Supporting Information S1
Reversible stereodivergent cycloaddition of racemic helicenes to [60]fullerene: a chiral resolution strategy Rosa M. Girón, Jiangkun Ouyang, Ludovic Favereau, Nicolas Vanthuyne, Jeanne Crassous,* Salvatore Filippone,* Nazario Martín* Contents 1. General Methods and Materials page S3 2. Experimental Procedures and Characterizations page S4 3. Representative NMR Spectra page S11 4. Representative Mass Spectra page S20 5. Representative HPLC Chromatograms page S21 6. Absorption and emission spectra page S25 7. References page S26 S2
1. General Methods and Materials The commercially available reagents and solvents were used without further purification. Iminoesters 2 1 were previously described in the literature. 1 H NMR and 13 C NMR spectra were recorded on a BRUKER AVANCE-300 and -700 in CDCl 3, or a BRUKER AVANCE AMX-700 in CDCl 3 at 23 C, and referenced to CDCl 3 ; coupling constants (J) are reported in Hz and the chemical shifts (δ) in ppm. Mass spectra was reported on a HP1100EMD (ESI). Reactions were monitored by thin-layer chromatography carried out on 0.2 mm TLC-aluminium sheets of silica gel (Merck, TLC Silica gel 60 F 254 ). Flash column chromatography was performed using silica gel (230-400 mesh). For conversions and diastereomeric excesses, HPLC column Buckyprep (Waters) (4.6 x 250 mm, 5µm) was used and for enantiomeric excesses, chiral HPLC Chiralpak IC (4.6 x 250 mm, 5µm). All these values were monitored in a 320 nm spectrophotometer detector. Circular Dichroism (DC) measurements were carried out on a JASCO J-815 DC SPECTROMETER. 1 López-Pérez A, Adrio J, Carretero JC. The phenylsulfonyl group as a temporal regiochemical controller in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Angewandte Chemie (International ed. in English). 2009;48(2):340-3 S3
2.1 General procedure for the synthesis of carbo[6]helicene-2- carboxaldehyde 1 Carbo[6]helicene-2-carboxaldehyde 1 was prepared following a previously reported procedure. 2 Analytical chiral HPLC separation for carbo[6]helicene-2-carboxaldehyde 1 The sample is dissolved in chloroform, injected on the chiral column, and detected with an UV detector at 254 nm and with CD at 254 nm. The flow-rate is 1 ml/min. Column Mobile Phase t1 k1 t2 k2 α Rs Chiralpak IC Heptane / Isopropanol /chloroform(80/10/10) 6.04(+) 1.05 6.98(-) 1.37 1.30 2.64 Chiralpak IC Heptane / Isopropanol /chloroform Signal: DAD1 C, Sig=254,4 Ref=off RT [min] Area Area% Capacity Factor Enantioselectivity Resolution (USP) 6.04 1204 52.02 1.05 6.98 1111 47.98 1.37 1.30 2.64 Sum 2315 100.00 2 El Sayed Moussa, M.. Srebro, M.; Anger, E.; Vanthuyne, N.; Roussel; C.; Lescop, C.; Autschbach, J.; Crassous, J. Chirality, 2013; 25, 455-465. S4
Semi-preparative separation for compound 1: Sample preparation: About 240 mg of compound 1 are dissolved in 27 ml of a mixture of hexane/isopropanol/chloroform 45/5/50. Chromatographic conditions: Chiralpak IC (250 x 10 mm), hexane / isopropanol / chloroform (80/10/10) as mobile phase, flow-rate = 5 ml/min, UV detection at 254 nm. Injections (stacked): 180 times 150 µl, every 2.5 minutes. Collection: the first eluted enantiomer is collected between 6 and 6.3 minutes and the second one between 7.1 and 7.5 minutes. First fraction: 71 mg of the first eluted enantiomer with ee > 99.5% RT [min] Area Area% 6.03 3989 99.80 6.97 8 0.20 Sum 3997 100.00 S5
Second fraction: 65 mg of the second eluted enantiomer with ee > 99% RT [min] Area Area% 6.05 5 0.50 6.99 996 99.50 Sum 1001 100.00 2.2 General procedure for the synthesis of helicene α-iminoesters 2 The α-iminoesters 2 were synthesized according to the method described in literature. Synthesis of racemic tert-butyl (E)-N-[(2-carbo[6]helicene)methylene]glycinate (2) N CO 2 tbu tbuo 2 C N (M) (P) S6
The racemic iminoester 2 was prepared according to the general procedure by using carbo[6]helicene-2-carbaldehyde 3 (20 mg, 0.056 mmol,) tert-butyl glycinate hydrochloride (14 mg, 0.080 mmol), triethylamine (12 µl, 0.080 mmol), and anhydrous sodium sulfate. Yellow solid (26 mg, 99%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.04 7.78 (m, 11H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.21 (t, J = 7.0 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H), δ 4.15 (d, J = 15.7 Hz, 1H), 4.03 (d, J = 16.0 Hz, 1H), 1.48 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ) δ 165.20, 133.88, 133.79, 133.67, 132.86, 132.11, 131.92, 131.80, 130.10, 130.06, 129.92, 129.70, 128.92, 128.82, 128.63, 128.28, 128.21, 128.02, 127.87, 127.80, 127.69, 127.65, 127.44, 126.63, 126.33, 125.27, 123.26, 81.61, 77.87, 77.44, 77.02, 62.88, 28.51. HRMS (ESI + ) [M+H] + Calc. for C 33 H 28 NO 2 : 470,2120; found: 470,2083. 3 El Sayed Moussa M, Srebro M, Anger E, Vanthuyne N, Roussel C, Lescop C, Autschbach J, Crassous J, Chiroptical properties of carbo[6]helicene derivatives bearing extended π-conjugated cyano substituents. Chirality, (2013);25:455-465. S7
Synthesis of tert-butyl (E)-N-[M-(2- carbo[6]helicene)methylene]glycinate (M-2) The iminoester M-2 was prepared according to the general procedure by using M-carbo[6]helicene-2- carbaldehyde (20 mg, 0.056 mmol,) tert-butyl glycinate hydrochloride (14 mg, 0.080 mmol), triethylamine (12 µl, 0.080 mmol), and anhydrous sodium sulfate. Yellow solid (25.5 mg, 96%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.03 7.86 (m, 10H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.21 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), δ 4.16 (dd, J = 16.0, 1.2 Hz, 1H), 4.03 (dd, J = 16.0, 1.1 Hz, 1H), 1.48 (s, 9H). Synthesis of tert-butyl (E)-N-[P-(2-carbo[6]helicene)methylene]glycinate (P-2) The iminoester P-2 was prepared according to the general procedure by using P-carbo[6]helicene-2- carbaldehyde (20 mg, 0.056 mmol,) tert-butyl glycinate hydrochloride (14 mg, 0.080 mmol), triethylamine (12 µl, 0.080 mmol), and anhydrous sodium sulfate. Yellow solid (25 mg, 94%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.03 7.83 (m, 10H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.21 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.69 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), δ 4.16 (dd, J = 16.0, 1.1 Hz, 1H), 4.03 (dd, J = 16.1, 1.0 Hz, 1H), 1.48 (s, 9H). S8
2.3 General procedure for catalytic 1,3-dipolar cycloaddition of heliceneazomethine ylides and [60]fullerene Chiral ligand (0.0022 mmol) and metal salt (0.0022 mmol) were dissolved in toluene (3 ml). The solution was stirred for 1h at room temperature, and then, a solution of α-iminoester (0.0074 mmol). Finally, C 60 (0.0149 mmol). The reaction mixture was stirred for 2.5 h, and afterwards, it was quenched with a saturated ammonium chloride solution (20 ml). The mixture was extracted with toluene (3 x 20mL), and the combinated extracts were washed with brine (30 ml). The organic layer was dried over MgSO 4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (1) CS 2 / 2) CS 2 :DCM 100:1 to 10:1)). Synthesis of (2S,5S)-tert-butoxycarbonyl-5-(M-2-carbo[6]helicene)pyrrolidino [3,4:1,2][60]fullerene (M,S,S-4) The adduct M,S,S-4 was prepared according to the general procedure by using the catalytic system (R p )-Fesulphos (1 mg, 0.0022 mmol) and Cu(OAc) 2 (4 mg, 0.0022 mmol), tert-butyl (E)-N- [M-(2-carbo[6]helicene)methylene]glycinate M-2 (3.5 mg, 0.0074 mmol,) and C 60 (11 mg, 0.0149 mmol). Brown solid (7.2 mg, 83%). 1 H NMR (700 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.00 7.94 (m, 6H), 7.90 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 5.43 (s, 1H), 5.30 (s, 1H), 2.80 (s, 1H), 1.59 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) δ 167.55, 153.40, 153.06, 151.61, 150.85, 147.02, 146.91, 146.83, 146.34, 146.30, 146.17, 146.02, 145.96, 145.95, 145.90, 145.79, 145.71, 145.65, 145.38, 145.33, 145.26, 145.18, 145.12, 145.07, 145.05, 145.02, 144.46, 144.36, 144.34, 144.11, 144.08, 143.11, 142.81, 142.60, 142.58, 142.48, 142.45, 142.24, 142.22, 142.08, 142.00, 141.83, 141.71, 141.65, 141.55, 141.23, 139.78, 139.43, 139.29, 138.80, 137.25, 135.66, 135.54, 135.14, 133.08, 131.89, 131.79, 131.66, 131.27, 130.09, 129.49, 129.26, 129.05, 128.33, 128.16, 128.07, 128.01, 127.71, 127.53, 127.50, 127.46, 127.16, 127.06, 126.90, 126.33, 125.75, 125.33, 123.93, 83.12, 76.51, 73.72, 28.32. HRMS (ESI + ) [M+H] + Calc. for C 93 H 28 NO 2 : 1190,2120; found: 1190.2144. S9
Synthesis of (2S,5S)-tert-butoxycarbonyl-5-(P-2-carbo[6]helicene)pyrrolidino [3,4:1,2][60]fullerene (P,S,S-3) The adduct P,S,S-3 was prepared according to the general procedure by using the catalytic system (R p )- Fesulphos (1 mg, 0.0022 mmol) and Cu(OAc) 2 (4 mg, 0.0022 mmol), tert-butyl (E)-N-[P-(2- carbo[6]helicene)methylene]glycinate P-2 (3.5 mg, 0.0074 mmol,) and C 60 (11 mg, 0.0149 mmol).brown solid (9.8 mg, 92%). 1 H NMR (700 MHz, CDCl 3 ) δ 8.12 (s, 1H), 8.03 (d, J = 8.3 Hz, 2H), 8.01 7.92 (m, 8H), 7.86 (d, J = 7.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.49 7.46 (m, 1H), 6.86 6.83 (m, 1H), 5.31 (s, 1H), 4.93 (s, 1H), 1.54 (s, 9H). 13 C NMR (176 MHz, CDCl 3 ) δ 168.50, 153.18, 152.84, 151.77, 150.92, 147.08, 146.95, 146.92, 146.39, 146.33, 146.26, 146.13, 146.08, 145.95, 145.93, 145.82, 145.76, 145.73, 145.58, 145.47, 145.45, 145.32, 145.25, 145.09, 145.05, 145.04, 144.96, 144.32, 144.23, 144.17, 143.11, 142.98, 142.85, 142.63, 142.61, 142.52, 142.46, 142.29, 142.27, 142.10, 142.04, 141.95, 141.93, 141.87, 141.72, 141.63, 141.61, 141.20, 139.58, 139.40, 139.18, 138.79, 137.25, 136.30, 135.90, 135.11, 133.13, 132.83, 131.76, 131.56, 131.49, 130.02, 129.12, 128.77, 128.31, 127.90, 127.77, 127.72, 127.61, 127.54, 127.35, 127.31, 127.26, 127.16, 127.12, 126.89, 126.40, 126.15, 124.99, 124.00, 83.56, 78.56, 74.76, 72.89, 28.26. HRMS (ESI + ) [M+H] + Calc. for C 93 H 28 NO 2 : 1190,2120; found: 1190.2112. S10
3. Representative NMR spectra 3.1. NMR spectra of α-iminoesters 2 1 H-NMR, 13 C-NMR, DEPT-135 spectra of tert-butyl (E)-N-[(2-carbo[6]helicene) methylene]glycinate (2) 1 H-NMR 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f1 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 13 C-NMR / DEPT-135 160 150 140 130 120 110 100 90 80 f1 (ppm) 70 60 50 40 30 20 10 0 S11
1 H-NMR, spectrum of tert-butyl (E)-N-[(M-2-carbo[6]helicene)methylene] glycinate (M-2) 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f1 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 H-NMR, spectrum of tert-butyl (E)-N-[(P-2-carbo[6]helicene)methylene] glycinate (P-2) 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f1 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 S12
3.2. Representative NMR spectra of pyrrolidino[3,4:1,2][60]fullerene derivatives 3-4 1 H-NMR, 13 C-NMR, DEPT-135, COSY, HMQC, HMBC spectra of (2S,5S)-tertbutoxycarbonyl-5-(M-2-carbo[6]helicene)pyrrolidino[3,4:1,2][60]fullerene (M,S,S- 4) 1 H-NMR S13
13 C-NMR / DEPT-135 170 160 150 140 130 120 110 100 90 80 f1 (ppm) 70 60 50 40 30 20 10 0 S14
S15 COSY 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 f2 (ppm) 2 3 4 5 6 7 8 Q07GR945-1A-700 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 f2 (ppm) 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 Q07GR945-1A-700
S16 HMQC 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 f2 (ppm) 30 40 50 60 70 80 90 100 110 120 130 140 150 160 Q07GR945-1A-700 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 f2 (ppm) 124.5 125.0 125.5 126.0 126.5 127.0 127.5 128.0 128.5 129.0 129.5 130.0 Q07GR945-1A-700
S17 HMBC 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 f2 (ppm) 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 f2 (ppm) 75 80 85 90 95 100 105 110 115 120 125 130 135
1 H-NMR, 13C-NMR and DEPT-135 spectra of (2S,5S)-tert-butoxycarbonyl-5-(P-2- carbo[6]helicene)pyrrolidino[3,4:1,2][60]fullerene (P,S,S-3) 1 H-NMR 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f1 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 13 C-NMR / DEPT-135 170 160 150 140 130 120 110 100 90 80 f1 (ppm) 70 60 50 40 30 20 10 0 S18
1 H-NMR, spectrum of (2R,5R)-tert-butoxycarbonyl-5-(P-2-carbo[6]helicene) pyrrolidino[3,4:1,2][60]fullerene (P,R,R-4) 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1 H-NMR, spectrum of (2R,5R)-tert-butoxycarbonyl-5-(M-2-carbo[6]helicene) pyrrolidino[3,4:1,2][60]fullerene (M,R,R-3) 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f1 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 S19
4. Representative Mass spectra Mass spectra of tert-butyl (E)-N-[(2-carbo[6]helicene) methylene]glycinate (2) Mass spectra of (2S,5S)-tert-butoxycarbonyl-5-(M-2- carbo[6]helicene)pyrrolidino[3,4:1,2][60]fullerene (M,S,S-4) Mass spectra of (2S,5S)-tert-butoxycarbonyl-5-(P-2- carbo[6]helicene)pyrrolidino[3,4:1,2][60]fullerene (P,S,S-3) S20
5. Representative HPLC chromatograms Buckyprep (Waters) (4.6 x 250 mm), toluene:acetonitrile:hexane 50:10:40, flow rate 1.00 ml/min. C 60 Figure S1. Diastereomeric ratio between (P,S,S)-3 (t R = 7.6 min) and (P,R,R)-4 (t R = 8.7 min) of enantioriched iminoester P-2 cycloaddition onto [60]fullerene. Buckyprep (Waters) (4.6 x 250 mm), toluene:acetonitrile:hexane 50:10:40, flow rate 1.00 ml/min. C 60 Figure S2. Diastereomeric ratio between (M,R,R)-3 (t R = 7.6 min) and (M,S,S)-4 (t R = 8.7 min) of enantioenriched iminoester M-2 cycloaddition onto [60]fullerene. S21
Buckyprep (Waters) (4.6 x 250 mm, 5µm), toluene:acetonitrile:hexane 50:10:40, flow rate 1.00 ml/min. C 60 Figure S3. Diastereomeric ratio of racemic iminoester 2 cycloaddition onto [60]fullerene. Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. Figure S4. Enantiomeric excess of diastereoisomer (M,S,S)-4/(P,R,R)-4. The main enantiomer is (M,S,S)-4 (t R = 7.1 min) while the enantiomer (P,R,R)-4, that usually is eluted at 15 min. is not detected. S22
Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. Figure S5. Enantiomeric excess of diastereoisomer, (M,R,R)-3 (t R = 14.4 min)/(p,s,s)-3 (t R = 7.8 min) Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. Figure S6. Racemic aldehyde 1. S23
Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. a) b) Figure S7. a)m-1. b) P-1. Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. C 60 Figure S8. Crude of retrocycloaddition of (P,S,S)-3. S24
Chiralpak IC (4.6 x 250 mm, 5µm), hexane:isopropanol 97:3, flow rate 2.00 ml/min. C 60 Figure S9. Crude of retrocycloaddition of (M,S,S)-4. 6. Absorption and emission spectra. Figure S10. Absorption and emission spectra of compounds 1 (black) and 3 (red) (excitation wavelength 350 nm, at this wavelength, the absorbance for the two compounds was 0.07) in dichloromethane. S25
7. References 1. López-Pérez, A.; Adrio, J.; Carretero, J. C. Angew. Chem. Int. Ed, 2009, 48, 340-343. 2. El Sayed Moussa, M.. Srebro, M.; Anger, E.; Vanthuyne, N.; Roussel; C.; Lescop, C.; Autschbach, J.; Crassous, J. Chirality, 2013; 25, 455-465. S26