Supporting Information Enantioselective Cyclopropanation of Indoles Construction of all-carbon Quaternary Stereocentres Gülsüm Özüduru, Thea Schubach and Mike M. K. Boysen* Institute of Organic Chemistry, Gottfried-Wilhelm-Leibniz University of Hannover, Schneiderberg 1B, D-3167 Hannover, Germany email: mike.boysen@oci.uni-hannover.de General Methods Dry solvents were obtained by distillation over appropriate drying reagents under nitrogen atmosphere (CH 2 Cl 2 was distilled over calcium hydride), were purchased in dried form from commercial sources (pyridine and triethylamine from ACROS) or were taken from a solvent purification system (M. Braun Group, toluene). All reactions involving reagents sensitive to air and moisture were carried out under a nitrogen atmosphere (glove box and/or Schlenk techniques). Reactions were monitored by TLC on 6 F254 aluminum plates (Merck) with detection by UV light and/or charring with 1% sulfuric acid in ethanol or a mixture of cerium(iv) sulfate and molybdophosphoric acid in 8% sulfuric acid. Flash chromatography was performed on Merck silica (grain size 4-63 µm). NMR spectra were recorded on an AVS 4 instrument (Bruker) at 4 MHz ( 1 H) and 1 MHz ( 13 C) respectively. Deuterated chloroform and DMSO were used as solvent and spectra were calibrated against the residual solvent peak (chloroform: 7.24 ppm for 1 H and 77. ppm for 13 C, DMSO: 2.5 ppm for 1 H and 39.7 ppm for 13 C). If not stated otherwise, NMR experiments were performed at room temperature. Chemical shifts δ are given in ppm, coupling constants J are given in Hz. Electrospray mass (ESI) spectra were recorded on a Micromass LCT device (Waters), injection into the HPLC instrument (Waters) was performed in loop modus. Determination of enantiomeric excesses by HPLC analysis was performed on a Chiralpak-ADH column purchased from DAICEL Co. Ltd. Determination of enantiomeric excesses by GC analysis was performed on a HP 589-II device (Hewlett-Packard) with a flame ionisation detector and hydrogen as carrier gas in constant flow modus. A Hydrodex-β PM capillary column (5 m, S1
.25 mm, 72337, Macherey-Nagel) was used for separation of enantiomers. Determination of enantiomeric excesses by 1 H NMR analysis was performed with Rh 2 [R-(+)-MTPA] 4 as a chiral complexing reagent (dirhodium method). 1 Optical rotations were recorded on a Perkin- Elmer 451 instrument under following standard conditions: Room temperature, wavelength 589.3 nm (sodium D line), cell length 1 dm, solvent and sample concentration (in 1 mg/ml) are given with the individual experiment. For the assignments of signals in the 1 H-and 13 C spectra the positions in the indole substrates, cyclopropane products and compounds derived thereof have been numbered as shown below: N-Acyl 3-methylindoles (Acyl = Ac, Boc) Ethyl-3-methyl-cycloporpa(N-acyl-2,3-dihydroindole)-2a-carboxylates (Acyl = Ac, Boc) Ethyl (3-methyl-3H-indole-3-yl) acetate 3,3a,8,8a-Tetrahydro-3a-methylfuro[2,3-b]-indol-2-one (X, Y = O, R = H) 3,3a,8,8a-Tetrahydro-3a,8-dimethylfuro[2,3-b]-indol-2-one (X, Y = O, R = Me) 3,3a,8,8a-Tetrahydro-1,3a,8-trimethylpyrrolo[2,3-b]-indol-2-one (X = NMe, Y = O, R = Me) Desoxyeseroline (X = NMe, Y = H 2, Z = Me) S2
General procedure for N-acetyl protection of indoles The respective indole (7.62 mmol) and tetrabutylammonium hydrogensulfate (.76 mmol) were dissolved in CH 2 Cl 2 (15 ml). Sodium hydroxide (19.5 mmol) was added and acetylchloride (11.43 mmol) dissolved in CH 2 Cl 2 (5 ml) was added dropwise. After a reaction time of 2 h the mixture was filtered and the residue was washed with CH 2 Cl 2. The solvent was evaporated under reduced pressure. Flash chromatography (PE/EE 2:1) afforded the N-acetylated indoles 4a or 7a. N-Acetyl indole (4a) The title compound 4a was obtained from indole (1.17 g, 1. mmol) as yellow solid (1.6 g, 6.68 mmol) in 67% yield. 1 H-NMR (4 MHz, CDCl 3 ): δ = 8.43 (d, J = 8.1 Hz, 1 H, H-7*), 7.55 (ddd, J = 7.7 Hz, J = 1.2 Hz, J =.8 Hz 1 H, H-4*), 7.4 (d, 3 J 2,3 = 3.7 Hz, 1 H, H-2), 7.34 (ddd, J = 8.4 Hz, 7.4 Hz, J =1.2 Hz, 1 H, H-6*), 7.24-7.28 (m, 1 H, H-5*), 6.63 (dd, 3 J 2,3 = 3.8 Hz, 4 J 3,4 =.7 Hz, 1 H, H-3), 2.63 (s, 3 H, COCH 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ) δ = 168.6 (C, COCH 3 ), 135.5, 13.4 (C, C-3a, C-7a), 125.2 (CH, C-2), 125.1, 123.6, 12.8, 116.5 (CH, C-4, C-5, C-6, C-7), 19.2 (CH, C-3), 24. (CH 3, COCH 3 ) ppm. HRMS (ESI+): calcd for C 1 H 1 N 1 O 1 [M+H] + 16.762; found: 16.755. N-Acetyl 3-methyl indole (7a) The title compound 7a was obtained from 3-methyl indole (5 mg, 3.81 mmol) as a yellow solid (616 mg, 3.56 mmol) in 93% yield. 1 H-NMR (4 MHz, CDCl 3 ): δ = 8.4 (d, J = 8. Hz, 1H, H-7*), 7.46-7.51 (m, 1H, H-4*), 7.34 (td, J = 8.2 Hz, J = 7.7 Hz, J = 1.4 Hz, 1H, H-6*), 7.28 (td, J = 7.4 Hz, J = 1.1 Hz, 1H, H-5*), 7.16 (bs, 1H, H-2), 2.58 (s, 3H,COCH 3 ), 2.27 (d, 4 J 2, CH3 = 1.3 Hz, 3H, CH 3 ) ppm. * Signals interchangeable. S3
13 C-NMR (1 MHz, CDCl 3 ): δ = 168.3 (C, COCH 3 ), 135.8, 131.4 (C, C-3a, C-7a), 125.1, 123.3, 122.2, 118.8, 118.4, 116.5 (CH, C-2, C-3, C-4, C-5, C-6, C-7), 24. (CH 3, COCH 3 ), 9.7 (CH 3, CH 3 ) ppm. HRMS (ESI+): calcd for C 11 H 12 NO [M+H] + 174.919; found: 174.913. General procedure for N-Boc-protection of indoles: 2 The respective indole substrate (7.62 mmol), Et 3 N (22.8 mmol) and DMAP (1.53 mmol) were dissolved in 15 ml CH 2 Cl 2 and subsequently (Boc) 2 O (8.46 mmol) dissolved in CH 2 Cl 2 (5 ml) was added dropwise. After 2 h water was added, the phases were separated the aqueous phase was extracted with CH 2 Cl 2 (3 x 5 ml). The combined organic phases were dried over Na 2 SO 4 and concentrated. Flash chromatography (PE/EE 1:1) afforded the N-Boc protected indoles 4b or 7b. N-(tert.-Butoxycarbonyl)-indole (4b) The title compound 4b was obtained from indole (2.5 g, 21.35 mmol) as colourless oil (4.56 g, 2.98 mmol) in 98% yield. 1 H-NMR (4 MHz, CDCl 3 ): δ = 8.1 (d, J = 8.1 Hz, 1 H, H-7*), 7.61 (d, 3 J 2,3 = 3.7 Hz, 1 H, H-2), 7.58 (ddd, J = 7.7 Hz, J = 1.2 Hz, 4 J 3,4 =.8 Hz, 1 H, H-4*), 7.33 (ddd, J = 8.3 Hz, J = 7.3 Hz, J = 1.2 Hz, 1 H, H-6*), 7.2-7.29 (m, 1H, H-5*), 6.58 (dd, 3 J 2,3 = 3.7 Hz, 4 J 3,4 =.7 Hz, 1 H, H-3), 1.69 (s, 9 H, CO 2 C(CH 3 ) 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ) δ = 149.8 (C, CO 2 C(CH 3 ) 3 ), 135.1, 13.5 (C, C-3a, C-7a), 125.9 (CH, C-2), 124.2, 122.6, 12.9, 115.1 (CH, C-4, C-5, C-6, C-7), 17.2 (CH, C-3), 83.6 (C, CO 2 C(CH 3 ) 3 ), 28.2 (CH 3, CO 2 (CH 3 ) 3 ) ppm. N-(tert-Butoxycarbonyl)-3-methylindole (7b) Me N Boc The title compound 7b was obtained from 3-methyl indole (1. g, 7.62 mmol) as colourless oil (1.76 g, 7.61 mmol) in quantitative yield. S4
1 H-NMR (4 MHz, CDCl 3 ): δ = 8.1 (d, J = 6.6 Hz, 1 H, H-7*), 7.48 (d, J = 7.6 Hz, 1 H, H- 4*), 7.34 (s, 1 H, H-2), 7.27-7.32 (m, 1H, H-6*), 7.2-7.25 (m, 1 H, H-5*), 2.25 (s, 3 H, CH 3 ), 1.65 (s, 9 H, CO 2 C(CH 3 ) 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ) δ = 149.8 (C, CO 2 C(CH 3 ) 3 ), 135.4, 131.4 (C, C-3a, C-7a), 124.2, 122.8, 122.3, 118.9, 116.3, 115.1 (CH, C-2, C-3, C-4, C-5, C-6, C-7), 83.2 (C, CO 2 C(CH 3 ) 3 ), 28.2 (CH 3, CO 2 (CH 3 ) 3 ), 9.6 (CH 3, CH 3 ) ppm. HRMS (ESI+): calcd for C 14 H 17 N 1 O 2 Na[M+Na] + 254.1157; found: 254.1162. S5
General procedure for copper(i)-catalysed asymmetric cyclopropanation of N-acyl indoles with ethyl diazoacetate: In a glove box, CuOTf..5 C 6 H 6 (3 mol%) and the respective Box ligand (3.3 mol%) were placed into a flame-dried flask. Under a nitrogen atmosphere, dry CH 2 Cl 2 (2 ml) was added, and the resulting mixture was stirred for 1 h at room temperature. To this preformed catalyst solution the respective indole component (R 2 = Ac or R 2 = Boc) (1 eq) was added and the mixture brought to the desired reaction temperature. Ethyl diazoacetate (2.5 eq) was dissolved in dry CH 2 Cl 2 (3 ml) and slowly added using a syringe pump (flow rate:.18 mmol/h). After stirring for an additional 16 h at the respective reaction temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent for 6a with R 2 = Ac: PE/EE 2:1; eluent for 6b with R 2 =Boc: PE/EE 1:1). Cyclopropanation of N-acteyl indole (4a) and N-Boc indole (4b): Table 1: Summary of all experiments with indole substrates 4a and 4b exo/endo c ee (exo) entry ligand temp indoles 4 products 6 3-O-R 1 [ C] R 2 yield [%] a, [%] 1 3g formyl rt 4a Ac 6a 75 84:16 34 d 2 3a Ac rt 4a Ac 6a 71 82:18 34 d 3 3g formyl rt 4b Boc 6b (67) b nd 45 e 4 3a Ac rt 4b Boc 6b (7) b nd 55 e 5 3b Bz rt 4b Boc 6b (54) b nd 45 e 6 3c Piv rt 4b Boc 6b (7) b nd 38 e 7 2 - rt 4b Boc 6b (68) b nd rac. e 8 3a Ac 1 4a Ac 6a 75 87:13 53 d 9 3a Ac 4a Ac 6a 76 92:8 51 d 1 3a Ac -5 4a Ac 6a 56 > 99:1 61 d 11 3a Ac -1 4a Ac 6a 9 > 99:1 45 d 12 3a Ac 1 4b Boc 6b (76) b nd 69 e 13 3a Ac Boc (57) b nd 72 e 14 3a Ac -1 Boc (62) b nd 55 e Ligand (3.3 mol %), CuOTf..5 C 6 H 6 (3 mol %), 4 (1 equiv), 5 (2.5 equiv). a Combined yield of 6 after chromatography. b Yield for of exo-6b; product contains.6-.4 equiv of diethyl fumarate; yield calculated from 1 H-NMR of ratio exo-6b:fumarate. c Determined after separation of the diastereomers. d Determined by GC. e Determined by HPLC. S6
exo- and endo-ethyl-cyclopropa(n-acetyl-2,3-dihydroindole)-2a-carboxylate (exo-6a and endo-6a) exo-6a: Starting material 4a (92 mg,.58 mmol); product exo-6a (79 mg,.32 mmol, 56%). Yellow solid [α] 2 D : + 9.8 (c = 1., CHCl 3 ) for 61% ee (Table 1, entry 1). 1 H-NMR (4 MHz, CDCl 3, 35 K): δ = 8.14 (d, J = 8.2 Hz, 1 H, H-7*), 7.37 (d, J = 7.5 Hz, 1 H, H-4*), 7.22 (dt, J = 8.2 Hz, J = 2. Hz, 1 H, H-6*), 7.4 (td, J = 7.5 Hz, J = 1. Hz 1 H, H-5*), 4.38 (dd, 3 J 2,3 = 6.9 Hz, 3 J 2,2a = 1.5 Hz, 1 H, H-2), 4.14-4.23 (m, 2 H, CO 2 CH 2 CH 3 ), 3.28 (dd, 3 J 2,3 = 6.9 Hz, 3 J 2a,3 = 3.1 Hz, 1 H, H-3), 2.39 (s, 3 H, CH 3 CO), 1.39 (dd, 3 J 2a,3 = 2.8 Hz, 3 J 2,2a = 1.8 Hz, 1 H, H-2a), 1.28 (t, 3 J CH2, CH3 = 7.1 Hz, 3 H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. The 1 H NMR data are in excellent agreement with those reported by Wenkert et al. for the same compound. 3 13 C NMR (1 MHz, CDCl 3 ): δ = 171.7 (C, CO 2 CH 2 CH 3 ), 169. (C, COCH 3 ), 142., 13.3 (C, C-3a, C-7a), 128.2, 124.4, 123.8, 117.5 (CH, C-4, C-5, C-6, C-7), 61.3 (CH 2, CO 2 CH 2 CH 3 ), 46.3 (CH, C-2), 29.6 (CH, C-3), 25.2 (CH 3, CH 3 CO), 24.4 (CH, C-2a), 14.2 (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 14 H 16 N 1 O 3 [M + H] + 246.113; found: 246.1131. Enantiomeric excesses for exo-6a were determined by GC. Starting temperature: 16 C, heating rate:.5 C/min; retention times: Racemic mixture: t R = 32.7 min, t R = 35.15 min Product from enantioselective experiments using ligands 2 and 3a-c,g: t R = 32.66 min (minor), t R = 34.95 min (major). endo-6a: Yellow solid. S7
1 H-NMR (4 MHz, CDCl 3 ): δ = 8.11 (d, J = 8.2 Hz, 1 H, H-7*), 7.29-7.33 (m, 1 H, H-4*), 7.19-7.25 (m, 1 H, H-6*), 7.1 (td, J = 7.5 Hz, J = 1. Hz, 1 H, H-5*), 4.28 (dd, 3 J 2,3 = 6.6 Hz, J 2,2a = 5.8 Hz, 1 H, H-2), 3.84 (q, 3 J CH2, CH3 = 7.1 Hz, 2 H, CO 2 CH 2 CH 3 ), 3.26 (dd, 3 J 2a,3 = 9.2 Hz, 3 J 2,3 = 6.7 Hz, 1 H, H-3), 2.36 (s, 3 H, CH 3 CO), 2.2 (dd, 3 J 2a,3 = 9.2 Hz, 3 J 2,2a = 5.7 Hz, 1 H, H-2a),.9 (t, 3 J CH2, CH3 = 7.1 Hz, 3 H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. The 1 H NMR data are in excellent agreement with those reported by Wenkert et al. for the same compound. 3 13 C-NMR (1 MHz, CDCl 3,): δ = 171.5 (C, CO 2 CH 2 CH 3 ), 166.7 (C, COCH 3 ), 133.6, 127.2 (C, C-3a, C-7a*), 128.2, 124.9, 123.4, 116.6 (CH, C-4, C-5, C-6, C-7), 6.6 (CH 2, CO 2 CH 2 CH 3 ), 44.3 (CH, C-2), 27.7 (CH, C-3), 24.4 (CH 3, CH 3 CO), 2.1 (CH, C-2a), 13.8 (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 14 H 15 N 1 O 3 Na [M + Na] + 268.95; found: 268.953. exo- and endo-ethyl-cyclopropa(n-tert-butoxycarbonyl-2,3-dihydroindole)-2acarboxylate (exo-6b and endo-6b) The diastereomeric products exo-6b and endo-6b were isolated as a mixture with diethyl fumarate and diethyl maleate as by-products. While the diastereomers could be separated by column chromatography, the removal of diethyl fumarate from exo-6b and the removal of diethyl maleate from endo-6b was not possible. The yields given in Table 1 refer to the diastereomer exo-6b and were calculated from the 1 H-NMR ratio of exo-6b to diethyl fumarate. Due restricted rotation around the N-acyl bond, 4 coalescence phenomena were observed for some proton signals of exo- and endo-6b in 1 H spectra recorded at room temperature. Therefore the 1 H spectra of these compounds were recorded in DMSO at elevated temperature (35 K), which led to well-resolved signals for all protons. exo-6b: Starting material 4b (1 mg,.46 mmol); product exo-6b (91 mg,.3 mmol, 65%). Colourless oil [α] D 2 : +116.2 (c = 1., CHCl 3 ) for 72% ee; (ratio exo-6b:fumarate 1:.27), (Table 1, entry 13). S8
1 H-NMR (4 MHz, DMSO-d6, 35 K): δ = 7.61 (d, J = 8. Hz, 1 H, H-7*), 7.47 (d, J = 7.2 Hz, 1 H, H-4*), 7.18-7.26 (m, 1 H, H-6*), 7.1 (t, J = 7.4 Hz, 1 H, H-5*), 4.48 (dd, 3 J 2,3 = 6.8 Hz, 3 J 2,2a = 1.7 Hz, 1 H, H-2), 4.15 (q, 3 J CH2, CH3 =7. Hz, 2 H, CO 2 CH 2 CH 3 ), 3.28 (dd, 3 J 2,3 = 6.8 Hz, 3 J 2a,3 = 3. Hz, 1 H, H-3), 1.56 (s, 9 H, (CH 3 ) 3 CO), 1.23 (t, 3 J CH2, CH3 =7.1 Hz, 3 H, CO 2 CH 2 CH 3 ), 1.18 (dd, 3 J 2a,3 = 3. Hz, J 2,2a = 1.7 Hz, 1 H, H-2a) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ): δ = 172.2 (C, CO 2 CH 2 CH 3 ), 152. (C, CO 2 C(CH 3 ) 3 ), 133.6, 13.4 (C, C-3a, C-7a), 127.7, 124.5, 122.4, 115.5 (CH, C-4, C-5, C-6, C-7), 82.4 (C, CO 2 C(CH 3 ) 3 ), 6.9 (CH 2, CO 2 CH 2 CH 3 ), 45.6 (CH, C-2), 28.3 (CH 3, (CH 3 ) 3 CO), 28.2 (CH, C- 3), 24.2 (CH, C-2a), 14.2 (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 17 H 21 N 1 O 4 Na [M + Na] + 326.1368; found: 326.137. Signals of by-product diethyl fumarate 1 H-NMR (4 MHz, CDCl 3 ) δ = 6.82 (s, 2 H, HC=CH), 4.23 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.29 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 1 H-NMR (4 MHz, DMSO-d6) δ = 6.75 (s, 2 H, HC=CH), 4.2 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.24 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, CDCl 3 ): δ = 165. (C, CO 2 Et), 133.6 (CH, HC=CH), 61.3 (CH 2, OCH 2 CH 3 ), 14.1 (CH 3, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, DMSO-d6): δ = 164.8 (C, CO 2 Et), 133.4 (CH, HC=CH), 61.3 (CH 2, OCH 2 CH 3 ), 14.1 (CH 3, OCH 2 CH 3 ) ppm. Enantiomeric excesses of exo-6b were determined by HPLC. on a Chiralpak-ADH column (hexane/2-propanol, 99.:1.); flow rate.4 ml/min; detector wavelength 254 nm; retention times: Racemic mixture: t R = 26.67 min, t R = 3.83 min Products from enantioselective experiments using ligands 2 and 3a-c,g: t R = 26.8 min (minor), t R = 3.92 min (major). Retention time of diethyl fumarate: t R = 2.55 min. endo-6b: S9
Starting material 4b (1 mg,.46 mmol); product endo-6b (11 mg,.37 mmol, 8%). Colourless oil [α] 2 D : +82.3 (c = 1., CHCl 3 ) (contains maleate) (Table 1, entry 13). 1 H-NMR (4 MHz, DMSO-d6, 38 K): δ = 7.56 (d, J = 8.1 Hz, 1 H, H-7*), 7.29-7.35 (m, 1 H, H-4*), 7.13-7.21 (m, 1 H, H-6*), 6.93 (td, J = 7.4 Hz, J = 1. Hz, 1 H, H-5*), 4.44 (dd t, 3 J 2,2a J 2,3 = 6.1 Hz, H-2), 3.71-3.85 (m, 2 H, CO 2 CH 2 CH 3 ), 3.27 (dd, 3 J 2a,3 = 9. Hz, 3 J 2,3 = 6.3 Hz, 1 H, H-3), 2.4 (dd, 3 J 2a,3 = 9. Hz, 3 J 2,2a = 5.9 Hz, 1 H, H-2a), 1.55 (s, 9 H, (CH 3 ) 3 CO),.91 (t, 3 J CH2, CH3 = 7.1 Hz, 3 H, CO 2 CH 2 CH 3 ) ppm. * signals interchangeable. 13 C-NMR (1 MHz, DMSO-d6): δ = 172.3 (CO 2 CH 2 CH 3 ), 152.1 (CO 2 C(CH 3 ) 3 ), 144.4 125.5 (C, C-3a, C-7a), 127.4, 125.3, 122.1, 114.1 (CH, C-4, C-5, C-6, C-7), 8.7 (C, CO 2 C(CH 3 ) 3 ), 59.6 (CH 2, CO 2 CH 2 CH 3 ), 39.7 (CH, C-2), 28.1 (CH 3, (CH 3 ) 3 CO), 27.2 (CH, C- 3), 17.6 (CH, C-2a), 14. (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 17 H 21 N 1 O 4 Na [M + Na] + 326.1368; found: 326.1376. Signals of by-product diethyl maleate 1 H-NMR (4 MHz, CDCl 3 ) δ = 6.21 (s, 2 H, HC=CH), 4.23 (q, 3 J = 7.2 Hz, 2 H, OCH 2 CH 3 ), 1.29 (t, 3 J = 7.2 Hz, 3 H, OCH 2 CH 3 ) ppm. 1 H-NMR (4 MHz, DMSO-d6) δ = 6.45 (s, 2 H, HC=CH), 4.14 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.21 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, CDCl 3 ): δ = 165.3 (C, CO 2 Et), 129.8 (CH, HC=CH), 61.2 (CH 2, OCH 2 CH 3 ), 14. (CH 3, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, DMSO-d6): δ = 165.2 (C, CO 2 Et), 13.3 (CH, HC=CH), 6.8 (CH 2, OCH 2 CH 3 ), 14. (CH 3, OCH 2 CH 3 ) ppm. Cyclopropanation of N-acetyl-3-methylindole (7a): Table 2: Summary of all experiments with indole 7a entry temp [ C] 8a yield [%] a exo/endo c ee (exo) [%] d 1 rt 66 65:35 48 2 1 52 67:33 56 3 4 b 71:29 52 4-1 29 b > 99:1 7 5-2 17 b > 99:1 71 Ligand (3.3 mo l%), CuOTf..5 C 6 H 6 (3.3 mol %), 7a (1 equiv), 5 (2.5 equiv). a Combined yield of 8a after chromatography. b Incomplete conversion, re-isolation 7a. c Determined after separation of diastereomers. d Determined by GC. S1
exo- and endo-ethyl-3-methyl-cyclopropa(n-acetyl-2,3-dihydroindole)-2a-carboxylate (8a) exo-8a: Starting material 7a (5 mg,.28 mmol); product exo-8a (21.3 mg,.8 mmol, 29%). Yellow solid [α] 2 D : + 77.8 (c = 1., CHCl 3 ) for 7% ee (Table 2, entry 4). 1 H-NMR (4 MHz, CDCl 3 ) δ = 8.13 (d, J = 8. Hz, 1H, H-7*), 7.32 (d, J = 7.4 Hz, 1H, H- 4*), 7.19-7.26 (m, 1H, H-5*), 7.7 (td, J = 7.4 Hz, J = 1.2 Hz 1H, H-6*), 4.3 (d, 3 J 2,2a = 2.3 Hz, 1H, H-2), 4.18 (q, 3 J CH2, CH3 = 7.2 Hz, 2H, CO 2 CH 2 CH 3 ), 2.37 (s, 3H, COCH 3 ), 1.7 (s, 3H, CH 3 ), 1.45 (d, 3 J 2,2a = 2.4 Hz, 1H, H-2a), 1.27 (t, 3 J CH2, CH3 = 7.1 Hz, 3H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ): δ = 17.7 (C, CO 2 CH 2 CH 3 ), 168.9 (C, NCOCH 3 ), 141.3, 135.2 (C, C-3a, C-7a), 128.1, 123.7, 122.9, 117.4 (CH, C-4, C-5, C-6, C-7), 61. (CH 2, CO 2 CH 2 CH 3 ), 5.6 (CH, C-2), 34.9 (C, C-3), 29.9 (CH, C-2a), 24.4 (CH 3, NCOCH 3 ), 14.3 (CH 3, CO 2 CH 2 CH 3 ),11.3 (CH 3, CH 3 ) ppm. HRMS (ESI+): calcd for C 12 H 14 N 2 ONa [M+Na] + 282.116; found: 282.118. Enantiomeric excesses of exo-8a were determined by GC. Starting temperature: 8 C, heating rate:.5 C/min; retention times: Racemic mixture: t R = 166.77 min, t R = 167.78 min Products from enantioselective experiments using 3: t R = 166.82 min (major), t R = 167.74 min (minor). endo-8a: Yellow solid. 1 H-NMR (4 MHz, CDCl 3 ): δ = 8.11 (d, J = 8.2 Hz, 1H, H-7*), 7.27 (dd, J = 7.5 Hz, 1H, H- 4*), 7.2-7.25 (m, 1H, H-5*), 7.7 (m, 1H, H-6*), 4. (d, 3 J 2,2a = 5.8 Hz, 1H, H-2), 3.81 (q, S11
3 J CH2,CH3 = 7.2 Hz, 2H, CO 2 CH 2 CH 3 ), 2.33 (s, 3H, COCH 3 ), 1.96 (d, J 2,2a = 5.8 Hz, 1H, H-2a), 1.69 (s, 3H, CH 3 ),.89 (t, 3 J CH2,CH3 = 7.1 Hz, 3H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, CDCl 3 ): δ = 169.5 (C, CO 2 Et), 166.8 (C, NCOCH 3 ), 143.3, 13.8 (C, C-3a, C-7a), 128.2, 123.5, 123.4, 116.5 (CH, C-4, C-5, C-6, C-7), 6.9 (CH 2, CO 2 CH 2 CH 3 ), 5.1 (CH, C-2), 34.4 (C, C-3), 26.2 (CH, C-2a), 24.4 (CH 3, NCOCH 3 ), 18.9 (CH 3, CH 3 ), 13.8 (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 12 H 14 N 2 ONa [M+Na] + 282.116; found: 282.114. Cyclopropanation of N-Boc-3-methylindole (7b): Table 3: Summary of all experiments with indole 7b entry ligand temp [ C] 11 13 3-O-R 1 yield [%] a yield [%] ee (exo) [%] b 1 3a Ac rt 17 63 87 (-) 2 3g formyl rt 14 78 82 (-) 3 (S)-1 - rt 2 >99 82 (+) 4 3a Ac 1 36 75 94 (-) 5 3a Ac 61 71 96 (-) 6 3a Ac -1 36 71 97 (-) 7 3a Ac -2 11 9 92 (-) Ligand (3.3 mol %), CuOTf..5 C 6 H 6 (3.3 mol %), 7 (1 equiv), 5 (2.5 equiv). a Isolated yield over two steps from 7b. b Determined by GC. exo- and endo-ethyl-3-methyl-cyclopropa(n-tert.-butoxycarbonyl-2,3-dihydroindole)-2acarboxylate (exo-8b and endo-8b) The diastereomeric products exo-8b and endo-8b were isolated as a mixture with diethyl fumarate and diethyl maleate as by-products. While the diastereomers could be separated by column chromatography, the removal of diethyl fumarate from exo-8b and the removal of diethyl maleate from endo-6b was not possible. Therefore the raw product exo-8b was directly transformed into imine 11. The enantiomeric excesses of the cyclopropanation step were determined by analysis of hemiaminal ester 13 which was obtained from 11 in one step. Due restricted rotation around the N-acyl bond, 4 coalescence phenomena were observed for some proton signals of exo- and endo-8b in 1 H spectra recorded at room temperature. Therefore the 1 H spectra of these compounds were recorded in DMSO at elevated temperature (35 K), which led to well-resolved signals for all protons. S12
exo-8b: Starting material 7b (1 mg,.43 mmol); product exo-8b (99 mg,.31 mmol, 73%). Colourless oil; [α] 2 D : -118.4 (c =.95, CHCl 3 ) (ratio exo-8b:fumarate =1:1) (Table 3, entry 5). 1 H-NMR (4 MHz, DMSO-d6, 35 K): δ = 7.62 (d, J = 8.1 Hz, 1 H, H-7*), 7.45 (dd, J = 7.5 Hz, J =.8 Hz, 1 H, H-4*), 7.19-7.29 (m, 1 H, H-6*), 7.6 (td, J = 7.5 Hz, J = 1. Hz, 1 H, H-5*), 4.43 (d, 3 J 2,2a = 2.3 Hz, 1 H, H-2), 4.16 (q, 3 J CH2, CH3 = 6.9 Hz, 2 H, CO 2 CH 2 CH 3 ), 1.65 (s, 3 H, CH 3 ), 1.56 (s, 9 H, (CH 3 ) 3 CO), 1.2 1.25 (m, 3 H, H-2a + CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, DMSO-d6): δ = 17.9 (C, CO 2 CH 2 CH 3 ), 151.6 (C, CO 2 C(CH 3 ) 3 ), 14.3, 135.4 (C, C-3a, C-7a), 128.2, 123.8, 123., 115.3 (CH, C-4, C-5, C-6, C-7) 82.3 (C, CO 2 C(CH 3 ) 3 ), 6.9 (CH 2, CO 2 CH 2 CH 3 ), 49.6 (CH, C-2), 33.7 (C, C-3), 28.6 (CH, C-2a), 28.3 (CH 3, (CH 3 ) 3 CO), 14.6 (CH 3, CO 2 CH 2 CH 3 ), 11.4 (CH 3, CH 3 ) ppm. HRMS (ESI+): calcd for C 18 H 23 N 1 O 4 Na [M+Na] + 34.1525; found: 34.1527. Signals of by-product diethyl fumarate 1 H-NMR (4 MHz, CDCl 3 ) δ = 6.82 (s, 2 H, HC=CH), 4.23 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.29 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 1 H-NMR (4 MHz, DMSO-d6) δ = 6.75 (s, 2 H, HC=CH), 4.2 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.24 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, CDCl 3 ): δ = 165. (C, CO 2 Et), 133.6 (CH, HC=CH), 61.3 (CH 2, OCH 2 CH 3 ), 14.1 (CH 3, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, DMSO-d6): δ = 164.8 (C, CO 2 Et), 133.4 (CH, HC=CH), 61.3 (CH 2, OCH 2 CH 3 ), 14.1 (CH 3, OCH 2 CH 3 ) ppm. endo-8b: Starting material 7b (1 mg,.43 mmol); product endo-8b (12 mg,.38 mmol, 9%). Colourless oil; [α] 2 D : +65.3 (c =.87, CHCl 3 ) (contains diethyl maleate) for experiment at - 1 C (Table 3, entry 6). S13
1 H-NMR (4 MHz, DMSO-d6, 38 K): δ = 7.62 (d, J = 8.2 Hz, 1 H, H-7*), 7.31 (ddd, J = 7.5 Hz, J = 1.3 Hz, J =.5 Hz, 1 H, H-4*), 7.18 (ddd, J = 8.1 Hz, J = 7.5 Hz, J = 1.3 Hz, 1 H, H-6*), 7.6 (td, J = 7.4 Hz, J = 1. Hz, 1 H, H-5*), 4.25 (d, 3 J 2,2a = 6. Hz, 1 H, H-2), 3.69 3.8 (m, 2 H, CO 2 CH 2 CH 3 ), 2.2 (d, 3 J 2,2a = 6.1 Hz, 1 H, H-2a), 1.63 (s, 3 H, CH 3 ), 1.55 (s, 9 H, (CH 3 ) 3 CO),.89 (t, 3 J = 7.1 Hz, 3 H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. 13 C-NMR (1 MHz, DMSO-d6): δ = 167.1 (C, CO 2 CH 2 CH 3 ), 152.3 (C, CO 2 C(CH 3 ) 3 ), 144., 133.7 (C, C-3a, C-7a), 13.5, 127.8, 122.4, 114.3 (CH, C-4, C-5, C-6, C-7), 8.9 (C, CO 2 C(CH 3 ) 3 ), 59.8 (CH 2, CO 2 CH 2 CH 3 ), 49.4 (CH, C-2), 34.1 (C, C-3), 28.4 (CH 3, (CH 3 ) 3 CO), 24. (CH, C-2a), 18.3 (CH 3, CH 3 ), 14.3 (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 18 H 23 N 1 O 4 Na [M+Na] + 34.1525; found: 34.1524. Signals of by-product diethyl maleate 1 H-NMR (4 MHz, CDCl 3 ) δ = 6.21 (s, 2 H, HC=CH), 4.23 (q, 3 J = 7.2 Hz, 2 H, OCH 2 CH 3 ), 1.29 (t, 3 J = 7.2 Hz, 3 H, OCH 2 CH 3 ) ppm. 1 H-NMR (4 MHz, DMSO-d6) δ = 6.45 (s, 2 H, HC=CH), 4.14 (q, 3 J = 7.1 Hz, 2 H, OCH 2 CH 3 ), 1.21 (t, 3 J = 7.1 Hz, 3 H, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, CDCl 3 ): δ = 165.3 (C, CO 2 Et), 129.8 (CH, HC=CH), 61.2 (CH 2, OCH 2 CH 3 ), 14. (CH 3, OCH 2 CH 3 ) ppm. 13 C-NMR (1 MHz, DMSO-d6): δ = 165.2 (C, CO 2 Et), 13.3 (CH, HC=CH), 6.8 (CH 2, OCH 2 CH 3 ), 14. (CH 3, OCH 2 CH 3 ) ppm. Ethyl (3-methyl-3H-indole-3-yl) acetate (11) A solution of TFA (18 µl, 1.41 mmol) in CH 2 Cl 2 (1 ml) was added dropwise to the raw product exo-8b (149 mg) dissolved in dry CH 2 Cl 2 (3 ml). This mixture was stirred at rt for 3 h, subequently diluted with diethyl ether and washed with saturated aqueous NaHCO 3 solution, water and brine. The organic layer was dried over Na 2 SO 4, concentrated and purified by flash chromatography on silica gel (PE/EE 3:1) to yield the title compound (32 mg, 14 µmol, 61%) as a yellow solid. [α] 2 D : -15.4 (c = 1., CHCl 3 ) (Table 3, entry 5). 1 H-NMR (4 MHz, CDCl 3 ): δ = 8.2 (s, 1H, H-2), 7.54 (dd, J = 7.1 Hz, J = 1.5 Hz, 1 H, H- 7*), 7.21 7.29 (m, 2 H, H-5*, H-6*), 7.17 (dd, J = 8.1 Hz, J = 6.6 Hz, 1 H, H-4*), 3.98 (q, 3 J CH2, CH3 = 7.1 Hz, 2 H, CO 2 CH 2 CH 3 ), 2.74 (d, 2 J C-3-CHH -CO2 = 15.2 Hz, 1 H, H-3), 2.45 (d, S14
2 J C-3-CHH -CO2 = 15.2 Hz, 1 H, H-3'), 1.32 (s, 3 H, CH 3 ), 1.6 (t, 3 J CH2, CH3 = 7.1 Hz, 3 H, CO 2 CH 2 CH 3 ) ppm. * Signals interchangeable. 13 C NMR (1 MHz, CDCl 3,): δ = 177.7 (CH, C-2), 17.1 (C, CO 2 CH 2 CH 3 ), 154.3, 142.5 (C, C-3a, C-7a), 128.2, 126.3, 121.6, 121.3 (CH, C-4, C-5, C-6, C-7), 6.7 (CH 2, CO 2 CH 2 CH 3 ), 54.6 (C, C-3), 4.4 (CH 2, CH 2 -CO 2 ), 19.8 (CH 3, CH 3 ), 14. (CH 3, CO 2 CH 2 CH 3 ) ppm. HRMS (ESI+): calcd for C 13 H 16 N 1 O 2 [M+H] + 218.1181; found: 218.1182. 3,3a,8,8a-Tetrahydro-3a-methylfuro[2,3-b]-indol-2-one (13) To a solution of 11 (16.7 mg, 78 µmol) in EtOH (3 ml) an aqueous solution NaOH (c = 6 mol/l) (.6 ml) was added and the resulting mixture was stirred at rt for 16 h. Subsequently the mixture was concentrated under reduced pressure and water (2 ml) was added to the residue. The mixture was acidified with 6 M HCl (.5 ml) and extracted with CH 2 Cl 2. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel (PE/EE 2:1). The title compound (1.5 mg, 55 µmol) was obtained as a yellow solid in 71% yield. [α] 2 D : -118.4 (c = 1., CHCl 3 ) for 96% ee (Table 3, entry 5). 1 H-NMR (4 MHz, CDCl 3 ): δ = 7.6-7.18 (m, 2 H, H-7*, H-4*), 6.84 (td, J = 7.5 Hz, J = 1. Hz, 1 H, H-5*), 6.67 (dd, J = 4.6 Hz, J = 4. Hz, 1 H, H-6*), 5.66 (s, 1 H, H-8a). 4.95 (s, 1 H, NH), 2.98 (d, 2 J 3,3' = 17.6 Hz, 1 H, H-3), 2.8 (d, 2 J 3,3' = 17.7 Hz, 1 H, H-3'), 1.46 (s, 3 H, CH 3 ) ppm. * Signals interchangeable. The 1 H NMR data are in excellent agreement with those reported by Wenkert et al. 3 and Ikeda et al. 5 for the same compound. 13 C NMR (1 MHz, CDCl 3,): δ = 174.8 (C, C-2), 146., 132.7 (C, C-3b, C-7a), 129.1, 123.1, 12.6, 19.8 (CH, C-4, C-5, C-6, C-7), 1.1 (C, C-8a), 54. (C, C-3a), 41.9 (CH 2, C- 3), 23.8 (CH 3, CH 3 ), ppm. HRMS (ESI+): calcd for C 11 H 12 N 1 O 2 [M + H] + 19.868; found: 19.871. Enantiomeric excesses of 13 were determined by GC. Starting temperature 16 C, heating rate:.5 C/min; retention times: Racemic mixture: t R = 32.7 min, t R = 35.15 min S15
Products from enantioselective experiments using ligands 3a and 3g: t R = 32.66 min (minor), t R = 34.95 min (major). Product from enantioselective experiments using ligand (S)-1: t R = 35.18 min (minor), t R = 32.54 min (major). 3,3a,8,8a-Tetrahydro-3a,8-dimethylfuro[2,3-b]-indol-2-one To a solution of 13 (3 mg, 159 µmol) in anhydrous acetone K 2 CO 3 (29 mg, 27 µmol) and dimethyl sulfate (18 µl, 25 mg, 196 µmol) were added and the reaction mixture was heated to reflux for 5 h. Subsequently the mixture was concentrated under reduced pressure and diluted with water. The reaction mixture was extracted with EE (3x1 ml). The organic layer was washed with brine, dried over Na 2 SO 4, concentrated and purified by flash chromatography on silica gel (PE/EE 1:1). The title compound (3 mg, 151 µmol, 95%) was obtained as a colorless solid. [α] 2 D : -29. (c = 1., CHCl 3 ). 1 H-NMR (4 MHz, CDCl 3 ): δ = 7.17 (td, J = 7.7 Hz, J = 1.1 Hz, 1 H, H-7*), 7.6 (d, J = 7.3 Hz, 1 H, H-4*), 6.8 (t, J = 7.4 Hz, 1 H, H-5*), 6.5 (d, J = 7.8 Hz, 1 H, H-6*), 5.52 (s, 1 H, H-8a). 3. (s, 3 H, NCH 3 ), 2.96 (d, 2 J 3,3' = 17.7 Hz, 1 H, H-3), 2.79 (d, 2 J 3,3 = 17.7 Hz, 1 H, H-3'), 1.45 (s, 3 H, CH 3 ) ppm. * Signals interchangeable. The 1 H NMR data are in excellent agreement with those reported by Wenkert et al. 3 and Ikeda et al. 5 for the same compound. 13 C NMR (1 MHz, CDCl 3,): δ = 175. (C, C-2), 148., 133.6 (C, C-3b, C-7a), 129.2, 122.7, 119.5, 17.3 (CH, C-4, C-5, C-6, C-7), 15.6 (C, C-8a), 48.6 (C, C-3a), 42.2 (CH 2, C- 3), 31.3 (CH 3, NCH 3 ), 23.8 (CH 3, CH 3 )+ ppm. HRMS (ESI+): calcd for C 12 H 14 N 1 O 2 [M + H] + 24.125; found: 24.122. S16
3,3a,8,8a-Tetrahydro-1,3a,8-trimethylpyrrolo[2,3-b]-indol-2-one 3,3a,8,8a-Tetrahydro-3a,8-dimethylfuro[2,3-b]-indol-2-one (46 mg, 226 µmol) was dissolved in dry MeOH and NH 2 Me (.35 ml of a 4 vol% solution in MeOH, 3.39 mmol NH 2 Me). was added. The reaction mixture was stirred for 5 h at rt and subsequently evaporated. The crude product was purified by flash chromatography on silica gel (PE/EE 1:1) to yield the title compound (42.4 mg, 19.6 µmol, 87%) as a colourless oil. [α] 2 D : -114.8 (c = 1., CHCl 3 ). 1 H-NMR (4 MHz, CDCl 3 ): δ = 7.12 (td, J = 7.7 Hz, J = 1.3 Hz, 1 H, H-7*), 7.2 (dd, J = 7.3 Hz, J =.8 Hz, 1 H, H-4*), 6.73 (dt, J = 7.4 Hz, J =.9 1 H, H-5*), 6.45 (d, J = 7.8 Hz, 1 H, H-6*), 4.6 (s, 1 H, H-8a). 3.6 (s, 3 H, NCH 3 ), 2.92 2 95 (m, 3 H, NCH 3 ), 2.71 2.78 (m, 1 H, H-3 ), 2.49 2.57 (m, 1 H, H-3), 1.43 (s, 3 H, CH 3 ) ppm. * Signals interchangeable. 13 C NMR (1 MHz, CDCl 3,): δ = 173.4 (C, C-2), 149.3, 135.5 (C, C-3b, C-7a), 128.6, 122.6, 118.8, 17.5 (CH, C-4, C-5, C-6, C-7), 92.4 (C, C-8a), 45.8 (C, C-3a), 44.3 (CH 2, C-3), 35.7 (CH 3, NCH 3 ), 28.7 (CH 3, NCH 3 ), 26.8 (CH 3, CH 3 ) ppm. HRMS (ESI+): calcd for C 13 H 17 N 2 O 1 [M + H] + 217.1341; found: 217.1344. (-)-Desoxyeseroline (14) To a stirred solution of LiAlH 4 (56 mg, 1.48 mmol) in dry THF (4 ml) 3,3a,8,8a-tetrahydro- 1,3a,8-trimethylpyrrolo[2,3-b]-indol-2-one (4 mg, 185 µmol) in THF (3 ml) was added. The mixture was heated at reflux for 2 h, subsequently cooled to C and the reaction was quenched by dropwise addition of EE (4 ml). The phases were separated and the organic layer was washed with brine, dried over Na 2 SO 4 and evaporated. The title compound (37.4 mg, 185 µmol) was obtained in quantitative yield as a colourless oil. [α] 2 D : -51.2 (c = 1., CHCl 3 ). 1 H-NMR (4 MHz, CDCl 3 ): δ = 7.7 (td, J = 7.7 Hz, J = 1. Hz, 1 H, H-7*), 6.98 (d, J = 7.3 Hz, 1 H, H-4*), 6.66 (t, J = 7.3 Hz, 1 H, H-5*), 6.4 (d, J = 7.8 Hz, 1 H, H-6*), 4.13 (s, 1 S17
H, H-8a). 2.93 (s, 3 H, NCH 3 ),2.69 2.77 (m, 1 H, H-2), 2.56 2.65 (m, 1 H, H-2'), 2.54 (s, 3 H, NCH 3 ), 1.91 2.2 (m, 2 H, H-3, H-3'), 1.42 (s, 3 H, CH 3 ) ppm. * Signals interchangeable. 13 C NMR (1 MHz, CDCl 3,): δ = 151.9, 136.6 (C, C-3b, C-7a), 127.7, 122.2, 117.6, 16.7 (CH, C-4, C-5, C-6, C-7), 97.3 (C, C-8a), 53.2 (CH 2, C-2), 52.7 (C, C-3a), 4.7 (CH 2, C-3), 38.2 (CH 3, NCH 3 ), 36.6 (CH 3, NCH 3 ), 27.3 (CH 3, CH 3 ) ppm. The 1 H and 13 C NMR data are in excellent agreement with those reported by Nakagawa et al. 6 Rainier et al. 7 and RajanBabu et al. 8 for the same compound. Contrary to the references 6-8, which reported an optical rotation of [α] 2 D ~ -74, we observed [α] 2 D = -51.2 (c = 1., CHCl 3 ). This prompted us to evaluate the enantiomeric excess for (-)-desoxyeseroline (14) obtained from our synthesis, which was determined to be 92 % ee by 1 H NMR using the dirhodium method. 1 HRMS (ESI+): calcd for C 13 H 19 N 2 [M + H] + 23.1548; found: 23.1545. S18
1 H and 13 C NMR spectra of compound 4a GAHA119J Ga118spot1 8.44 8.42 7.56 7.56 7.54 7.54 7.54 7.34 7.28 7.28 7.26 7.26 7.26 7.24 6.63 6.63 6.62 6.62 2.63 25 2 4 MHz, CDCl 3, rt 15 1 5.95 1.3 1.3 1.8 1. 1. 3.8 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. GACL119J Ga118spot1 168.62 135.53 13.39 125.19 125.11 123.64 12.82 116.52 19.16 77. 23.98 22 21 2 19 18 17 16 15 14 1 MHz, CDCl 3, rt 13 12 11 1 9 8 7 6 5 4 3 2 1-1 2 19 18 17 16 15 14 13 12 11 1 f1 (ppm) 9 8 7 6 5 4 3 2 1 S19
1 H and 13 C NMR spectra of compound 4b N Boc 4 MHz, CDCl 3, rt 1 MHz, CDCl 3, rt S2
1 H and 13 C NMR spectra of compound exo-6a 8.15 8.13 7.38 7.36 7.25 7.24 7.23 7.22 7.21 7.2 7.6 7.6 7.4 7.4 7.2 7.2 4.39 4.39 4.38 4.37 4.22 4.21 4.21 4.19 4.19 4.18 4.17 4.16 4.15 4.15 3.29 3.29 3.28 3.27 2.39 1.39 1.39 1.38 1.38 1.3 1.28 1.26 65 6 55 5 45 4 35 3 25 4 MHz, CDCl 3, rt 2 15 1 5-5.96 1.5 1.75 1.15 1.1 2.37 1. 3.5.94 3.51 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. 171.67 169.2 142.1 13.33 128.16 124.42 123.76 117.46 77. 61.25 46.28 29.56 25.21 24.41 14.21 32 3 28 26 24 22 1 MHz, CDCl 3, rt 2 18 16 14 12 1 8 6 4 2-2 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S21
1 H and 13 C NMR spectra of compound endo-6a 5 45 4 35 3 25 2 15 1 5.94 1. 2.29 1.12 1.26 2.15.95 3.3 1.19 8.12 8.1 7.32 7.32 7.32 7.3 7.3 7.3 7.24 7.22 7.22 7.2 7.2 7.3 7.3 7.1 7.1 7. 6.99 4.29 4.28 4.27 4.26 3.86 3.85 3.83 3.81 3.28 3.26 3.26 3.24 2.36 2.4 2.3 2.2 2.1.92.9.88 4 MHz, CDCl 3, rt 3.2-5 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. 171.49 166.7 133.62 128.15 127.17 124.9 123.44 116.63 77. 6.63 44.25 27.71 24.43 2.14 13.82 34 32 3 28 26 24 1 MHz, CDCl 3, rt 22 2 18 16 14 12 1 8 6 4 2-2 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S22
1 H and 13 C NMR spectra of compound exo-6b 4 MHz, DMSO-d6, 35 K GACL87BJ GA87 (51-68) 172.18 164.95 133.58 13.39 127.7 124.45 122.52 122.44 115.46 82.38 77. 6.87 45.6 28.33 28.15 24.2 14.21 6 55 5 45 4 1 MHz, CDCl 3, rt 35 3 25 2 15 1 5 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S23
1 H and 13 C NMR spectra of compound endo-6b 4 MHz, DMSO-d6, 38 K 1 MHz, DMSO-d6, rt S24
1 H- and 13 C-spectra of compound 7a: SBHA5J/1 3-metyl-1-Acindol 8.41 8.39 7.5 7.49 7.49 7.48 7.47 7.36 7.36 7.34 7.34 7.32 7.32 7.3 7.29 7.28 7.28 7.26 7.26 7.17 7.17 7.16 7.15 7.15 2.58 2.27 2.27 9 85 8 75 7 65 6 55 Me 5 45 N Ac 4 35 3 4 MHz, CDCl 3, rt 25 2 15 1 5.92 1. 1.1.97.92 3.7 3.15-5 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. 168.3 135.83 131.42 125.16 123.38 122.2 118.81 118.4 116.57 24.1 9.71 Me N Ac 1 MHz, CDCl 3, rt S25
1 H and 13 C NMR spectra of compound 7b Me N Boc 4 MHz, CDCl 3, rt Me N Boc 1 MHz, CDCl 3, rt S26
1 H- and 1 C-spectra of compound exo-8a: 1. 1.5.98 1.7.95 2.32 2.99 3.4.7.96 3.19 8.14 8.12 7.33 7.33 7.31 7.31 7.24 7.24 7.22 7.22 7.21 7.2 7.9 7.9 7.7 7.7 4.31 4.3 4.21 4.19 4.17 4.15 2.37 1.7 1.58 1.45 1.45 1.29 1.27 1.25 4 MHz, CDCl 3, rt SBCL16J/1 Cyclopropanierung Ac-Indol (exo) 7 65 6 55 5 1 MHz, CDCl 3, rt 45 4 35 3 25 2 15 1 5 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S27
1 H- and 1 C-spectra of compound endo-8a: 1..98 1.1 1.15 1.7 2.17 3.15 1.17 3.24 3.25 8.12 8.1 7.28 7.28 7.26 7.26 7.25 7.24 7.24 7.23 7.22 7.21 7.2 7.7 7.6 7.5 7.5 7.3 4.1 4. 3.83 3.82 3.8 3.78 2.33 1.97 1.95 1.69.9.89.87 4 MHz, CDCl 3, rt 169.5 166.81 143.81 13.76 128.17 123.48 123.42 116.49 6.51 5.12 34.43 26.28 24.44 18.94 13.84 1 MHz, CDCl 3, rt S28
1 H and 13 C NMR spectra of compound exo-8b 4 MHz, DMSO-d6, 35 K 1 MHz, DMSO-d6, rt S29
1 H and 13 C NMR spectra of compound endo-8b 4 MHz, DMSO-d6, 38 K 1 MHz, DMSO-d6, rt S3
1 H and 13 C NMR spectra of compound 11 GAHA179J GA183 13 12 11 1 9 8 7 6 4 MHz, CDCl 3, rt 5 4 3 2 1-1 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. 1 MHz, CDCl 3, rt S31
1 H and 13 C NMR spectra of compound 13 4 MHz, CDCl 3, rt 1 MHz, CDCl 3, rt S32
1 H and 13 C NMR spectra of compound 3,3a,8,8a-Tetrahydro-3a,8-dimethylfuro[2,3-b]- indol-2-one 1..97.96.94.94 2.98 1.5 1.3 3.21 7.19 7.19 7.17 7.17 7.15 7.15 7.7 7.5 6.81 6.8 6.51 6.49 5.52 3. 2.98 2.94 2.81 2.76 1.45 4 MHz, CDCl 3, rt 174.96 147.95 133.59 129.15 122.71 119.49 17.31 15.6 48.61 42.21 31.33 23.75 1 MHz, CDCl 3, rt S33
1 H and 13 C NMR spectra of compound 3,3a,8,8a-Tetrahydro-1,3a,8-trimethylpyrrolo[2,3- b]-indol-2-one 1.13 1.1 1.1.98 1. 3.8 3.2 1.14 1.5 3.43 7.14 7.14 7.12 7.12 7.11 7.1 7.3 7.3 7.1 7.1 6.73 6.73 6.46 6.44 4.6 3.6 2.94 2.77 2.77 2.73 2.73 2.55 2.55 2.51 2.51 1.43 4 MHz, CDCl 3, rt GACL257J GA316 173.38 149.3 135.48 128.63 122.59 118.8 17.49 92.44 45.77 44.25 35.7 28.65 26.79 2 19 18 17 16 15 14 13 1 MHz, CDCl 3, rt 12 11 1 9 8 7 6 5 4 3 2 1-1 -2 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S34
1 H and 13 C NMR spectra of compound 14 1 H NMR (4 MHz, CDCl 3) δ 1.42 (s, 3H). 11 1 9 8 7 6 5 4 4 MHz, CDCl 3, rt 3 2 1 9. 8.5 8. 7.5 7. 6.5 6. 5.5 5. 4.5 f1 (ppm) 4. 3.5 3. 2.5 2. 1.5 1..5. 151.88 136.56 127.73 122.22 117.63 16.65 97.3 53.17 52.7 4.71 38.22 36.62 27.31 3 28 26 24 22 2 1 MHz, CDCl 3, rt 18 16 14 12 1 8 6 4 2 19 18 17 16 15 14 13 12 11 1 9 f1 (ppm) 8 7 6 5 4 3 2 1 S35
References [1] Duddeck, H. Chem. Rec. 25, 5, 396. [2] Roy, S.; Gribble, G. W. Synth. Commun. 26, 36, 3487. [3] Wenkert, E.; Alonso, M. E.; Gottlieb, H. E.; Sanchez, E. L. J. Org. Chem. 1977, 42, 3945. [4] For restricted rotation in N-acylindoles see: Elugero, J.; Marzin, C.; Peek, M. E. Org. Magn. Res. 1975, 6, 445. [5] Ikeda, M.; Matsugashita, S.; Tamura, Y. J. Chem. Soc. Perkin Trans. 1 1977, 177. 6 Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2, 2, 675. 7 Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc. 21, 132, 8282. 8 Lim, H. J.; RajanBabu, T. V. Org. Lett. 211, 13, 6596. S36