SUPPORTING INFORMATION

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1 SUPPORTING INFORMATION The First Enantioselective Total Synthesis of ( )-trans-dihydronarciclasine Gábor Varró, László Hegedűs, András Simon, Attila Balogh, Alajos Grün, Ibolya Leveles,, Beáta G. Vértessy,, István Kádas,* Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8, H Budapest, Hungary MTA BME Organic Chemical Technology Research Group, Hungarian Academy of Sciences, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budafoki út 8, H-1111 Budapest, Hungary Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért tér 4, H Budapest, Hungary Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szt. Gellért tér 4, H-1111 Budapest, Hungary * Corresponding author. Tel.: , fax: , ikadas@mail.bme.hu, Table of Contents NMR spectra of compounds ( )-1, 9 ( )-13, 15, 16 and ( )-17 ( )-28 Chiral HPLC chromatograms of compounds ( )-1, (S)-( )-13, ( )-17, (+)-18 and ( )-2 ( )-25 XRD crystallographic data of compounds (S)-( )-13 and ( )-17 S2 S34 S46

2 Spectroscopic data for ( )-trans-dihydronarciclasine [( )-1] Figure S1. The 1 H NMR spectrum of ( )-trans-dihydronarciclasine [( )-1] at 3 MHz, in DMSO-d Figure S2. The 13 C (APT) NMR spectrum of ( )-trans-dihydronarciclasine [( )-1] at 75 MHz, in DMSOd 6. S2

3 Figure S3. The COSY spectrum of ( )-trans-dihydronarciclasine [( )-1] at 3 MHz, in DMSO-d 6. Figure S4. The HSQC spectrum of ( )-trans-dihydronarciclasine [( )-1] at 3 and 75 MHz, in DMSO-d 6. S3

4 Figure S5. The HMBC spectrum of ( )-trans-dihydronarciclasine [( )-1] at 3 and 75 MHz, in DMSO-d 6. Figure S6. The NOESY spectrum of ( )-trans-dihydronarciclasine [( )-1] at 3 MHz, in DMSO-d 6. S4

5 Spectroscopic data for iodovanillin (9) Figure S7. The 1 H NMR spectrum of iodovanillin (9) at 3 MHz, in CDCl Figure S8. The 13 C (APT) NMR spectrum of iodovanillin (9) at 75 MHz, in CDCl 3. S5

6 Spectroscopic data for 5-hydroxyvanillin (1) Figure S9. The 1 H NMR spectrum of 5-hydroxyvanillin (1) at 3 MHz, in CDCl Figure S1. The 13 C (APT) NMR spectrum of 5-hydroxyvanillin (1) at 75 MHz, in CDCl 3. S6

7 Spectroscopic data for myristicin aldehyde (11) Figure S11. The 1 H NMR spectrum of myristicin aldehyde (11) at 3 MHz, in CDCl Figure S12. The 13 C (APT) NMR spectrum of myristicin aldehyde (11) at 75 MHz, in CDCl 3. S7

8 Spectroscopic data for 4-(7-methoxybenzo[1,3]dioxol-5-yl)but-3-en-2-one (12) ppm (t1) Figure S13. The 1 H NMR spectrum of 4-(7-methoxybenzo[1,3]dioxol-5-yl)but-3-en-2-one (12) at 3 MHz, in CDCl Figure S14. The 13 C (APT) NMR spectrum of 4-(7-methoxybenzo[1,3]dioxol-5-yl)but-3-en-2-one (12) at 75 MHz, in CDCl 3. S8

9 Spectroscopic data for (S)-( )-4-(7-methoxybenzo[1,3]dioxol-5-yl)-5-nitro-pentan-2- one [(S)-( )-13] Figure S15. The 1 H NMR spectrum of (S)-( )-4-(7-methoxybenzo[1,3]dioxol-5-yl)-5-nitro-pentan-2-one [(S)-( )-13] at 3 MHz, in CDCl Figure S16. The 13 C (APT) NMR spectrum of (S)-( )-4-(7-methoxybenzo[1,3]dioxol-5-yl)-5-nitropentan-2-one [(S)-( )-13] at 75 MHz, in CDCl 3. S9

10 Spectroscopic data for (8R,9R)-9-amino(9-deoxy)epicinchonine (15) Figure S17. The 1 H NMR spectrum of (8R,9R)-9-amino(9-deoxy)epicinchonine (15) at 3 MHz, in CDCl Figure S18. The 13 C (APT) NMR spectrum of (8R,9R)-9-amino(9-deoxy)epicinchonine (16) at 75 MHz, in CDCl 3. S1

11 Spectroscopic data for (8S,9S)-9-amino(9-deoxy)epiquinine (16) ppm (t1) Figure S19. The 1 H NMR spectrum of (8S,9S)-9-amino(9-deoxy)epiquinine (16) at 3 MHz, in CDCl ppm (t1) 1 5 Figure S2. The 13 C (APT) NMR spectrum of (8S,9S)-9-amino(9-deoxy)epiquinine (16) at 75 MHz, in CDCl 3. S11

12 Spectroscopic data for (3R,4S,5S)-( )-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-nitrocyclohexanone [( )-(17)] Figure S21. The 1 H NMR spectrum of (3R,4S,5S)-( )-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4- nitrocyclohexanone [( )-(17)] at 3 MHz, in DMSO-d Figure S22. The 13 C (APT) NMR spectrum of (3R,4S,5S)-( )-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol- 5-yl)-4-nitrocyclohexanone [( )-(17)] at 75 MHz, in DMSO-d 6. S12

13 Spectroscopic data for (3R,4S,5S)-(+)-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-nitrocyclohexanone ethylene acetal [(+)-(18)] Figure S22. The 1 H NMR spectrum of (3R,4S,5S)-(+)-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4- nitrocyclohexanone ethylene acetal [(+)-(18)] at 3 MHz, in CDCl ppm (t1) 1 5 Figure S24. The 13 C (APT) NMR spectrum of (3R,4S,5S)-(+)-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol- 5-yl)- 4-nitrocyclohexanone ethylene acetal [(+)-(18)] at 75 MHz, in CDCl 3. S13

14 Spectroscopic data for (3R,4S,5S)-( )-4-amino-5-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohexan-3-ol ethylene acetal [( )-(19)] Figure S25. The 1 H NMR spectrum of (3R,4S,5S)-( )-4-amino-5-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohexan-3-ol ethylene acetal [( )-(19)] at 3 MHz, in CDCl Figure S26. The 13 C (APT) NMR spectrum of (3R,4S,5S)-( )-4-amino-5-(7-methoxybenzo[1,3]dioxol-5- yl)cyclohexan-3-ol ethylene acetal [( )-(19)] at 75 MHz, in CDCl 3. S14

15 Spectroscopic data for (3R,4S,5S)-( )-3-hydroxy-4-methoxycarbonylamino-5-(7- methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal [( )-(2)] Figure S27. The 1 H NMR spectrum of (3R,4S,5S)-( )-3-hydroxy-4-methoxycarbonylamino-5-(7- methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal [( )-(2)] at 3 MHz, in CDCl Figure S28. The 13 C (APT) NMR spectrum of (3R,4S,5S)-( )-3-hydroxy-4-methoxycarbonylamino-5-(7- methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal [( )-(2)] at 75 MHz, in CDCl 3. S15

16 Spectroscopic data for (1R,6S)-( )-[6-(7-methoxybenzo[1,3]dioxol-5-yl)-4- oxocyclohex-2-enyl]carbamic acid methyl ester [( )-21] Figure S29. The 1 H NMR spectrum of (1R,6S)-( )-[6-(7-methoxybenzo[1,3]dioxol-5-yl)-4-oxocyclohex- 2-enyl]carbamic acid methyl ester [( )-21] at 3 MHz, in CDCl ppm (t1) Figure S3. The 13 C (APT) NMR spectrum of (1R,6S)-( )-[6-(7-methoxybenzo[1,3]dioxol-5-yl)-4- oxocyclohex-2-enyl]carbamic acid methyl ester [( )-21] at 75 MHz, in CDCl 3. S16

17 Spectroscopic data for (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] Figure S31. The 1 H NMR spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 3 MHz, in CDCl Figure S32. The 13 C (APT) NMR spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol- 5-yl)cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 75 MHz, in CDCl 3. S17

18 Figure S33. The COSY spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 3 MHz, in CDCl 3. Figure S34. The HSQC spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 3 and 75 MHz, in CDCl 3. S18

19 Figure S35. The HMBC spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 3 and 75 MHz, in CDCl 3. Figure S36. The NOESY spectrum of (1R,4S,6S)-( )-[4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)- cyclohex-2-enyl]carbamic acid methyl ester [( )-22] at 3 MHz, in CDCl 3. S19

20 Spectroscopic data for (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]-dioxol-5- yl)-4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] Figure S37. The 1 H NMR spectrum of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]-dioxol-5- yl)-4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] at 3 MHz, in CDCl Figure S38. The 13 C (APT) NMR spectrum of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]- dioxol-5-yl)-4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] at 75 MHz, in CDCl 3. S2

21 Figure S39. The COSY spectrum of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]-dioxol-5-yl)- 4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] at 3 MHz, in CDCl 3. Figure S4. The HSQC spectrum of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]-dioxol-5-yl)- 4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] at 3 and 75 MHz, in CDCl 3. S21

22 Figure S41. The HMBC spectrum of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]-dioxol-5-yl)- 4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] at 3 and 75 MHz, in CDCl 3. S22

23 Spectroscopic data for (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] Figure S42. The 1 H NMR spectrum of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] at 3 MHz, in CDCl Figure S43. The 13 C (APT) NMR spectrum of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] at 75 MHz, in CDCl 3. S23

24 Figure S44. The COSY spectrum of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] at 3 MHz, in CDCl 3. Figure S45. The HSQC spectrum of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] at 3 and 75 MHz, in CDCl 3. S24

25 Figure S46. The HMBC spectrum of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] at 3 and 75 MHz, in CDCl 3. S25

26 Spectroscopic data for (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] Figure S47. The 1 H NMR spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 3 MHz, in CDCl Figure S48. The 13 C (APT) NMR spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 75 MHz, in CDCl 3. S26

27 Figure S49. The COSY spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 3 MHz, in CDCl 3. Figure S5. The HSQC spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 3 and 75 MHz, in CDCl 3. S27

28 Figure S51. The HMBC spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 3 and 75 MHz, in CDCl 3. Figure S52. The NOESY spectrum of (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] at 3 MHz, in CDCl 3. S28

29 Spectroscopic data for (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-6,7- dimethoxy-1,2,3,4,4a,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (26) Figure S53. The 1 H NMR spectrum of (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-6,7-dimethoxy- 1,2,3,4,4a,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (26) at 3 MHz, in CDCl Figure S54. The 13 C (APT) NMR spectrum of (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-6,7-dimethoxy-1,2,3,4,4a,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (26) at 75 MHz, in CDCl 3. S29

30 Spectroscopic data for (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-7-methoxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (27) Figure S55. The 1 H NMR spectrum of (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-7-methoxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (27) at 3 MHz, in CDCl Figure S56. The 13 C (APT) NMR spectrum of (2R,3S,4R,4aS,11bS)-benzoic acid 3,4-diacetoxy-7- methoxy-6-oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester (27) at 75 MHz, in CDCl 3. S3

31 Spectroscopic data for (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7- hydroxy-6-oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] Figure S57. The 1 H NMR spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7-hydroxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 3 MHz, in CDCl Figure S58. The 13 C (APT) NMR spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7- hydroxy-6-oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 75 MHz, in CDCl 3. S31

32 Figure S59. The COSY spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7-hydroxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 3 MHz, in CDCl 3. Figure S6. The HSQC spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7-hydroxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 3 and 75 MHz, in CDCl 3. S32

33 Figure S61. The HMBC spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7-hydroxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 3 and 75 MHz, in CDCl 3. Figure S62. The NOESY spectrum of (2R,3S,4R,4aS,11bS)-( )-benzoic acid 3,4-diacetoxy-7-hydroxy-6- oxo-1,2,3,4,4a,5,6,11b-octahydro[1,3]dioxolo[4,5-j]phenanthridin-2-yl ester [( )-28] at 3 MHz, in CDCl 3. S33

34 Chiral HPLC chromatograms of racemic (rac-1) and optically active ( )-transdihydronarciclasine [( )-1] ( ) t R = 12.9 min O O OH NH OH OH OH O rac-1 (+) t R = 18.8 min Figure S63. The chiral HPLC chromatogram of racemic trans-dihydronarciclasine (rac-1) using TADDOL AS-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). ( ) t R = 12.1 min ee 92% (+) t R = 17.9 min Figure S64. The chiral HPLC chromatogram of ( )-trans-dihydronarciclasine [( )-1] using TADDOL AS-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S34

35 Chiral HPLC chromatograms of racemic (rac-13) and optically active (S)-( )-4-(7- methoxybenzo[1,3]dioxol-5-yl)-5-nitro-pentan-2-one [(S)-( )-13] ( ) t R = 21.1 min (+) t R = 28.7 min Figure S65. The chiral HPLC chromatogram of racemic 4-(7-methoxybenzo[1,3]dioxol-5-yl)-5-nitropentan-2-one (rac-13) using TADDOL AS-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). ( ) t R = 29.5 min ee >99% Figure S66. The chiral HPLC chromatogram of (S)-( )-4-(7-methoxybenzo[1,3]dioxol-5-yl)-5-nitropentan-2-one [(S)-( )-13] using TADDOL AS-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S35

36 Chiral HPLC chromatograms of racemic (rac-17) and optically active (3R,4S,5S)-( )- 3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-nitrocyclohexanone [( )-17] Contaminant t R = 38.4 min (+) t R = 33.3 min ( ) t R = 4.5 min Figure S67. The chiral HPLC chromatogram of racemic 3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-nitrocyclohexanone (rac-17) using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate.8 ml min 1, 256 nm, 2 C). Contaminant t R = 12.2 min ( ) t R = 17.4 min ee 95% (+) t R = 14. min Figure S68. The chiral HPLC chromatogram of (3R,4S,5S)-( )-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-nitrocyclohexanone [( )-17] using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S36

37 Chiral HPLC chromatograms of racemic (rac-18) and optically active (3R,4S,5S)-(+)- 3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-nitrocyclohexanone ethylene acetal [(+)-18] (+) t R = 18.2 min Contaminant t R = 15.9 min ( ) t R = 39.5 min Figure S69. The chiral HPLC chromatogram of racemic 3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-nitrocyclohexanone ethylene acetal (rac-18) using TADDOL AD-H column (hexane/isopropyl alcohol = 8:2, flow rate 2. ml min 1, 256 nm, 2 C). (+) t R = 21. min ee 99% Contaminant t R = 25.2 min Figure S7. The chiral HPLC chromatogram of (3R,4S,5S)-(+)-3-hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-nitrocyclohexanone ethylene acetal [(+)-18] using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S37

38 Chiral HPLC chromatograms of racemic (rac-2) and optically active (3R,4S,5S)-( )- 3-hydroxy-4-methoxycarbonylamino-5-(7-methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal [( )-2] (+) t R = 13.6 min ( ) t R = 19.9 min Figure S71. The chiral HPLC chromatogram of racemic 3-hydroxy-4-methoxycarbonylamino-5-(7- methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal (rac-2) using TADDOL AS-H column (hexane/isopropyl alcohol= 8:2, flow rate 2. ml min 1, 256 nm, 2 C). ( ) t R = 2.8 min ee 99% Figure S72. The chiral HPLC chromatogram of (3R,4S,5S)-( )-3-hydroxy-4-methoxycarbonylamino-5- (7-methoxybenzo[1,3]dioxol-5-yl)cyclohexanone ethylene acetal [( )-2] using TADDOL AS-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S38

39 Chiral HPLC chromatograms of racemic (rac-21) and optically active (1R,6S)-( )-[6- (7-methoxybenzo[1,3]dioxol-5-yl)-4-oxocyclohex-2-enyl]carbamic acid methyl ester [( )-21] ( ) t R = 18.2 min (+) t R = 2.9 min Figure S73. The chiral HPLC chromatogram of racemic [6-(7-methoxybenzo[1,3]dioxol-5-yl)-4-oxocyclohex-2-enyl]carbamic acid methyl ester (rac-21) using TADDOL AD-H column (hexane/isopropyl alcohol= 8:2, flow rate.8 ml min 1, 256 nm, 2 C). ( ) t R = 18.3 min ee 93% (+) t R = 2.8 min Contaminant t R = 23.2 min Figure S74. The chiral HPLC chromatogram of (1R,6S)-( )-[6-(7-methoxybenzo[1,3]dioxol-5-yl)-4-oxocyclohex-2-enyl]carbamic acid methyl ester [( )-21] using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate.8 ml min 1, 256 nm, 2 C). S39

40 Chiral HPLC chromatograms of racemic (rac-22) and optically active (1R,4S,6S)-( )- [4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)cyclohex-2-enyl]carbamic acid methyl ester [( )-22] ( ) t R = 15.5 min (+) t R = 32.6 min Figure S75. The chiral HPLC chromatogram of racemic [4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5- yl)cyclohex-2-enyl]carbamic acid methyl ester (rac-22) using TADDOL AD-H column (hexane/isopropyl alcohol= 8:2, flow rate.8 ml min 1, 256 nm, 2 C). ( ) t R = 15. min ee 99% Figure S76. The chiral HPLC chromatogram of (1R,4S,6S)-( )- [4-hydroxy-6-(7-methoxybenzo[1,3]dioxol-5-yl)cyclohex-2-enyl]carbamic acid methyl ester [( )-22] using TADDOL AD-H column (hexane/ isopropyl alcohol=8:2, flow rate.8 ml min 1, 256 nm, 2 C). S4

41 Chiral HPLC chromatograms of racemic (rac-23) and optically active (1R,4R,5S)-(+)- benzoic acid 5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohex- 2-enyl ester [(+)-23] ( ) t R = 19. min (+) t R = 23.1 min Contaminant t R = 26.8 min Figure S77. The chiral HPLC chromatogram of racemic benzoic acid 5-(7-methoxybenzo[1,3]dioxol-5- yl)-4-methoxycarbonylaminocyclohex-2-enyl ester (rac-23) using TADDOL AD-H column (hexane/ isopropyl alcohol=8:2, flow rate.8 ml min 1, 256 nm, 2 C). (+) t R = 26.1 min ee 97% ( ) t R = 2.8 min Figure S78. The chiral HPLC chromatogram of (1R,4R,5S)-(+)-benzoic acid 5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohex-2-enyl ester [(+)-23] using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate.8 ml min 1, 256 nm, 2 C). S41

42 Chiral HPLC chromatograms of racemic (rac-24) and optically active (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-methoxycarbonylaminocyclohexyl ester [(+)-24] (+) t R = 16.5 min ( ) t R = 23. min Figure S79. The chiral HPLC chromatogram of racemic benzoic acid 2,3-dihydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester (rac-24) using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). (+) t R = 17.5 min ee 95% ( ) t R = 23.4 min Figure S8. The chiral HPLC chromatogram of (1R,2R,3R,4S,5S)-(+)-benzoic acid 2,3-dihydroxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [(+)-24] using TADDOL AD- H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S42

43 Chiral HPLC chromatograms of racemic (rac-25) and optically active (1R,2S,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)- 4-methoxycarbonylaminocyclohexyl ester [( )-25] (+) t R = 8.3 min ( ) t R = 14.4 min Figure S81. The chiral HPLC chromatogram of racemic benzoic acid 2,3-diacetoxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester (rac-25) using TADDOL AD-H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). ( ) t R = 14.6 min ee 95% (+) t R = 8.3 min Figure S82. The chiral HPLC chromatogram of (1R,2R,3R,4S,5S)-( )-benzoic acid 2,3-diacetoxy-5-(7- methoxybenzo[1,3]dioxol-5-yl)-4-methoxycarbonylaminocyclohexyl ester [( )-25] using TADDOL AD- H column (hexane/isopropyl alcohol=8:2, flow rate 2. ml min 1, 256 nm, 2 C). S43

44 Chiral HPLC chromatograms of compound 13 obtained by asymmetric Michael addition using organocatalysts ( ) t R = 3.8 min ee 72% (+) t R = 43.5 min Figure S83. The chiral HPLC chromatogram of compound 13 obtained by asymmetric Michael addition in the presence of Jørgensen s catalyst (14) using TADDOL AS-H column (hexane/isopropyl alcohol =8:2, flow rate 2. ml min 1, 256 nm, 2 C). (+) t R = 43.8 min ee 78% ( ) t R = 31. min Figure S84. The chiral HPLC chromatogram of compound 13 obtained by asymmetric Michael addition in the presence of (8R,9R)-9-amino(9-deoxy)epicinchonine (15) organocatalyst using TADDOL AS-H column (hexane/isopropyl alcohol =8:2, flow rate 2. ml min 1, 256 nm, 2 C). S44

45 ( ) t R = 26.8 min ee >99% Figure S85. The chiral HPLC chromatogram of compound 13 obtained by asymmetric Michael addition in the presence of (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst using TADDOL AS-H column (hexane/isopropyl alcohol =8:2, flow rate 2. ml min 1, 256 nm, 2 C). S45

46 XRD crystallographic data of (S)-( )-13 (S)-( )-4-(7-Methoxybenzo[1,3]dioxol-5-yl)-5-nitropentan-2-one [(S)-( )-13] crystallises from methanol in the orthorhombic crystal system, in the space group P All crystal data and refinement parameters are summarized in Table S1, while its molecular structure is shown in Figure S86. Crystallographic data for the crystal structure of (S)-( )-13 have been deposited with the Cambridge Crystallographic Data Centre ( as supplementary publication number CCDC Table S1. Crystal data and structure refinement Empirical formula C 13 H 15 NO 6 Formula weight Chemical name (S)-( )-4-(7-Methoxybenzo[1,3]dioxol-5-yl)- 5-nitropentan-2-one Temperature 295 K Radiation and wavelength Cu K, = Å Crystal system orthorhombic Space group P Unit cell dimensions a = (3) Å b = (4) Å c = 37.59(18) Å Volume (13) Å 3 Z 4 Density (calculated) g/cm 3 Absorption coefficient,.921 mm 1 F() 592. Crystal colour clear light yellow Crystal description needle Crystal size.2 x.1 x.5 mm Absorption correction MULTI-SCAN Max. and min. transmission.259 and 1. range for data collection Index ranges -6 h 6; -8 k 8; -45 l 45 Computing data collection CrysAlis Pro [1] Reflections collected Completeness to 2.99 Independent reflections 2658 [R(int) =.665] Reflections I>2 (I) 2256 Refinement method SHELXL [2] Data / restraints / parameters 2658 / 3 / 227 Goodness-of-fit on all reflections 1.59 Final R indices [I>2 (I)] R 1 =.5, wr 2 =.1451 R indices (all data) R 1 =.66, wr 2 =.1566 Max. and mean shift/esd.;. S46

47 Figure S86. Molecular structure of compound (S)-( )-13 determined by the single-crystal X-ray diffraction method (ORTEP representation). Displacement ellipsoids are drawn at the 5% probability level. S47

48 XRD crystallographic data of compound ( )-17 (3R,4S,5S)-( )-3-Hydroxy-5-(7-methoxybenzo[1,3]dioxol-5-yl)-4-nitrocyclohexanone [( )-17] crystallises from isopropyl alcohol in the monoclinic crystal system, in the space group P 2 1. All crystal data and refinement parameters are summarized in Table S2, while its molecular structure is shown in Figure S87. Crystallographic data for the crystal structure of compound ( )-17 have been deposited with the Cambridge Crystallographic Data Centre ( as supplementary publication number CCDC Table S2. Crystal data and structure refinement Empirical formula C 14 H 15 NO 7 Formula weight Chemical name (3R,4S,5S)-( )-3-Hydroxy-5-(7-methoxybenzo[1,3]dioxol- 5-yl)-4-nitrocyclohexanone Temperature 295 K Radiation and wavelength Cu K, = Å Crystal system monoclinic Space group P 2 1 Unit cell dimensions a = (11) Å b = (14) Å c = (3) Å (16) 9 Volume 75.76(2) Å 3 Z 2 Density (calculated) g/cm 3 Absorption coefficient, 1.12 mm 1 F() 324 Crystal colour clear light white Crystal description needle Crystal size.5 x.5 x.1 mm Absorption correction MULTI-SCAN Max. and min. transmission.779 and 1. range for data collection Index ranges -7 h 7; -6 k 6; -24 l 24 Computing data collection CrysAlis Pro [1] Reflections collected Completeness to 2.99 Independent reflections 2577 [R(int) =.296] Reflections I>2 (I) 2329 Refinement method SHELXL [2] Data / restraints / parameters 2544 / 1 / 21 Goodness-of-fit on all reflections.917 Final R indices [I>2 (I)] R 1 =.381, wr 2 =.195 R indices (all data) R 1 =.36, wr 2 =.116 Max. and mean shift/esd.;. S48

49 Figure S87. Molecular structure of compound ( )-17 defined by the single-crystal X-ray diffraction method (ORTEP representation). Displacement ellipsoids are drawn at the 5% probability level. References [1] CrysAlis Pro, Agilent Technologies Ltd, Yarnton, Oxfordshire, England, 214. [2] Sheldrick, G. M. Acta Cryst. 215, C71, 3 8. S49

Supporting information. (+)- and ( )-Ecarlottones, Uncommon Chalconoids. from Fissistigma latifolium with Proapoptotic

Supporting information. (+)- and ( )-Ecarlottones, Uncommon Chalconoids. from Fissistigma latifolium with Proapoptotic Supporting information (+)- and ( )-Ecarlottones, Uncommon Chalconoids from Fissistigma latifolium with Proapoptotic Activity Charlotte Gény, Alma Abou Samra, Pascal Retailleau, Bogdan I. Iorga, Hristo