Supporting Information

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1 J. Am. Chem. Soc. Supporting Information S 1 The Productive rger of Iodonium Salts and rganocatalysis. A on-photolytic Approach to the Enantioselective α- Trifluoromethylation of Aldehydes Anna E. Allen and David W. C. MacMillan* rck Center for Catalysis at Princeton University, Princeton, ew Jersey Supporting Information I. General Information. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego. 1 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole was purchased from Aldrich and used as received, which behaved identically to that prepared through literature procedures. 2 All solvents were purified according to the method of Grubbs. 3 rganic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Chromatographic purification of products was accomplished using force-flow chromatography on Silicycle or Iatrobeads silica gel according to the method of Still. 4 Thin-layer chromatography (TLC) was performed on Silicycle 250 µm silica gel plates. TLC visualization was performed by fluorescence quenching or KMn 4 stain. All yields reported are averages of at least two experimental runs. 1 and 19 F MR spectra were recorded on a Varian Inova 400 (400 Mz or 376 Mz) and are referenced relative to residual CDCl 3 proton signals at δ 7.27 ppm and (1) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; 3 rd ed., Pergamon Press, xford, (2) (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, (b) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754. (3) Pangborn, A. B.; Giardello, M. A.; Grubbs, R..; Rosen, R. K.; Timmers, F. J. rganometallics 1996, 15, (4) Still, W. C.; Kahn, M.; Mitra, A. J. J. rg. Chem. 1978, 43, 2923.

2 J. Am. Chem. Soc. Supporting Information S 2 CFCl 3 (δ 0.0 ppm) respectively. Data for 1 and 19 F MR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, h = heptet, m = multiplet, ap = apparent), integration, coupling constant (z) and assignment. 13 C spectra were recorded on a Bruker 500 (125 Mz) and are referenced relative to CDCl 3 at δ ppm. Data for 13 C MR are reported in terms of chemical shift and multiplicity where appropriate. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in terms of frequency of absorption (cm -1 ). igh Resolution 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 liquid chromatography (PLC) was performed on ewlett-packard 1100 Series chromatographs using a chiral column (25 cm) and guard column (5 cm) as noted for each compound. ptical rotations were measured on a Jasco P-1010 polarimeter with [α] D values reported in degrees; concentration (c) is in g/100 ml. II. Enantioselective Aldehyde Trifluoromethylation. (20 mol %) R I Ph TFA CuCl (5 mol %) CCl 3, 20 ºC R General procedure (A) for the enantioselective trifluoromethylation using copper(i) chloride: To an oven-dried 8 ml vial equipped with a magnetic stir bar and Teflon septum was added (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.20 equiv.), copper(i) chloride (3.0 mg, equiv.), and 3,3-dimethyl-1-(trifluoromethyl)- 1,2-benziodoxole (0.200 g, 1.00 equiv.). The vial was sealed and purged with a stream of argon and cooled below 20 ºC before CCl 3 was added. The aldehyde (1.20 mmol, 2.0 equiv.) was then added and the vial was placed in a 20 C acetone-containing cryocool, unless otherwise noted. After 20 hours, the vial was removed, cooled to 78 C, and

3 J. Am. Chem. Soc. Supporting Information S 3 diluted with cold C 2 Cl 2 (2.0 ml, 78 C). ab 4 (0.230 g, 10 equiv.) was then added, followed by cold (1.0 ml, 78 C). The reaction was stirred for one hour at 78 C then transferred to a flask containing cold saturated aqueous ammonium chloride solution (10 ml, 0 ºC). The resulting solution was warmed to room temperature, extracted with C 2 Cl 2 ( 3), and the combined organic layers were dried over MgS 4 and concentrated in vacuo. The crude oil was then purified by column chromatography on silica gel or Iatro beads using the noted solvent mixture to furnish the desired alcohol product. (20 mol %) R I Ph TFA FeCl 2 (10 mol %) CCl 3, t-amyl alcohol 20 ºC R General procedure (B) for the enantioselective trifluoromethylation using iron(ii) chloride: To an oven-dried 8 ml vial equipped with a magnetic stir bar and Teflon septum was added (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.20 equiv.), iron(ii) chloride (7.6 mg, 0.10 equiv.), and 3,3-dimethyl-1-(trifluoromethyl)-1,2- benziodoxole (0.200 g, 1.00 equiv.). The vial was sealed and purged with a stream of argon and cooled below 20 ºC before CCl 3 and tert-amyl alcohol were added. The aldehyde (1.20 mmol, 2.0 equiv.) was then added and the vial was placed in a 20 C acetone-containing cryocool, unless otherwise noted. After 20 hours, the vial was removed, cooled to 78 C, and diluted with cold C 2 Cl 2 (2.0 ml, 78 C). ab 4 (0.230 g, 10 equiv.) was then added, followed by cold (1.0 ml, 78 C). The reaction was stirred for one hour at 78 C then transferred to a flask containing cold saturated aqueous ammonium chloride solution (10 ml, 0 ºC). The resulting solution was warmed to room temperature, extracted with C 2 Cl 2 ( 3), and the combined organic layers were dried over MgS 4 and concentrated in vacuo. The crude oil was then purified

4 J. Am. Chem. Soc. Supporting Information S 4 by column chromatography on silica gel or Iatro beads using the noted solvent mixture to furnish the desired alcohol product. (S)-2-Benzyl-3,3,3-trifluoropropan-1-ol (Table 2, entry 1). Prepared following the general procedure (A) outlined above using 3-phenylpropanal (160 µl, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1-(trifluoromethyl)-1,2- benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography on Iatro beads using 2% EtAc in CCl 3 to provide the title compound ( g, 81% yield, 94% ee) as a clear oil, which was identical to the reported literature compound. 5 2 [α] 6 D = (c = 1.01, CCl 3 ); 2 3 literature: [α] D = (c = 1.10, CCl 3 ). 6 PLC analysis (AS, 2% Et/hexanes, 1.0 ml/min, 214 nm) indicated 94% ee: t R (major) = 12.7 minutes, t R (minor) = 16.1 minutes. (S)-3,3,3-Trifluoro-2-(4-methoxybenzyl)propan-1-ol (Table 2, entry 2). Prepared following the general procedure (A) outlined above using 3-(4-methoxybenzyl)propanal (0.199 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3- dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.35 ml). After 20 hours, the reaction mixture was subjected to the workup (5) agib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, (6) Absolute stereochemical correlation made by comparison, see ref 5.

5 J. Am. Chem. Soc. Supporting Information S 5 protocol outlined in the general procedure (A) and purified by flash chromatography using 20% Et 2 in petroleum ether to provide the title compound (0.123 g, 87% yield, 96% ee) as a clear oil. IR (thin film) 3425, 2941, 2904, 2839, 1613, 1586, 1513, 1466, 1389, 1243, 1152, 1119, 1031 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ: 7.16 (d, 2, J = 8.8 z, Ar), 6.87 (d, 2, J = 8.8 z, Ar), 3.81 (s, 3, C 3 ), 3.79 (m, 1, C 2 ), 3.69 (dd, 1, J = 11.6, 5.6 z, C 2 ), 2.97 (dd, 1, J = 14.0, 4.3 z, C 2 Ar), 2.79 (dd, 1, J = 14.0, 10.4 z, C 2 Ar), 2.47 (m, 1, C ), 1.64 (bs, 1, ); 13 C MR (125 Mz, CDCl 3 ) δ: 158.4, 130.1, 129.4, (q, J 1 = z), 114.0, 58.6 (q, J 3 = 2.6 z), 55.2, 47.3 (q, J 2 = 23.7 z), 29.6 (q, J 3 = 2.5 z); 19 F MR (376 Mz, CDCl 3 ) δ: 69.5 (d, J = 9.0 z); RMS (ESI-TF) calculated for C F 3 2 [M+] + m/z , found [α] D = (c = 1.21, CCl 3 ). PLC analysis of the alcohol (AS, 4% Et/hexanes, 1.0 ml/min, 254 nm) indicated 96% ee: t R (major) = 11.5 minutes, t R (minor) =13.9 minutes. (S)-3,3,3-Trifluoro-2-(4-(trifluoromethyl)benzyl)propan-1-ol (Table 2, entry 3). Prepared following the general procedure (A) outlined above using 3-(4- (trifluoromethyl)benzyl)propanal (0.245 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl- 5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography using 10% EtAc in hexanes to provide the title compound (0.128 g, 78% yield, 93% ee) as a clear oil. IR (thin film) 3385, 2947, 2905, 1621, 1452, 1421, 1393, 1324, 1256, 1158, 1120, 1066, 1019 cm -1 ; 1 MR (400 Mz, CDCl 3 ) δ: 7.59 (d, 2, J = 8.0 z, Ar), 7.38 (d, 2, J = 8.0 z, Ar), 3.81 (m, 1, C 2 ), 3.66 (m, 1,

6 J. Am. Chem. Soc. Supporting Information S 6 C 2 ), 3.06 (dd, 1, J = 14.0, 4.8 z, C 2 Ar), 2.99 (dd, 1, J = 14.0, 9.6 z, C 2 Ar), 2.52 (m, 1, C ), 1.60 (bs, 1, ); 13 C MR (125 Mz, CDCl 3 ) δ: 141.8, 129.5, (q, J 2 = 32.5 z), (q, J 1 = z), (q, J 3 = 3.8 z), (q, J 1 = z), 58.3 (q, J 3 = 2.6 z), 47.0 (q, J 2 = 24.2 z), 30.2 (q, J 3 = 2.5 z); 19 F MR (376 Mz, CDCl 3 ) δ: 63.0 (s), 69.4 (d, J = 9.0 z); RMS (EI+) calculated for C F 6 [M+] m/z , found [α] D = (c = 1.09, CCl 3 ). PLC analysis of the alcohol (AS, 2% Et/hexanes, 1.0 ml/min, 254 nm) indicated 93% ee: t R (major) = 16.1 minutes, t R (minor) =17.9 minutes. (S)-Ethyl 6,6,6-trifluoro-5-(hydroxymethyl)hexanoate (Table 2, entry 4). Prepared following the general procedure (B) outlined above using ethyl 6-oxohexanoate (0.192 g, 1.2 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), FeCl 2 (7.6 mg, mmol, 0.10 equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.), CCl 3 (1.00 ml), and tert-amyl alcohol (0.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (B) and purified by flash chromatography using 35% EtAc in hexanes to provide the title compound (0.109 g, 79% yield, 93% ee) as a clear oil, which was identical to the reported literature compound. 5 2 [α] 6 D = (c = 0.99, CCl 3 ). The enantiomeric excess was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2- naphthoyl chloride (2.0 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. SFC analysis of the 2-naphthoyl ester derivative (D, 10% i-pr, 1.0 ml/min, 220 nm) indicated 93% ee: t R (major) = 3.0 minutes, t R (minor) = 3.6 minutes. C 2 Et

7 J. Am. Chem. Soc. Supporting Information S 7 (S)-5-(Benzyloxy)-2-(trifluoromethyl)pentan-1-ol (Table 2, entry 5). Prepared following the general procedure (B) outlined above using 5-(benzyloxy)pentanal (0.233 g, 1.2 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), FeCl 2 (7.6 mg, mmol, 0.10 equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.), CCl 3 (1.00 ml), and tert-amyl alcohol (0.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (B) and purified by flash chromatography using 15% EtAc in hexanes to provide the title compound (0.122 g, 77% yield, 93% ee) as a clear oil, which was identical to the reported literature compound. 5 2 [α] 4 D = (c = 1.05, CCl 3 ). PLC analysis of the alcohol (AS, 3% Bn Et/hexanes, 1.0 ml/min, 214 nm) indicated 93% ee: t R (major) = 12.2 minutes, t R (minor) = 14.2 minutes. Cbz (S)-Benzyl 6,6,6-trifluoro-5-(hydroxymethyl)hexylcarbamate (Table 2, entry 6). Prepared following the general procedure (A) outlined above using benzyl 6- oxohexylcarbamate (0.302 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4- imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (200 mg, 0.60 mmol, 1.00 equiv.) and CCl 3 (0.80 ml) at 30 ºC. After 20 hours at 30 ºC, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography using 60% Et 2 in petroleum ether to provide the title compound (0.165 g, 85% yield, 96% ee) as a clear oil. IR (thin film) 3405, 3337, 2945, 2873, 1694, 1524, 1456, 1398, 1333, 1251, 1158, 1340 cm -1 ; 1 MR (400 Mz, CDCl 3 )

8 J. Am. Chem. Soc. Supporting Information S 8 δ: (m, 5, Ar), 5.10 (s, 2, C 2 Ph), 4.83 (bs, 1, ), 3.81 (dd, 1, J = 12.0, 5.6 z, C 2 ), 3.75 (dd, 1, J = 12.0, 4.4 z, C 2 ), 3.23, (m, 2, C 2 CBz), 2.20, (m, 1, C ), 2.12 (bs, 1, ), 1.66 (m, 2, C 2 C 2 CBz), (m, 4, C( )C 2 C 2 ); 13 C MR (125 Mz, CDCl 3 ) δ: 156.7, 136.4, 128.5, 128.2, 128.1, (q, J 1 = z), 66.7, 59.2, 45.2, 40.1 (q, J 2 = 24.0 z), 30.0, 23.8, 23.3; 19 F MR (376 Mz, CDCl 3 ) δ: 69.5 (d, J = 9.4 z); RMS (ESI-TF) calculated for C F 3 3 [M+] + 2 m/z , found [α] 6 D = (c = 1.01, CCl 3 ). The enantiomeric excess was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2-naphthoyl chloride (2.0 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. PLC analysis of the 2-naphthoyl ester derivative (AS, 10% i-pr/hexanes, 1.0 ml/min, 254 nm) indicated 96% ee: t R (major) = 26.8 minutes, t R (minor) = 30.2 minutes. (S)-2-(5,5,5-Trifluoro-4-(hydroxymethyl)pentyl)isoindoline-1,3-dione (Table 2, entry 7). Prepared following the general procedure (A) outlined above using 5-(1,3- dioxoisoindolin-2-yl)pentanal (0.280 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5- benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.35 ml) at 30 ºC. After 20 hours at 30 ºC, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography using 30% EtAc in hexanes to provide the title compound (0.129 g, 71% yield, 96% ee) as a clear oil, which was identical to the reported literature compound. 5 2 [α] 8 D = (c = 1.00, CCl 3 ). The enantiomeric excess

9 J. Am. Chem. Soc. Supporting Information S 9 was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2-naphthoyl chloride (2.0 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. SFC analysis of the 2-naphthoyl ester derivative (AS, 10% i-pr, 1.0 ml/min, 254 nm) indicated 96% ee: t R (major) = 3.8 minutes, t R (minor) = 4.2 minutes. Boc (S)-tert-Butyl-4-(1,1,1-trifluoro-3-hydroxypropan-2-yl)piperidine-1-carboxylate (Table 2, entry 8). Prepared following the general procedure (B) outlined above using tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.275 g, 1.2 mmol, 2.00 equiv.), (5S)- 2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), FeCl 2 (7.6 mg, mmol, 0.10 equiv.), 3,3-dimethyl-1-(trifluoromethyl)-1,2- benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.), CCl 3 (1.00 ml), and tert-amyl alcohol (0.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (B) and purified by flash chromatography using 30% EtAc in hexanes to provide the title compound (0.144 g, 80% yield, 94% ee) as a white solid, which was identical to the reported literature compound. 5 2 [α] 5 D = (c = 1.15, CCl 3 ). The enantiomeric excess was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2-naphthoyl chloride (2 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. SFC analysis of the 2-naphthoyl ester derivative (D, 5 10% gradient over 9.0 minutes then isocratic 10%, 1.0 ml/min, 220 nm) indicated 94% ee: t R (major) = 5.5 minutes, t R (minor) = 6.3

10 J. Am. Chem. Soc. Supporting Information S 10 minutes. (S)-2-Cyclohexyl-3,3,3-trifluoropropan-1-ol (Table 2, entry 9). Prepared following the general procedure (B) outlined above using 2-cyclohexylacetaldehyde (0.153 g, 1.2 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), FeCl 2 (7.6 mg, mmol, 0.10 equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.), CCl 3 (0.75 ml), and tert-amyl alcohol (0.25 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (B). 19 F MR showed the crude yield of the desired alcohol as 72% based on hexafluorobenzene as an internal standard (δ 162 (singlet)). The desired alcohol was obtained by flash chromatography using 20% Et 2 in petroleum ether to provide the title compound (94% ee) as a clear oil, which was identical to the reported literature compound [α] D = (c = 0.98, CCl 3 ). The enantiomeric excess was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2-naphthoyl chloride (2.0 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. PLC analysis of the 2-naphthoyl ester derivative (D, 2% Et/hexanes, 1.0 ml/min, 254 nm) indicated 94% ee: t R (major) = 6.0 minutes, t R (minor) = 7.9 minutes. (S)-2-Adamantyl-3,3,3-trifluoropropan-1-ol (Table 2, entry 10). Prepared following the general procedure (A) outlined above using 2-(adamantyl)acetaldehyde (0.216 g, 1.20

11 J. Am. Chem. Soc. Supporting Information S 11 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.00 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A). 19 F MR showed the crude yield of the desired alcohol as 70% based on hexafluorobenzene as an internal standard (δ 162 (singlet)). The desired alcohol was obtained by flash chromatography using 60% CCl 3 in hexanes to provide the title compound (97% ee) as a white solid, which was identical to the reported literature compound [α] D = (c = 0.97, CCl 3 ). The enantiomeric excess was determined on the 2-naphthoyl ester derivative, which was prepared by treating a solution of the corresponding alcohol (1.0 equiv.) in C 2 Cl 2 (0.20 M) with DMAP (2.0 equiv.) and 2-naphthoyl chloride (2.0 equiv.). After consumption of the alcohol was complete (as judged by TLC analysis), the reaction was concentrated in vacuo and purified by preparative TLC. PLC analysis of the 2-naphthoyl ester derivative (D, 2% Et/hexanes, 1.0 ml/min, 254 nm) indicated 97% ee: t R (major) = 5.9 minutes, t R (minor) = 7.9 minutes. (2S,3S)-3-Phenyl-2-(trifluoromethyl)butan-1-ol (Table 2, entry 11). Prepared following the general procedure outlined above using (S)-3-phenylbutanal (0.180 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.35 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography using 45% CCl 3 and 5% EtAc in hexanes to provide the title compound ( g, 76% yield, >20:1 dr determined by crude 19 F MR) as a white solid, which was identical to the reported

12 J. Am. Chem. Soc. Supporting Information S 12 literature compound. 5 [α] D 2 5 = (c = 1.35, CCl 3 ). (2S,3R)-3-Phenyl-2-(trifluoromethyl)butan-1-ol (Table 2, entry 12). Prepared following the general procedure (A) outlined above using (R)-3-phenylbutanal (0.180 g, 1.20 mmol, 2.00 equiv.), (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), CuCl (3.0 mg, mmol, equiv.), 3,3-dimethyl-1- (trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.) and CCl 3 (1.00 ml). After 20 hours, the reaction mixture was subjected to the workup protocol outlined in the general procedure (A) and purified by flash chromatography using 45% CCl 3 and 5% EtAc in hexanes to provide the title compound ( g, 74% yield, 19:1 dr determined by crude 19 F MR) as a white solid, which was identical to the reported literature compound. 5 2 [α] 6 D = 3.60 (c = 1.08, CCl 3 ). III. Access to Enantioenriched rganofluorine Synthons. (20 mol %) Bn I Ph TFA CuCl (5 mol %) CCl 3, 20 ºC Bn ab 4 C 2 Cl 2, 20 ºC Bn β- alcohol: General procedure for enantioselective trifluoromethylation, followed by in situ reduction: To an oven-dried 8 ml vial equipped with a magnetic stir bar and Teflon septum was added (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), copper(i) chloride (3.0 mg, mmol, equiv.), and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.). The vial was sealed and purged with a stream of argon and cooled below

13 J. Am. Chem. Soc. Supporting Information S ºC before CCl 3 (1.35 ml) was added. 3-Phenylpropanal (160 µl, 1.20 mmol, 2.0 equiv.) was added by syringe and the vial was placed in a 20 C acetone-containing cryocool. After 20 hours, the vial was removed, cooled to 78 C, and diluted with cold C 2 Cl 2 (2.0 ml, 78 C). ab 4 (0.230 g, 10 equiv.) was then added followed by cold (1.0 ml, 78 C). The reaction was stirred for one hour at 78 C then transferred to a flask containing cold saturated aqueous ammonium chloride solution (10 ml, 0 ºC). The resulting solution was warmed to room temperature, extracted with C 2 Cl 2 ( 3), and the combined organic layers were dried over MgS 4 and concentrated in vacuo. The crude oil was purified by flash chromatography on Iatro beads using 2% EtAc in CCl 3 to provide the title compound ( g, 81% yield over two steps, 99% yield from α- hydrocinnamaldehyde, 94% ee) as a clear oil, which was identical to the reported literature compound. 5 2 [α] 6 D = (c = 1.01, CCl 3 ). PLC analysis (AS, 2% Et/hexanes, 1.0 ml/min, 214 nm) indicated 94% ee: t R (major) = 12.7 minutes, t R (minor) = 16.1 minutes. (20 mol %) Bn I Ph TFA CuCl (5 mol %) CCl 3, 20 ºC Bn TEMP, PhI(Ac) 2 C, 2 20 ºC Bn α-cf3 acid: General procedure for enantioselective trifluoromethylation, followed by oxidation: To an oven-dried 8 ml vial equipped with a magnetic stir bar and Teflon septum was added (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), copper(i) chloride (3.0 mg, mmol, equiv.), and 3,3- dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.). The vial was sealed and purged with a stream of argon and cooled below 20 ºC before CCl 3 (1.35 ml) was added. 3-Phenylpropanal (160 µl, 1.20 mmol, 2.0 equiv.) was added by syringe and the vial was placed in a 20 C acetone-containing cryocool. After 20 hours, the solution was transferred by precooled pipette to a round bottom flask containing cold

14 J. Am. Chem. Soc. Supporting Information S 14 C (3.0 ml, 20 ºC). Additional cold C (4.0 ml, 20 ºC) was then used to transfer the remaining residue and TEMP (40 mg, 0.24 mmol, 0.40 equiv.) and PhI(Ac) 2 (720 mg, 2.4 mmol, 4.0 equiv.) were added. The reaction flask was then stirred at 20 C for 12 hours. The reaction was quenched by the addition of 1 M a 2 S 3 solution (~ 10 ml) and C 2 Cl 2 (~ 10 ml). The mixture was poured into a separatory funnel and the organic layer was extracted with 1 M a ( 4). The aqueous extracts were then acidified with 3 M Cl and extracted with C 2 Cl 2 ( 3), followed by EtAc ( 3). The organic layers were combined, dried over MgS 4, filtered, and concentrated in vacuo. Purification of the product was achieved using flash chromatography eluting with 30% Et 2 and 1% Ac in petroleum ether to provide the title compound (0.104 g, 80% yield over two steps, 93% yield from the α- hydrocinnamaldehyde, 94% ee) as a clear, colorless oil, which was identical to the reported literature compound. 5 [α] D 2 5 = (c = 1.20, CCl 3 ). The enantiomeric excess was determined on the corresponding alcohol, which was prepared by treating a solution of the acid (1.0 equiv.) in TF (0.20 M) with LiAl 4 (4.0 equiv.) at 78 ºC and allowing to warm to room temperature over 1 hour. After consumption of the acid was complete (as judged by TLC analysis), the reaction was quenched with water and purified by preparative TLC. PLC analysis of the alcohol (AS, 2% Et/hexanes, 1.0 ml/min, 214 nm) indicated 94% ee: t R (major) = 14.0 minutes, t R (minor) = 17.9 minutes. (20 mol %) Bn I Ph TFA CuCl (5 mol %) CCl 3, 20 ºC Bn Bn 2 Ac acb 3 C 2 Cl 2 40 to 25 ºC Bn Bn β- amine: General procedure for enantioselective trifluoromethylation, followed by reductive amination: To an oven-dried 8 ml vial equipped with a magnetic stir bar and Teflon septum was added (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone TFA (38.4 mg, 0.12 mmol, 0.20 equiv.), copper(i) chloride (3.0 mg, mmol, 0.050

15 J. Am. Chem. Soc. Supporting Information S 15 equiv.), and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (0.200 g, 0.60 mmol, 1.00 equiv.). The vial was sealed and purged with a stream of argon and cooled below 20 ºC before CCl 3 (1.35 ml) was added. 3-Phenylpropanal (160 µl, 1.20 mmol, 2.0 equiv.) was added by syringe and the vial was placed in a 20 C acetone-containing cryocool. After 20 hours, the vial was removed, cooled to 78 C, and transferred by precooled pipette to a separatory funnel containing cold Et 2 (precooled to 78 ºC) and the resulting solution was washed with cold p = 4 buffer (potassium biphthalate buffer, Fisher Scientific) ( 4) until the solution was colorless. The combined organic washings were dried over a mixture of a 2 S 4 and MgS 4 then filtered into a precooled flask and concentrated in vacuo, keeping the crude product below 0 ºC at all times. 7 The crude product was then taken up in cold C 2 Cl 2 (2.5 ml, 78 ºC) and acb 3 (0.095 g, 4.0 equiv.) and Bn 2 Ac (0.762 g, 12.0 equiv.) were added at this temperature. The reaction flask was then stirred at 40 C for two hours before being allowed to warm to room temperature overnight. The reaction was quenched by addition of saturated ac 3 solution (~ 4 ml) followed by brine. The aqueous layer was then extracted with C 2 Cl 2 ( 3) followed by EtAc ( 3). The organic layers were combined, dried over MgS 4, filtered, and concentrated in vacuo. Purification of the product was achieved using flash chromatography using basic silica (packed using 3% triethylamine in hexanes), eluting with 15% C 2 Cl 2 and 5% EtAc in hexanes to provide the title compound (0.136 g, 77% yield over two steps, 90% yield from the α- hydrocinnamaldehyde, 86% ee) as a clear, colorless oil, which was identical to the reported literature compound. 5 2 [α] 5 D = (c = 1.19, CCl 3 ). PLC analysis (J, 3% i-pr/hexanes, 1.0 ml/min, 214 nm) indicated 86% ee: t R (minor) = 10.1 minutes, t R (major) = 10.8 minutes. IV. Spectroscopic Data. 1, 13 C, and 19 F MR spectra for all new compounds are included below. (7) Allowing the crude α- aldehyde to warm to room temperature during the workup procedure resulted in slightly lower enantiopurity (81-84% ee).

16 J. Am. Chem. Soc. Supporting Information S 16 Table 2, Entry 2: 1 MR, 400 Mz, CDCl 3 13 C MR, 125 Mz, CDCl 3

17 J. Am. Chem. Soc. Supporting Information S F MR, 376 Mz, CDCl 3 Table 2, Entry 3: 1 MR, 400 Mz, CDCl 3

18 J. Am. Chem. Soc. Supporting Information S C MR, 125 Mz, CDCl 3 19 F MR, 376 Mz, CDCl 3

19 J. Am. Chem. Soc. Supporting Information S 19 Table 2, Entry 6: Cbz 1 MR, 400 Mz, CDCl 3 13 C MR, 125 Mz, CDCl 3

20 J. Am. Chem. Soc. Supporting Information S F MR, 376 Mz, CDCl 3