www.sciencemag.org/cgi/content/full/338/6106/504/DC1

Supplementary Materials for

Chiral Cyclopentadienyl Ligands as Stereocontrolling Element in Asymmetric C–H Functionalization

Baihua Ye and Nicolai Cramer*

*To whom correspondence should be addressed. E-mail: nicolai.cramer@epfl.ch

Published 26 October 2012, Science 338, 504 (2012) DOI: 10.1126/science.1226938

This PDF file includes:

Materials and Methods Figs. S1 to S4 Table S1 References

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Materials and Methods

General techniques and reported starting materials All reactions were carried out under nitrogen atmosphere in oven-dried glassware

with magnetic stirring, unless stated otherwise. Toluene, THF, diethyl ether, DCM were purified by an Innovative Technology Solvent Delivery System. All other reagents were used as obtained from the suppliers. Flash Chromatography was performed with Fluka silica gel 60 (0.040-0.063 µm grade). Analytical thin-layer chromatography was performed with commercial glass plates coated with 0.25 mm silica gel (E. Merck, Kieselgel 60 F254). Compounds were visualized by UV-light at 254 nm and by dipping the plates in an ethanolic vanillin/sulfuric acid solution or an aqueous potassium permanganate solution followed by heating. Proton nuclear magnetic resonance (1H-NMR) data were acquired on a Bruker AV400 (400 MHz) and Bruker DRX600 (600 MHz) spectrometers. Chemical shifts are reported in delta () units, in parts per million (ppm) downfield from tetramethylsilane. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, multiplet, br, broad. Proton decoupled Carbon-13 nuclear magnetic resonance (13C-NMR) data were acquired at 100 MHz on a Bruker AV400 spectrometer and at 150MHz on a Bruker DRX600. Chemical shifts are reported in ppm relative to the center line of a triplet at 77.0 ppm for chloroform-d and at 128.0 ppm for Benzene-d6. Infrared (IR) data were recorded on an Alpha-P Bruker FT-IR Spectrometer. Absorbance frequencies are reported in reciprocal centimeters (cm-1). High resolution mass spectra were recorded by a Agilent LC-MS TOF and are given in m/z. HRMS with APPI were performed by the Biomolecular Mass Spectroscopy Laboratory at the EPF Lausanne. Optical rotations were measured on a Polartronic M polarimeter using a 0.5 cm cell with a Na 589 nm filter. The specific solvents and concentrations (in g/100 mL) are indicated.

(4S,7S)-4,7-Dimethyl-1,3,2-dioxathiepane 2,2-dioxide (10) was prepared according to (38). (3aS,4R,8R,8aS)-2,2,4,8-Tetramethyltetrahydro-[-[1,3]dioxolo[4,5-e][1,3,2]dioxathiepine 6,6-dioxide (13) was prepared according to (39). 9,9-Dimethoxy-9H-xanthene was prepared according to (40). Aryl hydroxamic acids were prepared according to (41).

3

Ligand syntheses (6R,9R)-6,9-Dimethylspiro[4.4]nona-1,3-diene (12) and (4R,7R)-4,7-dimethyl-

4,5,6,7-tetrahydro-2H-indene (13a): To a cold (0°C) suspension of sodium hydride (308 mg, 12.8 mmol) in THF (60.0 mL) was added dropwise a solution of sodium cyclopentadienylide (12.8 mL, 12.82 mmol, 1M in THF) followed a solution of (4S,7S)-4,7-dimethyl-1,3,2-dioxathiepane 2,2-dioxide 11 (2.20 g, 12.2 mmol) in THF (21.0 mL) and 15-crown-5 (4.89 mL, 24.4 mmol). The mixture was then refluxed for 4.5 hours. After cooling to 23°C, the mixture was quenched with water (10 mL) and was extracted with ether (3X100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (pentane) afforded a mixture of 12 and 13a as colorless oils (1.18g, 65% total yield, ratio 3 : 2). A mixture of compounds 12 and 13a (59.3 mg, 0.4 mmol) was dissolved in degassed toluene (40.0 mL) and stirred at 140°C for 18 hours in a sealed tube. After cooling down to 23°C, the solvent was evaporated under reduced and the residue was purified on silica gel (pentane) affording 40.3mg (68% yield) of 13a as colorless oil.

1H-NMR (400 MHz, CDCl3): δ (ppm) = 6.27 (s, 4H), 2.43–2.24 (m,

2H), 2.20–2.07 (m, 2H), 1.49–1.39 (m, 2H), 0.85 (d, J = 7.0 Hz, 6H) 13C-NMR (100 MHz, CDCl3) δ (ppm) = 141.3, 129.2, 70.8, 38.5, 33.6, 18.0; IR

(ATR): ~

= 2953, 2926, 2869, 1646, 1514, 1454, 1373, 1331, 1057, 990, 948, 885, 721, cm-1; HRMS (ESI) calc’d. for [C11H17]

+: 149.1325, found: 149.1320; [α]D

20 = -75.6 (c = 0.3, CH2Cl2); Rf: 0.88 (Pentane);

1H-NMR (400 MHz, CDCl3): δ (ppm) 6.46 (d, J = 5.4 Hz, 1H), 6.26 (dd, J = 5.5, 1.3 Hz, 2H), 3.03–2.77 (m, 2H), 2.54–2.39 (m, 2H), 1.95–1.79 (m, 2H), 1.33–1.15 (m, 4H), 1.09 (t, J = 6.9 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ (ppm) = 143.9, 142.4, 132.7, 130.3, 41.3, 32.0, 31.9, 31.2, 29.9,

21.3, 20.3; IR (ATR): ~ = 2954, 2923, 2866, 2853, 1451, 1375, 807, cm-1; HRMS (ESI) calc’d. for [C11H15]

-: 147.1179, found: 147.1184; [α]D20 = -64.4 (c = 0.3,

CH2Cl2); Rf: 0.80 (Pentane);

4

(3aR,4R,8R,8aR)-2,2,4,8-Tetramethyl-4,5,8,8a-tetrahydro-3aH-indeno[5,6-d][1,3]dioxole (13b): To a cold (0°C) suspension of sodium hydride (62.8 mg, 2.62 mmol) in THF (3.0 mL) was added dropwise a solution of sodium cyclopentadienylide (1.25 mL, 1.25 mmol, 1M in THF) followed a solution of (3aS,4R,8R,8aS)-2,2,4,8-tetramethyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxathiepine 6,6-dioxide (300 mg, 1.19 mmol) (14) in THF (5.0 mL) and 15-crown-5 (0.48 mL, 2.38 mmol). The mixture was then heated up to 100°C and stirred for 7 hours. The mixture was cooled to -78°C, then quenched with water (5.0 mL) and extracted with ether (3X50 mL). The combined organic layers were dried over Na2SO4 then concentrated under reduced pressure. Purification on silica gel (pentane:EtOAc 20:1) afforded 141mg (54% yield) of the product 13b as pale yellow solid.

1H-NMR (400 MHz, C6D6): δ (ppm) = 6.22–6.17 (m, 2H), 4.07–

3.99 (m, 2H), 2.89–2.79 (m, 2H), 2.78–2.70 (m, 1H), 2.39 (dd, J = 23.3, 1.2 Hz, 1H), 1.47 (d, J = 2.0 Hz, 6H), 1.17 (d, J = 7.1 Hz, 3H), 1.10 (d, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, C6D6): δ (ppm) = 142.2, 142.1, 133.3, 132.5, 109.7, 75.1, 75.0, 41.7, 33.7, 32.9, 27.4,

27.38, 14.9, 13.7; IR (ATR): ~

= 2986, 2967, 2932, 2891, 1454, 1373, 1231, 1180, 1144, 1106, 1070, 1037, 854, 803 cm-1; HRMS (ESI) calc’d. for [C14H19O2]

-: 219.1391, found: 219.1398; [α]D

20 = -227.8 (c = 0.3, CH2Cl2); Rf: 0.33 (Pentane:EtOAc 20:1); m.p.: 73.0-76.0°C.

(4R,5R,6R,7R)-4,7-Dimethyl-4,5,6,7-tetrahydro-1H-indene-5,6-diol (13c): To a cold

(0°C) solution of (3aR,4R,8R,8aR)-2,2,4,8-tetramethyl-4,6,8,8a-tetrahydro-3aH-indeno[5,6-d][1,3]dioxole 13b (150 mg, 0.68 mmol) in methanol (2.20 mL) was added pTsOH (3.24 mg, 17 µmol) and 150 µL of water. The ice-bath was removed and the reaction mixture was stirred for 1 hour at 23°C. The mixture was diluted with ether (20.0 mL) and washed with saturated NaHCO3 solution (15.0 mL). The aqueous layer was back extracted with with ether (2X15.0 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on a silica gel (pentane:EtOAc 1:1) affording 100 mg (82% yield) of the diol 13c as colorless solid.

1H-NMR (400 MHz, C6D6): δ (ppm) = 6.31–6.25 (m, 1H), 6.19 (d,

J = 5.5 Hz, 1H), 3.81–3.68 (m, 2H), 2.79–2.64 (m, 3H), 2.49 (d, J = 23.0 Hz, 1H), 1.56–1.50 (m, 2H), 1.10 (d, J = 7.1 Hz, 3H), 1.03 (d, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, C6D6) δ (ppm) = 140.8, 140.7,

133.3, 131.8, 70.6, 70.4, 41.9, 35.0, 34.1, 15.7, 14.6; IR (ATR): ~ = 3339, 2963, 2930, 2872, 1451, 1374, 1284, 1095, 1072, 1049, 1027, 992, 942, 680, 645, 1514, 1454, 1373, 1331, 1057, 990, 948, 885, 721 cm-1; HRMS (ESI) calc’d. for [C11H17O2]

+: 181.1223, found: 181.1218; [α]D20 = -132.2 (c = 0.3, CH2Cl2); Rf: 0.36

(Pentane:EtOAc 1:1); m.p.: 92.0-94.0°C.

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(3aR,4R,8R,8aR)-2,2-Di-tert-butyl-4,8-dimethyl-4,5,8,8a-tetrahydro-3aH-indeno[5,6-d][1,3]dioxole (13f): To a cold (0°C) suspension of the diol 13c (20.0 mg, 0.11 mmol) in CH2Cl2 (200 µL) was added 2,6-dimethylpyridine (78 µL, 0.67 mmol) followed by di-tert-butylsilanediyl bis(trifluoromethanesulfonate) (83 µL, 0.26 mmol). The mixture warmed to 23°C and stirred for 11 hours. The mixture was filtered through a short pad of silica eluting with CH2Cl2 and concentrated under reduced pressure. Purification on silica gel (pentane:EtOAc 50:1) afforded 19.7 mg (56% yield) of the product 13f as colorless solid.

1H-NMR (400 MHz, C6D6): δ (ppm) = 6.21 (dt, J = 3.5, 1.3

Hz, 2H), 4.23–4.15 (m, 2H), 2.99–2.84 (m, 2H), 2.81–2.72 (m, 1H), 2.49–2.39 (m, 1H), 1.21 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 1.8 Hz, 18H), 1.12 (d, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, C6D6) δ (ppm) = 141.7, 141.6, 133.5, 132.2, 75.0, 74.8, 42.0, 36.0, 35.2,

27.6, 21.5, 15.1, 14.0; IR (ATR): ~

= 2964, 2931, 2891, 2859, 1474, 1453, 1366, 1141, 1095, 1049, 1029, 1011, 941, 876, 845, 821, 654 cm-1; HRMS (ESI) calc’d. for [C19H33O2Si]+: 321.2244, found: 321.2242; [α]D

20 = -89.8 (c = 0.3, CH2Cl2); Rf: 0.48 (pentane:EtOAc 50:1); m.p.: 170-172°C.

(3aR,4R,8R,8aR)-4,8-Dimethyl-4,5,8,8a-tetrahydro-3aH-spiro[indeno[5,6-

d][1,3]dioxole-2,9'-xanthene (13e): Diol 13c (19.0 mg, 0.11 mmol), 9,9-dimethoxy-9H-xanthene (51.1 mg, 0.21 mmol) and PPTS (2.65 mg, 10.5 µmol) were loaded into a dry reaction tube followed by 200 µL acetonitrile. The mixture was heated to 60°C, stirred for 5 hours and subsequently filtered through a short pad of silica using CH2Cl2 (5 mL) as eluent. The CH2Cl2 solution was concentrated purified on a silica gel (pentane:EtOAc 30:1) affording 23.3mg (59% yield) of 12e as colorless gum.

1H-NMR (400 MHz, C6D6): δ (ppm) = 7.99–7.88 (m, 2H),

7.19 (dd, J = 7.7, 1.8 Hz, 2H), 7.11–7.00 (m, 4H), 6.26–6.16 (m, 2H), 4.51–4.42 (m, 2H), 2.95–2.80 (m, 2H), 2.78–2.69 (m, 1H), 2.45–2.35 (m, 1H), 1.22 (d, J = 7.1 Hz, 3H), 1.11 (d, J = 7.1 Hz, 3H).13C-NMR (100 MHz, C6D6) δ (ppm) = 152.5, 141.9, 141.9, 133.1, 132.8, 129.8, 129.79, 126.5, 126.45, 125.4, 125.4, 123.4,

117.2, 101.7, 76.74, 76.68, 41.6, 34.1, 33.4, 15.3, 14.1; IR (ATR): ~

= 3078, 3041, 2968, 2931, 2878, 1603, 1575, 1476, 1453, 1375, 1321, 1246, 1208, 1152, 1100, 1069, 1035, 967, 929, 824, 764, 752 cm-1; HRMS (ESI) calc’d. for [C24H23O3]

+: 359.1642, found: 359.1631; [α]D

20 = -27.8 (c = 0.3, CH2Cl2); Rf: 0.45 (Pentane:EtOAc 15:1); (3aR,4R,8R,8aR)-4,8-Dimethyl-2,2-diphenyl-4,5,8,8a-tetrahydro-3aH-indeno[5,6-

d][1,3]dioxole (13d): Diol 13c (180 mg, 1.00 mmol), dimethoxydiphenylmethane (1.14 g, 5.00 mmol) and PPTS (25.1 mg, 0.10 mmol) were loaded in dry reaction tube followed by 2.50 mL acetonitrile. The mixture was heated to 45°C, stirred for 16 hours and subsequently filtered through a short pad of silica using CH2Cl2 (50.0 mL) as eluent. The CH2Cl2 solution was concentrated and purified on Prep-HPLC (Hexane:EtOAc 150:1) affording 113.7 mg (33% yield) of 13d as colorless solid.

6

1H-NMR (400 MHz, C6D6): δ (ppm) = 7.86–7.80 (m, 4H), 7.22–7.17 (m, 4H), 7.10–7.03 (m, 2H), 6.14 (s, 2H), 4.20–4.12 (m, 2H), 2.93–2.79 (m, 2H), 2.67 (dd, J = 23.3, 2.6 Hz, 1H), 2.33 (dd, J = 23.3, 1.1 Hz, 1H), 1.18 (d, J = 7.1 Hz, 3H), 1.10 (d, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, C6D6) δ (ppm) = 145.0, 141.9, 141.8, 133.1, 132.7, 126.7, 110.4, 76.3, 76.2, 41.6, 33.9,

33.2, 15.4, 14.3. IR (ATR): ~

=3057, 2971, 2929, 2895, 1491, 1449, 1433, 1376, 1224, 1200, 1185, 1174, 1114, 1082, 1046, 1033, 991, 966, 944, 791, 752, 700 cm-1; HRMS (ESI) calc’d. for [C24H23O2]

-: 343.1704, found: 343.1710; [α]D20 = -90.0 (c = 0.3,

CH2Cl2); Rf: 0.67 (Pentane:EtOAc 16:1); m.p.: 120-121°C. Synthesis of the Rh(I) complexes (1a-1e):

Exemplified general procedure: To a solution of cyclopentadiene 12d (99.0 mg, 0.29 mmol) in degassed benzene (2.00 mL) at 23°C was added a solution of thallium(I) ethanolate (86.0 mg, 0.35 mmol, 1.2 equiv.) in benzene (1.00 mL). The mixture was stirred for 2 hours at 23°C protected from light. Benzene (2.50 mL) was added, followed by [Rh(C2H4)2Cl]2 (67.1mg, 0.17 mmol, 0.6 equiv). After stirring for 4 hours, the mixture was filtered through a short pad of celite topped with a layer of neutral aluminum oxide. The yellow filtrate was concentrated under reduced pressure to afford 139 mg (96% yield) of 1c as yellow solid.

Complex (1c):

(yellow solid, 96% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) = 7.88–7.75 (m, 2H), 7.23–7.15 (m, 2H), 7.11–7.01 (m, 4H), 5.05 (ddd, J = 3.2, 2.5, 0.9 Hz, 2H), 4.75–4.69 (m, 1H), 4.41 (dd, J = 10.2, 6.0 Hz, 1H), 4.03 (dd, J = 10.1, 6.6 Hz, 1H), 3.80 (t, J = 2.1 Hz, 1H), 2.93 (p, J = 6.9 Hz, 1H), 2.71 (ddd, J =

11.7, 8.9, 2.6 Hz, 2H), 2.37–2.20 (m, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.24–1.14 (m, 2H), 1.10 (d, J = 7.2 Hz, 3H), 1.06–0.98 (m, 2H).13C-NMR (100 MHz, C6D6) δ (ppm) = 144.9, 144.7, 128.4, 128.2, 126.6, 126.5, 111.27 (d, J = 4.4 Hz), 110.9, 105.4 (d, J = 3.4 Hz), 87.18 (d, J = 4.2 Hz), 84.57 (d, J = 4.0 Hz), 84.41 (d, J = 4.0 Hz), 76.1, 75.7, 41.56

(d, J = 13.6 Hz), 37.33 (d, J = 13.4 Hz), 30.7, 30.4, 22.3, 16.3; IR (ATR): ~ = 3057, 2971, 2929, 2895, 1491, 1449, 1433, 1376, 1224, 1200, 1185, 1174, 1114, 1082, 1046, 1033, 991, 966, 944, 791, 752 cm-1; HRMS (APPI) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 538.1374, found: 538.1380; [α]D

20 = -76.3 (c = 1.0, CH2Cl2); m.p.: 141-143°C, decomposition.

Complex (1a):

(yellow oil, 83% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) = 5.24 (dt, J = 2.7, 1.2 Hz, 1H), 4.76–4.69 (m, 1H), 4.43–4.35 (m, 1H), 2.69 (ddd, J = 12.1, 9.0, 2.4 Hz, 2H), 2.57 (ddd, J = 10.9, 8.6, 2.2 Hz, 2H), 2.43–2.29 (m, 1H), 1.63–1.52 (m, 3H), 1.45–1.36 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H), 1.20–0.96 (m, 4H), 0.93 (d, J = 6.6 Hz, 3H). 13C-NMR

(100 MHz, C6D6): δ (ppm) = 112.5 (d, J = 4.3 Hz), 105.2 (d, J = 3.6 Hz), 84.5 (d, J = 4.6 Hz), 83.4 (d, J = 4.1 Hz), 83.2 (d, J = 4.0 Hz), 39.4 (d, J = 13.7 Hz), 36.3 (d, J = 13.5

Rh

Rh

OOPh

Ph

7

Hz), 33.3, 32.6, 30.5, 27.0, 23.6, 21.6; IR (ATR): ~

= 3054, 3010, 2987, 2957, 2923, 2863, 2848, 1454, 1432, 1371, 1324, 1195, 1183, 1083 cm-1; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 342.0849, found: 342.0849; [α]D20 = 20.3 (c = 0.3,

CH2Cl2); Complex (1f):

(yellow oil, 72% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) 5.43–5.37 (m, 1H), 4.75–4.66 (m, 1H), 4.53–4.46 (m, 1H), 2.70–2.55 (m, 4H), 2.23 (dd, J = 11.5, 0.9 Hz, 1H), 2.01–1.91 (m, 1H), 1.84–1.72 (m, 1H), 1.67–1.58 (m, 1H), 1.57-1.50 (m, 1H), 1.45–1.37 (m, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.23–0.99 (m, 7H), 0.85 (d, J = 6.9 Hz, 3H),

0.76 (d, J = 6.9 Hz, 3H). 13C-NMR (100 MHz, C6D6): δ (ppm) 110.20 (d, J = 4.2 Hz), 102.75 (d, J = 4.2 Hz), 85.04 (d, J = 4.2 Hz), 84.52 (d, J = 4.2 Hz), 83.95 (d, J = 4.2 Hz), 41.9, 40.0 (d, J = 13.8 Hz), 37.7, 36.8 (d, J = 13.5 Hz), 31.3, 30.8, 24.2, 23.7, 22.9, 20.6,

17.6, 17.0; IR (ATR): ~ = 3053, 2986, 2955, 2934, 2869, 1463, 1383, 1366, 1196, 1183, 783 cm-1; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 398.1475, found: 398.1475;; [α]D

20 = 7.70 (c = 1.0, CH2Cl2). Complex (1b):

(yellow solid, 79% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) = 5.14–5.04 (m, 1H), 4.77 (t, J = 2.2 Hz, 1H), 4.24 (dd, J = 10.0, 6.0 Hz, 1H), 3.93–3.83 (m, 2H), 2.89 (p, J = 6.8 Hz, 1H), 2.78 (t, J = 10.3 Hz, 2H), 2.43–2.31 (m, 2H), 2.24 (p, J = 6.9 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H), 1.48 (s, 3H), 1.42 (s, 3H), 1.38–

1.13 (m, 6H), 1.10 (d, J = 7.1 Hz, 3H). 13C-NMR (100 MHz, C6D6): δ (ppm) = 111.86 (d, J = 4.4 Hz), 110.27 , 105.94 (d, J = 4.4 Hz), 86.99 (d, J = 4.4 Hz), 84.70–84.53 (m), 75.0,

74.5, 42.0–40.8 (m), 37.8– 37.0 (m), 30.6, 30.1, 27.4, 21.8, 15.7; IR (ATR): ~ = 2977, 2931, 2887, 1453, 1378, 1367, 1229, 1200, 1187, 1171, 1113, 1076, 1046, 965, 857, 785 cm-1; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 414.1061, found: 414.1061; [α]D

20 = -113 (c = 0.3, CH2Cl2); m.p.: 129-133°C, decomposition. Complex (1d):

(yellow gum, 67% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) = 8.17 (dd, J = 5.9, 3.5 Hz, 1H), 7.84 (dd, J = 7.6, 1.9 Hz, 1H), 7.22–7.15 (m, 2H), 7.11–7.02 (m, 4H), 5.11 (d, J = 2.6 Hz, 1H), 4.82–4.77 (m, 1H), 4.71 (dd, J = 10.1, 6.1 Hz, 1H), 4.36 (dd, J = 10.1, 6.6 Hz, 1H), 3.87 (t, J = 2.0 Hz, 1H), 2.99 (p, J = 6.8 Hz, 1H), 2.82–

2.70 (m, 2H), 2.38 (t, J = 9.7 Hz, 2H), 2.26 (p, J = 6.9 Hz, 1H), 1.70 (d, J = 7.0 Hz, 3H), 1.33–1.12 (m, 4H), 1.10 (d, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, C6D6): δ (ppm) = 152.49, 152.42, 130.01, 129.88, 128.59, 126.45, 126.36, 125.21, 123.57, 123.35, 117.27, 111.23 (d, J = 4.1 Hz), 105.31 (d, J = 2.8 Hz), 102.26, 87.39 (d, J = 4.1 Hz), 84.72 (d, J =

Rh

iPr

iPr

Rh

OO

Rh

OO

O

8

3.5 Hz), 84.52 (d, J = 3.6 Hz), 76.95, 75.78, 41.57 (d, J = 13.9 Hz), 37.43 (d, J = 13.6

Hz), 30.96, 30.42, 22.61, 16.11. IR (ATR): ~

= 3055, 2969, 2927, 1604, 1575, 1477, 1455, 1377, 1322, 1247, 1200, 1185, 1153, 1111, 1102, 1073, 1045, 931, 766, 752 cm-1; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 552.1166, found: 552.1178; [α]D

20 = -65.6 (c = 0.3, CH2Cl2); Complex (1e):

(yellow oil, 79% yield). 1H-NMR (600 MHz, C6D6): δ (ppm) = 5.08 (t, J = 2.8 Hz, 1H), 4.82 (t, J = 2.2 Hz, 1H), 4.37 (dd, J = 10.4, 6.0 Hz, 1H), 4.03 (dd, J = 10.5, 6.6 Hz, 1H), 3.88 (t, J = 2.1 Hz, 1H), 2.96 (p, J = 6.9 Hz, 1H), 2.79 (t, J = 11.0 Hz, 2H), 2.41 (t, J = 10.9 Hz, 2H), 2.32 (p, J = 7.1

Hz, 1H), 1.61 (d, J = 7.0 Hz, 3H), 1.32–1.26 (m, 4H), 1.19 (d, J = 0.9 Hz, 9H), 1.15–1.12 (m, 12H).13C-NMR (150 MHz, C6D6) δ (ppm) = 111.33 (d, J = 4.4 Hz), 105.02 (d, J = 3.4 Hz), 86.92 (d, J = 4.3 Hz), 84.8–84.7 (m), 74.52, 74.12, 41.33 (d, J = 13.6 Hz), 37.18

(d, J = 13.3 Hz), 32.7, 32.3, 27.51, 27.5, 22.4, 21.6, 21.4, 15.9; IR (ATR): ~

= 3056, 2964, 2931, 2858, 1474, 1372, 1199, 1186, 1052, 878, 850, 824, 781, 653 cm-1; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 514.1769, found: 514.1772; [α]D20 = -

78.1 (c = 1.0, CH2Cl2). Complex (1g):

(yellow solid, 86% yield). 1H-NMR (400 MHz, C6D6): δ (ppm) = 4.89 (td, J = 2.6, 0.8 Hz, 1H), 4.42 (t, J = 2.2 Hz, 1H), 4.30 (t, J = 2.2 Hz, 1H), 4.07 (ddd, J = 10.5, 9.0, 5.2 Hz, 1H), 3.49 (ddd, J = 11.0, 9.0, 5.9 Hz, 1H), 2.77 (dd, J = 14.4, 5.2 Hz,

1H), 2.65 (dd, J = 14.4, 5.9 Hz, 1H), 2.50 (dt, J = 14.2, 8.7 Hz, 5H), 2.37 (dd, J = 14.4, 10.5 Hz, 1H), 1.45 (d, J = 13.7 Hz, 6H), 1.37–1.17 (m, 4H). 13C-NMR (100 MHz, C6D6): δ (ppm) = 110.7, 102.13 (d, J = 3.8 Hz), 100.5 (d, J = 3.7 Hz), 85.8 (d, J = 4.6 Hz), 85.7 (d, J = 3.9 Hz), 78.9, 78.1, 41.7 (d, J = 13.9 Hz), 40.8 (d, J = 13.8 Hz), 28.6, 27.5, 27.4, 27.2; HRMS (APPI, toluene) calc’d. for [M-2(C2H4)+(C7H8)]

•+: 386.0748, found: 386.0748; [α]D

20 = 4.80 (c = 0.3, CH2Cl2); m.p.: 92.0-93.0°C, decomposition.

Rh

OOSitBu

tBu

Rh

OO

9

Syntheses of the O-Boc hydroxamates 2a-2i

Procedure A:

Modification of the reported procedure (31): The aryl hydroxamic acid (2.00 mmol), dimethylaminopyridine (24.0 mg, 200 µmol, 0.10 equiv) and di-tert-butyl dicarbonate (480 mg, 2.20 mmol, 1.10 equiv.) were dissolved in THF (9.0 mL). The mixture was stirred at 23°C for 18 hours and then concentrated under reduced pressure. The residue was diluted with CH2Cl2 (50.0 mL) and washed with saturated NaHCO3 solution. The organic layer was dried over Na2SO4, concentrated in vacuo, and then purified by chromatography on silica gel.

Procedure B: To a suspension of the aryl hydroxamic acid (2.50 mmol) in CH2Cl2 (25.0 mL) were

sequentially added NaOH (1.38 mL, 2 M, 1.1 equiv.) and di-tert-butyl dicarbonate (600 mg, 2.75 mmol, 1.1 equiv.). The mixture was stirred at 23°C for 4-12 hours. Upon complete consumption of the hydroxamic acid (monitored by TLC), the mixture was diluted with CH2Cl2 (25.0 mL) and washed with water (30.0 mL). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica gel.

10

N-((tert-Butoxycarbonyl)oxy)benzamide (2a) (prepared according to (31) N-((tert-Butoxycarbonyl)oxy)-3-methylbenzamide (2b) (procedure B):

(79% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.42 (s, 1H), 7.73 (s, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.49–7.35 (m, 2H), 2.47 (s, 3H), 1.67–1.63 (m, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.9, 152.8,

138.7, 133.4, 130.5, 128.6, 128.1, 124.4, 85.9, 27.5, 21.2; IR (ATR): ~

= 3201, 2981, 2938, 1785, 1659, 1606, 1587, 1509, 1479, 1396, 1371, 1268, 1242, 1152, 1052, 957, 939, 819, 767 cm-1; HRMS (ESI) calc’d. for [C13H16NO4]

-: 250.1085, found: 250.1087; Rf: 0.29 (CH2Cl2); m.p.: 117-119°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-4-methylbenzamide (2c) (procedure B):

(65% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.50–9.40 (m, 1H), 7.68 (d, J=7.1 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 2.37 (s, 3H), 1.52 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.8, 152.8, 143.2,

129.3, 127.7, 127.4, 85.8, 27.5, 21.5; IR (ATR): ~

= 3211, 2980, 2939, 1784, 1657, 1612, 1574, 1523, 1487, 1396, 1371, 1266, 1239, 1144, 1048, 1019, 959, 909, 853, 832, 795, 769, 736, 646 cm-1; HRMS (ESI) calc’d. for [C13H16NO4]

-: 250.1085, found: 250.1086; Rf: 0.29 (CH2Cl2); m.p.: 133-135°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-4-methoxybenzamide (2d) (procedure B):

(51% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.28 (s, 1H), 7.77 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 3.83 (s, 3H), 1.53 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.6, 163.1, 153.0,

129.4, 122.7, 114.0, 85.8, 55.4, 27.5; IR (ATR): ~

= 3207, 2980, 1784, 1656, 1606, 1577, 1493, 1371, 1241, 1146, 1050, 1026, 960, 909, 844, 759, 616 cm-1; HRMS (ESI) calc’d. for [C13H16NO5]

-: 266.1034, found: 266.1036; Rf: 0.29 (CH2Cl2); m.p.: 127-129°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-4-nitrobenzamide (2e) (procedure A):

(52% yield, pale yellow solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.64 (s, 1H), 8.28 (d, J=8.2 Hz, 2H), 7.99 (d, J=8.2 Hz, 2H), 1.54 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 164.5, 152.3, 150.2, 136.2,

128.8, 123.9, 86.7, 27.5; IR (ATR): ~

= 3198, 2984, 1787, 1672, 1603, 1526, 1482, 1397, 1372, 1347, 1244, 1147, 1111, 1050, 1013, 955, 911, 867, 844, 768 cm-1; HRMS (ESI) calc’d. for [C12H13N2O6]

-: 281.0779, found: 281.0784; Rf: 0.5 (pentane:EtOAc 2:1); m.p.: 175-178°C, decomposition.

11

4-Bromo-N-((tert-butoxycarbonyl)oxy)benzamide (2f) (procedure B): (70% yield, colorless solid). 1H-NMR (400 MHz,

CDCl3): δ (ppm) = 8.94 (s, 1H), 7.70–7.66 (m, 2H), 7.63–7.59 (m, 2H), 1.55 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ (ppm) = 165.9, 152.7, 132.1, 129.4, 129.0, 127.6,

86.3, 27.6; IR (ATR): ~

= 3209, 2981, 2936, 1786, 1669, 1590, 1514, 1478, 1396, 1371, 1267, 1244, 1147, 1072, 1049, 1010, 958, 907, 843, 775, 751 cm-1; HRMS (ESI) calc’d. for [C12H13BrNO4]

-: 314.0033, found: 314.0037; Rf: 0.3 (pentane:EtOAc 5:1); m.p.: 134-138°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-4-chlorobenzamide (2g) (procedure A):

(71% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.70 (s, 1H), 7.72 (dd, J=8.6, 1.9 Hz, 2H), 7.40–7.35 (m, 2H), 1.52 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 165.7, 152.6, 139.0, 129.0, 128.9,

128.9, 86.2, 27.5; IR (ATR): ~

= 3205, 2982, 2940, 1784, 1656, 1596, 1572, 1515, 1479, 1397, 1371, 1267, 1240, 1145, 1113, 1092, 1049, 1013, 958, 908, 844, 775, 752 cm-1; HRMS (ESI) calc’d. for [C12H13ClNO4]

- 270.0539, found: 270.0539; Rf: 0.26 (Pentane:EtOAc, 5:1); m.p.: 130-133°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-4-fluorobenzamide (2h) (procedure B):

(60% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.43 (s, 1H), 7.85–7.79 (m, 2H), 7.14–7.05 (m, 2H), 1.53 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.6, 165.8, 164.1, 152.7, 130.0, 129.9, 126.8, 126.7, 116.0, 115.8, 86.1, 27.5; 19F NMR (376 MHz,

CDCl3) δ (ppm) = -94.6; IR (ATR): ~

= 3202, 2982, 2942, 1786, 1664, 1603, 1493, 1372, 1238, 1147, 1050, 1013, 909, 805, 758, 612 cm-1; HRMS (ESI) calc’d. for [C12H13FNO4]

-: 254.0834, found: 254.0838; Rf: 0.29 (CH2Cl2); m.p.: 106-108°C, decomposition.

N-((tert-Butoxycarbonyl)oxy)-2-naphthamide (2i) (procedure B):

(70% yield, colorless solid). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 9.70 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.72 (dd, J = 7.9, 1.6 Hz, 1H), 7.69–7.64 (m, 1H), 7.33–7.27 (m, 1H), 1.55 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ

(ppm) = 165.2, 152.6, 135.6, 132.4, 130.6, 130.2, 125.9, 122.8, 86.2, 27.5; IR (ATR): ~

= 3204, 2981, 1785, 1664, 1566, 1509, 1467, 1371, 1240, 1145, 1050, 957, 918, 854, 802, 774 cm-1; HRMS (ESI) calc’d. for [C12H13BrNO4]-: 314.0033, found: 314.0037; Rf: 0.41 (CH2Cl2); m.p.: 180-181°C, decomposition.

12

Representative Procedure for the catalytic enantioselective Rh-catalyzed isoquinolinone synthesis: Without protective precaution from air and moisture, catalyst 1c (1.04 mg, 2.00 µmol, 0.02 equiv.), dibenzoylperoxide (0.48 mg, 2.00 µmol, 0.02 equiv.), 2a (23.7 mg, 0.10 mmol) were weighed into a vial equipped with a magnetic stir bar and sealed with a rubber septum. 100 µL EtOH was added followed by styrene (23.0 µL, 0.20 mmol, 2.00 equiv.) and the reaction was stirred for 16 hours at 23°C. The volatiles were evaporated in vacuo and the residue was purified on a silica gel (CH2Cl2:EtOAc 5:1) giving 19.2 mg (86%, 96 : 4 er) of 4aa as colorless solid.

13

(R)-3-Phenyl-3,4-dihydroisoquinolin-1(2H)-one (4aa) (reaction at 0°C): (Colorless solid, 84% yield). 1H-NMR (400 MHz, CDCl3): δ

(ppm) = 8.12 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42–7.31 (m, 6H), 7.18 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 4.86 (ddd, J = 11.1, 4.9, 1.1 Hz, 1H), 3.23-3.09 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 13C NMR (101 MHz, CDCl3) δ 166.3, 140.9, 137.5, 132.5, 129.0, 128.4, 128.3, 128.0, 127.29, 127.26, 126.4, 56.1, 37.4.; IR

(ATR): ~

= 3210, 3065, 3032, 2897, 1664, 1604, 1578, 1464, 1390, 1333, 1317, 1155, 761, 743, 698 cm-1; HRMS (ESI) calc’d. for [C15H14NO]+: 224.1070, found: 224.1075; [α]D

20 = 196.3 (c = 1.0, CHCl3); Rf: 0.31 (CH2Cl2:EtOAc, 5:1); m.p.: 111-112°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 11.2 min, tr (major) = 10.5 min), er = 96.5 : 3.5.

14

(R)-3-(m-Tolyl)-3,4-dihydroisoquinolin-1(2H)-one (4ab):

(Colorless solid, 91% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.12 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 8.3, 6.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.31–7.25 (m, 1H), 7.24–7.13 (m, 4H), 6.01 (s, 1H), 4.82 (dd, J = 11.4, 4.7 Hz, 1H), 3.26–2.98 (m, 2H), 2.37 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 140.9, 138.8, 137.6, 132.5, 129.1, 128.9, 128.3, 128.0, 127.3,

127.2, 127.1, 123.4, 56.2, 37.5, 21.4; IR (ATR): ~ = 3230, 3066, 2915, 1666, 1606, 1578, 1464, 1386, 1329, 1155, 789, 744 cm-1; HRMS (ESI) calc’d. for [C16H16NO]+: 238.1226, found: 238.1224; [α]D

20 = 164.6 (c = 0.5, CHCl3); Rf: 0.37 (CH2Cl2:EtOAc, 5:1); HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 15.6 min, tr (major) = 17.3 min), er = 95 : 5.

15

(R)-3-(p-Tolyl)-3,4-dihydroisoquinolin-1(2H)-one (4ac):

(Colorless solid, 89% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 7.7 Hz, 1H), 7.50–7.43 (m, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.33–7.25 (m, 2H), 7.23–7.15 (m, 3H), 5.97 (s, 1H), 4.82 (dd, J = 11.4, 4.7 Hz, 1H), 3.29–3.02 (m, 2H), 2.36 (s, 3H).13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 138.2, 1387.9, 137.7, 132.5, 129.6, 128.3, 128.0, 127.3, 127.2, 126.3,

56.0, 37.5, 21.1; IR (ATR): ~ = 3203, 3056, 2918, 1665, 1604, 1578, 1514, 1463, 1387, 1331, 1317, 1154, 811, 744 cm-1; HRMS (ESI) calc’d. for [C16H16NO]+: 238.1226, found: 238.1220; [α]D

20 = 169.3 (c = 0.5, CHCl3); Rf: 0.39 (CH2Cl2:EtOAc, 5:1); m.p.: 128-131°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 11.6 min, tr (major) = 10.6 min), er = 96 : 4.

16

(R)-3-(4-(tert-Butyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one (4ad):

(Colorless solid, 91% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 7.7 Hz, 1H), 7.51–7.30 (m, 6H), 7.19 (d, J = 7.6 Hz, 1H), 5.96 (s, 1H), 4.84 (dd, J = 11.5, 4.6 Hz, 1H), 3.27–3.01 (m, 2H), 1.33 (s, 9H). 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 151.5, 137.8, 137.7, 132.5, 128.3, 128.0, 127.3, 127.2, 126.1, 125.9, 55.9, 37.5, 34.6, 31.3; IR (ATR):

~ = 3208, 3066, 2961, 2902, 2867, 1666, 1605, 1578, 1514, 1463, 1411, 1391, 1363, 1331, 1316, 1269, 1155, 827, 743 cm-1; HRMS (ESI) calc’d. for [C19H22NO]+: 280.1696, found: 280.1690; [α]D

20 = 146.7 (c = 0.5, CHCl3); Rf: 0.4 (CH2Cl2:EtOAc, 8:1); m.p.: 155-159°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 10% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 15.5 min, tr (major) = 11.5 min), er = 95.5 : 4.5.

17

(R)-3-(4-Methoxyphenyl)-3,4-dihydroisoquinolin-1(2H)-one (4ae):

(Colorless solid, 88% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.11 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.01 (s, 1H), 4.80 (dd, J = 11.5, 4.6 Hz, 1H), 3.81 (s, 3H), 3.26–3.00 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 159.5, 137.7,

132.9, 132.4, 128.3, 128.0, 127.6, 127.3, 127.2, 114.3, 55.6, 55.3, 37.5; IR (ATR): ~ = 3205, 3069, 2936, 2901, 2835, 1663, 1609, 1578, 1512, 1463, 1441, 1422, 1387, 1331, 1317, 1305, 1286, 1249, 1177, 1155, 1110, 1032, 825, 744 cm-1; HRMS (ESI) calc’d. for [C16H15NO2]

+: 254.1176, found: 254.1170; [α]D20 = 152.0 (c = 0.5, CHCl3); Rf: 0.4

(CH2Cl2:EtOAc, 3:1); m.p.: 116-121°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 17.2 min, tr (major) = 14.4 min), er = 96 : 4.

18

(R)-3-(4-Fluorophenyl)-3,4-dihydroisoquinolin-1(2H)-one (4af):

(Colorless solid, 87% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.10 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.42–7.33 (m, 2H), 7.18 (d, J = 7.5 Hz, 1H), 7.07 (td, J = 8.5, 1.5 Hz, 2H), 6.17 (s, 1H), 4.85 (dd, J = 10.2, 5.5 Hz, 1H), 3.26–2.98 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 163.7, 161.3, 137.3, 136.72, 136.7, 132.6, 128.25, 128.2, 128.1, 128.0,

127.35, 127.3, 116.0, 115.8, 55.5, 37.4; 19F NMR (376 MHz, CDCl3) δ (ppm) = -113.4; IR (ATR): ~ = 3220, 3071, 2896, 1666, 1604, 1578, 1509, 1464, 1420, 1387, 1330, 1279, 1225, 1157, 827, 745 cm-1; HRMS (ESI) calc’d. for [C15H13FNO]+: 242.0976, found: 242.0969; [α]D

20 = 168.7 (c = 0.5, CHCl3); Rf: 0.39 (CH2Cl2:EtOAc, 5:1); m.p.: 108-111°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 12.5 min, tr (major) = 10.6 min), er = 95.5 : 4.5.

19

(R)-3-(4-(Trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one (4ag):

(Colorless solid, 81% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.12 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 (td, J = 7.4, 1.5 Hz, 1H), 7.39 (td, J = 7.6, 1.2 Hz, 1H), 7.18 (dd, J = 7.5, 1.1 Hz, 1H), 6.20 (s, 1H), 4.99–4.88 (m, 1H), 3.27–3.10 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.24, 144.97, 136.82, 132.74,

131.13, 130.81, 130.48, 130.16, 128.13, 127.52, 127.38, 126.79, 126.05, 126.02, 125.98, 125.94, 125.20, 122.50, 55.64, 37.16; 19F NMR (376 MHz, CDCl3) δ (ppm) = -62.64; IR (ATR): ~ = 3219, 3075, 2898, 1665, 1620, 1606, 1578, 1465, 1421, 1390, 1323, 1163, 1121, 1067, 1018, 841, 745, 607 cm-1; HRMS (ESI) calc’d. for [C16H13F3NO]+: 292.0944, found: 292.0941; [α]D

20 =172.6 (c = 0.5, CHCl3); Rf: 0.41 (CH2Cl2:EtOAc, 5:1); m.p.: 169-171°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 11.3 min, tr (major) = 9.02 min), er = 95 : 5.

20

(R)-3-(Naphthalen-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (4ah):

(Colorless solid, 79% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.15 (d, J = 7.7 Hz, 1H), 7.86 (q, J = 8.4 Hz, 4H), 7.58–7.43 (m, 4H), 7.39 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.18 (s, 1H), 5.03 (dd, J = 10.9, 4.9 Hz, 1H), 3.41–3.08 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 138.2, 137.5, 133.2, 133.1, 132.6, 128.9, 128.3, 128.1, 127.9, 127.7,

127.34, 127.31, 126.6, 126.4, 125.4, 124.0, 56.2, 37.3; IR (ATR): ~ = 3204, 3056, 2987, 2900, 1732, 1664, 1602, 1578, 1509, 1463, 1393, 1381, 1318, 1270, 1242, 1154, 1066, 1047, 818, 743 cm-1; HRMS (ESI) calc’d. for [C19H16NO]+: 274.1226, found: 274.1224; [α]D

20 = 158.9 (c = 0.3, CHCl3); Rf: 0.56 (CH2Cl2:EtOAc, 5:1); m.p.: 155-157°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 14.4 min, tr (major) = 15.7 min), er = 96.5 : 3.5.

NH

O

21

(R)-3-((Triisopropylsilyl)ethynyl)-3,4-dihydroisoquinolin-1(2H)-one (4ai):

(Colorless solid, 70% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.05 (dd, J = 7.7, 1.5 Hz, 1H), 7.49–7.41 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.29 (s, 1H), 4.54 (ddd, J = 8.5, 4.7, 2.1 Hz, 1H), 3.19 (qd, J = 15.5, 6.7 Hz, 2H), 1.02–0.93 (m, 21H); 13C-NMR (100 MHz, CDCl3) δ (ppm) =

165.4, 137.0, 132.4, 128.1, 128.0, 127.43, 127.40, 105.2, 85.4, 43.8, 35.5, 18.4, 10.9; IR (ATR): ~ = 3187, 3068, 2942, 2892, 2864, 1666, 1604, 1463, 1384, 1314, 1157, 1063, 1044, 998, 906, 881, 731, 673, 647 cm-1; HRMS (ESI) calc’d. for [C20H30NOSi]+: 328.2091, found: 328.2094; [α]D

20 = 10.7 (c = 0.5, CHCl3); Rf: 0.43 (CH2Cl2:EtOAc, 10:1); m.p.: 128-130°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 10% i-PrOH / hexane, 1.0 mL/min, 234 nm; tr (minor) = 5.9 min, tr (major) = 6.8 min), er = 92 : 8.

22

(S)-4-(Trimethylsilyl)-3,4-dihydroisoquinolin-1(2H)-one (4aj):

(Colorless solid, 74% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.07 (dd, J = 7.6, 1.6 Hz, 1H), 7.47–7.39 (m, 1H), 7.32–7.27 (m, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.59 (s, 1H), 3.99–3.90 (m, 1H), 3.57 (dd, J = 11.9, 5.2 Hz, 1H), 2.39 (d, J = 4.8 Hz, 1H), 0.06 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.8, 142.7, 131.9, 128.2, 127.8, 126.5, 125.4, 41.9, 31.2, -2.3; IR (ATR): ~ = 3208, 3068, 2953, 2892, 2855, 1666,

1602, 1481, 1460, 1403, 1334, 1249, 1139, 1064, 846, 779 cm-1; HRMS (ESI) calc’d. for [C12H18NOSi]+: 220.1152, found: 220.1149; [α]D

20 = -276.7 (c = 0.5, CHCl3); Rf: 0.17 (CH2Cl2:EtOAc, 5:1); m.p.: 126-128°C; HPLC separation (Chiralpak OZH, 4.6 x 250 mm; 10% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 10.9 min, tr (major) = 12.5 min), er = 85 : 15.

23

(3aS,9bS)-2,3,3a,4-Tetrahydro-1H-cyclopenta[c]isoquinolin-5(9bH)-one (4ak):

(Colorless solid, 83% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.10 (dd, J = 7.7, 1.4 Hz, 1H), 7.45 (td, J = 7.5, 1.5 Hz, 1H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 5.64 (s, 1H), 4.28–4.12 (m, 1H), 3.11 (td, J = 9.1, 5.6 Hz, 1H), 2.22–2.01 (m, 2H), 1.99–1.89 (m, 1H), 1.81 (dddt, J = 12.2, 7.6, 3.3, 1.7 Hz, 3H); 13C-NMR (100

MHz, CDCl3) δ (ppm) = 165.3, 141.6, 132.3, 128.2, 127.5, 126.9, 126.5, 56.0, 43.1, 34.5, 33.4, 23.0; IR (ATR): ~ = 3189, 3065, 2963, 2898, 1662, 1604, 1460, 1404, 1330, 1055, 762 cm-1; HRMS (ESI) calc’d. for [C12H14NO]+: 188.1070, found: 188.1064; [α]D

20 = 54.0 (c = 0.3, CHCl3); Rf: 0.26 (CH2Cl2:EtOAc, 3:1); m.p.: 146-147°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 80% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 7.3 min, tr (major) = 8.1 min), er = 91 : 9.

24

(3aS,9bS)-1,3a,4,9b-Tetrahydrofuro[2,3-c]isoquinolin-5(2H)-one (4al):

(Colorless solid, 81% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.16 (dd, J = 7.7, 1.5 Hz, 1H), 7.57 (td, J = 7.4, 1.5 Hz, 1H), 7.53–7.45 (m, 2H), 6.82 (s, 1H), 4.87–4.77 (m, 1H), 4.35 (ddt, J = 5.5, 3.2, 1.9 Hz, 1H), 4.12–3.95 (m, 2H), 2.44 (dtd, J = 13.2, 8.9, 5.7 Hz, 1H), 2.19 (dddd, J = 13.1, 7.0, 3.8, 2.1 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ

(ppm) = 164.6, 135.3, 132.7, 129.3, 129.0, 128.0, 127.3, 75.2, 66.6, 54.2, 34.9; IR (ATR): ~ = 3254, 2885, 1665, 1605, 1581, 1470, 1441, 1409, 1333, 1294, 1167, 1134, 1044, 761 cm-1; HRMS (ESI) calc’d. for [C11H12NO2]

+: 190.0863, found: 190.0866; [α]D

20 = 36.7 (c = 0.5, CHCl3); Rf: 0.14 (EtOAc); m.p.: 122-126°C; HPLC separation (Chiralpak AYH, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 26.2 min, tr (major) = 16.9 min), er = 93 : 7.

NH

O

OH

H

25

(4aS,10bS)-1,4a,5,10b-Tetrahydrophenanthridin-6(2H)-one (4am):

(Colorless solid, 59% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.08 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29–7.21 (m, 1H), 6.03 (dt, J=8.5, 3.8 Hz, 1H), 5.87–5.69 (m, 2H), 4.27 (t, J=4.9 Hz, 1H), 2.94 (d, J=12.2 Hz, 1H), 2.30–2.15 (m, 2H), 2.05–1.91 (m, 1H), 1.74–1.65 (m, 1H); ); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 164.8, 142.8, 132.5, 132.5, 128.0, 127.5, 127.2, 127.1, 124.3, 124.3,

48.0, 37.8, 25.2, 25.0; IR (ATR): ~ = 3206, 3073, 3028, 2923, 1667, 1603, 1576, 1465, 1396, 1313, 1295, 751 cm-1; HRMS (ESI) calc’d. for [C13H14NO]+: 200.1070, found: 200.1063; [α]D

20 = 40.8 (c = 0.5, CHCl3); Rf: 0.21 (CH2Cl2:EtOAc, 5:1); m.p.: 135-137°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 210 nm; tr (minor) = 8.9 min, tr (major) = 11.0 min), er = 91.5 : 8.5.

26

(R)-7-Methyl-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4ba):

(Colorless solid, 80% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 7.94 (s, 1H), 7.44–7.30 (m, 5H), 7.27 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 5.98 (s, 1H), 4.83 (dd, J = 10.8, 4.8 Hz, 1H), 3.21–3.04 (m, 2H), 2.39 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.5, 141.0, 137.1, 134.5, 133.3, 129.0, 128.45, 128.4, 128.0, 127.2, 126.4, 56.3, 37.1, 21.0; IR (ATR): ~

= 3199, 3030, 2917, 1662, 1614, 1575, 1496, 1454, 1370, 1328, 1315, 1146, 820, 781, 757, 718 cm-1; HRMS (ESI) calc’d. for [C16H16NO]+: 238.1226, found: 238.1217; [α]D

20 = 173.3 (c = 0.5, CHCl3); Rf: 0.44 (CH2Cl2:EtOAc, 5:1); m.p.: 100-101°C; HPLC separation (Chiralpak IB, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 9.3 min, tr (major) = 7.7 min), er = 96 : 4.

27

(R)-6-Methyl-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4ca):

(Colorless solid, 85% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.01 (d, J = 7.9 Hz, 1H), 7.43–7.29 (m, 5H), 7.18 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 5.99 (s, 1H), 4.83 (dd, J = 10.9, 4.8 Hz, 1H), 3.12 (qd, J = 15.7, 7.9 Hz, 2H), 2.38 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.5, 143.1, 141.0, 137.5, 129.0, 128.3, 128.1, 127.9, 126.4, 125.7, 56.2, 37.5, 21.6; IR (ATR): ~ =

3203, 2986, 2901, 1736, 1666, 1614, 1575, 1453, 1373, 1328, 1307, 1237, 1044, 937, 846, 775, 738, 699 cm-1; HRMS (ESI) calc’d. for [C16H16NO]+: 238.1226, found: 238.1225; [α]D

20 = 178.3 (c = 0.5, CHCl3); Rf: 0.33 (CH2Cl2:EtOAc, 5:1); m.p.: 123-124°C; HPLC separation (Chiralpak IB, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 9.3 min, tr (major) = 8.1 min), er = 97 : 3.

28

(R)-6-Methoxy-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4da):

(colorless solid, 68% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.08 (d, J = 8.6 Hz, 1H), 7.45–7.31 (m, 5H), 6.89 (dd, J = 8.7, 2.6 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 5.79 (s, 1H), 4.84 (ddd, J = 11.1, 4.7, 1.3 Hz, 1H), 3.85 (s, 3H), 3.25–3.01 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.3, 162.9, 141.0, 139.70, 130.2, 129.0, 128.4, 126.4, 121.1,

112.6, 112.5, 56.3, 55.4, 37.9; IR (ATR): ~ = 3201, 3063, 2930, 2838, 1661, 1605, 1497, 1454, 1385, 1322, 1277, 1256, 1155, 1094, 1086, 1030, 849, 776, 699 cm-1; HRMS (ESI) calc’d. for [C16H16NO2]

+: 254.1176, found: 254.1172; [α]D20 = 134.5 (c =

0.5, CHCl3); Rf: 0.25 (CH2Cl2:EtOAc, 5:1); m.p.: 118-120°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 210 nm; tr (minor) = 27.6 min, tr (major) = 20.3 min), er = 96.5 : 3.5.

29

(R)-6-Nitro-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4ea):

(Yellow gum, 76% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.30 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.45–7.35 (m, 5H), 6.19 (s, 1H), 4.92 (t, J = 7.7 Hz, 1H), 3.28 (t, J = 8.3 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 164.1, 150.1, 139.8, 139.0, 133.5, 129.6, 129.3, 128.9, 126.3, 122.6, 122.3, 55.8, 37.2; IR (ATR): ~ =

3366, 3220, 3066, 2899, 1670, 1612, 1588, 1526, 1455, 1344, 1318, 810, 795, 757 cm-1; HRMS (ESI) calc’d. for [C15H13N2O3]

+: 269.0921, found: 269.0914; [α]D20 = 183.3 (c =

0.2, CHCl3); Rf: 0.43 (CH2Cl2:EtOAc, 5:1); HPLC separation (Chiralpak IB, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 28.0 min, tr (major) = 22.9 min), er = 96.5 : 3.5.

30

(R)-6-Bromo-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4fa):

(Colorless solid, 78% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 7.98 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.44–7.32 (m, 6H), 6.05 (s, 1H), 4.85 (dd, J = 10.7, 4.8 Hz, 1H), 3.14 (qd, J = 15.8, 7.8 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 165.5, 140.4, 139.3, 130.7, 130.3, 129.8, 129.1, 128.6, 127.25, 127.2, 126.3, 56.0, 37.1; IR (ATR): ~ = 3219, 3068,

2898, 1734, 1667, 1592, 1567, 1494, 1454, 1421, 1376, 1328, 1306, 1240, 1157, 1123, 771 cm-1; HRMS (ESI) calc’d. for [C15H13BrNO]+: 302.0175, found: 302.0179; [α]D

20 = 133.33 (c = 0.3, CHCl3); Rf: 0.33 (CH2Cl2:EtOAc, 5:1); m.p.: 113-116°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 245 nm; tr (minor) = 20.9 min, tr (major) = 15.2 min), er = 96.5 : 3.5.

31

(R)-6-Chloro-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4ga):

(Colorless solid, 81% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.05 (d, J = 8.3 Hz, 1H), 7.45–7.31 (m, 6H), 7.18 (s, 1H), 6.04 (s, 1H), 4.85 (dd, J = 10.6, 4.8 Hz, 1H), 3.14 (qd, J = 15.8, 7.8 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 165.4, 140.4, 139.2, 138.6, 129.7, 129.1, 128.6, 127.7, 127.4, 126.8, 126.4, 56.0, 37.2; IR (ATR): ~ = 3227, 3062, 2894,

1668, 1597, 1495, 1454, 1425, 1379, 1329, 1079, 773 cm-1; HRMS (ESI) calc’d. for [C15H13ClNO]+: 258.0680, found: 258.0682; [α]D

20 = 154.0 (c = 0.5, CHCl3); Rf: 0.36 (CH2Cl2:EtOAc, 5:1); m.p.: 103-105°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 210 nm; tr (minor) = 17.1 min, tr (major) = 13.1 min), er = 96.5 : 3.5.

32

(R)-6-Fluoro-3-phenyl-3,4-dihydroisoquinolin-1(2H)-one (4ha):

(Colorless solid, 81% yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.14 (dd, J = 8.3, 6.1 Hz, 1H), 7.46–7.29 (m, 5H), 7.05 (t, J = 8.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 5.99 (s, 1H), 4.86 (dd, J = 10.8, 4.7 Hz, 1H), 3.16 (qd, J = 15.8, 7.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 166.55, 165.5, 163.9, 140.5, 140.4, 140.3, 130.9, 130.8, 129.1, 128.6, 126.4, 124.6, 114.7,

114.5, 114.3, 114.1, 56.0, 37.4; 19F NMR (376 MHz, CDCl3) δ (ppm) = -106.4; IR (ATR): ~ = 3204, 3062, 2899, 1734, 1666, 1611, 1587, 1492, 1454, 1384, 1328, 1307, 1247, 1141, 1103, 1084, 1045, 1030, 1003, 953, 926, 860, 832, 774, 751, 697, 660 cm-1; HRMS (ESI) calc’d. for [C15H13FNO]+: 242.0976, found: 242.0977; [α]D

20 = 164.7 (c = 0.5, CHCl3); Rf: 0.32 (CH2Cl2:EtOAc, 5:1); HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 12.2 min, tr (major) = 10.6 min), er =96 : 4.

33

(R)-3-Phenyl-3,4-dihydrobenzo[g]isoquinolin-1(2H)-one (4ia):

(Colorless solid, 83% total yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 8.26 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.1, 2.2 Hz, 1H), 7.45–7.30 (m, 5H), 7.07 (d, J = 8.1 Hz, 1H), 6.08–5.94 (m, 1H), 4.92–4.76 (m, 1H), 3.23–2.97 (m, 2H).; 13C-NMR (100 MHz, CDCl3) δ (ppm) = 164.9, 140.5, 136.3, 135.4, 131.0, 130.0, 129.1, 129.1, 128.6, 126.4, 121.2, 56.0, 36.9; IR (ATR):

~ = 3664, 3212, 2987, 2900, 1667, 1594, 1454, 1429, 1368, 1330, 1311, 1158, 1099, 1075, 1066, 1056, 780, 758 cm-1; HRMS (ESI) calc’d. for [C15H13BrNO]+: 302.0175, found: 302.0180; [α]D

20 = 135.6 (c = 0.3, CHCl3); Rf: 0.50 (CH2Cl2:EtOAc, 5:1); m.p.: 123-124°C HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 9.2 min, tr (major) = 10.8 min), er = 95 : 5.

34

(R)-2-Phenyl-2,3-dihydrobenzo[f]isoquinolin-4(1H)-one (4ia’):

(Colorless solid, 83% total yield). 1H-NMR (400 MHz, CDCl3): δ (ppm) = 7.97 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.1, 1.9 Hz, 1H), 7.40–7.28 (m, 3H), 7.25–7.16 (m, 3H), 6.24 (s, 1H), 4.76 (dd, J = 9.2, 5.2 Hz, 1H), 3.21 (dd, J = 13.6, 5.2 Hz, 1H), 2.77 (dd, J = 13.6, 9.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ (ppm) = 168.5, 145.3, 136.5, 134.8, 133.9, 129.1, 129.0, 127.4, 127.2, 124.3, 122.5, 57.8,

41.3; IR (ATR): ~ = 3665, 3213, 2987, 2900, 1670, 1594, 1560, 1451, 1392, 1332, 1315, 1251, 1103, 1066, 1056, 880, 757 cm-1; HRMS (ESI) calc’d. for [C15H13BrNO]+: 302.0175, found: 302.0182; [α]D

20 = 126.7 (c = 0.3, CHCl3); Rf: 0.29 (CH2Cl2:EtOAc, 5:1); m.p.: 128-131°C; HPLC separation (Chiralpak IA, 4.6 x 250 mm; 20% i-PrOH / hexane, 1.0 mL/min, 254 nm; tr (minor) = 10.5 min, tr (major) = 9.1 min), er = 88.5 : 11.5.

35

NMR-Spectra

1a

1a

36

1f

1f

37

1b

1b

38

1c

1c

39

1d

1d

40

1e

1e

41

1g

1g

42

2b

2b

43

2c

2c

44

2d

2d

45

NH

O

O O

OO2N

2e

NH

O

O O

OO2N

2e

46

2f

2f

47

2g

2g

48

2h

2h

49

2i

2i

50

4aa

4aa

51

4ab

NH

O

4ab

NH

O

52

4ac

NH

O

4ac

NH

O

53

4ad

4ad

54

4ae

4ae

55

4af

4af

56

4ag

4ag

57

4ah

4ah

58

4ai

4ai

59

4aj

4aj

60

4ak

4ak

61

4al

4al

62

4am

4am

63

4ba

4ba

64

4ca

4ca

65

4da

4da

66

NH

O

O2N

4ea

NH

O

O2N

4ea

67

4fa

4fa

68

4ga

4ga

69

4ha

4ha

70

4ia

4ia

71

4ia’

4ia’

72

12

12

73

13a

13a

74

O

O

13b

O

O

13b

75

13c

13c

76

13d

13d

77

13e

13e

78

13f

13f

79

Fig. S1.

Fig. S1. Synthesis of the C2-symmetric cyclopentadienes 13. The C2-symmetric cyclopentadiene progenitors 13 were prepared by a double alkylation of cyclopentadiene with the cyclic sulfates 11 and 14 under basic conditions using sodium hydride (Fig. S1). The backbone substitution has an influence on the ratio between 1,2- and spiro-alkylation and the reaction of 14 provided exclusively the desired cyclopentadiene 13b without any spiro cyclic byproduct. Removal of the acetal group under acidic conditions allowed to access derivatives 13c-13f with a different back side shielding.

80

Fig. S2.

Fig. S2. Synthesis and structure of the Cpx*Rh(I) complexes 1: Deprotonation of cyclopentadienes 13 with thallium(I) ethoxide delivered a clean precipitate which was be subsequently reacted smoothly with {[Rh(C2H4)2Cl]2} to give ethylene complexes 1. This method is general and provides 1a-1g in excellent purity and good yields (67-96 %). These Rh(I)-complexes are relatively air-stable, easy to handle.

81

Fig. S3.

Fig. S3. X-Ray crystal structure of 1c. CCDC 898196 contains the crystallographic data for 1c. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystallization conditions and crystallographic details: Complex 1c was dissolved in warm EtOH (10 mg/mL). The solution was allowed to stand at -30°C for 48 h. From the crystallized material, a block-like canary-yellow crystal (0.30 x 0.22 x 0.18 mm3) was picked. X-ray diffraction studies were carried out at the EPFL Crystallography Facility. The data collections for the crystal structures were performed at low temperature (140(2) K) using Mo Kα radiation on a Bruker APEX II CCD diffractometer equipped with a kappa geometry goniometer. The data were reduced by EvalCCD.(42) The solution and refinement was performed by SHELX.(43) The structure was refined using full-matrix least squares based on F2 with all non-hydrogen atoms anisotropically defined. Hydrogen atoms were placed in calculated positions by means of the “riding” model. Crystallographic Details for 1c: A total of 6598 reflections (−13 < h < 13, −20 < k < 21, −21 < l < 21) were collected at T = 140(2) K in the range 2.45−30.05°, 6598 of which were unique (Rint = 0.0000), with Mo Kα radiation (λ = 0.71073 Å). The structure was solved by direct methods. All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were placed in calculated idealized positions. The residual peak and hole electron densities were 1.592 and −1.804 e Å−3, respectively. The absorption coefficient was 0.768 mm−1. The least-squares refinement converged normally with residuals of R(F) = 0.0608 and Rw(F2) = 0.1432 and GOF = 1.118 (I > 2σ(I)). Crystal data for C28H31O2Rh: Mw = 502.44, space group P212121, orthorhombic, a = 9.842(3) Å, b = 15.001(3) Å, c = 15.504(4) Å, α = 90°, β = 90°, γ = 90°, V = 2289.0(10) Å3, Z = 4, ρcalcd = 1.458 Mg/m3.

82

Fig. S4.

Fig. S4. Presumed catalytic cycle for the cyclization.

83

Table S1. Optimization of the asymmetric C-H functionalization.

Entry Solvent (0.2 M) R Cat. 1 % Yield* er†

1 EtOH tBu 1g 90 48 : 52 2 EtOH tBu 1a 84 27 : 73 3 EtOH tBu 1f 49 50 : 50 4 EtOH Ph 1a 85 22 : 78 5 EtOH Me 1a 68 20 : 80 6 EtOH Me 1b 67 90 : 10 7 EtOH Me 1c 71 92 : 8 8 EtOH OtBu 1b 78 92 : 8 9 EtOH OtBu 1e 78 95.5 : 4.5 10 EtOH OtBu 1c 86 96 : 4 11 EtOH OtBu 1d 81 95 : 5 12 CH3CN OtBu 1c 49 94 : 6 13 CH2Cl2 OtBu 1c 81 96 : 4 14 toluene OtBu 1c 76 95 : 5 15 acetone OtBu 1c 85 95 : 5 16 EtOH OtBu 1c (1 %) 91‡ 96 : 4 17 EtOH OtBu 1c (at 0°C) 84 96.5 : 3.5

* Determined by 1H-NMR with internal standard; † Determined by HPLC on a chiral stationary phase (R)-4aa : (S)-4aa; ‡ Isolated yield on a 0.1 mmol scale.

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References 1. R. H. Crabtree, The Organometallic Chemistry of the Transition Metals (Wiley, New York, ed. 3,

2001).

2. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds., Comprehensive Asymmetric Catalysis: Vol. I-III, Suppl. I-II, (Springer, New York, 1999).

3. A. H. Hoveyda, J. P. Morken, Enantioselective C-C and C-H bond formation mediated or catalyzed by chiral ebthi complexes of titanium and zirconium. Angew. Chem. Int. Ed. Engl. 35, 1262 (1996). doi:10.1002/anie.199612621

4. U. Siemeling, Chelate complexes of cyclopentadienyl ligands bearing pendant o-donors. Chem. Rev. 100, 1495 (2000). doi:10.1021/cr990287m Medline

5. R. L. Halterman, K. P. C. Vollhardt, Synthesis and asymmetric reactivity of enantiomerically pure cyclopentadienylmetal complexes derived from the chiral pool. Organometallics 7, 883 (1988). doi:10.1021/om00094a015

6. R. L. Halterman, Synthesis and applications of chiral cyclopentadienylmetal complexes. Chem. Rev. 92, 965 (1992). doi:10.1021/cr00013a011

7. H. Schumann et al., Synthesis, structure, and catalytic activity of some new chiral 2-menthylindenyl and 2-menthyl-4,7-dimethylindenyl rhodium complexes. Eur. J. Inorg. Chem. 2002, 211 (2002). doi:10.1002/1099-0682(20021)2002:1<211::AID-EJIC211>3.0.CO;2-3

8. R. L. Halterman, L. D. Crow, Preparation of chiral annulated indenes derived from nopinone, verbenone and menthone. Tetrahedron Lett. 44, 2907 (2003). doi:10.1016/S0040-4039(03)00430-1

9. A. Gutnov, B. Heller, H.-J. Drexler, A. Spannenberg, G. Oehme, Tartrate-derived cyclopentadienes for the synthesis of chiral substituted (η5-cyclopentadiene)(η4-cycloocta-1,5-diene)cobalt(I) complexes. Organometallics 22, 1550 (2003). doi:10.1021/om020982b

10. A. Gutnov, H.-J. Drexler, A. Spannenberg, G. Oehme, B. Heller, Syntheses of chiral nonracemic half-sandwich cobalt complexes with menthyl-derived cyclopentadienyl, indenyl, and fluorenyl ligands. Organometallic 23, 1002 (2004). doi:10.1021/om030357m

11. G. P. McGlacken, C. T. O’Brien, A. C. Whitwood, I. J. S. Fairlamb, Chiral mono- and bis-annelated cyclopentadienyl ligands derived from tartaric acid: Synthesis of [(η5-Cyclopentadienyl)RuCl(cod)] and [(η5-Cyclopentadienyl)(η6-benzene)Ru]PF 6 derivatives. Organometallics 26, 3722 (2007). doi:10.1021/om700393b

12. A. Gutnov et al., Cobalt(I)-catalyzed asymmetric[2+2+2] cycloaddition of alkynes and nitriles: Synthesis of enantiomerically enriched atropoisomers of 2-Arylpyridines. Angew. Chem. Int. Ed. 43, 3795 (2004). doi:10.1002/anie.200454164

13. B. Heller et al., Phosphorus-bearing axially chiral biaryls by catalytic asymmetric cross-cyclotrimerization and a first application in asymmetric hydrosilylation. Chemistry 13, 1117 (2007). doi:10.1002/chem.200600826 Medline

14. M. Hapke et al., Asymmetric synthesis of axially chiral 1-aryl-5,6,7,8-tetrahydroquinolines by cobalt-catalyzed [2 + 2 + 2] cycloaddition reaction of 1-aryl-1,7-octadiynes and nitriles. J. Org. Chem. 75, 3993 (2010). doi:10.1021/jo100122d Medline

85

15. Sandwich complexes containing two Cp moieties such as ansa-ebthi metallocenes of Ti, Zr, or Hf are versatile catalysts for several asymmetric reactions. For an overview, see (16).

16. A. H. Hoveyda, J. P. Morken, Enantioselective C-C and C-H bond formation mediated or catalyzed by chiral ebthi complexes of titanium and zirconium. Angew. Chem. Int. Ed. Engl. 35, 1262 (1996). doi:10.1002/anie.199612621

17. C. P. Lenges, M. Brookhart, Co(I)-catalyzed inter- and intramolecular hydroacylation of olefins with aromatic aldehydes. J. Am. Chem. Soc. 119, 3165 (1997). doi:10.1021/ja9639776

18. H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Thermal, catalytic, regiospecific functionalization of alkanes. Science 287, 1995 (2000). doi:10.1126/science.287.5460.1995 Medline

19. J. F. Hartwig et al., Rhodium boryl complexes in the catalytic, terminal functionalization of alkanes. J. Am. Chem. Soc. 127, 2538 (2005). doi:10.1021/ja045090c Medline

20. B. M. Trost, M. U. Frederiksen, M. T. Rudd, Ruthenium-catalyzed reactions: A treasure trove of atom-economic transformations. Angew. Chem. Int. Ed. 44, 6630 (2005). doi:10.1002/anie.200500136

21. A. H. Roy, C. P. Lenges, M. Brookhart, Scope and mechanism of the intermolecular addition of aromatic aldehydes to olefins catalyzed by Rh(I) olefin complexes. J. Am. Chem. Soc. 129, 2082 (2007). doi:10.1021/ja066509x Medline

22. A. D. Bolig, M. Brookhart, Activation of sp3 C-H bonds with cobalt(I): Catalytic synthesis of enamines. J. Am. Chem. Soc. 129, 14544 (2007). doi:10.1021/ja075694r Medline

23. M. Zhou, N. D. Schley, R. H. Crabtree, Cp* iridium complexes give catalytic alkane hydroxylation with retention of stereochemistry. J. Am. Chem. Soc. 132, 12550 (2010). doi:10.1021/ja1058247 Medline

24. H. Brunner, Optically active organometallic compounds of transition elements with chiral metal atoms. Angew. Chem. Int. Ed. 38, 1194 (1999). doi:10.1002/(SICI)1521-3773(19990503)38:9<1194::AID-ANIE1194>3.0.CO;2-X

25. E. B. Bauer, Chiral-at-metal complexes and their catalytic applications in organic synthesis. Chem. Soc. Rev. 41, 3153 (2012). doi:10.1039/c2cs15234g Medline

26. Although Fig. 1 depicts solely the differences of the two most stable conformers, we assume that reactions proceed under Curtin-Hammett conditions. Therefore, no judgment on the reactive conformer, the one with a lower transition state, is possible.

27. Materials and methods are available as supplementary materials on Science Online. For the syntheses and an x-ray structure of 1c, see figs. S1 to S3.

28. D. N. Tran, N. Cramer, syn-Selective rhodium(i)-catalyzed allylations of ketimines proceeding through a directed C-H activation/allene addition sequence. Angew. Chem. Int. Ed. 49, 8181 (2010). doi:10.1002/anie.201004179

29. D. N. Tran, N. Cramer, Enantioselective rhodium(I)-catalyzed [3+2] annulations of aromatic ketimines induced by directed C-H activations. Angew. Chem. Int. Ed. 50, 11098 (2011). doi:10.1002/anie.201105766

86

30. G. Song, F. Wang, X. Li, C-C, C-O and C-N bond formation via rhodium(III)-catalyzed oxidative C-H activation. Chem. Soc. Rev. 41, 3651 (2012). doi:10.1039/c2cs15281a Medline

31. N. Guimond, S. I. Gorelsky, K. Fagnou, Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: Improved reactivity and mechanistic studies. J. Am. Chem. Soc. 133, 6449 (2011). doi:10.1021/ja201143v Medline

32. S. Rakshit, C. Grohmann, T. Besset, F. Glorius, Rh(III)-catalyzed directed C-H olefination using an oxidizing directing group: Mild, efficient, and versatile. J. Am. Chem. Soc. 133, 2350 (2011). doi:10.1021/ja109676d Medline

33. Related Cp*Rh(III) bis-carboxylate complexes are most likely the active catalytic species in the racemic reaction and are usually generated in situ from {[Cp*Rh(Cl2)]2} by silver salts and carboxylate additives.

34. D. Lapointe, K. Fagnou, Overview of the mechanistic work on the concerted metallation–deprotonation pathway. Chem. Lett. 39, 1118 (2010). doi:10.1246/cl.2010.1118

35. L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, Computational elucidation of the internal oxidant-controlled reaction pathways in Rh(III)-catalyzed aromatic C-H functionalization. J. Org. Chem. 77, 3017 (2012). doi:10.1021/jo202431q Medline

36. F. A. Davis, Y. W. Andemichael, Asymmetric synthesis of 4-hydroxy-3-phenyltetrahydroisoquinoline derivatives using enantiopure sulfinimines (N -sulfinyl imines). J. Org. Chem. 64, 8627 (1999). doi:10.1021/jo991119x

37. J. A. Gladysz, B. J. Boone, Chiral recognition in π complexes of alkenes, aldehydes, and ketones with transition metal Lewis acids: Development of a general model for enantioface binding selectivities. Angew. Chem. Int. Ed. Engl. 36, 550 (1997). doi:10.1002/anie.199705501

38. A. Zhang, T. V. RajanBabu, Fine-tuning monophosphine ligands for enhanced enantioselectivity: Influence of chiral hemilabile pendant groups. Org. Lett. 6, 1515 (2004). doi:10.1021/ol0495063 Medline

39. W. Li, Z. Zhang, D. Xiao, X. Zhang, Synthesis of chiral hydroxyl phospholanes from D-mannitol and their use in asymmetric catalytic reactions. J. Org. Chem. 65, 3489 (2000). doi:10.1021/jo000066c Medline

40. M. R. Odrowaz-Sypniewski, P. G. Tsoungas, G. Varvounis, P. Cordopatis, Xanthone in synthesis: A reactivity profile via directed lithiation of its dimethyl ketal. Tetrahedron Lett. 50, 5981 (2009). doi:10.1016/j.tetlet.2009.08.050

41. Y. Hoshino, M. Okuno, E. Kawamura, K. Honda, S. Inoue, Base-mediated rearrangement of free aromatic hydroxamic acids (ArCO-NHOH) to anilines. Chem. Commun. 17, 2281 (2009). doi:10.1039/b822806j Medline

42. A. J. M. Duisenberg, L. M. J. Kroon-Batenburg, A. M. M. Schreurs, An intensity evaluation method: EVAL-14. J. Appl. Cryst. 36, 220 (2003). doi:10.1107/S0021889802022628

43. G. M. Sheldrick, A short history of SHELX. Acta Crystallogr. A 64, 112 (2008). doi:10.1107/S0108767307043930 Medline