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1 . Supporting nline Material for Merging Photoredox Catalysis with rganocatalysis: The Direct Asymmetric Alkylation of Aldehydes David A. Nicewicz and David W. C. MacMillan* This PDF file includes: *To whom correspondence should be addressed. Materials and Methods Figs. S1 to S3 References Published 4 September 2008 on Science Express DI: /science

2 Merging Photoredox Catalysis with rganocatalysis: The Direct Asymmetric Alkylation of Aldehydes David A. Nicewicz and David W. C. MacMillan* Merck Center for Catalysis, Princeton University Washington Road, Princeton, NJ , (USA) FAX: (+1) Materials and Methods. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego (S1). All solvents were purified according to the method of Grubbs (S2). Non-aqueous reagents were transferred under nitrogen or argon via syringe or cannula. rganic solutions were concentrated under reduced pressure on a Büchi rotary evaporator using a water bath. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN mesh silica gel 63 or Davisil Grade 643 silica gel according to the method of Still (S3). Thin-layer chromatography (TLC) was performed on Silicycle 0.25 mm silica gel F-254 plates. Visualization of the developed chromatogram was performed by fluorescence quenching or by anisaldehyde, ceric ammonium molybdate, or KMn 4 stain. 1 and 13 C NMR spectra were recorded on a Varian 500 (500 Mz and 125 Mz) unless otherwise noted, and are internally referenced to residual protio solvent signals. Data for 1 NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet), integration, coupling constant (z) and assignment. Data for 13 C NMR are reported in terms of chemical shift relative to CDCl 3 (77.15 ppm). IR spectra were recorded on a Perkin Elmer Spectrum 100 FTIR spectrometer and are reported in wavenumbers (cm -1 ). Mass spectra were obtained from the Princeton University Mass Spectral Facility. Supercritical Fluid Chromatography (SFC) was performed on a Berger Minigram equipped with a diode array UV detector (λ = nm) using a chiral column (25 cm) and guard column (5 cm) as noted for each compound. igh Pressure

3 Liquid Chromatography (PLC) was performed on a ewlett-packard 1100 Series chromatographs using a chiral column (25 cm) and guard column (5 cm) as noted for each compound. Gas liquid chromatography (GLC) was performed on ewlett-packard 6850 and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using a chiral column (30 m 0.25 mm) as noted. ptical rotations were measured on a Jasco P-1010 polarimeter with [α] D values reported in degrees; concentration (c) is in g/100 ml. General Procedure: An oven-dried 8 ml vial equipped with a Teflon septum and magnetic stir bar was charged with tris-(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), the corresponding bromide (0.385 mmol, 1.0 equiv), and (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv). The vial was purged with a stream of nitrogen and 0.8 ml of dry DMF was added via syringe, followed by the corresponding aldehyde (0.769 mmol, 2.0 equiv) and 2,6-lutidine (0.769 mmol, 2.0 equiv). The resultant mixture was degassed for 10 min by bubbling nitrogen through the reaction medium. After the reaction was thoroughly degassed, the vial was sealed with parafilm and placed approximately 8 cm from a 15 W fluorescent lamp. After the reaction was complete (as judged by TLC analysis), the mixture was poured into a separatory funnel containing 5 ml of Et 2 and 5 ml of 2. The layers were separated and the aqueous layer was extracted with Et 2 (3 5 ml). The combined organic layers were dried (MgS 4 ) and concentrated in vacuo. Purification of the crude product by flash chromatography on Davisil Grade 643 silica gel using the indicated solvent system afforded the desired α- alkylated aldehyde. C 2 Et C 2 Et ( ) 5 Me (R)-Diethyl 2-(1-oxohexan-2-yl)propanedioate (entry 1, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II)

4 chloride hexahydrate (1.9 µmol, equiv), 66.0 µl of diethyl bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 5 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 103 mg (93% yield, 90% ee) of the title compound as a colorless oil. IR (film) 2930, 2860, 1650, 1465, 1370, 1256, 1176, 1155 cm -1 ; 1 NMR (400 Mz, CDCl 3 ) δ 9.77 (d, J = 1.2 z, 1, C), (m, 4, 2 C 2 C 2 C 3 ), 3.73 (d, J = 8.8 z, 1, C(C 2 Et) 2 ), (m, 1, CC), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 14, C 2 (C 2 ) 4 C 3, 2 C 2 C 2 C 3 ), 0.87 (t, J = 6.8 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 201.8, 168.2, 168.1, 61.9, 61.8, 51.7, 50.3, 31.5, 29.3, 27.1, 26.4, 22.5, 14.1, 14.0, 13.9; RMS (EI+) exact mass calculated for [M+Na] + (C Na) requires m/z , found m/z ; [α] 3 D = (c = 0.94, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)- pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in CDCl 3 at 3.70 ppm (minor) and 3.66 ppm (major) arising from the resultant diastereomeric acetals. C 2 Et C 2 Et Et (2R,6Z)-Diethyl 2-(1-oxonon-6-en-2-yl)propanedioate (entry 2, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 66 µl of diethyl

5 bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 128 µl of (Z)-non-6-enal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 7 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 100 mg (87% yield, 90% ee) of the title compound as a colorless oil. IR (film) 2963, 2937, 2872, 2719, 1730, 1463, 1370, 1303, 1264, 1220, 1179, 1155, 1033 cm -1 ; 1 NMR (400 Mz, CDCl 3 ) δ 9.76 (d, J = 1.2 z, 1, C), (m, 1, C 2 CCC 2 ), (m, 1, C 2 CCC 2 ), (m, 4, 2 C 2 C 2 C 3 ), 3.73 (d, J = 8.8 z, 1, C(C 2 Et) 2 ), 3.11 (dddd, J = 0.8, 5.2, 8.8, 8.8 z, 1, CC), (m, 4, C 2 CCC 2 ), (m, 1, C 2 C 2 C 2 CCC 2 C 3 ), (m, 1, C 2 C 2 C 2 CCC 2 C 3 ), (m, 2, C 2 C 2 C 2 CCC 2 C 3 ), 1.28 (t, J = 7.2 z, 3, C 2 C 2 C 3 ), 1.26 (t, J = 7.2 z, 3, C 2 C 2 C 3 ), 0.94 (t, J = 7.6 z, 3, C 2 C 2 C 2 CCC 2 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 201.6, 168.2, 168.1, 132.7, 127.9, 61.9, 61.8, 51.7, 50.2, 26.9, 26.5, 25.6, 20.6, 14.4, 14.0, 13.9; RMS (EI+) exact mass calculated for [M+Na] + (C Na) requires m/z , found m/z ; [α] 23 D = (c = 0.94, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)-pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in CDCl 3 at 3.69 ppm (minor) and 3.67 ppm (major) arising from the resultant diastereomeric acetals. C 2 Et C 2 Et Ph (R)-Diethyl 2-(1-oxo-3-phenylpropan-2-yl)propanedioate (entry 3, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -

6 bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 66.0 µl of diethyl bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 101 µl of hydrocinnamaldehyde (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 7 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 105 mg (93% yield, 91% ee) of the title compound as a colorless oil. IR (film) 2983, 2938, 1725, 1455, 1370, 1155 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.78 (s, 1, C), 7.31 (dd, J = 7.3, 7.4 z, 2, Ar), 7.24 (t, J = 7.4 z, 1, Ar), 7.19 (d, 7.2 z, 2, Ar), (m, 4, 2 C 2 C 2 C 3 ), 3.67 (d, J = 7.1 z, 1, C(C 2 Et) 2 ), (m, 1, CC), 3.12 (dd, J = 7.5, 14.2 z, 1, C 2 Ph), 2.82 (dd, J = 7.3, 14.2 z, 1, C 2 Ph), 1.27 (t, J = 7.1 z, 6, 2 C 2 C 2 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 201.2, 168.1, 168.0, 137.4, 129.1, 128.8, 126.9, 62.1, 62.0, 51.8, 51.4, 33.2, 14.0, 13.9; RMS (EI+) exact mass calculated for [M+Na] + 2 (C Na) requires m/z , found m/z ; [α] 3 D = (c = 1.16, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)-pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in CDCl 3 at 4.93 ppm (major) and 4.83 ppm (minor) arising from the resultant diastereomeric acetals. C 2 Et C 2 Et (R)-Diethyl 2-(1-cyclohexyl-2-oxoethyl)propanedioate (entry 4, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 66.0 µl of diethyl

7 bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 107 µl of 2-cyclohexylethanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 7 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 93 mg (85% yield, 95% ee) of the title compound as a colorless oil. IR (film) 2983, 2929, 2855, 2730, 1749, 1731, 1449, 1369, 1308, 1256, 1195, 1154 cm -1 ; 1 NMR (400 Mz, CDCl 3 ) δ 9.84 (d, J = 1.6 z, 1, C), (m, 4, 2 C 2 C 2 C 3 ), 3.85 (d, J = 10.0 z, 1, C(C 2 Et) 2 ), 3.15 (ddd, J = 1.6, 4.8, 10.0 z, 1, CC), (m, 5, cyc), (m, 12, cyc & 2 C 2 C 2 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 202.3, 168.5, 168.3, 61.9, 61.8, 55.7, 50.3, 37.7, 31.4, 29.3, 26.8, 26.3, 26.1, 14.1, 14.0; RMS (EI+) exact mass calculated for [M+Na] + (C Na) requires m/z , found m/z ; [α] 23 D = (c = 1.13, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)-pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in CDCl 3 at 3.83 ppm (minor) and 3.71 ppm (major) arising from the resultant diastereomeric acetals. C 2 Et C 2 Et N Boc (R)-Diethyl 2-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2- oxoethyl)propanedioate (entry 5, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 66.0 µl of diethyl bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg

8 of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 175 mg of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 12 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using hexanes:acetone (4:1) as the eluent to afford 100 mg (68% yield, 91% ee) of the title compound as a colorless, viscous oil. IR (film) 2980, 2934, 2850, 1729, 1692, 1423, 1367, 1248, 1169 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.84 (d, J = 1.5 z, 1, C), (m, 6, 2 C 2 C 2 C 3 & C 2 NBoc), 3.85 (d, J = 9.0 z, 1, C(C 2 Et) 2 ), 3.15 (ddd, J = 1.5, 5.0, 9.0 z, 1, CC), 2.63 (br s, 2, C 2 NBoc), (m, 1, C(C 2 ) 2 NBoc) (m, 2, C 2 C 2 NBoc), (m, 11, C 2 C 2 NBoc & C(C 3 ) 3, (m, 6, 2 C 2 C 2 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 201.3, 168.3, 168.0, 154.6, 79.7, 62.1, 62.0, 54.7, 50.4, 50.2, 35.9, 29.9, 28.4, 14.1, 14.0; RMS (EI+) exact mass calculated for [M+Na] + 2 (C N 7 Na) requires m/z , found m/z ; [α] 3 D = (c = 1.16, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)-pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in CDCl 3 at 5.10 ppm (major) and 5.06 ppm (minor) arising from the resultant diastereomeric acetals. C 2 Et C 2 Et (R)-Diethyl 2-adamantylpropanedioate (entry 6, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 66 µl of diethyl bromomalonate (0.385 mmol, 1.0 equiv), 49.3 mg of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one

9 trifluoromethanesulfonic acid salt (154 µmol, 0.4 equiv), 267 µl of 2-adamantylethanal (1.54 mmol, 4.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 24 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 80 mg (62% yield, 89% ee) of the title compound as a colorless oil. IR (film) 2983, 2905, 2850, 2732, 1750, 1730, 1447, 1368, 1283, 1201, 1150, 1028 cm -1 ; 1 NMR (400 Mz, CDCl 3 ) δ 9.96 (d, J = 2.4 z, 1, C), (m, 4, 2 C 2 C 2 C 3 ), 3.82 (d, J = 8.8 z, 1, C(C 2 Et) 2 ), 3.03 (dd, J = 2.4, 8.8 z, 1, CC), (br s, 3, adamantyl-(c) 3 ), (m, 12, adamantyl- (C 2 ) 6 ), 1.27 (t, J = 7.2 z, 3, C 2 C 2 C 3 ), 1.24 (t, J = 7.2 z, 3, C 2 C 2 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 205.7, 169.1, 168.9, 63.3, 62.0, 59.9, 49.8, 40.1, 36.5, 36.4, 28.3, 14.0; RMS (EI+) exact mass calculated for [M+] + (C ) requires m/z , found m/z ; [α] 22 D = (c = 1.12, C 2 Cl 2 ). The enantiomeric excess was determined by derivatization to the corresponding (S) α methylbenzylamide by Pinnick oxidation followed by amide coupling. To this end, 23 mg ( mmol, 1.0 equiv) of the title compound was dissolved in 1 ml of a t-bu/ 2 water mixture (5/3). To this solution was added 47.0 mg of Na 2 P 4 (0.342 mmol, 5.0 equiv) and 47.3 mg of 1,3-dimethoxybenzene (0.342 mmol, 5.0 equiv; Cl scavenger). This mixture was cooled to 0 C and 61.8 mg of NaCl 2 (0.684 mmol, 10.0 equiv) was added in one portion. The resultant yellow solution was warmed to ambient temperature. After 4 h, complete disappearance of starting material (as judged by TLC) was achieved and 2 ml of brine solution was added. The reaction was extracted with EtAc (3 5 ml) and the combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. The obtained crude carboxylic acid was taken up in 1 ml of C 2 Cl 2 and 26 µl of (S)-αmethylbenzylamine (0.205 mmol, 3.0 equiv; >99% ee), 8.4 mg of N,Ndimethylaminopyridine ( mmol, 1.0 equiv), and 39.3 mg of 1-ethyl-3-(3 - dimethylaminopropyl)carbodiimide (EDCI; mmol, 3.0 equiv) were added sequentially. After stirring at ambient temperature for 18 h, 2 ml of 1M Cl was added and the reaction was extracted with EtAc (3 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Integration of the methine doublets at

10 2.68 and 2.65 ppm revealed a diastereomeric ratio of 94.5:5.5, and hence an 89% ee of the title compound. Ph hex (R)-2-(2-xo-2-phenylethyl)hexanal (entry 7, Table 1): Prepared by employing a slight modification of the general procedure using 30.3 mg of tris(2,2'- bipyridyl)ruthenium (II) chloride hexahydrate (40.5 µmol, equiv), 1.61 g of 2- bromoacetophenone (8.10 mmol, 1.0 equiv), 519 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (1.60 mmol, 0.2 equiv), 2.5 ml of octanal (16.0 mmol, 2.0 equiv), and 1.90 ml of 2,6-lutidine (16.0 mmol, 2.0 equiv). The reaction was irradiated 8 cm from a 125W fluorescent lamp for 8 h, then subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 1.7 g (85% yield, 96% ee) of the title compound as a colorless oil. IR (film) 2928, 2857, 1726, 1685, 1449, 1224 cm -1 ; 1 NMR (300 Mz, CDCl 3 ) δ 9.83 (s, 1, C), (m, 2, Ar), (m, 1, Ar), (m, 2, Ar), 3.48 (dd, 1, J = 7.7, 17.6 z, C 2 CPh), (m, 2, C 2 CPh & CC), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 8, C 2 (C 2 ) 4 C 3 ), 0.88 (t, 3, C 3 ); 13 C NMR (75 Mz, CDCl 3 ) δ 203.7, 198.0, 136.6, 133.3, 128.6, 128.1, 46.7, 37.6, 31.6, 29.3, 28.9, 27.1, 22.5, 14.0; RMS (EI+) exact mass calculated for [M] + 23 (C ) requires m/z , found m/z ; [α] D = (c = 1.30, CCl 3 ). The enantiomeric excess was determined by SFC analysis using a Chiralcel AS- (25 cm 0.46 cm) column (5% to 10% C3CN, linear gradient, 100 bar, 35 C oven, flow = 4.0 ml/min); (S)-isomer: t r = 1.95 min, (R)-isomer: t r = 2.12 min. The spectral data for the title compound were identical to the previously reported data (S4): The absolute configuration of the title compound was determined by comparison of the 2 3 observed optical rotation ([α] D = (c = 1.30, CCl 3 ), 96% ee) to the reported

11 optical rotation for the (R)-isomer ([α] D 2 3 = (c = 1.30, CCl 3 ), 90% ee) (S4). Therefore, the absolute configuration of the title compound is (R). Me n-c 5 11 (R)-2-(2-(4-Methoxyphenyl)-2-oxoethyl)octanal (entry 8, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 88.2 mg of 2-bromo-1-(4- methoxyphenyl)ethanone (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 10 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:etac (4:1) as the eluent to afford 94 mg (88% yield, 96% ee) of the title compound as a colorless oil. IR (film) 2955, 2928, 2856, 2720, 1724, 1673, 1599, 1576, 1511, 1462, 1420, 1258, 1170, 1030 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.82 (d, J = 1.0 z, 1, C), (m, 2, Ar), (m, 2, Ar), 3.87 (s, 3, Me), 3.42 (dd, J = 8.0, 17.5 z, 1, C 2 CAr), (m, 1, CC), 2.99 (dd, J = 5.0, 17.5 z, 1, C 2 CAr), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 8, C 2 (C 2 ) 4 C 3 ), 0.87 (t, J = 6.9 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 204.0, 196.6, 163.6, 130.4, 129.6, 113.7, 55.5, 46.8, 37.4, 31.6, 29.4, 28.9, 27.1, 22.6, 14.1; RMS (EI+) exact mass calculated for [M+] + 2 (C ) requires m/z , found m/z ; [α] 3 D = (c = 1.14, C 2 Cl 2 ). The enantiomeric excess was determined by SFC analysis using a Chiralcel AS- (25 cm 0.46 cm) column (5% to 25% C3CN, linear gradient, 100 bar, 35 C oven, flow = 4.0 ml/min); (S)-isomer: t r = 2.50 min, (R)-isomer: t r = 2.68 min.

12 N 2 n-c 5 11 (R)-2-(2-(4-Nitrophenyl)-2-oxoethyl)octanal (entry 9, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 94.0 mg of 2-bromo-1-(4- nitrophenyl)ethanone (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 10 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using hexanes:acetone (4:1) as the eluent to afford 98 mg (87% yield, 96% ee) of the title compound as a low-melting yellow solid. IR (film) 2928, 2857, 2721, 1724, 1693, 1603, 1525, 1466, 1345, 1319, 1211, 1109, 1004 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.80 (s, 1, C), (m, 2, Ar), (m, 2, Ar), 3.51 (dd, J = 8.5, 18.0 z, 1, C 2 CAr), (m, 1, CC), 2.96 (dd, J = 4.2, 18.0 z, 1, C 2 CAr), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 8, C 2 (C 2 ) 4 C 3 ), 0.88 (t, J = 6.9 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 203.1, 196.8, 150.4, 141.0, 129.2, 124.1, 46.9, 37.8, 31.6, 29.3, 28.7, 27.1, 22.6, 14.1; RMS (EI+) exact mass calculated for [M+] + (C N 4 ) requires m/z , found m/z ; [α] 3 D = (c = 0.94, C 2 Cl 2 ). The enantiomeric excess was determined by SFC analysis using a Chiralcel AS- (25 cm 0.46 cm) column (5% to 50% C3CN, linear gradient, 100 bar, 35 C oven, flow = 4.0 ml/min); (S)-isomer: t r = 2.44 min, (R)- isomer: t r = 2.59 min.

13 C 2 CF 3 hex (R)-2,2,2-Trifluoroethyl 3-formylnonanoate (entry 10, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 49.0 µl of 2,2,2-trifluoroethyl 2- bromoethanoate (S5) (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5- dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 12 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (9:1) as the eluent to afford 82 mg (80% yield, 92% ee) of the title compound as a colorless oil. IR (film) 2931, 2860, 1759, 1729, 1457, 1412, 1281, 1110 cm -1 ; 1 NMR (300 Mz, CDCl 3 ) δ 9.71 (s, 1, C), (m, 2, C 2 C 2 CF 3 ), (m, 1, CC), 2.82 (dd, J = 8.7, 16.5 z, 1, C 2 C 2 C 2 CF 3 ), 2.49 (dd, J = 4.5, 16.2 z, 1, C 2 C 2 C 2 CF 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 8, C 2 (C 2 ) 4 C 3 ), 0.89 (t, J = 6.9 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 202.4, 170.6, (q, 1 J CF = 275 z), 60.4 (q, 2 J CF = 37.5 z), 47.6, 33.4, 31.5, 29.7, 28.2, 26.5, 22.6, 14.6; RMS (EI+) exact mass calculated for [M+Na] + (C F 3 Na) requires m/z , found m/z ; [α] 3 D = 64.7 (c = 1.0, C 2 Cl 2 ). The enantiomeric excess was determined by GLC analysis on a ydrodex B-TBDAc (50 m 0.25 mm) column (130 C isotherm, 1.0 ml/min) (S)-isomer: t r = 75.1 min, (R)-isomer: t r = 78.6 min. Me C 2 Et C 2 Et n-c 5 11 (R)-Diethyl 2-methyl-2-(1-oxooctan-2-yl)propanedioate (entry 11, Table 1): Prepared according to the the general procedure using 1.40 mg of tris(2,2 bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 74 µl of diethyl

14 2-bromo-2-methylpropanedioate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tertbutyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 13 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 93 mg (80% yield, 88% ee) of the title compound as a colorless oil. IR (film) 2931, 2859, 2720, 1730, 1465, 1381, 1249, 1098, 1021 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.77 (d, J = 1.6 z, 1, C), (m, 4, 2 C 2 C 2 C 3 ), (m, 1, CC), (m, 1, C 2 (C 2 ) 4 C 3 ), 1.48 (s, 3, C(C 2 Et) 2 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 14, C 2 (C 2 ) 4 C 3, 2 C 2 C 2 C 3 ), 0.86 (t, J = 6.8 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 202.0, 170.9, 61.9, 56.1, 54.8, 31.5, 29.2, 28.1, 25.5, 22.6, 18.1, 14.1; RMS (EI+) exact mass calculated for [M+Na] + (C Na) requires m/z , found m/z ; [α] 23 D = 5.1 (c = 1.05, C 2 Cl 2 ). The enantiomeric excess was determined as follows: 20 mg of the title compound was added to a mixture of 8.5 mg of (2S,4S)-(+)-pentanediol (>99% ee) and 1.5 mg of p-toluenesulfonic acid monohydrate in C 2 Cl 2 (1 ml). After consumption of the aldehyde was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and the enantiomeric excess of the title compound was determined by the integration of the two 1 NMR signals (both doublets) in C 6 D 6 at 5.08 ppm (major) and 5.04 ppm (minor) arising from the resultant diastereomeric acetals. t-bu 2 C hex (2R)-tert-Butyl 1-oxo-2-((2R)-1-oxooctan-2-yl)-2,3-dihydro-1-indene-2- carboxylate (entry 12, Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 120 mg of (±)-tert-butyl 2-bromo-1-oxo-2,3-dihydro-1-indene-2-carboxylate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one

15 trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). After 12 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent (minor diastereomer eluted first) to afford 105 mg (76% yield, 99.5% ee) of the title compound as a low melting solid in a 5:1 ratio of diastereomers as determined by 1 NMR analysis of the crude reaction mixture. IR (film) 2955, 2930, 2858, 2733, 1711, 1608, 1465, 1369, 1244, 1148, 845 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.67 (d, J = 1.0 z, 1, C), 7.75 (d, J = 7.5 z, 1, Ar), 7.59 (t, J = 7.5 z, 1, Ar), 7.46 (d, J = 7.5 z, 1, Ar), 7.37 (t, J = 7.5 z, 1, Ar) 3.62 (d, J = 17.0 z, 1, ArC 2 ), 3.53 (app. dd, J = 2.0, 10.0 z, 1, CC), 2.98 (d, J = 17.0 z, 1, ArC 2 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 18, C 2 (C 2 ) 4 C 3, C 2 (C 2 ) 4 C 3, C 2 (C 3 ) 3 ), 0.88 (t, J = 7.0 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 201.9, 201.1, 168.2, 153.1, 135.3, 135.2, 127.6, 126.2, 124.6, 82.8, 63.7, 55.5, 34.5, 31.4, 29.5, 28.4, 27.7, 26.5, 22.5, 14.1; RMS (EI+) exact mass calculated for [M+Na] + (C Na) requires m/z , found m/z ; [α] 21 D = 23.4 (c = 2.34, C 2 Cl 2 ). The enantiomeric excess was determined by PLC using a Chiracel J column (10% Et isocratic, flow = 4.0 ml/min, 38 bar, 35 C oven temperature); (S,S)- enantiomer: t r = 5.26 min, (R,R)-enantiomer: t r = 6.90 min. C 2 Et hex (R)-Ethyl 3-formylnonanoate (not depicted in Table 1): Prepared according to the general procedure using 1.40 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.9 µmol, equiv), 43 µl of ethyl bromomalonate (0.385 mmol, 1.0 equiv), 24.6 mg of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (76.9 µmol, 0.2 equiv), 120 µl of octanal (0.769 mmol, 2.0 equiv), and 90.0 µl 2,6-lutidine (0.769 mmol, 2.0 equiv). DMS (0.8 ml) was used in place of DMF for this reaction. After 12 h, the reaction mixture was

16 subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:et 2 (4:1) as the eluent to afford 43.3 mg (53% yield, 94% ee) of the title compound as a colorless oil. IR (film) cm , 2928, 2858, 1733, 1465, 1374, 1248, 1185, 1031; 1 NMR (500 Mz, CDCl 3 ) δ 9.71 (s, 1, C), 4.14 (m, 2, C 2 C 2 C 3 ), (m, 1, CC), 2.69 (dd, J = 8.2, 16.6 z, 1, C 2 C 2 Et), 2.40 (dd, J = 5.2, 16.5 z, C 2 C 2 Et), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 1, C 2 (C 2 ) 4 C 3 ), (m, 11, C 2 (C 2 ) 4 C 3, C 2 C 2 C 3 ), 0.87 (t, J = 6.9 z, 3, C 2 (C 2 ) 4 C 3 ); 13 C NMR (125 Mz, CDCl 3 ) δ 203.2, 172.2, 60.8, 47.7, 33.1, 31.6, 29.3, 28.6, 26.8, 22.6, 14.2, 14.1; RMS (EI+) exact mass calculated for [M+Na] + 23 (C Na) requires m/z , found m/z ; [α] D = (c = 0.44, C 2 Cl 2 ). The enantiomeric excess was determined by GLC analysis on a ydrodex B-TBDAc (50 m 0.25 mm) column (130 C isotherm, 1.0 ml/min) (S)- isomer: t r = 83.7 min, (R)-isomer: t r = 85.5 min. Reaction of 2-(2-phenylcyclopropyl)ethanal with 2-bromoacetophenone: Me N Tf Me 20 mol% N Me Me Me Ph Ph (±) Ph Br 2,6-lutidine, DMF 0.5% Ru(bpy) 3 Cl 2 15 W fluorescent lamp Ph Ph 4-xo-4-phenyl-2-(2-phenylcyclopropyl)butanal: Prepared according to the general procedure using 0.9 mg of tris(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate (1.25 µmol, equiv), 49.7 mg of 2-bromoacetophenone (0.250 mmol, 1.0 equiv), 16.0 mg of (2R,5S)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt (50.0 µmol, 0.2 equiv), 80 mg of (±)-2-(2-phenylcyclopropyl)ethanal (0.500 mmol, 2.0 equiv), and 58.0 µl of 2,6-lutidine (0.500 mmol, 2.0 equiv). After 12 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure and purified by flash chromatography using petroleum ether:acetone (4:1) as the eluent to afford 58 mg (83% yield) of the title compound as an inseparable mixture of diastereomers (1:1 ratio) as determined by 1 NMR analysis of the crude reaction

17 mixture. (1:1 mixture of diastereomers) IR (film) 3064, 3028, 2904, 2825, 2721, 1723, 1682, 1598, 1497, 1449, 1361, 1245, 1209, 1002 cm -1 ; 1 NMR (500 Mz, CDCl 3 ) δ 9.90 (s, 1, C), 9.88 (s, 1, C), 7.92 (d, J = 7.5 z, 2, Ar), 7.88 (d, J = 7.5 z, 2, Ar), (m, 2, Ar), (m, 4, Ar), (m, 6, Ar), (m, 2, Ar), 7.02 (d, J = 7.3 z, 2, Ar), 6.95 (d, J = 7.3 z, 2, Ar), 3.58 (dd, J = 5.5, 7.9 z, 1, C 2 CPh), 3.54 (dd, J = 5.4, 7.9 z, 1, C 2 CPh), 3.40 (dd, J = 4.5, 10.7 z, 1, C 2 CPh), 3.10 (dd, J = 4.5, 10.8 z, 1, C 2 CPh), (m, 2, CC), (m, 1, cyclopropyl-), (m, 1, cyclopropyl-), (m, 1, cyclopropyl-), (m, 1, cyclopropyl-), (m, 1, cyclopropyl-), (m, 1, cyclopropyl-); 13 C NMR (125 Mz, CDCl 3 ) δ (three coincidental aryl carbons) 202.3, 202.2, 198.1, 198.0, 142.1, 141.9, 136.7, 136.6, 133.6, 133.5, 128.9, 128.8, 128.7, 128.6, 128.4, 126.2, 126.2, 126.1, 126.0, 51.9, 51.8, 38.7, 38.4, 22.9, 22.5, 22.5, 22.3, 15.3, 14.6; RMS (EI+) exact mass calculated for [M+] + (C ) requires m/z , found m/z t-bu 2 C hex 1) NaB 4 C 2 Cl 2 /Me 2) p-ts (cat) C 2 Cl 2 hex 3) PDC, C 2 Cl 2 Relative Stereochemical Proof: To a solution of 53.3 mg (0.149 mmol, 1.0 equiv) of the aldehyde (Table 1, entry 12) in 2 ml of C 2 Cl 2 /Me (50/50) was added 28.1 mg (0.743 mmol, 5.0 equiv) of NaB 4 in three equal portions. After 30 min, 2 ml of saturated N 4 Cl solution was added. The layers were separated and the aqueous layer was extracted with C 2 Cl 2 (2 10 ml). The combined organics were dried (Na 2 S 4 ) and concentrated in vacuo to provide a 1:1 mixture of secondary alcohol diastereomers resulting from ketone reduction. The mixture of diastereomers was cyclized to the lactone by dissolution in C 2 Cl 2 (2 ml) and treatment with 2 mg of p-ts. After stirring at ambient temperature for 30 min, the reaction was passed through a plug of silica gel using petroleum ether:acetone (4:1) as eluent and concentrated in vacuo. The

18 resultant crude mixture of diastereomers was dissolved in C 2 Cl 2 (2 ml) and treated with 112 mg (0.298 mmol, 2.0 equiv) of pyridinium dichromate. After stirring for 1.5 h at ambient temperature, 5 ml of Et 2 was added, and the resultant heterogeneous mixture was filtered through a pad of celite (washing with additional Et 2 ) and concentrated in vacuo. The crude material was purified by flash chromatography using petroleum ether:acetone (4:1) as the eluent to furnish 22.9 mg (54%, 3 steps) of the pure product as an oil. 1 NMR (500 Mz, CDCl 3 ) δ 7.75 (d, J = 7.5 z, 1, Ar), 7.65 (dt, J = 7.5, 1.5 z, 1, Ar), 7.50 (d, J = 7.5 z, 1, Ar), 7.42 (dt, J = 7.5, 1.0 z, 1, Ar), (m, 2, -C 2 C 2 ), 3.79 (d, J = 17.5 z, 1, ArC 2 ), 3.07 (d, J = 17.5 z, 1, ArC 2 ), (m, 1, C(C 2 ) 5 C 3 ), (m, 2, C 2 (C 2 ) 4 C 3 ), (m, 10, C 2 (C 2 ) 4 C 3, C 2 (C 2 ) 4 C 3 ), 0.81 (t, J = 7.0 z, 3, C 2 (C 2 ) 4 C 3 ). The relative stereochemistry was assigned based on the observed ne enhancement: ne hex Emission Quenching Experiments: Emission intensities were recorded using a Jobin- Yvon Fluorolog-3 spectrometer equipped with double monochromators and a amamatsu-928 photomultiplier tube (PMT) as the detector. Front face detection was used for all experiments. All tris-(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate solutions were excited at 465 nm and the emission intensity at 612 nm was observed. In a typical experiment, a 2.38 mm solution of tris-(2,2 -bipyridyl)ruthenium (II) chloride hexahydrate in DMF was added to the appropriate amount of quencher in a screw-top 1.0 cm quartz cuvette. After degassing with a stream of N 2 for 10 min, the emission spectrum of the sample was collected.

19 Figure S1: Ru(bpy) 3 Cl 2 Emission Quenching by 2-Bromoacetophenone (S6) Figure S2: Ru(bpy) 3 Cl 2 Emission Quenching by Bromodiethylmalonate (S6)

20 Figure S3: Ru(bpy) 3 Cl 2 Emission Quenching by Enamine 8 (S6, S7) References S1. D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals (Pergamon Press, xford, 1988) ed 3. S2. A. B. Pangborn, M. A. Giardello, R.. Grubbs, R. K. Rosen, F. J. Timmers, rganometallics 15, 1518 (1996). S3. W. C. Still, M. Kahn, A. J. Mitra, J. rg. Chem. 43, 2923 (1978). S4.. Jang, J. B. ong, D. W. C. MacMillan, J. Am. Chem. Soc. 129, 7004 (2007). S5. J. R. Morphy, Z. Rankovic, M. York, Tetrahedron 59, 2137 (2003). S6. I 0 = Emission intensity of Ru(bpy) 3 2+ in the absence of quencher. I = Emission intensity of Ru(bpy) 3 2+ in the presence of quencher. S7. Enamine 8 was prepared according to the method of Gellman: T. J. Peelen, Y. Chi, S.. Gellman, J. Am. Chem. Soc. 59, 2137 (2003).