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2 Ma, an, Krishnan, Virgil and Stoltz Catalytic Enantioselective Stereoablative Alkylation of 3-alooxindoles: Facile Access to C(3) All- Carbon Quaternary Stereocenters Sandy Ma, Xiaoqing an, Shyam Krishnan, Scott C. Virgil, and ian M. Stoltz The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA Table of Contents Materials and Methods Base ptimization for Enantioselective Malonate Alkylation Lewis Acid Metal Screen for Enantioselective Malonate Alkylation S2 S3 S3 General Synthesis of 3-Alkyl omooxindoles Substrates from Corresponding 3-Alkyl Indoles S3 General Synthesis of 3-Aryl alooxindoles Substrates from Isatin General Synthesis of [Cu((R)-Ph-BX)(SbF 6 ) 2 ] General Procedures of Enantioselective Malonate Alkylation Synthesis of Pyrrolidinone-spirooxindole S10 S13 S13 S20 Synthesis of ther Pyrrolidinone-spirooxindole: Further Confirmation of Absolute Stereochemistry S24 Synthesis of Fused Indolinopyrrolidinone References S27 S28 S1

3 Ma, an, Krishnan, Virgil and Stoltz Materials and Methods Unless stated otherwise, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents (distilled or passed over a column of activated alumina). Commercially obtained reagents were used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, or ceric ammonium molybdate staining. SiliaFlash P60 Academic Silica gel (particle size mm) was used for flash chromatography. Analytical chiral PLC was performed with an Agilent 1100 Series PLC utilizing a Chiralpak AD column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd with visualization at 254 nm and flow rate of 1mL/min, unless otherwise stated. 1 and 13 C MR spectra were recorded on a Varian Inova 500 (at 500 Mz and 126 Mz, respectively) and a Varian Mercury 300 spectrometer (at 300 Mz and 75 Mz, respectively) and are reported relative to Me 4 Si (δ 0.0). Data for 1 MR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (z), integration). Data for 13 C MR spectra are reported in terms of chemical shift relative to Me 4 Si (δ 0.0). IR spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometer and are reported in frequency of absorption (cm -1 ). igh resolution mass spectra were either obtained from the Caltech Mass Spectral Facility or an Agilent 6200 Series TF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) or mixed (MM) ionization mode. ptical rotations were measured on either a Jasco P-1010 using a 50 mm path-length cell or Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. Melting points were determined using a Thomas capillary melting point apparatus and the values reported are uncorrected. Crystallographic data have been deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number. S2

4 Ma, an, Krishnan, Virgil and Stoltz Base ptimization for Enantioselective Malonate Alkylation TIPS Me Me 2 + 2SbF 6 Cu Ph Ph 20 mol% Me 2 C C 2 Me (3 equiv) Base (2 equiv), 3ÅMS DCM, 23 C Me 2 C C 2 Me TIPS Entry Base Yield [%] b ee[%] c 1 a Pyridine a 2,6-di-tert-butylpyridine a -Methylmorpholine a DMAP Methyl-dicyclohexylamine Cs 2 C Entry Base Yield [%] b ee[%] c 7 a Imidazole a TEA a DABC a,-dimethylcyclohexylamine i-pr 2 Et a a. o product observed. b. Isolated yield. c. Measured by chiral PLC. Lewis Metal Screen for Enantioselective Malonate Alkylation TIPS Metal Salt (20 mol%) (S)-Ph-BX (20 mol%) Me 2 C C 2 Me (3 equiv) i-pr 2 Et (2 equiv), 3ÅMS DCM, 23 C Me 2 C Entry Metal Salt Yield[%] b ee[%] c 1 Cu(Tf) Mg(Tf) a La(Tf) icl a. Performed with (R)-Ph-BX. b. Isolated yield. c. Measured by chiral PLC. C 2 Me TIPS General Synthesis of 3-Alkyl omooxindoles From Corresponding 3-Alkyl Indoles. TIPS BS TF/t-Bu/ 2 TIPS TIPS 0 ºC 23 ºC 1 S1 30% yield 34% yield 1. LiMDS, TF, -78 C 2. BS, TF, dark -78 C -40 C 3. aq. 4 Cl (78% yield) 3-(2-(triisopropylsilyloxy)ethyl)-1-indole (2.01 g, 6.33 mmol, 1.0 equiv) was dissolved in a mixture of TF (63 ml), t-bu (63 ml), and 2 (1.3 ml). The solution was cooled to 0 5 ºC and solid - bromosuccinimide (1.58 g, 8.86 mmol, 1.4 equiv) was added in small portions over 60 minutes. The reaction mixture was then allowed to warm to ambient temperature and concentrated under reduced pressure. The residue obtained was purified by column chromatography (Si 2, 6% ethyl acetate in hexanes 10% ethyl acetate in hexanes) to afford bromooxindole 1 as an off-white solid (790.6 mg, 30% yield) and oxindole S1 as a colorless oil (711.8 mg, 34% yield). TIPS oxindole S1: R f = 0.30 (Si 2, 25% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.31 (br s, 1), 7.27 (d, J = 7.5 z, 1), 7.20 (tt, J = 8.0, 1.0 z, 1), 7.02 (td, J = 7.5, 1.0 z, 1), 6.88 (d, J = 7.5 z, 1), 3.92 (m, 2), 3.66 (app. t, J = 6.5 z, 1), 2.25 (m, 1), 2.07 (m, 1), 1.04 (m, 21); 13 C MR (75 Mz, CDCl 3 ) δ 180.5, 141.5, 129.7, 127.8, 124.6, 122.2, 109.6, 60.1, 42.8, 33.7, 18.1, 12.1; IR (neat film, acl) 3215, S3

5 Ma, an, Krishnan, Virgil and Stoltz 2941, 2863, 1711, 1620, 1471, 1109, 747 cm -1 ; RMS (FAB+) m/z calc d for C Si[M+] + : , found xindole S1 could be brominated to give bromooxindole 1 as follows: To a solution of oxindole S1 (485.3 mg, mmol, 1.0 equiv) in TF (15 ml) that had been pre-cooled to 78 ºC was added a freshly prepared solution of LiMDS (535.6 mg, mmol, 2.2 equiv) in TF (4 ml) dropwise. The reaction mixture was then maintained at 78 ºC for 30 minutes, and then transferred via cannula to a solution of BS (517.9 mg, 2.91 mmol, 2.0 equiv) in TF (10 ml) that had been pre-cooled to 78 ºC and wrapped in aluminum foil to protect from light. The reaction mixture was allowed to warm to 40 ºC and maintained at this temperature for 2 hours. The reaction mixture was then poured into saturated aqueous 4 Cl (60 ml). 1M aqueous a 2 S 2 3 (40 ml) was then added and the mixture was stirred for 10 minutes to reduce any excess BS. The mixture was then extracted with EtAc (3 100 ml). The combined EtAc extracts were washed with brine (100 ml), dried (MgS 4 ) and concentrated under reduced pressure to afford a pale yellow solid. Purification by column chromatography (Si 2, 10% ethyl acetate in hexanes) afforded bromooxindole 1 as a pale yellow solid (467.7 mg, 78% yield). R f = 0.35 (Si 2, 25% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 9.56 (s, 1), 7.37 (dd, J = 7.5, 0.5 z, 1), 7.26 (app. t, J = 5.0 z, 1), 7.07 (app. dt, J = 7.5, 1.0 z, 1), 6.94 (d, J = 7.5 z, 1), 3.62 (m, 2), 2.89 (m, 1), 2.61 (m, 1), 0.91 (m, 21); 13 C MR (75 Mz, CDCl 3 ) δ 177.4, 140.2, 130.1, 129.7, 124.8, 123.0, 111.0, 60.1, 55.8, 41.7, 17.8, 11.9; IR (neat film, acl) 3202, 2946, 2866, 1725, 1619, 1474, 1115 cm 1 ; MRS (FAB+) m/z calc d for C Si [M+] + : , found TIPS C 3 To a (53 mg, 60%, mmol, 1.2 equiv) in DMF (1 ml) was added a solution of 3-(2- (triisopropylsilyloxy)ethyl)-1-indole (0.351 g, mmol, 1.0 equiv) in DMF (4 ml) at ambient temperature. The reaction solution was stirred for 20 min and then MeI (103 µl, mmol, 1.5 equiv) was added dropwise. The reaction solution was stirred for additional 30 min at ambient temperature. Water (5 ml) and brine (5 ml) were added, and the mixture was extracted with a mixture of hexanes/etac (1:2) (2 x 15 ml). The combined extracts were dried with magnesium sulfate prior to concentration. The residue obtained was purified by column chromatography (Si 2, 2% ethyl acetate in hexanes) to afford 1-methyl-3-(2-(triisopropylsilyloxy)ethyl)-1-indole as a pale yellow viscous oil (303 mg, 83% yield). R f = 0.66 (22% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 7.61 (d, J = 8.1. z, 1), 7.30 (d, J = 8.1 z, 1), 7.23 (td, J = 7.2, 1.2 z, 1), 7.11 (ddd, J = 6.9, 6.6, 1.2 z, 1), 6.91(s, 1), 394 (t, J = 7.2 z, 2), 3.75 (s, 3), 3.04 (t, J = 7.2 z, 2), (comp. m, 21); 13 C MR (75 Mz, CDCl 3 ) δ 137.0, 128.2, 127.1, 121.5, 119.1, 118.8, 111.6, 109.2, 64.5, 32.7, 29.2, 18.2, 12.2; IR (neat film, acl) 3056, 2942, 2865, 1616, 1470, 1382, 1328, 1248, 1100, 1069, 1013, 918, 883 cm 1 ; RMS (FAB+) m/z calc d for C Si [M] + : , found TIPS C 3 Prepared according to the procedure used for oxindole S1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 2% ethyl acetate in hexanes 5% ethyl acetate in hexanes). Isolated as a colorless viscous oil. 43% yield. R f = 0.41 (17% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ (comp. m, 2), (m, 1), 6.81 (d, J = 7.5 z, 1), (comp. S4

6 Ma, an, Krishnan, Virgil and Stoltz m, 2), 3.63 (t, J = 6.6 z, 1), 3.19 (s, 3), 2.23 (dq, J = 13.8, 6.6 z, 1), 2.02 (dq, J = 13.8, 6.6 z, 1), (comp. m, 21); 13 C MR (75 Mz, CDCl 3 ) δ 178.3, 144.5, 129.3, 127.8, 124.2, 122.3, 108.0, 60.3, 42.4, 33.9, 26.2, 18.1, 12.1; IR (neat film, acl) 3056, 2941, 2865, 1712, 1613, 1494, 1468, 1375, 1344, 1263, 1263, 1193, 1095, 1019, 921 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found C 3 TIPS Prepared according to the procedure used for bromooxindole 1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 2% ethyl acetate in hexanes 5% ethyl acetate in hexanes). Isolated as a pale yellow viscous oil. 28% yield. R f = 0.56 (17% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 7.39 (dd, J = 7.5, 1.2 z, 1), 7.31 (td, J = 7.8, 1.2 z, 1), 7.08 (td, J = 7.5, 1.2 z, 1), 6.80 (d, J = 7.8 z, 1), (m, 2), 3.21 (s, 3), 2.84 (ddd, J = 14.1, 7.2, 6.6 z, 1), 2.60 (ddd, J = 13.8, 5.4, 4.5 z, 1), 0.91 (s, 21); 13 C MR (75 Mz, CDCl 3 ) δ 174.2, 142.7, 130.1, 129.7, 124.8, 123.1, 108.8, 60.3, 55.3, 41.8, 26.8, 17.9, 11.9; IR (neat film, acl) 2943, 2891, 2866, 1732, 1614, 1494, 1471, 1422, 1372, 1344, 1244, 1137, 1104, 1071, 1018, 958 cm 1 ; RMS (FAB+) m/z calc d for C Si 81 [M] + : , found TBDPS To a solution of tryptophol (1.069 g, mmol, 1 equiv) and imidazole (0.993 g, mmol, 2.2 equiv) in DMF (25 ml) was added TIPSCl (1.90 ml, mmol, 1.1 equiv) dropwise at ambient temperature. The reaction solution was stirred for 18 hours. Saturated aqueous ac 3 (50 ml) was added and the mixture was extracted with EtAc (2 x 50 ml). The combined extracts were dried with magnesium sulfate prior to concentration. The residue obtained was purified by column chromatography (Si 2, 9% ethyl acetate in hexanes) to afford 3-(2-(tert-butyldiphenylsilyloxy)ethyl)-1-indole as a yellow viscous oil (2.60 g, 98% yield). R f = 0.60 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 7.89 (br s, 1), 7.67 (dd, J = 7.5, 1.5 z, 4), (m, 3), (m, 5), 7.18 (td, J = 7.5, 1.0 z, 1), 7.06 (td, J = 7.5, 1.0 z, 1), 7.00 (d, J = 2.5 z, 1), 3.95 (t, J = 7.5 z, 2), 3.05 (t, J = 7.5 z, 2), 1.08 (s, 9); 13 C MR (126 Mz, CDCl 3 ) δ 135.7, 134.1, 129.7, 127.8, 127.7, 122.3, 122.0, 119.3, 119.0, 113.1, 111.1, 64.6, 28.8, 27.0, TBDPS Prepared according to the procedure used for oxindole S1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 57% yield. R f = 0.30 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.08 (br s, 1), 7.66 (dt, J = 6.5, 1.5 z, 2), 7.52 (dt, J = 6.5, 1.5 z, 2), (comp. m, 4), 7.33 (tt, J = 7.5, 1.0 z, 2), 7.22 (tt, J = 8.0, 1.0 z, 1), 7.11 (d, J = 7.5 z, 1), 6.98 (td, J = 7.5, 1.0 z, 1), 6.87 (d, J = 7.5 z, 1), 3.86 (ddd, J = 12.5, 7.0, 5.5 z, 1), 3.78 (dt, J = 10.5, 6.0 z, 1), 3.69 (t, J = 7.5 z, 1), 2.27 (dq, J = 14.0, 6.0 z, 1), (m, 1), 1.01 (s, 9); 13 C MR (126 Mz, CDCl 3 ) δ 180.3, 141.6, 135.8, 135.6, , , 129.8, 129.7, 129.4, , , , 124.7, 122.3, 109.7, 60.6, 42.9, 32.9, 26.9, 19.2; IR (neat film, acl) 3198, 3071, 2956, 2930, 2889, 2857, 1709, 1621, 1472, 1428, 1390, 1335, 1307, 1235, 1111, 1073, 953 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found S5

7 Ma, an, Krishnan, Virgil and Stoltz TBDPS Prepared according to the procedure used for bromooxindole 1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 13% yield. R f = 0.46 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.48 (br s, 1), 7.50 (dt, J = 6.5, 1.5 z, 2), 7.41 (tt, J = 7.5, 1.5 z, 1), (comp. m, 5), (comp. m, 4 ), 7.10 (td, J = 8.0, 1.0 z, 1), 6.94 (d, J = 8.0 z, 1), (m, 2), 3.01 (ddd, J = 15.5, 9.0, 6.5 z, 1), 2.60 (dt, J = 14.0, 4.0 z, 1), 0.92 (s, 9); 13 C MR (126 Mz, CDCl 3 ) δ 176.4, 140.1, 135.7, 135.4, 133.1, 132.9, 130.3, 129.9, 129.7, 129.7, 127.8, 127.7, 125.2, 123.2, 110.8, 60.7, 55.4, 41.2, 26.6, 19.0; IR (neat film, acl) 3209, 3175, 3107, 2930, 2879, 2857, 1731, 1614, 1470, 1427, 1388, 1332, 1195, 1107, 1084, 824, 758, 748 cm 1 ; RMS (FAB+) m/z calc d for C Si 81 [M+] + : , found TIPS To a solution of indole-3-butyric acid (1.500 g, mmol, 1.0 equiv) in TF (20 ml) at 0 ºC was added a solution of LA (5.5 ml, mmol, 2.0 M in TF, 1.5 equiv) dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 6 hours. Water (2 ml), 10 % aqueous a (2 ml), and water (6 ml) were added in order and the mixture was stirred at ambient temperature for additional 30 min, filtered through celite, concentrated under vacuum to get indole-3- butanol as pale yellow viscous oil (1.40 g). Crude product was used for next step without further purification. To a solution of above crude alcohol (1.395 g, mmol) and imidazole (1.103 g, mmol, 2.2 equiv) in DMF (20 ml) was added TIPSCl (1.74 ml, mmol, 1.1 equiv) dropwise at ambient temperature. The reaction solution was stirred for 18 hours. Saturated aqueous ac 3 (30 ml) was added and the mixture was extracted with EtAc (4 x 30 ml). The combined extracts were dried with magnesium sulfate prior to concentration. The residue obtained was purified by column chromatography (Si 2, 5% ethyl acetate in hexanes) to afford 3-(4-(triisopropylsilyloxy)butyl)-1-indole as a pale yellow viscous oil (2.50 g, 98% yield). R f = 0.45 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 7.90 (br s, 1 ), 7.62 (dd, J = 7.5, 1.0 z, 1 ), 7.35 (dt, J = 8.0, 1.0 z, 1 ), 7.19 (td, J = 7.5, 1.0 z, 1 ), 7.11 (td, J = 7.5, 1.0 z, 1 ), 6.98 (t, J = 1.0 z, 1 ), 3.74 (t, J = 6.5 z, 2 ), 2.79 (t, J = 7.5 z, 2 ), (m, 2 ), (m, 2 ), (comp. m, 21 ); 13 C MR (126 Mz, CDCl 3 ) δ 136.5, 127.8, 121.9, 121.2, , , 117.1, 111.1, 63.5, 33.1, 26.5, 25.1, 18.2, 12.2; IR (neat film, acl) 3420, 3057, 2941, 2864, 1458, 1420, 1382, 1351, 1336, 1246, 1228, 1105, 1070, 1012, 995, 969, 882, 796, 739 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found TIPS Prepared according to the procedure used for oxindole S1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 15% yield. R f = 0.11 (29% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.80 (br s, 1), 7.24 (d, J = 7.0 z, 1), 7.20 (t, J = 7.0 z, 1), 7.01 (td, J = 7.5, 1.0 z, S6

8 Ma, an, Krishnan, Virgil and Stoltz 1), 6.90 (d, J = 7.5 z, 1), (m, 2), 3.48 (t, J = 6.5 z, 1), (m, 1), (m, 1), (m, 2), (m, 2), (m, 21); 13 C MR (126 Mz, CDCl 3 ) δ 180.8, 141.7, 129.9, 127.9, 124.4, 122.4, 109.8, 63.2, 46.2, 33.0, 30.6, 22.4, 18.1, 12.1; IR (neat film, acl) 3209, 3091, 2942, 2892, 2866, 1711, 1621, 1486, 1472, 1383, 1338, 1233, 1106, 1070, 1015, 996, 883 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found TIPS Prepared according to the procedure used for bromooxindole 1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a pale yellow viscous oil. 15% yield. R f = 0.34 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 9.03 (br s, 1), 7.37 (d, J = 7.0 z, 1), 7.26 (td, J = 7.0, 1.0 z, 1), 7.08 (td, J = 7.5, 0.5 z, 1), 6.93 (d, J = 8.0 z, 1), (m, 2), 2.42 (t, J = 8.0 z, 2), (m, 2), (m, 2), (m, 21); 13 C MR (126 Mz, CDCl 3 ) δ 177.0, 139.8, 130.5, 130.1, 124.9, 123.5, 110.8, 62.8, 56.9, 39.4, 32.6, 22.1, 18.1, 12.1; IR (neat film, acl) 3239, 2943, 2865, 2732, 1619, 1472, 1383, 1331, 1246, 1208, 1180, 1112, 1069, 1014, 996, 882, 749 cm 1 ; RMS (FAB+) m/z calc d for C Si 81 [M+] + : , found Bz To a solution of benzoic acid (0.970 g, mmol, 1.0 equiv) and EDCI (1.675 g, mmol, 1.1 equiv) in C 2 Cl 2 (15 ml) was added DMAP (0.107 g, mmol, 0.11 equiv) and tryptophol (1.409 g, mmol, 1.1 equiv) at 23 ºC. The reaction mixture was stir at 23 ºC for 14 hours. Saturated aqueous ac 3 solution (30 ml) was added and the mixture was extracted with C 2 Cl 2 (2 x 30 ml). The combined extracts were dried with magnesium sulfate prior to concentration. Purification by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes) afforded 2-(1indol-3-yl)ethyl benzoate as a yellow solid (1.05 g, 50% yield). 1 1 MR (300 Mz, CDCl 3 ) δ (comp. m, 3), (m, 1), 7.57 (tt, J = 7.5, 1.2 z, 1), (comp. m, 2), (m, 1), 7.23 (td, J = 6.9, 1.5 z, 1), 7.17 (td, J = 7.5, 1.5 z, 1), 7.11 (d, J = 2.4 z, 1), 4.63 (t, J = 7.5 z, 2), 3.26 (td, J = 6.9, 0.9 z, 2); 13 C MR (75 Mz, CDCl 3 ) δ 166.8, 136.3, 133.1, 130.5, 129.7, 128.5, 127.6, 122.3, 122.2, 119.6, 118.9, 112.2, 111.3, 65.2, Bz Prepared according to the procedure used for oxindole S1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 5% ethyl acetate in hexanes 25% ethyl acetate in hexanes). Isolated as a white solid. 47% yield. R f = 0.21 (33% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.99 (br s, 1), (comp. m, 2), 7.50 (t, J = 7.2 z, 1), 7.39 (t, J = 7.8 z, 2), 7.27 (d, J = 7.5 z, 1), 7.20 (t, J = 7.5 z, 1), 7.02 (td, J = 7.5, 0.9 z, 1), 6.89 (d, J = 7.8 z, 1), 4.52 (dt, J = 11.4, 7.2 z, 1), 4.41 (dt, J = 11.1, 6.8 z, 1), 3.66 (t, J = 6.0 z, 1), 2.48 (q, J = 6.3 z, 2); 13 C MR (75 Mz, CDCl 3 ) δ 181.1, 166.5, 141.6, 133.1, 130.1, 129.7, 128.6, 128.4, 128.3, 124.4, 122.6, 110.2, 61.8, 43.4, 29.2; IR (neat film, acl) 3207, 3059, 2961, 1715, 1620, 1471, 1452, 1335, 1314, 1272, 1176, 1116, 1070, 1026 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found S7

9 Ma, an, Krishnan, Virgil and Stoltz Bz Prepared according to the procedure used for bromooxindole 1 using -bromosuccinimide (1.0 equiv). Purified by flash chromatography (Si 2, 5% ethyl acetate in hexanes 25% ethyl acetate in hexanes). Isolated as a pale yellow solid. 23% yield. R f = 0.48 (33% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.64 (br s, 1), (comp. m, 2), 7.48 (td, J = 7.8, 1.2 z, 1), 7.42 (d, J = 7.8 z, 1), 7.35 (t, J = 7.5 z, 2), 7.25 (td, J = 7.5, 1.6 z, 1), 7.07 (td, J = 7.5, 1.2 z, 1), 6.85 (t, J = 7.1, 1), 4.34 (dt, J = 11.7, 5.7 z, 1), 4.16 (ddd, J = 11.4, 8.1, 4.8 z, 1), 3.06 (ddd, J = 14.4, 8.4, 6.0 z, 1), 2.89 (dt, J = 14.4, 5.4 z, 1); 13 C MR (75 Mz, CDCl 3 ) δ 176.4, 166.2, 139.8, 133.3, 130.6, 129.6, 129.6, 129.5, 128.4, 125.0, 123.7, 111.2, 61.4, 54.5, 38.2; IR (neat film, acl) 3256, 3090, 3064, 3033, 2961, 1723, 1619, 1602, 1473, 1451, 1329, 1316, 1273, 1192, 1114, 1071, 1028, 752 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found Phth Prepared from -phthalimidotryptamine according to the procedure used for oxindole S1. 54% yield. R f = 0.12 (Si 2, 50% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 7.82 (bs, 1), 7.75 (m, 2), 7.66 (m, 2), 7.29 (d, J = 7.7 z, 1), 7.08 (d, J = 7.7 z, 1), 6.87 (t, J = 7.7 z, 1), 6.80 (d, J = 8.0 z, 1), 3.97 (m, 1), 3.80 (m, 1), 3.53 (t, J = 6.0 z, 1), 2.51 (m, 1), 2.32 (m, 1); 13 C MR (75 Mz, CDCl 3 ) δ 178.7, 168.2, 141.3, 133.9, 132.1, 128.6, 128.0, 124.1, 123.2, 122.4, 109.7, 43.9, 35.2, 28.5; IR (eat film, acl) 3271, 1772, 1711, 1621, 1471, 1398, 1220, 1022, 718 cm -1 ; RMS (FAB+) m/z calc d for C [M+] + : , found Phth Prepared from -phthalimidotryptamine according the the procedure used for bromooxindole 1. 9% yield. R f = 0.31 (Si 2, 50% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.71 (s, 1), 7.71 (m, 2), 7.62 (m, 2), 7.28 (m, 1), 7.06 (m, 1), 6.80 (m, 2), 3.81 (m, 1), 3.65 (m, 1), 3.01 (m, 1), 2.86 (m, 1); 13 C MR (75 Mz, CDCl 3 ) δ 175.5, 167.8, 139.8, 134.0, 131.8, 130.2, 129.5, 124.4, 123.2, 123.1, 111.1, 54.2, 36.5, 34.6; IR (eat film, acl) 3256, 1711, 1615, 1471, 1398, 1184, 716 cm - 1 ; RMS (FAB+) m/z calc d for C [M+] , found Phth Prepared from -(indol-3-yl)methyl]phthalimide according to procedure used for oxindole S1 using - bromosuccinimide (1.0 equiv). 2 Purified by flash chromatography (Si 2, 25% ethyl acetate in hexanes 50% ethyl acetate in hexanes; then 9% ethyl acetate in methylene chloride). Isolated as a pale yellow solid with 35% (w/w) of succinimide. 23% yield (corrected for succinimide). R f = 0.17 (9% ethyl acetate in methylene chloride); 1 MR (500 Mz, CDCl 3 ) δ 8.15 (br s, 1), (m, 2), (m, 2), 7.22 (td, J = 7.5, 1.0 z, 1), 7.19 (d, J = 7.0 z, 1), 6.99 (td, J = 7.5, 1.0 z, 1), 6.87 (d, J = 8.0 z, 1), 4.20 (dd, J = 14.0, 9.0 z, 1), 4.14 (dd, J = 14.0, 6.0 z, 1), 3.99 (dd, J = 9.0, 6.0 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 177.5, 168.3, 141.6, 134.2, 132.1, 128.8, 126.6, 124.6, 123.7, 122.6, 110.1, 43.5, 38.2; RMS (FAB+) m/z calc d for C [M+] + : , found S8

10 Ma, an, Krishnan, Virgil and Stoltz Phth Prepared from -(indol-3-yl)methyl]phthalimide according to procedure used for bromooxindole 1 using -bromosuccinimide (1.0 equiv). 2 Purified by flash chromatography (Si 2, 25% ethyl acetate in hexanes 50% ethyl acetate in hexanes; then 9% ethyl acetate in methylene chloride). Isolated as a white solid. 22% yield. R f = 0.30 (9% ethyl acetate in methylene chloride); 1 MR (500 Mz, CDCl 3 ) δ 8.13 (br s, 1), (comp. m, 2), (comp. m, 2), 7.47 (d, J = 7.5 z, 1), 7.20 (td, J = 8.0, 1.5 z, 1), 7.02 (td, J = 7.5, 1.0 z, 1), 6.83 (d, J = 8.0 z, 1), 4.64 (ABq, J = 14.5 z, 2); 13 C MR (126 Mz, CDCl 3 ) δ 174.6, 167.4, 140.3, 134.4, 131.5, 130.9, 127.4, 126.3, 123.8, 123.3, 110.8, 53.7, 43.9; IR (neat film, acl) 3268, 1778, 1734, 1719, 1617, 1472, 1389, 1335, 1192, 1142, 986, 967, 876 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found Me Phth C 3 I (0.89 ml, mmol, 5 equiv) was added to a solution of 5-methoxy-gramine (0.580 g, mmol, 1 equiv) in TF (25 ml) at 0 ºC over 30 min. After stirring of the reaction mixture at ambient temperature for 1 hour, the solvent was removed in vacuo. The residue was heated with potassium phthalimide (0.526 g, mmol, 1 equiv) at 140 ºC for 6 hours. Upon cooling to ambient temperature, reaction mixture was then diluted with water (20 ml) and brine (20 ml) and then extracted with ethyl acetate (3 x 50 ml). rganic layers were collected and dried with magnesium sulfate. Purification by column chromatography (Si 2, 33% ethyl acetate in hexanes) afforded -(5-methoxyindol-3-yl)methyl]phthalimide as a yellow solid (0.441 g, 51% yield). R f = 0.23 (33% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.06 (br s, 1), (comp. m, 2), (comp. m, 2), 7.44 (d, J = 2.5 z, 1), 7.38 (d, J = 2.5 z, 1), 7.22 (dd, J = 9.0, 0.5 z, 1), 6.85 (dd, J = 8.5, 2.5 z, 1), 4.99 (s, 2), 3.91 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 168.4, 154.5, 133.9, 132.4, 131.1, 127.1, 125.9, 123.3, 113.0, 111.9, 111.3, 101.0, 55.9, 32.8; IR (neat film, acl) 3401, 2938, 1767, 1708, 1488, 1432, 1394, 1334, 1216, 1178, 1056 cm 1 ; RMS (FAB+) m/z calc d for C [M] + : , found Me Phth Prepared according to the procedure similar to that used to synthesize oxindole S1 using - bromosuccinimide (1.6 equiv). Purified by column chromatography (Si 2, 9% ethyl acetate in C 2 Cl 2 17% ethyl acetate in C 2 Cl 2 ). Isolated as a white solid. 33% yield. R f = 0.06 (9% ethyl acetate in methylene chloride); 1 MR (500 Mz, CDCl 3 ) δ (comp. m, 2), (comp. m with broad singlet at δ 7.73, 3), 6.80 (s, 1), 6.77 (d, J = 8.0, 1), 6.74 (dd, J = 8.5, 2.0 z, 1), 4.19 (dd, J = 14.0, 9.5 z, 1), 4.12 (dd, J = 14.0, 7.0 z, 1), 3.95 (dd, J = 9.0, 7.0 z, 1), 3.72 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 176.9, 168.3, 155.9, 134.8, 134.3, 132.1, 127.8, 123.7, 113.6, 111.7, 110.3, 55.9, 43.8, 38.2; RMS (FAB+) m/z calc d for C [M+] + : , found Me Phth S9

11 Ma, an, Krishnan, Virgil and Stoltz Prepared according to the procedure similar to that used to synthesize bromooxindole 1 using - bromosuccinimide (1.6 equiv). Purified by column chromatography (Si 2, 9% ethyl acetate in methylene chloride) and then recrystallized from methylene chloride. Isolated as a yellow solid. 78% yield. R f = 0.18 (9% ethyl acetate in methylene chloride); 1 MR (500 Mz, CDCl 3 ) δ (comp. m, 2), (comp. m, 2), 7.61 (br s, 1), 7.07, (d, J = 2.5 z, 1), 6.75 (dd, J = 7.5, 2.5 z, 1), 6.70 (d, J = 7.5, 1), 4.62 (ABq, J = 150 z, 2), 3.77 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 174.2, 167.4, 156.1, 134.4, 133.3, 131.6, 128.3, 123.8, 117.1, 111.9, 111.2, 56.0, 53.9, 43.9; IR (neat film, acl) 3271, 2997, 1777, 1721, 1492, 1389, 1299, 1205, 719 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found General Synthesis of 3-Aryl aloxindoles from Isatin S2 PhMg (2.5 equiv) TF C S3 SCl 2 (5 equiv) Pyridine (10 equiv) Et 2 0 C To a solution of isatin (S2, 1.0 g, 6.8 mmol, 1.0 equiv) in TF (60 ml) cooled to 40 C was added PhMg (3M in Et 2, 5.7 ml, 17 mmol, 2.5 equiv). The reaction mixture was allowed to warm to ambient temperature. After 6 hours, 1 hydrochloric acid (30 ml) was added dropwise to quench the reaction, and the phases were separated. The aqueous phase was extracted with ether (2 x 50 ml), dried with sodium sulfate and concentrated to afford S3 as a yellow solid in 99% yield. 3 o further purification necessary. R f = 0.18 (20% ethyl acetate in methylene chloride); 1 MR (500 Mz, MeD) δ (comp. m, 2), (comp. m, 4), 7.17 (d, J = 7.5 z, 1), 7.06 (ddd, J = 8.5, 8.5, 0.97 z, 1), 6.97 (d, J = 7.8 z, 1); 13 C MR (126 Mz, MeD) δ 181.8, 143.2, 142.2, 135.0, 130.8, 129.4, 129.1, 126.8, 126.2, 124.2, 111.5, 79.5; IR (neat film, acl) 3312, 1711, 1622, 1473, 1183 cm -1 ; RMS (FAB+) m/z calc d for C [M + ] , found To solution of hydroxyoxindole S3 (321.9 mg, mmol, 1.0 equiv) and pyridine (1.2 ml, mmol, 3.0 equiv) in TF (10 ml) cooled to 0 C in a round bottom flask equipped with a stirbar, thionyl chloride (522 µl, mg, 5.0 equiv) added dropwise. The reaction solution was stirred at 0 C for one hour or when complete by TLC. Water (60 ml) then added and the mixture was extracted with EtAc (3 x 100 ml). The combined extracts washed with brine (1 x 100 ml), and then dried with magnesium sulfate prior to concentration. Purification by flash chromatography (Si 2, 10% ethyl acetate in hexanes) afforded chlorooxindole S4 as a white powder (83% yield). R f = 0.27 (25% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.20 (bs, 1), (comp. m, 2), (comp. m, 5), 7.14 (ddd, J = 7.6, 7.6, 0.9 z, 1), 6.97 (d, J = 7.8 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 175.2, 139.9, 136.5, 131.0, 130.6, 129.1, 128.7, 127.6, 126.5, 123.9, 110.8, 66.8; IR (neat film, acl) 3247, 1729, 1619, 1472, 1322, 1211 cm -1 ; RMS (FAB+) m/z calc d for C Cl [M+] + : , found Cl S4 Prepared according to procedure used for hydroxyoxindole S3. Purified by flash chromatography (Si 2, 50% ethyl acetate in hexanes). Isolated as a white powder. 80% yield. R f = 0.33 (50% ethyl acetate in hexanes); 1 MR (500 Mz, MeD) δ 7.38 (app. d, J = 8.5 z, 2), (comp. m, 3), 7.08 S10

12 Ma, an, Krishnan, Virgil and Stoltz (d, J = 7.3 z, 1), 6.96 (dd, J = 7.6, 7.6 z, 1), 6.88 (d, J = 7.8 z, 1); 13 C MR (126 Mz, MeD) δ 179.9, 141.9, 140.2, 133.2, 131.2, 129.8, 127.6, 124.9, 123.0, 121.7, 110.3, 77.8; IR (neat film, acl) 3234, 1718, 1621, 1472, 1184 cm -1 ; RMS (EI + ) m/z calc d for C [M] + : , found Cl Prepared according to procedure used for chlorooxindole S4. Purified by flash chromatography (Si 2, 20% ethyl acetate in hexanes). Isolated as a white solid. 63% yield. R f = 0.67 (50% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.59 (s, 1), 7.49 (app. d, J = 8.8 z, 2), 7.42 (app. d, J = 8.8 z, 2), 7.53 (dd, J = 6.1, 6.1 z, 2), 7.16 (dd, J = z, 1), 6.98 (d, J = 7.5 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 175.2, 140.0, 135.6, 131.9, 130.9, 130.4, 129.4, 127.6, 126.3, 124.0, 111.2, 66.2; IR (neat film, acl) 3247, 1728, 1619, 1472, 1395, 1322, 1211, 1011 cm -1 ; RMS (EI + ) m/z calc d for C Cl 81 [M] + : , found Prepared according to procedure used for hydroxyoxindole S3. Purified by flash chromatography (Si 2, 20% ethyl acetate in methylene chloride). Isolated as a pale yellow solid. 46% yield. R f = 0.50 (50% ethyl acetate in hexanes); 1 MR (500 Mz, MeD) δ 7.29 (ddd, J = 7.8, 7.8, 1.2 z, 1), 7.16 (d, J = 7.6 z, 1), 7.04 (ddd, J = 7.6, 7.6, 1.0 z, 1), (comp. m, 3), 6.92 (s, 1), 2.26 (s, 6); 13 C MR (126 Mz, MeD) δ 182.0, 143.2, 142.0, 139.2, 135.3, 130.8, 130.6, 126.2, 124.5, 124.2, 111.5, 79.5, 21.6; IR (neat film, acl) 3270, 1720, 1620, 1472, 1186, 1109 cm -1 ; MS (EI + ) m/z calc d for C [M] + : , found Cl Prepared according to procedure used for chlorooxindole S4. Purified by flash chromatography (Si 2, 20% ethyl acetate in hexanes). Isolated as a light yellow solid. 85% yield. R f = 0.40 (25% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ (comp. m, 2), (comp. m, 3), (comp. m, 2), 2.30 (s, 6); 13 C MR (126 Mz, CDCl 3 ) δ 175.7, 140.0, 138.4, 136.2, 131.5, 130.9, 130.4, 126.3, 125.2, 123.8, 110.9, 67.0, 21.5; IR (neat film, acl) 3247, 1729, 1619, 1473, 1192 cm -1 ; RMS (FAB+) m/z calc d for C Cl [M+] + : , found Prepared according to procedure used for hydroxyoxindole S3. Purified by flash chromatography (Si 2, 50% ethyl acetate in hexanes). Isolated as a yellow solid. 86% yield. R f = 0.46 (50% ethyl acetate in hexanes); 1 MR (500 Mz, MeD) δ 7.84 (d, J = 1.5 z, 1), (comp. m, 2), 7.69 (d, J = S11

13 Ma, an, Krishnan, Virgil and Stoltz 8.5 z, 1), (comp. m, 2), 7.31 (dd, J = 8.8, 2.0 z, 1), 7.22 (ddd, J = 7.8, 7.8, 1.2 z, 1), 7.12 (d, J = 7.6 z, 1), 6.96 (dd, J = 8.0, 8.0 z, 1), 6.92 (d, J = 7.8 z, 1); 13 C MR (126 Mz, MeD) δ 181.5, 143.2, 139.3, 134.8, 134.5, 134.5, 130.8, 129.2, 129.0, 128.6, 127.3, 127.2, 126.2, 125.6, 124.7, 124.1, 111.5, 79.5; IR (eat Film, acl) 3235, 1727, 1711, 1619, 1471, 1339, 1180, 1109, 1074, 893, 929, 859, 811, 754, 740 cm -1 ; RMS (EI + ) m/z calc d for C [M] + : , found Cl Prepared according to procedure used for chlorooxindole S4. Purified by flash chromatography (Si 2, 0% ethyl acetate in hexanes 40% ethyl acetate in hexanes). Isolated as a pale yellow solid. 67% yield. R f = 0.30 (50% ethyl acetate in hexanes); 1 MR (500 Mz, MeD) δ 7.83 (s, 1), (comp. m, 3), 7.38 (comp. m, 2), 7.29 (dd, J = 8.5, 1.7 z, 1), 7.22 (dd, J = 7.8, 7.8 z, 1), 7.11 (d, J = 7.6 z, 1), 6.96 (dd, J = 7.6, 7.6 z, 1), 6.91 (d, J = 7.8 z, 1); 13 C MR (126 Mz, MeD) δ 180.4, 142.0, 138.2, 133.6, 133.4, 133.3, 129.6, 128.0, 127.9, 127.4, 126.1, 126.0, 125.0, 124.4, 123.5, 122.9, 110.3, 78.4; IR (neat film, acl) 3261, 1726, 1679, 1622, 1474, 1342, 1268, 1180, 1126, 1111, 933, 894, 810, 752 cm -1 ; RMS (EI + ) m/z calc d for C Cl [M] + : , found Me Ph Prepared according to procedure used for hydroxyoxindole S3. Purified by flash chromatography (Si 2, 20% ethyl acetate in hexanes 50% ethyl acetate in hexanes). Isolated as a pale pink solid. 86% yield. R f = 0.25 (50% ethyl acetate in hexanes); 1 MR (500 Mz, MeD) δ (comp. m, 2), (comp. m, 3), (comp. m, 2), 6.78 (d, J = 1.4 z, 1); 13 C MR (126 Mz, MeD) δ 181.7, 157.8, 142.0, 136.1, 129.3, 129.0, 126.7, 115.6, 112.6, 111.9, 79.8, 56.2; IR (neat film, acl) 3271, 1708, 1489, 1203, 1026, 758, 733 cm 1 ; RMS (EI + ) m/z calc d for C [M] + : , found Me Cl Ph Prepared according to procedure used for chlorooxindole S4. Purified by flash chromatography (Si 2, 20% ethyl acetate in hexanes). Isolated as a white powder. 66% yield. R f = 0.70 (50% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.20 (s, 1), 7.56 (comp. m, 2), (comp. m, 3), 6.95 (app. s, 1), (comp. m, 2); 13 C MR (126 Mz, CDCl 3 ) δ 175.4, 156.8, 136.6, 133.2, 132.2, 129.2, 128.9, 127.6, 127.6, 116.0, 112.6, 111.5, 67.2, 56.0; IR (neat film, acl) 3206, 2961, 1726, 1613, 1492, 1440, 1300, 1206, 1146, 1104, 1031, 959, 846, 814, 750, 734, 695 cm -1 ; MS (FAB + ) m/z calc d for C Cl 2 [M] + : , found C 3 Prepared according to procedure used for hydroxyoxindole S3. Purified by flash chromatography (Si 2, 33% ethyl acetate in hexanes 50% ethyl acetate in hexanes) and recrystallized from ethyl acetate and hexanes. Isolated as a white solid. 29% yield. R f = 0.47 (33% ethyl acetate in hexanes); 1 MR (300 S12

14 Ma, an, Krishnan, Virgil and Stoltz Mz, CDCl 3 ) δ 7.82 (br s, 1), 7.37 (dd, J = 7.2, 0.6 z, 1), 7.27 (td, J = 7.5, 1.2 z, 1), 7.09 (td, J = 7.5, 1.2 z, 1), 6.88 (d, J = 7.8 z, 1), 2.76 (s, 1), (comp. m, 2), (comp. m, 3), (comp. m, 1), 0.82 (t, J = 7.2 z, 3); 13 C MR (75 Mz, CDCl 3 ) δ 181.0, 140.6, 130.7, 129.7, 124.4, 123.3, 110.5, 77.2, 38.4, 25.3, 22.9, 13.9; IR (neat film, acl) 3401, 3189, 2951, 2934, 2860, 1718, 1624, 1474, 1400, 1338, 1234, 1194, 1103, 1083, 1059, 1010, 961, 774, 748 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found C 3 To solution of 3-butyl-3-hydroxyindolin-2-one (188 mg, mmol, 1.0 equiv) and pyridine (0.89 ml, 0.99 mmol, 12 equiv) in TF (8 ml) cooled to 0 C in a round bottom flask equipped with a stirbar, a solution of P 3 (1.050g, 3.66 mg, 4.0 equiv) in TF (2 ml) was added dropwise. The reaction solution was stirred at 0 C for 20 min. Water (20 ml) then added and the mixture was extracted with EtAc (3 x 30 ml). The combined extracts were dried with magnesium sulfate prior to concentration. Purification by flash chromatography (Si 2, 10% ethyl acetate in hexanes) afforded 3-bromo-3- butylindolin-2-one as a pale yellow viscous oil (31% yield). R f = 0.48 (33% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 9.45 (br s, 1), 7.38 (dd, J = 7.2, 0.6 z, 1), 7.27 (td, J = 7.5, 1.2 z, 1), 7.09 (td, J = 7.8, 1.2 z, 1), 6.98 (d, J = 7.1 z, 1), (comp. m, 2), (comp. m, 4), 0.83 (t, J = 7.2 z, 3); 13 C MR (75 Mz, CDCl 3 ) δ 177.3, 139.9, 130.6, 130.1, 124.8, 123.5, 111.0, 57.1, 39.3, 27.6, 22.6, 13.9; IR (neat film, acl) 3247, 2957, 2930, 2872, 1722, 1618, 1472, 13.81, 1331, 1223, 1193, 1139, 1118, 1102, 1018, 863, 837 cm 1 ; RMS (FAB+) m/z calcd. for C [M+] + : , found Synthesis of [Cu((R)-Ph-BX)(SbF 6 ) 2 ] Ph Me Me Ph CuCl 2 C 2 Cl 2, 23 ºC (> 99% yield) Ph Me Me Cu Cl Cl Ph 2AgSbF 6, dark C 2 Cl 2, 23 ºC (92% yield) Ph Me Me Cu (R)-Ph-BX (194.5 mg, mmol, 1.0 equiv) was stirred along with copper(ii) chloride (82.1 mg, mmol, 1.05 equiv) in C 2 Cl 2 (8 ml) for 24 hours at ambient temperature in a glovebox. The reaction mixture was then filtered through celite, and the green solution was concentrated under reduced pressure to afford [Cu((R)-Ph-BX)Cl 2 ] as a light green powder (272.0 mg, >99% yield). A 25 ml reaction flask equipped with a magnetic stir bar was charged with [Cu((R)-PhBX)Cl 2 ] (102.9 mg, mmol. 1.0 equiv) and silver hexafluoroantimonate (150.2 mg, 2.0 equiv) in a glovebox. The flask was wrapped with aluminum foil to prevent exposure to light, and C 2 Cl 2 (11 ml) was added. The flask was capped and the reaction mixture stirred in the glovebox for 14 hours, then filtered through a pad of celite. The dark green filtrate was concentrated under reduced pressure to afford [Cu((R)- PhBX)(SbF 6 ) 2 ] as a dark green powder (174.0 mg, 92% yield). 4 Ph 2+ 2SbF 6 S13

15 Ma, an, Krishnan, Virgil and Stoltz General Procedure for Enantioselective Malonate Alkylation X R' Me Me Cu Ph Ph Me 2 C mol% 2SbF 6 C 2 Me (3 equiv) Base (2 equiv), 3ÅMS C 2 Cl 2 R' = Alkyl, Base = i-pr 2 Et R' = Aryl, Base = Et 3 To 1 dram vial equipped with a stirbar, [Cu((R)-Ph-BX)(SbF 6 ) 2 ] (17.4 mg, 0.02 mmol, 0.2 equiv) and 3ÅMS (32.3 mg) were added in the glovebox. After the reaction vial was removed from the glove box, methylene chloride (0.25 ml of 0.5 ml added, 0.2 M solution) was added and allowed to stir for 15 minutes. Upon cooling to reaction temperature, malonate (34.3 ul, 0.3 mmol, 3.0 equiv) followed by halooxindole (0.1 mmol, 1.0 equiv) dissolved in remaining methylene chloride were added via syringe to give a dark blue-green solution. 5 Base (0.2 mmol, 2.0 equiv) was then added to give a dark brown solution. Upon completion of reaction, saturated aqueous ammonium chloride solution (2 ml) added. Upon extraction with methylene chloride (3 x 2 ml), the collected organic layers were then dried with sodium sulfate and purified as stated. Me 2 C C 2 Me TIPS Table 2, Entry 1 Purified by flash chromatography (Si 2, 5% acetonitrile in benzene). Isolated as a white solid. 77% yield. R f = 0.53 (17% acetonitrile in benzene); 1 MR (300 Mz, CDCl 3 ) δ 7.54 (m, 2), 7.21 (td, J = 7.7, 1.0 z, 1), 7.01 (td, J = 7.6, 1.0 z, 1), 6.84 (d, J = 7.7 z, 1), 4.17 (s, 1), 3.79 (s, 3), 3.52 (s, 3), 3.51 (m, 1), 3.35 (m, 1), 3.25 (m, 2), 0.93 (s, 21); 13 C MR (75 Mz, CDCl 3 ) δ 179.3, 168.0, 167.1, 141.4, 129.4, 128.6, 125.4, 122.5, 109.5, 58.9, 57.1, 52.6, 52.5, 50.9, 38.5, 17.9, 11.9; IR (neat film, acl) 3251, 2941, 2863, 1747, 1721, 1687, 1471, 1321, 1197, 1114 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + 25 : , found ; [α] D 28.6 (c 0.43, C 2 Cl 2, 88% ee). Et 2 C C 2 Et TIPS Table 2, Entry 2 Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 73% yield. R f = 0.24 (33% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 7.80 (br s, 1), 7.61 (d, J = 7.5 z, 1), 7.20 (td, J = 8.0, 1.0 z, 1), 7.00 (td, J = 7.5, 1.0 z, 1), 6.83 (d, J = 8.0 z, 1), (m, 2), 4.14 (s, 1), (m, 2), 3.52 (ddd, J = 12.0, 8.0, 7.0 z, 1), 3.36 (ddd, J = 13.5, 8.5, 5.0 z, 1), (m, 2), 1.29 (t, J = 7.0 z, 3), 0.99 (t, J = 7.0 z, 3), 0.93 (s, 21); 13 C MR (126 Mz, CDCl 3 ) δ 179.5, 167.8, 166.9, 141.6, 129.7, 128.7, 125.9, 122.7, 109.5, 61.82, 61.81, 59.1, 57.6, 51.0, 38.9, 18.1, 14.2, 13.8, 12.1; IR (neat film, acl) 3218, 2942, 2866, 1731, 1716, 1621, 1472, 1197 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found ; [α] D (c 0.78, C 2 Cl 2, 84% ee). Me 2 C C 2 Me R' S14

16 Ma, an, Krishnan, Virgil and Stoltz Bn 2 C C 2 Bn TIPS Table 2, Entry 3 Purified by flash chromatography (Si 2, 7% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 78% yield. R f = 0.25 (33% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 7.80 (br s, 1), 7.52 (d, J = 7.5 z, 1), (comp. m, 8), 7.16 (td, J = 7.5, 1.0 z, 1), 7.07 (dd, J = 8.0, 1.5 z, 2), 6.94 (td, J = 7.5, 0.5 z, 1), 6.69 (d, J = 8.0 z, 1), 5.20 (ABq, J = 17.0 z, 2), 4.91 (ABq, J = 18.5 z, 2), 4.27 (s, 1), 3.50 (dt, J = 9.5, 6.0 z, 1), 3.50 (ddd, J = 10.0, 8.5, 5.0 z, 1), (m, 2), 0.92 (s, 21); 13 C MR (126 Mz, CDCl 3 ) δ 179.3, 167.5, 166.6, 141.5, 135.2, 135.1, 129.4, 128.8, 128.7, 128.6, , , 125.7, 122.7, 109.8, 67.7, 67.5, 59.1, 57.6, 51.1, 38.9, 18.1, 12.1; IR (neat film, acl) 3251, 2941, 2863, 1747, 1721, 1687, 1471, 1321, 1197, 1114 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + 25 : , found ; [α] D 17.7 (c 0.71, C 2 Cl 2, 88% ee). Me 2 C C 2 Me TBDPS Table 2, Entry 4 Purified by flash chromatography (Si 2, 5% acetonitrile in benzene). Isolated as a white solid. 78% yield. R f = 0.48 (17% acetonitrile in benzene); 1 MR (500 Mz, CDCl 3 ) δ 7.56 (br s, 1 ), 7.51(dd, J = 8.0, 1.5 z, 2), (comp. m, 3), (comp. m, 2), (comp. m, 4), 7.21 (td, J = 7.5, 1.5 z, 1), 6.98 (td, J = 7.5, 1.0 z, 1), 6.80 (d, J = 7.5 z, 1), 4.13 (s, 1), 3.73 (s, 3), 3.51 (s, 3), 3.46 (ddd, J = 14.0, 7.5, 6.5 z, 1), 3.34 (ddd, J = 12.0, 7.5, 4.5 z, 1), 2.38 (dt, J = 13.5, 8.0 z, 1), 2.25 (ddd, J = 13.5, 6.5, 4.5 z, 1), 0.94 (s, 9); 13 C MR (126 Mz, CDCl 3 ) δ 179.1, 168.1, 167.1, 141.5, 135.6, 135.5, 133.5, 133.4, 129.7, 129.6, 129.1, 128.6, , , 125.6, 122.6, 109.6, 59.8, 57.5, 52.7, 52.6, 51.0, 38.2, 26.8, 19.1; IR (neat film, acl) 3369, 3071, 2953, 2930, 2857, 1736, 1717, 1620, 1472, 1429, 1325, 1237, 1198, 1156, 1112, 1088, 1022, 823, 740 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + 25 : , found ; [α] D 17.3 (c 0.94, C 2 Cl 2, 88% ee). Me 2 C C 2 Me TIPS Table 2, Entry 5 Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a white solid. 47% yield. R f = 0.16 (22% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 7.80 (br s, 1), 7.53 (d, J = 7.5 z, 1), 7.20 (td, J = 7.5, 1.0 z, 1), 7.01 (td, J = 7.5, 1.0 z, 1), 6.84 (d, J = 7.5 z, 1), 4.15 (s, 1), 3.79 (s, 3), (comp. m with a singlet at δ 3.51, 5), (comp. m, 2), (comp. m, 2), (comp. m, 1), (comp. m, 22); 13 C MR (126 Mz, CDCl 3 ) δ 179.6, 168.2, 167.3, 141.5, 129.9, 128.5, 125.2, 122.8, 109.4, 63.0, 57.2, 52.9, 52.8, 52.7, 36.4, 33.0, 20.0, 18.1, 12.1; IR (neat film, acl) 3248, 2944, 2866, 1736, 1716, 1620, 1472, 1436, 1326, 1225, 1155, 1109, 1058, 995, 883, 752 cm 1 ; RMS (FAB+) m/z calc d for C Si [M+] + : , found ; [α] D (c 0.58, C 2 Cl 2, 86% ee). S15

17 Ma, an, Krishnan, Virgil and Stoltz Me 2 C C 2 Me Bz Table 2, Entry 6 Purified by flash chromatography (Si 2, 9% acetonitrile in benzene). Isolated as a white solid. 51% yield. R f = 0.13 (33% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.23 (br s, 1), 7.85 (dd, J = 8.1, 1.2 z, 2), 7.57 (d, J = 7.5 z, 1), 7.51 (tt, J = 7.5, 1.2 z, 1), 7.37 (t, J = 7.5 z, 2), 7.19 (td, J = 7.5, 1.2 z, 1), 7.01 (td, J = 7.8, 1.2 z, 1), 6.84 (d, J = 7.8 z, 1), 4.19 (s, 1), 4.08 (comp. m, 2), 3.78 (s, 3), 3.51 (s, 3), 2.53 (t, J = 6.6 z, 2); 13 C MR (75 Mz, CDCl 3 ) δ 179.2, 167.8, 166.9, 166.2, 141.6, 133.0, 129.9, 129.7, 130.1, 128.8, 128.3, 125.5, 122.9, 110.1, 60.7, 57.3, 52.8, 52.7, 51.2, 34.6; IR (neat film, acl) 3307, 2955, 1723, 1620, 1473, 1452, 1436, 1318, 1274, 1199, 1158, 1117, 1026, 756, 714 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found ; [α] 25 D 52.5 (c 1.40, C 2 Cl 2, 83% ee). Me 2 C C 2 Me C 3 Table 2, Entry 7 Purified by flash chromatography (Si 2, 9% ethyl acetate in hexanes 17% ethyl acetate in hexanes). Isolated as a pale yellow solid. 47% yield. R f = 0.22 (33% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.11 (br s, 1), 7.54 (d, J = 7.5 z, 1), 7.22 (td, J = 7.8, 2.0 z, 1), 7.02 (td, J = 7.5, 1.5 z, 1), 6.87 (d, J = 7.8 z, 1), 4.15 (s, 1), 3.79 (s, 3), 3.50 (s, 3), (comp. m, 2), (comp. m, 3), (comp. m with a triplet at δ 0.75, J = 7.5 z, 4); 13 C MR (75 Mz, CDCl 3 ) δ 179.9, 168.2, 167.3, 141.6, 130.1, 128.5, 125.2, 122.7, 109.5, 57.3, 52.8, 52.7, 52.6, 36.2, 25.5, 22.8, 13.9; IR (neat film, acl) 3249, 2956, 2930, 2862, 1736, 1716, 1620, 1486, 1472, 1436, 1327, 1292, 1230, 1198, 1157, 1057, 1022, 755 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + 25 : , found ; [α] D 10.6 (c 1.46, C 2 Cl 2, 84% ee). Me 2 C C 2 Me Phth Table 2, Entry 8 Purified by flash chromatography (Si 2, 17% acetone in hexanes). Isolated as a white solid. 63% yield. R f = 0.22 (33% acetone in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.07 (br s, 1), (comp. m, 2), (comp. m, 2), 7.55 (d, J = 7.5 z, 1), 7.07 (td, J= 7.5, 1.0 z, 1), 6.88 (td, J = 7.5, 1.0 z, 1), 6.84 (d, J = 7.5 z, 1), 4.18 (s, 1), 3.82 (s, 3), 3.56 (t, J = 7.5 z, 2), 3.50 (s, 3), 2.52 (dt, J = 13.5, 8.0 z, 1), 2.35 (pentet, J = 7.0 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 178.5, 167.9, 167.8, 166.9, 141.4, 133.9, 132.1, 128.9, 128.8, 125.4, 123.2, 122.9, 110.0, 57.0, 52.9, 52.7, 51.3, 33.55, 33.49; IR (neat film, acl) 3261, 3034, 2935, 1755, 1724, 1698, 1473, 1398, 1347, 1272, 1153, 1060, 719 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + 25 : , found ; [α] D 4.4 (c 0.56, Me, 94% ee). Me 2 C C 2 Me Phth S16

18 Ma, an, Krishnan, Virgil and Stoltz Table 2, Entry 9 Purified by flash chromatography (Si 2, 5% acetonitrile in benzene 25% acetonitrile in benzene). Isolated as a white solid. 42% yield. R f = 0.48 (17% acetonitrile in benzene); 1 MR (500 Mz, CDCl 3 ) δ 7.79 (br s, 1), (m, 2), 7.72 (d, J = 7.5 z, 1), (m, 2), 7.18 (td, J = 7.5, 1.5 z, 1), 7.00 (td, J = 8.0, 1.0 z, 1), 6.81 (d, J = 7.5 z, 1), 4.62 (d, J = 14.5 z, 1), 4.30 (s, 1 ), 4.15 (d, J = 14.5 z, 1), 3.90 (s, 3), 3.50 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 177.2, 168.1, 168.0, 167.3, 141.2, 134.2, 131.8, 129.3, 127.8, 126.5, 123.6, 122.7, 109.9, 54.7, 52.95, 52.87, 52.4, 41.3; IR (neat film, acl) 3340, 2954, 2924, 2853, 1776, 1732, 1718, 1618, 1472, 1434, 1394, 1354, 1316, 1295, 1225, 1197, 1158, 1001, 905 cm 1 ; RMS (FAB+) m/z calc d for C [M] + : , found ; [α] 25 D 3.3 (c 0.55, C 2 Cl 2, 81% ee). Me 2 C Me C 2 Me Phth Table 2, Entry 10, Malonate Adduct 8 Purified by flash chromatography (Si 2, 33% ethyl acetate in hexanes 50% ethyl acetate in hexanes; then 9% acetonitrile in benzene 17% acetonitrile in benzene). Isolated as a white solid. 42% yield. R f = 0.22 (17% acetonitrile in benzene); 1 MR (500 Mz, CDCl 3 ) δ (m, 2), (m, 2), 7.48 (br s, 1), 7.41 (d, J = 2.0 z, 1), (comp. m, 2), 4.62 (d, J = 14.5 z, 1), 4.30 (s, 1), 4.10 (d, J = 14.5 z, 1), 3.92 (s, 3), 3.77 (s, 3), 3.52 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 177.1, 168.1, 168.0, 167.2, 155.7, 134.6, 134.1, 131.8, 129.1, 123.6, 114.6, 113.2, 110.4, 55.9, 54.6, 53.0, 52.9, 52.8, 41.3; IR (neat film, acl) 3350, 3003, 2954, 2840, 1776, 1722, 1602, 1488, 1468, 1435, 1394, 1331, 1301, 1265, 1206, 1160, 1051, 1032, 1004, 909, 815, 720 cm 1 ; RMS (FAB+) m/z calc d for C [M+] + : , found ; [α] 25 D 2.3 (c 1.10, CCl 3, 95% ee). Me 2 C C 2 Me Ph Table 3, Entry 1; Malonate Adduct 12 Purified by flash chromatography (Si 2, 10% acetonitrile in toluene 15% acetonitrile in toluene). Isolated as a pale yellow solid. 76% yield. R f = 0.22 (33% ethyl acetate in hexanes); 1 MR (500 Mz, CDCl 3 ) δ 8.08 (bs, 1), 7.71 (d, J = 7.6 z, 1), (comp. m, 5), 7.06 (ddd, J = 7.6, 7.6, 0.9 z, 1), 6.84 (d, J= 7.8 z, 1), 4.85 (s, 1), 3.50 (s, 3), 3.32 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 178.7, 167.8, 167.3, 141.8, 137.3, 129.2, 128.7, 128.4, 128.0, 127.1, 122.8, 110.1, 58.5, 56.7, 52.7, 52.6; IR (neat film, acl) 3254, 2954, 1734, 1620, 1473, 1436, 1325, 1156, 1039, 912, 733 cm -1 ; RMS (FAB) m/z calc d for C [M+] + 25 : , found ; [α] D 66.6 (c 1.12, C 2 Cl 2, 76% ee). C 2 Me C 2 Me Table 3, Entry 2 Purified by flash chromatography (Si 2, 0% acetonitrile in toluene 20% acetonitrile in toluene). Isolated as a 74% yield. Isolated as a pale yellow oil. 84% yield. R f = 0.45 (20% acetonitrile in S17

19 Ma, an, Krishnan, Virgil and Stoltz toluene); 1 MR (500 Mz, CDCl 3 ) δ 7.97 (d, J = 7.6 z, 1), 7.66 (s, 1), 7.38 (app. d, J = 8.5 z, 2), 7.33 (dd, J = 8.8, 8.8 z, 1), 7.20 (app. d, J = 6.8 z, 2), 7.15 (dd, J = 7.8, 7.8 z, 1), 6.93 (d, J = 7.6 z), 4.85 (s, 1), 3.61 (s, 3), 3.43 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 178.0, 167.7, 167.2, 141.6, 136.5, 131.9, 129.6, 129.0, 128.4, 128.2, 123.2, 122.6, 110.2, 58.5, 56.3, 52.9, 52.8; IR (neat film, acl) 3307, 1736, 1619, 1472, 1435, 1323, 1158 cm -1 ; RMS (EI + ) m/z calc d for C [M] + : , found ; [α] D (c 1.52, C 2 Cl 2, 81% ee). C 2 Me C 2 Me Table 3, Entry 3 Purified by flash chromatography (Si 2, 0% acetonitrile in toluene 10% acetonitrile in toluene). Isolated as a yellow oil. 69% yield. R f = 0.25 (15% acetonitrile in toluene); 1 MR (500 Mz, CDCl 3 ) δ 8.24 (bs, 1), 7.95 (d, J = 7.1 z, 1), 7.29 (ddd, J = 7.8, 7.8, 1.2 z, 1), 7.12 (ddd, J= 7.6, 7.6, 1.0 z, 1), 6.91 (d, J = 7.6 z, 1), (comp. m, 3), 4.90 (s, 1), 3.60 (s, 3), 3.38 (s, 3), 2.21 (s, 6); 13 C MR (500 Mz, CDCl 3 ) δ 178.9, 167.9, 167.5, 141.8, 138.1, 137.3, 129.8, 129.1, 129.0, 128.3, 124.7, 122.8, 110.0, 58.4, 56.7, 52.6, 52.5, 21.6; IR (neat film, acl) 3248, 2956, 1737, 1718, 1618, 1473, 1324, 1199, 1155 cm -1 ; RMS (FAB) m/z calc d for C [M+] + : , 25 found ; [α] D (c 0.84, C 2 Cl 2, 84% ee). C 2 Me C 2 Me Table 3, Entry 4 Purified by flash chromatography (Si 2, 0% acetonitrile in toluene 20% acetonitrile in toluene). Isolated as a light yellow solid. 74% yield. R f = 0.65 (50% ethyl acetate in hexanes); 1 MR (300 Mz, CDCl 3 ) δ 8.06 (d, J = 7.8 z, 1), 8.01 (s, 1), (comp. m, 2), (comp. m, 1), 7.23 (app. s, 1), 7.58 (dd, J = 8.5, 2.0 z, 1), (comp. m, 2), 7.33 (ddd, J = 7.8, 7.8, 1.2 z, 1), 7.19 (ddd, J = 7.8, 7.8, 1.0 z, 1), 6.94 (d, J = 7.8 z, 1), 5.05 (s, 1), 3.52 (s. 3), 3.42 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ 178.6, 167.9, 167.5, 141.9, 134.8, 133.3, 133.0, 129.4, 128.8, 128.6, 128.5, 127.7, 126.8, 126.6, 126.4, 124.6, 123.1, 110.2, 58.5, 56.9, 52.8, 52.7; IR (neat film, acl) 3256, 3059, 2953, 1732, 1619, 1597, 1472, 1435, 1323, 1294, 1198, 1157, 1037, 912, 732, 648 cm -1 ; RMS (FAB + ) m/z calc d for C [M+] + 25 : , found ; [α] D (c 1.20, C 2 Cl 2, 74% ee). Me 2 C Me C 2 Me Ph Table 3, Entry 5 Purified by flash chromatography (Si 2, 0% acetonitrile in toluene 10% acetonitrile in toluene). Isolated as an orange solid. 82% yield. R f = 0.23 (15% acetonitrile in toluene); 1 MR (500 Mz, CDCl 3 ) δ 7.90 (s, 1), 7.6 (app. s, 1), (app. d, J = 6.6 z, 2), (comp. m, 5), 4.92 (s, 1), 3.83 (s, 3), 3.57 (s, 3), 3.45 (s, 3); 13 C MR (126 Mz, CDCl 3 ) δ , , S18

20 Ma, an, Krishnan, Virgil and Stoltz , , , , , , , , , , , 58.39, 57.09, 55.97, 52.72, 52.59; IR (neat film, acl) 3271, 2953, 1733, 1600, 1487, 1437, 1301, 1266, 1207, 1156, 1058, 1033 cm -1 ; RMS (FAB + ) m/z calc d for C [M] + : , found ; [α] D (c 1.09, C 2 Cl 2, 84% ee). Table 1. Chiral PLC Assay conditions Malonate Adduct Conditions Time ee Me 2 C Et 2 C Bn 2 C Me 2 C Me 2 C Me 2 C Me 2 C Me 2 C Me 2 C C 2 Me TIPS C 2 Et TIPS C 2 Bn TIPS C 2 Me TBDPS C 2 Me C 2 Me C 2 Me TIPS Bz C 2 Me Phth C 2 Me 5% IPA/exanes 28.9 min (major) 35.3 min (minor) 4% Et/exanes 16.4 min (major) 19.0 min (minor) 4% Et/exanes 24.4 min (major) 28.1 min (minor) 10% IPA/exanes 16.8 min (major) 24.4 min (minor) 5% IPA/exanes 17.7 min (major) 41.9 min (minor) 20% IPA/exanes 19.9 min (major) 33.1 min (minor) C 3 10% IPA/exanes 19.5 min (major) 24.4 min (minor) 80% Et/exanes 17.2 min (major) 22.8 min (minor) Phth 80% Et/exanes 18.6 min (major) 26.0 min (minor) C 2 Me Me 2 C Me Phth 80% Et/exanes 21.7 min (major) 35.4 min (minor) 88% 84% 88% 88% 86% 83% 84% 94% 81% 91% S19

21 Ma, an, Krishnan, Virgil and Stoltz Me 2 C C 2 Me Ph 20% IPA/exanes 7.6 min (major) 19.5 min (minor) 76% C 2 Me C 2 Me 15% IPA/exanes 26.1 min (minor) 37.5 min (major) 81% C 2 Me C 2 Me 15% IPA/exanes 14.1 min (minor) 34.5 min (major) 84% Me 2 C Me C 2 Me 20 % IPA/exanes 29.2 min (minor) 41.2 min (major) C 2 Me C 2 Me Ph 15% IPA/exanes 21.4 min (minor) 40.5 min (major) 74% 84% Synthesis of Pyrrolidinone-spirooxindole Me 2 C Me Phth Phthalimidoester 9 To a round bottom flask equipped with a stirbar, malonate adduct 8 (99% ee, mg, mmol, 1 equiv) and sodium chloride (29.7 mg, mmol, 2 equiv) were dissolved in water (23 µl, 1.27 mmol, 5 equiv) and DMS (5 ml). 6 The reaction flask was then heated to 150 C for 5 hours. Upon cooling to ambient temperature, reaction mixture was then diluted with water (5 ml) and brine (5 ml) and then extracted with ethyl acetate (3 x 20 ml). rganic layers were collected and dried with magnesium sulfate. Purification by column chromatography (Si 2, 9% acetonitrile in benzene 17% acetonitrile in benzene) afforded phthalimidoester 9 as a pale yellow solid (57.5 mg, 58% yield). R f = 0.09 (17% acetonitrile in benzene); 1 MR (500 Mz, CDCl 3 ) δ 7.82 (dd, J = 5.0, 3.0 z, 2), 7.71 (dd, J = 5.0, 3.0 z, 2), 7.54 (br s, 1), 6.82 (d, J = 2.5 z, 1), 6.79 (d, J = 9.0 z, 1), 6.74 (dd, J = 9.0, 2.5 z, 1), 4.00 (ABq, J = 14.0 z, 2), 3.74 (s, 3), 3.51 (s, 3), 3.15 (ABq, J = 17.0 z, 2); 13 C MR (126 Mz, CDCl 3 ) δ 178.4, 170.2, 168.2, 155.7, 134.5, 134.3, 131.9, 130.8, 123.7, 113.7, 110.9, 110.5, 55.9, 51.9, 50.4, 43.1, 38.6; IR (neat film, acl) 3306, 2997, 2952, 2838, 1776, 1719, 1604, 1490, 1468, 1437, 1395, 1363, 1302, 1207, 1140, 1027, 928, 908, 812 cm -1 ; RMS (FAB+) m/z calc d for C [M+] + : , found ; [α] D (c 1.00, C 2 Cl 2 ). S20

22 Ma, an, Krishnan, Virgil and Stoltz Spirocyclic xindole 10 To phthalimidoester 9 (12.5 mg, mmol, 1 equiv) in Et (3 ml), (16 µl, 0.317, 10 equiv) was added at 23 C. The reaction flask was then heated to 95 C for 13 hours. Upon cooling to ambient temperature, reaction mixture was filtered though a short plug of celite and concentrated. Purification by preparative TLC (Si 2, 9% Me in methylene chloride) afforded spirocyclic oxindole 10 as a white solid (6.5 mg, 88% yield). R f = 0.36 (9% Me in methylene chloride); 1 MR (500 Mz, CDCl 3 ) δ 7.82 (br s, 1), 6.95 (d, J = 2.0 z, 1), 6.83 (d, J = 7.5 z, 1), 6.80 (dd, J = 7.5, 2.0 z, 1), 5.98 (br s, 1), 3.87 (d, J = 9.5 z, 1), 3.79 (s, 3), 3.59 (dd, J = 9.5, 0.5 z, 1), 2.98 (d, J = 16.5 z, 1), 2.50 (d, J = 17.0 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 179.0, 175.3, 156.7, 134.9, 132.9, 113.8, 110.7, 109.6, 56.1, 51.0, 50.4, 40.4; IR (neat film, acl) 3231, 2956, 2925, 2847, 1699, 1494, 1439, 1306, 1207, 1179, 1033 cm -1 ; RMS (FAB+) m/z calc d for C [M+] + : , 23.0 found ; [α] D (c 0.65, Me). Bis(p--benzyl)lactam 11 To a (3.4 mg, 60 %, mmol, 3 equiv) in TF (1 ml) at 0 C, a solution of spirocylic oxindole 10 (6.5 mg, mmol, 1 equiv) in TF (2.0 ml) was added dropwise via syringe at 23 C. The flask was rinsed with TF (1 ml) and the solutions were also added dropwise via syringe at 0 C. The reaction was allowed to stir for 30 minutes at 23 C before addition of 4-bromobenzyl bromide (21 mg, mmol, 3 equiv). After stirring for 14 hours at 23 C, the reaction was quenched with brine (3 ml) and extracted with C 2 Cl 2 (3 x 5 ml). rganic layers were collected and dried with magnesium sulfate. Purification by column chromatography (Si 2, 25% ethyl acetate in C 2 Cl 2 ) afforded bis(p-benzyl)lactam 11 as a white solid (10.1 mg, 67% yield). M.p C from C 2 Cl 2 /hexanes; R f = 0.66 (50% ethyl acetate in C 2 Cl 2 ); 1 MR (500 Mz, CDCl 3 ) δ 7.48 (dt, J = 8.5, 2.5 z, 2), 7.43 (dt, J = 9.0, 2.5 z, 2), 7.22 (dt, J = 8.5, 2.5 z, 2), 7.11 (dt, J = 8.5, 2.5 z, 2), (comp. m, 2), 6.60 (d, J = 9.5 z, 1), 4.80 (ABq, J = 16.0 z, 2), 4.66 (d, J = 14.5 z, 1), 4.41 (d, J = 15.0 z, 1), 3.74 (d, J = 9.5 z, 1), 3.69 (s, 3 ), 3.31 (d, J = 9.5 z, 1), 3.12 (d, J = 17.0 z, 1), 2.63 (d, J = 17.0 z, 1); 13 C MR (126 Mz, CDCl 3 ) δ 177.4, 171.7, 156.9, 135.0, 134.9, 134.6, 134.4, 132.2, 130.2, 129.1, 122.1, 122.0, 113.5, 110.0, 109.4, 105.1, 55.9, 55.3, 47.1, 46.5, 43.7, 41.7; IR (neat film, acl) 2930, 1700, 1601, 1488, 1435, 1406, 1366, 1294, 1200, 1177, 1071, 1034, 1012, 798 cm -1 ; RMS (FAB+) m/z calc d for C [M+] + : , found ; [α] D (c 0.39, C 2 Cl 2 ). S21

23 Ma, an, Krishnan, Virgil and Stoltz Crystallographic data have been deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number Table 1. Crystal data and structure refinement for XQ02 (CCDC ). Empirical formula C Formula weight Crystallization Solvent Crystal abit Dichloromethane/hexanes Blade Crystal size 0.31 x 0.15 x 0.04 mm 3 Crystal color Type of diffractometer Wavelength Data Collection Temperature Colorless Data Collection uker KAPPA APEX II Å MoKα 100(2) K θ range for 9806 reflections used in lattice determination 2.31 to Unit cell dimensions Volume (2) Å 3 Z 4 Crystal system Space group P2 1 a = (10) Å b = (3) Å β= (3) c = (14) Å Monoclinic Density (calculated) Mg/m 3 F(000) 1144 Data collection program uker APEX2 v2.1-0 θ range for data collection 1.59 to S22