 -131.7(2) O3 N3 C18 C17 176.2(2) C7 C8 C9 C12 108.0(3) O3 N3 C18 C19 -2.1(4) C7 C8 C11 C10 131.7(2) O4 N4 C20 C15 6.2(4) C7 C8 C11 C13 -104.9(3) O4 N4 C20 C19 -176.2(2) C8 C9 C10 C11 14.2(2) O5 N4 C20 C15 -171.7(2) C8 C11 C13 N1 -111.5(3) O5 N4 C20 C19 5.9(3) C8 C11 C13 C14 66.9(3) N1 N2 C15 C16 -0.4(4) C9 C8 C11 C10 14.0(2) N1 N2 C15 C20 179.2(2) C9 C8 C11 C13 137.4(2) N2 N1 C13 C11 177.8(2) C9 C10 C11 C8 -14.3(2) N2 N1 C13 C14 -0.4(4) C9 C10 C11 C13 -134.2(2) N2 C15 C16 C17 -178.8(2) C10 C11 C13 N1 -5.8(4) N2 C15 C20 N4 -3.9(4) C10 C11 C13 C14 172.7(2) N2 C15 C20 C19 178.6(2) C11 C8 C9 C10 -14.0(2) N3 C18 C19 C20 178.6(2) C11 C8 C9 C12 -134.2(3) C1 C2 C3 Br1 -179.4(2) C12 C9 C10 C11 136.1(3) C1 C2 C3 C4 1.0(4) C13 N1 N2 C15 177.5(2) C1 C6 C7 O1 -175.9(3) C15 C16 C17 C18 -0.4(4) C1 C6 C7 C8 1.2(4) C16 C15 C20 N4 175.7(2) C2 C1 C6 C5 -1.2(4) C16 C15 C20 C19 -1.7(4) C2 C1 C6 C7 179.0(3) C16 C17 C18 N3 -178.8(2) C2 C3 C4 C5 -1.5(5) C16 C17 C18 C19 -0.5(4) C3 C4 C5 C6 0.6(4) C17 C18 C19 C20 0.3(4) C4 C5 C6 C1 0.7(4) C18 C19 C20 N4 -176.7(2) C4 C5 C6 C7 -179.5(3) C18 C19 C20 C15 0.8(4) C5 C6 C7 O1 4.3(4) C20 C15 C16 C17 1.5(4)

Table S9. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for S3. Atom x y z U(eq) H2 4840(60) 2596(16) 8066(13) 13(7) H1 7260 4377 5618 25 H2A 5876 4601 4637 28 H4 11574 3176 4055 33 H5 12982 2968 5030 28 H8 7842 3916 6501 20 H9 13230 4627 6597 25 H10A 13067 4388 7600 27 H10B 9713 4534 7637 27 H11 12470 3307 7157 21 H12A 9591 5341 6189 47 H12B 10711 5670 6797 47 H12C 7825 5244 6785 47 H14A 7816 2071 7497 33 H14B 9154 2332 6886 33 H14C 5910 2465 7018 33 H16 6275 4160 8769 21 H17 4252 4562 9637 23 H19 -856 2853 9688 24 Data Collection for 3c A colorless crystal with approximate dimensions 0.4 x 0.3 x 0.2 mm3 was selected under oil under ambient conditions and attached to the tip of a MiTeGen MicroMount©. The crystal was

mounted in a stream of cold nitrogen at 100(1) K and centered in the X-ray beam by using a video camera. The crystal evaluation and data collection were performed on a Bruker SMART APEXII diffractometer with Cu Kα (λ = 1.54178 Å) radiation and the diffractometer to crystal distance of 4.03 cm.

The initial cell constants were obtained from three series of ω scans at different starting angles. Each series consisted of 41 frames collected at intervals of 0.6º in a 25º range about ω with the exposure time of 5 seconds per frame. The reflections were successfully indexed by an automated indexing routine built in the APEXII program. The final cell constants were calculated from a set of 7160 strong reflections from the actual data collection. The data were collected by using the full sphere data collection routine to survey the reciprocal space to the extent of a full sphere to a resolution of 0.82 Å. A total of 29131 data were harvested by collecting 19 sets of frames with 0.5º scans in ω and φ with an exposure time 5-10 sec per frame. These highly redundant datasets were corrected for Lorentz and polarization effects. The absorption correction was based on fitting a function to the empirical transmission surface as sampled by multiple equivalent measurements (40).

O O

Me

MeBr 3c

Structure Solution and Refinement The systematic absences in the diffraction data were consistent for the space groups P21 and P21/m. The E-statistics strongly suggested the non-centrosymmetric space group P21 that yielded chemically reasonable and computationally stable results of refinement (41-43). A successful solution by the direct methods provided most non-hydrogen atoms from the E-map. The remaining non-hydrogen atoms were located in an alternating series of least-squares cycles and difference Fourier maps. All non-hydrogen atoms were refined with anisotropic displacement coefficients. All hydrogen atoms were included in the structure factor calculation at idealized positions and were allowed to ride on the neighboring atoms with relative isotropic displacement coefficients. The absolute configuration was unequivocally established by anomalous dispersion. 3c has stereocenters at atoms C8, C9, and C11 (R, S, S). No inversion twinning was present in the crystal. The only crystal large enough for the single-crystal X-ray diffraction experiment proved to be a three-component non-merohedral twin with 48(1)%, 49(1)% and 2.8(6)% first, second, and third component contributions, respectively. The final least-squares refinement of 158 parameters against 2250 data resulted in residuals R (based on F2 for I≥2σ) and wR (based on F2 for all data) of 0.0848 and 0.1838, respectively. The final difference Fourier map had several peaks of approximately 1.5 e-/A3 near the bromine atom in the structure. These were interpreted as noise. Summary Crystal Data for C14H15BrO2 (M =295.17): monoclinic, space group P21 (no. 4), a = 9.4545(15) Å, b = 5.3009(9) Å, c = 13.4484(15) Å, β = 104.941(8)°, V = 651.21(17) Å3, Z = 2, T = 100.0 K, µ(CuKα) = 4.200 mm-1, Dcalc = 1.505 g/mm3, 2250 reflections measured (6.802 ≤ 2Θ ≤ 140.096), 2250 unique (Rint = 0.0754, Rsigma = 0.0921) which were used in all calculations. The final R1 was 0.0848 (I > 2σ(I)) and wR2 was 0.1838 (all data).

Fig. S3. A molecular drawing of 3c shown with 50% probability ellipsoids.

Table S10. Crystal data and structure refinement for 3c Identification code Yoon31 (CCDC-988977) Empirical formula C14H15BrO2 Formula weight 295.17 Temperature/K 100.0 Crystal system monoclinic Space group P21 a/Å 9.4545(15) b/Å 5.3009(9) c/Å 13.4484(15) α/° 90 β/° 104.941(8) γ/° 90 Volume/Å3 651.21(17) Z 2 ρcalc mg/mm3 1.505 µ/mm-1 4.200 F(000) 300.0 Crystal size/mm3 0.4 × 0.3 × 0.2 Radiation CuKα (λ = 1.54178) 2Θ range for data collection 6.802 to 140.096° Index ranges -11 ≤ h ≤ 11, -6 ≤ k ≤ 5, -16 ≤ l ≤ 16 Reflections collected 29131 Independent reflections 2250 [Rint = 0.0754, Rsigma = 0.0921] Data/restraints/parameters 2250/1/158 Goodness-of-fit on F2 1.125 Final R indexes [I>=2σ (I)] R1 = 0.0848, wR2 = 0.1810 Final R indexes [all data] R1 = 0.0865, wR2 = 0.1838 Largest diff. peak/hole / e Å-3 1.49/-0.46 Table S11. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 3c. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Br1 1084.0(9) 737(3) 6898.0(5) 60.8(5) O1 4269(8) 4929(13) 3162(5) 58.1(17) O2 932(7) 3659(16) 1770(5) 55.9(16) C1 3282(9) 4062(18) 4916(7) 54(2) C2 2712(9) 3620(20) 5761(6) 54.0(19) C3 1904(9) 1433(18) 5770(6) 53(2) C4 1638(9) -304(19) 4979(7) 53.1(19)

C5 2234(10) 193(19) 4139(6) 56(2) C6 3042(9) 2355(17) 4103(6) 48.7(18) C7 3664(9) 2925(19) 3213(6) 50.6(18) C8 3639(8) 910(20) 2417(5) 49.4(17) C9 4060(9) 1656(18) 1422(6) 53.6(19) C10 2896(9) -190(20) 826(7) 55(2) C11 2161(9) -195(16) 1743(6) 47.1(17) C12 5646(10) 1280(20) 1373(7) 65(3) C13 856(9) 1449(15) 1522(6) 46.9(19) C14 -572(9) 260(20) 940(7) 57(2) Table S12. Anisotropic Displacement Parameters (Å2×103) for 3c. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+...+2hka×b×U12] Atom U11 U22 U33 U23 U13 U12 Br1 76.4(7) 63.2(7) 46.5(6) 6.2(4) 22.7(3) 8.5(5) O1 77(3) 45(5) 56(3) 0(2) 22(3) -9(3) O2 66(3) 51(5) 53(3) -1(3) 19(3) 5(3) C1 61(4) 46(6) 51(4) -3(4) 11(3) 0(3) C2 67(4) 53(5) 42(4) -3(3) 13(3) -1(4) C3 60(4) 62(7) 40(4) 7(3) 20(3) 8(3) C4 66(4) 43(5) 53(5) 3(3) 22(3) 0(3) C5 71(4) 55(7) 45(4) -2(3) 17(3) -3(4) C6 58(4) 42(5) 47(4) 4(3) 13(3) 3(3) C7 58(4) 46(5) 47(4) 2(3) 11(3) -3(3) C8 59(3) 45(5) 47(3) 9(4) 17(3) -1(4) C9 67(4) 49(5) 46(4) 5(3) 17(3) 2(3) C10 64(4) 60(6) 44(4) -1(3) 18(3) 5(3) C11 68(4) 33(4) 44(4) -2(3) 21(3) -4(3) C12 69(4) 78(9) 52(4) 1(4) 23(3) -3(4) C13 70(4) 36(6) 38(3) -1(3) 20(3) -2(3) C14 64(4) 55(7) 52(4) 3(4) 16(3) -1(4) Table S13. Bond Lengths for 3c. Atom Atom Length/Å Atom Atom Length/Å Br1 C3 1.909(8) C6 C7 1.494(13) O1 C7 1.217(12) C7 C8 1.508(14) O2 C13 1.215(12) C8 C9 1.543(10) C1 C2 1.396(13) C8 C11 1.569(11) C1 C6 1.392(12) C9 C10 1.534(13) C2 C3 1.391(14) C9 C12 1.531(12) C3 C4 1.380(13) C10 C11 1.564(11)

C4 C5 1.411(13) C11 C13 1.477(12) C5 C6 1.385(13) C13 C14 1.513(12) Table S14. Bond Angles for 3c. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ C6 C1 C2 120.8(9) C7 C8 C9 118.3(9) C3 C2 C1 118.3(8) C7 C8 C11 121.5(7) C2 C3 Br1 120.3(6) C9 C8 C11 89.2(6) C4 C3 Br1 116.9(7) C10 C9 C8 88.8(7) C4 C3 C2 122.8(8) C12 C9 C8 118.6(7) C3 C4 C5 117.5(9) C12 C9 C10 118.3(8) C6 C5 C4 121.4(9) C9 C10 C11 89.7(6) C1 C6 C7 118.7(8) C10 C11 C8 86.8(6) C5 C6 C1 119.3(8) C13 C11 C8 118.0(7) C5 C6 C7 122.0(8) C13 C11 C10 110.9(7) O1 C7 C6 120.7(8) O2 C13 C11 121.8(8) O1 C7 C8 119.9(8) O2 C13 C14 121.7(8) C6 C7 C8 119.2(8) C11 C13 C14 116.5(7) Table S15. Torsion Angles for 3c. A B C D Angle/˚ A B C D Angle/˚ Br1 C3 C4 C5 179.8(7) C6 C7 C8 C11 62.5(11) O1 C7 C8 C9 -14.1(11) C7 C8 C9 C10 -143.7(7) O1 C7 C8 C11 -122.2(9) C7 C8 C9 C12 94.4(11) C1 C2 C3 Br1 -179.5(6) C7 C8 C11 C10 140.7(9) C1 C2 C3 C4 -0.3(13) C7 C8 C11 C13 28.6(11) C1 C6 C7 O1 -5.6(12) C8 C9 C10 C11 17.9(7) C1 C6 C7 C8 169.6(7) C8 C11 C13 O2 6.5(11) C2 C1 C6 C5 -0.3(12) C8 C11 C13 C14 -175.5(7) C2 C1 C6 C7 179.5(8) C9 C8 C11 C10 17.5(7) C2 C3 C4 C5 0.6(13) C9 C8 C11 C13 -94.6(8) C3 C4 C5 C6 -0.7(13) C9 C10 C11 C8 -17.6(7) C4 C5 C6 C1 0.6(13) C9 C10 C11 C13 101.2(7) C4 C5 C6 C7 -179.2(8) C10 C11 C13 O2 -91.3(9) C5 C6 C7 O1 174.1(8) C10 C11 C13 C14 86.7(9) C5 C6 C7 C8 -10.6(12) C11 C8 C9 C10 -17.8(7) C6 C1 C2 C3 0.2(13) C11 C8 C9 C12 -139.7(9) C6 C7 C8 C9 170.6(7) C12 C9 C10 C11 140.1(8)

Table S16. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 3c. Atom x y z U(eq) H1 3839 5543 4896 64 H2 2873 4786 6315 65 H4 1075 -1779 5000 64 H5 2078 -979 3587 68 H8 4278 -518 2750 59 H9 3747 3430 1230 64 H10A 3295 -1847 698 66 H10B 2267 526 183 66 H11 1956 -1935 1957 56 H12A 6275 2516 1821 97 H12B 5711 1517 664 97 H12C 5967 -427 1604 97 H14A -612 200 205 85 H14B -1392 1268 1042 85 H14C -637 -1456 1195 85

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