Supporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007

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1 Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007

2 Asymmetric Friedel-Crafts Alkylations of Indoles with Ethyl Glyoxylate Catalyzed by (S)-BIL-Ti (IV) Complex: Direct Access to Enantiomerically Enriched 3-Indolyl-hydroxyacetates Hong-Ming Dong, Hai-Hua Lu, Liang-Qiu Lu, Cai-Bao Chen and Wen-Jing Xiao* The Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China ormal University, 152 Luoyu Road, Wuhan, Hubei , China Supporting Information Table of Contents General information S2 General procedures for the Friedel-Crafts reaction and data of 3a-l, 5, 7, 9 S2-S8 Determination of absolute stereochemistry of 3l S8-S17 MR spectra for compounds 3a-l, 5, 7, 9, 10 S18-S33 HPLC spectra for compounds 3a-l, 5, 7, 9, 10 S34-S43 S1

3 General Information 1 H MR spectra were recorded on 400 (400 MHz) spectrophotometers. Chemical shifts are reported in ppm from the solvent resonance as the internal standard (CDCl 3 : 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = single, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz) and integration. 13 C MR spectra were recorded on 100 MHz with complete proton decoupling spectrophotometers (CDCl 3 : 77.0 ppm). Chiral HPLC was performed with chiral columns (Chirapak AS, AD and D columns, (Daicel Chemical Ind., Ltd.)). -Protected indoles and p-chlorophenyl glyoxal were prepared according to literature procedures. [1,2] The solvents were purified prior to use following the guidelines of Perrin and Armarego. [3] Petroleum ether and ethyl acetate for flash column chromatography were distilled before use. ther commercially available materials were used as received. Flash column chromatography was performed using mesh silica gel. rganic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. General Procedure for Enantioselective Friedel-Crafts Reaction of Indoles with Ethyl Glyoxylate Catalyzed by (S)-BIL-Ti Complex To a 5-mL flask equipped with a magnetic stirrer, in which the air was replaced by nitrogen, was added (S)-BIL (28.6 mg, 0.1 mmol), diethyl ether (1 ml), and Ti( i Pr) 4 (14.9 μl, 0.05 mmol). The mixture was stirred at room temperature for 1 h. Then the resulting orange solution was cooled to the specific temperature, indoles (0.5 mmol) and ethyl glyoxylate (0.15 ml, 50% in toluene, 0.75 mmol) were introduced into the reaction system. After the completion of the reaction (monitored by TLC), H 2 (3 ml) and dichloromethane (5 ml) were added to the mixture. Insoluble material was filtered off through a pad of Celite, and the filtrate was extracted three times with dichloromethane. The combined organic layer was washed with brine, dried over MgS 4, and the solvent was removed under reduced pressure. The residue was submitted to flash chromatography separation on silica gel using petroleum S2

4 ether-ethyl acetate (3:1) as an eluent to give the corresponding Friedel-Crafts reaction product 3a-l. Ethyl 3-(1-metheyl)indolyl-hydroxylacetate (3a) Following the general procedure, compound 3a was obtained after 48 hr at -20 C as a colorless oil in 88% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.69 (d, J = 8 Hz, 1H), (m, 4H), 5.44 (s, 1H), (m, 1H), (m, 1H), 3.73 (br, 1H), 3.33 (br, 1H), 1.22 (t, J = 7.2 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ) δ 174.1, 137.2, 127.7, 125.8, 122.0, 119.6, 119.5, 112.2, 109.4, 67.1, 60.9, 32.8, MS (EI) m/z (rel intensity). Chiral HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 75:25, 1.0 ml/min, λ = 254 nm) indicated 90% ee, t minor = 12.8 min, t major = 11.2 min. Allyl Ethyl 3-(1-allyl)indolyl-hydroxylacetate (3b) Following the general procedure, compound 3b was obtained after 45 hr at -20 C as a colorless oil in 72% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.71 (d, J = 8 Hz, 1H), (m, 4H), (m, 1H), 5.45 (d, J = 4 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 3.28 (d, J = 4.4 Hz, 1H), (t, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 174.1, 136.7, 133.0, 126.7, 126.1, 122.1, 119.8, 119.6, 117.7, 112.7, 109.8, 67.2, 62.0, 48.9, MS (EI) m/z (rel intensity). Chiral HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 75:25, 1.0 ml/min, λ = 254 nm) indicated 90% ee, t minor = 12.1 min, t major = 9.9 min. Ethyl 3-(1-phenyl)indolyl-hydroxylacetate (3c) Following the general procedure, compound 3c was obtained Bn after 64 hr at -20 C as a colorless oil in 86% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.73 (d, J = 8 Hz, 1H), (m, 9H), 5.46 (d, J = 5.6 Hz, 1H), 5.26 (s, 2H), (m, H), (m, 1H), 3.30 (d, J = 5.6 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 174.0, S3

5 136.9(4), 136.8(8), 127.7, 127.1, 126.9, 126.1, 122.3, 119.9, 119.7, 113.0, 109.9, 67.2, 62.0, 50.1, MS (EI) m/z (rel intensity). Chiral HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 75:25, 1.0 ml/min, λ = 254 nm) indicated 91% ee, t minor = 19.3 min, t major = 14.7 min. Ethyl 3-indolyl-hydroxylacetate (3d) Following the general procedure, compound 3d was obtained H after 48 hr at -20 C as a colorless oil in 72% yield. 1 H MR (400 MHz, CDCl 3 ): δ 8.23 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), (m, 3H), 5.47 (d, J = 5.2 Hz, 1H), (m, 1H), (m, 1H), 3.33 (d, J = 5.6 Hz, 1H), 1.22 (t, J = 7.0 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 174.0, 136.4, 125.2, 123.4, 122.4, 120.0, 119.3, 113.5, 111.4, 67.2, 62.0, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AS column, n-hexane/i-prh = 80:20, 1.0 ml/min, λ = 254 nm) indicated 84% ee, t minor = 20.1 min, t major = 12.5 min. Ethyl 3-(1-metheyl-5-bromo)indolyl-hydroxylacetate Br (3e) Following the general procedure, compound 3e was obtained after 72 hr at -20 C as a colorless oil in 71% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.56 (d, J = 8 Hz, 1H), (m, 3H), 5.41 (s, 1H), (m, 1H), (m, 1H), 3.59 (s, 1H), 3.37 (br, 1H), 2.42 (s, 1H), 1.16 (t, J = 7.0 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 173.7, 135.9, 128.7, 127.4, 124.9, 122.2, 113.1, 111.9, 110.9, 67.0, 62.2, 33.0, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 90:10, 1.0 ml/min, λ = 254 nm) indicated 90% ee, t minor = 30.4 min, t major = 26.7 min. F Ethyl (3f) 3-(1-metheyl-5-fluoro)indolyl-hydroxylacetate S4

6 Following the general procedure, compound 3f was obtained after 54 hr at -20 C as a colorless oil in 80% yield. 1 H MR (400 MHz, CDCl 3 ): δ (m, 4H), (m, 1H), (m, 2H), (m, 2H), (m, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 173.8, 159.0, 156.6, 133.8, 129.2, 126.1, 126.0, 112.1, 110.5, 110.3, 110.2, 110.1, 104.6, 104.4, 67.0, 62.2, 33.0, 14.0; MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 90:10, 1.0 ml/min, λ = 254 nm) indicated 92% ee, t minor = 31.0 min, t major = 26.3 min. Ethyl 3-(1-allyl-6-chloro)indolyl-hydroxylacetate (3g) Following the general procedure, compound 3g was Cl Allyl obtained after 60 hr at -20 C as a colorless oil in 70% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.61 (d, J = 8.4 Hz, 1H), (m, 3H), (m, 1H), 5.41 (s, 1H), 5.24 (d, J = 5.2 Hz, 2H), 5.11 (d, J = 17.2 Hz, 1H), 4.65 (d, J = 5.2 Hz, 2H), (m, 1H), (m, 1H), 3.29 (br, 1H), 1.22 (t, J = 7.2 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 173.7, 137.0, 132.5, 128.0, 127.3, 124.5, 120.6, 120.3, 117.8, 112.9, 109.8, 66.9, 61.9, 48.8, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 80:20, 1.0 ml/min, λ = 254 nm) indicated 92% ee, t minor = 15.8 min, t major = 11.1 min. Et thyl 3-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-methylindole-5-carboxylate (3h) Following the general procedure, compound 3h was obtained after 72 hr at -20 C as a colorless oil in 81% yield. 1 H MR (400 MHz, CDCl 3 ): δ (m, 4H), 5.40 (s, 1H), (m, 1H), (m, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 3.38 (br, 1H), 1.22 (t, J = 7.2 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 173.9, 154.1, 153.7, 132.5, 128.1, 126.1, 112.4, 111.6, 110.2, 101.0, 67.8, 61.8, 55.7, 32.8, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AS column, n-hexane/i-prh = 80:20, 1.0 ml/min, λ = 254 nm) indicated 80% ee, t minor = 36.7 min, t major = 22.7 min. S5

7 Et Ethyl 3-(1-metheyl-5-methoxy)indolyl-hydroxylacetate (3i) Following the general procedure, compound 3i was Allyl obtained after 72 hr at -20 C as a colorless oil in 64% yield. 1 H MR (400 MHz, CDCl 3 ): δ (m, 3H), (m, 1H), (m, 1H), 5.40 (d, J = 16 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 3.90 (s, 2H), (m, 2H), (m, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 174.0, 154.2, 132.5, 128.1, 126.2, 112.5, 111.7, 110.2, 101.0, 67.1, 61.9, 55.8, 32.9, 29.6, 14.1; MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 80:20, 1.0 ml/min, λ = 254 nm) indicated 87% ee, t minor = 17.5 min, t major = 14.9 min. Ethyl 3-(1, 5-dimetheyl)indolyl-hydroxylacetate (3j) Following the general procedure, compound 3j was obtained after 60 hr at -40 C as a colorless oil in 75% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.48 (s, 1H), (m, 3H), 5.41 (s, 1H), (m, 1H), (m, 1H), 3.71 (s, 3H), 3.22 (br, 1H), 1.23 (t, J = 7.0 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 174.1, 135.7, 129.0, 127.7, 126.1, 123.7, 119.1, 111.6, 109.1, 67.2, 61.9, 32.8, 21.4, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 80:20, 1.0 ml/min, λ = 254 nm) indicated 66% ee, t minor = 14.4 min, t major = 13.3 min. Ethyl 3-(1, 2-dimetheyl)indolyl-hydroxylacetate (3k) Following the general procedure, compound 3k was obtained after 55 hr at -20 C as a colorless oil in 70% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.56 (d, J = 8.0 Hz, 1H), (m, 3H), 5.41 (s, 1H), (m, 1H), (m, 1H), 3.59 (s, 3H), 3.37 (s, 1H), 2.42 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 174.4, 136.6, 135.6, 125.5, 121.0, 119.6, 118.3, 108.7, 108.2, 66.5, 61.8, 29.4, 14.0, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = S6

8 90:10, 1.0 ml/min, λ = 254 nm) indicated 66% ee, t minor = 27.2 min, t major = 23.3 min. Br Bn Ethyl 3-(1- phenyl -5-bromo)indolyl-hydroxylacetate (3l) Following the general procedure, compound 3e was obtained after 96 hr at -20 C as a white solid in 64% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.87 (d, J = 1.6 Hz, 1H), (m, 9H), 5.41 (d, J = 4 Hz, 1H), 5.26 (s, 2H), (m, 2H), 3.32 (d, J = 4.8 Hz, 1H), 1.25 (t, J = 14.4 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 173.7, 136.4, 135.5, 128.8, 128.1, 127.9, 127.7, 126.8, 125.1, 122.4, 113.3, 112.5, 111.4, 67.0, 62.2, 50.3, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 70:30, 1.0 ml/min, λ = 254 nm) indicated 96% ee, t minor = 26.4 min, t major = 15.3 min. CF 3 C thyl 2-[3-(1-methyl)]indolyl-2-hydroxy-trifluoro propionate (5) Following the general procedure, compound 5 was obtained after 40 hr at -20 C as a colorless oil in 88% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.84 (d, J = 8.0 Hz, 1H), (m, 3H), 4.34 (s, 1H), 3.91 (s, 3H), 3.74 (s, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 167.0, 137.1, 128.7, 125.6, 124.9, 122.2, 120.9, 120.2, 109.5, 106.6, 54.4, 32.9; MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak D column, n-hexane/i-prh = 90:10, 1.0 ml/min, λ = 254 nm) indicated 10% ee, t minor = 16.8 min, t major = 12.3 min. CH 3 thyl 2, 2-bis[3-(1-methyl)]indolyl-propionate (7) Following the general procedure, compound 7 was obtained after 60 hr at -20 C as a white solid in 99% yield. 1 H MR (400 MHz, CDCl 3 ): δ 7.51 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), (m, 2H), (t, 2H), 6.83 (s, 2H), 3.70 (s, 6H), 3.66 (s, 3H), 2.11 (s, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 176.0, 137.5, 127.5, S7

9 126.4, 121.3, 118.7, 117.5, 109.2, 52.2, 46.1, 32.7, 26.2; MS (EI) m/z (rel intensity). Cl Bis[3-(1-methyl)]indolyl-p-chloroacetophenone (9) Following the general procedure, compound 9 was obtained after 18 hr at -20 C as a white solid in 97% yield. 1 H MR (400 MHz, CDCl 3 ): δ 8.04 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), (m, 5H), 7.09 (s, 1H), 6.86 (s, 1H), 6.44 (s, 1H), 3.70 (s, 6H). 13 C MR (100 MHz, CDCl 3 ): δ 197.3, 139.2, 137.3, 135.2, 130.2, 128.9, 128.5, 126.9, 121.8, 119.2, 118.9, 112.4, 109.4, 41.9, 32.8; MS (EI) m/z (rel intensity). Determination of absolute stereochemistry: Br Bn C 2 Et CH 3 H 2 /CH 3 H rt Br Bn 3l 10 (S)-2-(1-benzyl-5-bromo-1H-indol-3-yl)-2-hydroxy--methylacetamide 3l (98% ee, 0.5 mmol) was dissolved in H 2 methanol soultion (5 ml, 32%), sealed and the mixture was stirred at rt for 14 h. The solution was then concentrated under reduced pressure, which is subjeted to flash chromatography to afford the title compoud (10) as a white solid. 1 H MR (400 MHz, CDCl 3 ): δ 8.05 (d, J = 4.8 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), (m, 9H), 5.96 (d, J = 4 Hz, 1H), 5.38 (s, 2H), 5.12 (d, J = 4.4 Hz, 1H), 2.64 (d, J = 4.4 Hz, 3H). 13 C MR (100 MHz, CDCl 3 ): δ 172.7, 137.9, 134.9, 128.8, 128.6, 128.1, 127.5, 127.2, 123.7, 122.6, 114.8, 112.2, 111.7, 67.9, 49.1, MS (EI) m/z (rel intensity). HPLC analysis (Chiralpak AD column, n-hexane/i-prh = 70:30, 1.0 ml/min, λ = 254 nm) indicated >99% ee, t minor = 8.9 min, t major = 17.4 min. H S8

10 Br H H H 10 Table 1. Crystal data and structure refinement for 10. Identification code 10 Empirical formula C18 H17 Br 2 2 Formula weight Temperature 296(2) K Wavelength Å Crystal system Monoclinic Space group P 21 Unit cell dimensions a = (6) Å α= 90. b = (11) Å β= (2). c = (2) Å γ = 90. Volume (17) Å 3 Z 2 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 380 Crystal size 0.20 x 0.20 x 0.10 mm 3 Theta range for data collection 2.21 to Index ranges -6<=h<=5, -11<=k<=12, -22<=l<=24 Reflections collected 5321 Independent reflections 3482 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and S9

11 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3482 / 1 / 215 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.015(7) Largest diff. peak and hole and e.å -3 Table 2. Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for t. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) Br(1) 11469(1) -3199(1) 7371(1) 64(1) C(1) 6534(6) 39(3) 8158(1) 39(1) C(2) 8019(6) -1216(3) 8073(1) 43(1) C(3) 9654(6) -1411(3) 7480(1) 39(1) C(4) 9924(5) -383(2) 6965(1) 34(1) C(5) 8429(5) 900(2) 7037(1) 30(1) C(6) 6757(5) 1082(3) 7638(1) 32(1) C(7) 8163(5) 2179(2) 6626(1) 32(1) C(8) 6355(5) 3059(3) 6971(1) 36(1) C(9) 3612(5) 3018(3) 8100(1) 40(1) C(10) 5304(5) 3531(3) 8781(1) 36(1) C(11) 7243(6) 4648(3) 8761(1) 48(1) C(12) 8776(7) 5135(4) 9376(2) 69(1) C(13) 8399(8) 4520(5) 10034(2) 76(1) C(14) 6496(9) 3411(4) 10071(2) 73(1) C(15) 4936(7) 2922(3) 9443(1) 55(1) C(16) 9457(5) 2509(2) 5930(1) 35(1) C(17) 7595(5) 1810(3) 5307(1) 34(1) C(18) 3941(7) 2177(3) 4284(1) 54(1) (1) 5491(5) 2407(2) 7579(1) 36(1) (2) 5881(5) 2677(2) 4890(1) 40(1) (1) 9600(4) 4007(2) 5866(1) 47(1) (2) 7673(4) 508(2) 5222(1) 47(1) S10

12 Table 3. Bond lengths [Å] and angles [ ] for t. Br(1)-C(3) 1.895(2) C(1)-C(2) 1.378(4) C(1)-C(6) 1.386(3) C(1)-H(1A) C(2)-C(3) 1.397(4) C(2)-H(2) C(3)-C(4) 1.372(3) C(4)-C(5) 1.400(3) C(4)-H(4) C(5)-C(6) 1.416(3) C(5)-C(7) 1.425(3) C(6)-(1) 1.375(3) C(7)-C(8) 1.369(3) C(7)-C(16) 1.498(3) C(8)-(1) 1.371(3) C(8)-H(8) C(9)-(1) 1.467(3) C(9)-C(10) 1.500(3) C(9)-H(9A) C(9)-H(9B) C(10)-C(11) 1.378(4) C(10)-C(15) 1.380(3) C(11)-C(12) 1.363(4) C(11)-H(11) C(12)-C(13) 1.376(5) C(12)-H(12) C(13)-C(14) 1.365(5) C(13)-H(13) C(14)-C(15) 1.389(5) C(14)-H(14) C(15)-H(15) C(16)-(1) 1.418(3) C(16)-C(17) 1.524(3) C(16)-H(16) C(17)-(2) 1.236(4) C(17)-(2) 1.331(3) S11

13 C(18)-(2) 1.448(3) C(18)-H(18A) C(18)-H(18B) C(18)-H(18C) (2)-H(2A) 0.87(3) (1)-H(1) 0.91(4) C(2)-C(1)-C(6) 117.5(2) C(2)-C(1)-H(1A) C(6)-C(1)-H(1A) C(1)-C(2)-C(3) 120.4(2) C(1)-C(2)-H(2) C(3)-C(2)-H(2) C(4)-C(3)-C(2) 122.9(2) C(4)-C(3)-Br(1) (18) C(2)-C(3)-Br(1) (18) C(3)-C(4)-C(5) 117.9(2) C(3)-C(4)-H(4) C(5)-C(4)-H(4) C(4)-C(5)-C(6) 118.8(2) C(4)-C(5)-C(7) 134.2(2) C(6)-C(5)-C(7) 107.0(2) (1)-C(6)-C(1) 129.9(2) (1)-C(6)-C(5) 107.5(2) C(1)-C(6)-C(5) 122.6(2) C(8)-C(7)-C(5) (19) C(8)-C(7)-C(16) 125.3(2) C(5)-C(7)-C(16) (19) C(7)-C(8)-(1) 110.1(2) C(7)-C(8)-H(8) (1)-C(8)-H(8) (1)-C(9)-C(10) 113.0(2) (1)-C(9)-H(9A) C(10)-C(9)-H(9A) (1)-C(9)-H(9B) C(10)-C(9)-H(9B) H(9A)-C(9)-H(9B) C(11)-C(10)-C(15) 118.0(2) S12

14 C(11)-C(10)-C(9) 120.7(2) C(15)-C(10)-C(9) 121.3(2) C(12)-C(11)-C(10) 121.3(3) C(12)-C(11)-H(11) C(10)-C(11)-H(11) C(11)-C(12)-C(13) 120.3(3) C(11)-C(12)-H(12) C(13)-C(12)-H(12) C(14)-C(13)-C(12) 119.8(3) C(14)-C(13)-H(13) C(12)-C(13)-H(13) C(13)-C(14)-C(15) 119.6(3) C(13)-C(14)-H(14) C(15)-C(14)-H(14) C(10)-C(15)-C(14) 121.0(3) C(10)-C(15)-H(15) C(14)-C(15)-H(15) (1)-C(16)-C(7) (18) (1)-C(16)-C(17) 113.1(2) C(7)-C(16)-C(17) (18) (1)-C(16)-H(16) C(7)-C(16)-H(16) C(17)-C(16)-H(16) (2)-C(17)-(2) 123.8(2) (2)-C(17)-C(16) 120.3(2) (2)-C(17)-C(16) 116.0(2) (2)-C(18)-H(18A) (2)-C(18)-H(18B) H(18A)-C(18)-H(18B) (2)-C(18)-H(18C) H(18A)-C(18)-H(18C) H(18B)-C(18)-H(18C) C(8)-(1)-C(6) 108.7(2) C(8)-(1)-C(9) 126.5(2) C(6)-(1)-C(9) 124.8(2) C(17)-(2)-C(18) 122.7(2) C(17)-(2)-H(2A) 121(2) C(18)-(2)-H(2A) 116(2) S13

15 C(16)-(1)-H(1) 106(2) Symmetry transformations used to generate equivalent atoms: Table 4. Anisotropic displacement parameters (Å 2 x 10 3 ) for t. The anisotropic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 Br(1) 78(1) 35(1) 81(1) 14(1) 20(1) 15(1) C(1) 49(2) 39(1) 31(1) 2(1) 8(1) -6(1) C(2) 58(2) 37(1) 35(1) 11(1) 2(1) -3(1) C(3) 44(1) 30(1) 43(1) 2(1) -1(1) 3(1) C(4) 36(1) 33(1) 33(1) -3(1) 2(1) 0(1) C(5) 32(1) 31(1) 26(1) -3(1) 1(1) -5(1) C(6) 36(1) 32(1) 26(1) -2(1) 0(1) -4(1) C(7) 37(1) 28(1) 30(1) -1(1) 2(1) -2(1) C(8) 44(1) 30(1) 33(1) -1(1) 1(1) 2(1) C(9) 38(1) 44(1) 40(1) -2(1) 8(1) 4(1) C(10) 41(1) 35(1) 35(1) -5(1) 10(1) 6(1) C(11) 53(2) 47(2) 45(1) -6(1) 5(1) -3(1) C(12) 58(2) 65(2) 81(2) -26(2) -5(2) -4(2) C(13) 78(2) 86(3) 58(2) -34(2) -21(2) 36(2) C(14) 113(3) 77(3) 31(2) 4(2) 10(2) 44(2) C(15) 75(2) 50(2) 41(2) 3(1) 21(1) 6(2) C(16) 40(1) 29(1) 37(1) 3(1) 7(1) 0(1) C(17) 46(1) 29(1) 28(1) 2(1) 14(1) 2(1) C(18) 66(2) 58(2) 36(1) 4(1) -4(1) -1(1) (1) 43(1) 36(1) 30(1) -2(1) 7(1) 1(1) (2) 55(1) 32(1) 33(1) 2(1) 3(1) 2(1) (1) 68(1) 30(1) 45(1) 3(1) 15(1) -10(1) (2) 72(1) 28(1) 41(1) -3(1) 5(1) 5(1) S14

16 Table 5. Hydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for t. x y z U(eq) H(1A) H(2) H(4) H(8) H(9A) H(9B) H(11) H(12) H(13) H(14) H(15) H(16) H(18A) H(18B) H(18C) H(1) 10880(80) 4180(40) 5528(18) 81 H(2A) 5720(70) 3580(30) 4998(16) 65 Table 6. Torsion angles [ ] for t. C(6)-C(1)-C(2)-C(3) -0.5(4) C(1)-C(2)-C(3)-C(4) 1.3(4) C(1)-C(2)-C(3)-Br(1) (2) C(2)-C(3)-C(4)-C(5) -1.4(4) Br(1)-C(3)-C(4)-C(5) (17) C(3)-C(4)-C(5)-C(6) 0.8(3) C(3)-C(4)-C(5)-C(7) (2) C(2)-C(1)-C(6)-(1) 178.8(2) C(2)-C(1)-C(6)-C(5) 0.0(4) C(4)-C(5)-C(6)-(1) (2) C(7)-C(5)-C(6)-(1) 1.2(2) S15

17 C(4)-C(5)-C(6)-C(1) -0.1(3) C(7)-C(5)-C(6)-C(1) (2) C(4)-C(5)-C(7)-C(8) 179.5(2) C(6)-C(5)-C(7)-C(8) -1.0(3) C(4)-C(5)-C(7)-C(16) 2.1(4) C(6)-C(5)-C(7)-C(16) (2) C(5)-C(7)-C(8)-(1) 0.4(3) C(16)-C(7)-C(8)-(1) 177.8(2) (1)-C(9)-C(10)-C(11) 65.1(3) (1)-C(9)-C(10)-C(15) (3) C(15)-C(10)-C(11)-C(12) 0.5(4) C(9)-C(10)-C(11)-C(12) 179.4(3) C(10)-C(11)-C(12)-C(13) -0.3(5) C(11)-C(12)-C(13)-C(14) 0.4(5) C(12)-C(13)-C(14)-C(15) -0.6(5) C(11)-C(10)-C(15)-C(14) -0.7(4) C(9)-C(10)-C(15)-C(14) (2) C(13)-C(14)-C(15)-C(10) 0.7(4) C(8)-C(7)-C(16)-(1) 25.1(3) C(5)-C(7)-C(16)-(1) (2) C(8)-C(7)-C(16)-C(17) -97.9(3) C(5)-C(7)-C(16)-C(17) 78.9(3) (1)-C(16)-C(17)-(2) 167.5(2) C(7)-C(16)-C(17)-(2) -72.7(3) (1)-C(16)-C(17)-(2) -14.3(3) C(7)-C(16)-C(17)-(2) 105.5(2) C(7)-C(8)-(1)-C(6) 0.4(3) C(7)-C(8)-(1)-C(9) 178.4(2) C(1)-C(6)-(1)-C(8) (2) C(5)-C(6)-(1)-C(8) -1.0(2) C(1)-C(6)-(1)-C(9) 1.9(4) C(5)-C(6)-(1)-C(9) (2) C(10)-C(9)-(1)-C(8) (3) C(10)-C(9)-(1)-C(6) 76.2(3) (2)-C(17)-(2)-C(18) -0.7(3) C(16)-C(17)-(2)-C(18) (2) Symmetry transformations used to generate equivalent atoms: S16

18 References 1. (a) ttoni,.; Cruz, R.; Alves, R. Terahedron 1998, 54, (b) Heaney, H.; Ley, S. V. rg. synth. 1977, 54, (a) Kornblum,.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H..; Levand,.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, (b) Bauer, D. P.; Macomber, R. S. J. rg. Chem. 1975, 40, Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals; Fourth ed.; Butterworth-Heinemann: xford, S17

19 MR Spectra 3a Ethyl 3-(1-metheyl)indolyl-hydroxyacetate S18

20 Allyl 3b Ethyl 3-(1-allyl)indolyl-hydroxyacetate S19

21 Bn 3c Ethyl 3-(1-phenyl)indolyl-hydroxyacetate S20

22 H 3d Ethyl 3-indolyl-hydroxyacetate S21

23 Br 3e Ethyl 3-(1-metheyl-5-bromo)indolyl-hydroxyacetate S22

24 F 3f Ethyl 3-(1-metheyl-5-fluoro)indolyl-hydroxyacetate S23

25 Cl Allyl 3g Ethyl 3-(1-metheyl-6-chloro)indolyl-hydroxyacetate S24

26 Et thyl 3-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-methyl-indole-5-carboxylate 3h S25

27 Allyl 3i Et Ethyl 3-(1-metheyl-5-methoxy)indolyl-hydroxyacetate S26

28 3j Ethyl 3-(1, 5-dimetheyl)indolyl-hydroxyacetate S27

29 3k Ethyl 3-(1, 2-dimetheyl)indolyl-hydroxyacetate S28

30 Br Bn 3l Ethyl 3-(1- phenyl -5-bromo)indolyl-hydroxylacetate S29

31 5 CF 3 C 2 thyl 2-[3-(1-methyl)]indolyl-2-hydroxy-trifluoro propionate S30

32 CH 3 thyl 2, 2-bis[3-(1-methyl)]indolyl-propionate 7 S31

33 Cl Bis[3-(1-methyl)]indolyl-p-chloroacetophenone 9 S32

34 Br Bn 10 H (S)-2-(1-benzyl-5-bromo-1H-indol-3-yl)-2-hydroxy--methylacetamide S33

35 HPLC Spectra HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm racemic 3a HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm 3a HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm Allyl racemic 3b S34

36 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm Allyl 3b HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm Bn racemic 3c HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm Bn 3c S35

37 HPLC Conditions: Daicel chiralpak AS, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm H racemic 3d HPLC Conditions: Daicel chiralpak AS, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm H 3d HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm Br racemic 3e S36

38 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm Br 3e HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm F racemic 3f HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm F 3f S37

39 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm Cl Allyl racemic 3g HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm Cl Allyl 3g HPLC Conditions: Daicel chiralpak AS, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm Et racemic 3h S38

40 HPLC Conditions: Daicel chiralpak AS, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm Et 3h HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm Allyl Et racemic 3i HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm Allyl Et 3i S39

41 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm racemic 3j HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 80:20, 1.0 ml/min, λ 254 nm 3j HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm racemic 3k S40

42 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm 3k HPLC Conditions: Daicel chiralpak AD, Hexane:IPA,70:30, 1.0 ml/min, λ 254 nm Br Bn racemic 3l HPLC Conditions: Daicel chiralpak AD, Hexane:IPA,70:30, 1.0 ml/min, λ 254 nm Br Bn 3l S41

43 HPLC Conditions: Daicel chiralpak D, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm CF 3 C racemic 5 HPLC Conditions: Daicel chiralpak D, Hexane:IPA, 90:10, 1.0 ml/min, λ 254 nm CF 3 C 5 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA,70:30, 1.0 ml/min, λ 254 nm Br Bn H racemic 10 S42

44 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA,70:30, 1.0 ml/min, λ 254 nm Br Bn H 10 HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm 20 mmol % (R)-6,6 -Br 2 -BIL was used HPLC Conditions: Daicel chiralpak AD, Hexane:IPA, 75:25, 1.0 ml/min, λ 254 nm 20 mmol % (S)-H 8 -BIL was used S43