Supporting Information

Transcription

1 Supporting Information Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors Peng-Cheng Wang a, Jim-Min Fang a,b, *, Keng-Chang Tsai c, Shi-Yun Wang b, Wen-I Huang b, Yin-Chen Tseng b, Yih-Shyun E. Cheng b, Ting-Jen Rachel Cheng b, and Chi-Huey Wong b a Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan. b The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. c National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 112, Taiwan. Corresponding Author J.-M.F.: phone, ; fax, ; , jmfang@ntu.edu.tw. Contents Page number ADMET prediction of peramivir phosphonate derivatives 6a 8c S2 Figure S1. Structures of peramivir 5 and phosphono-peramivir 6a S3 Figure S2. Overlay of the molecular modeling structures in the NA active S4 site. Figures S3 S6. Stability test of phosphonate monoethyl ester 7b. S5 S13 1 H, 13 C and 31 P NMR spectra, HPLC diagram, and X-ray data of compound S14 S21 6a 1 H, 13 C and 31 P NMR spectra, and HPLC diagram of compounds 6b 8c. S22 S37 1 H and 13 C NMR spectra of compound 10a. S38 1 H and 13 C NMR spectra, and X-ray data of compounds 11 and 12. S39 S65 1 H, 13 C, 31 P and 2D NMR spectra of compounds 13 and 13-isomer. S66 S70 1 H, 13 C and 31 P NMR spectra of compounds S71 S93 S1

2 Table S1. ADMET prediction of peramivir phosphonate derivatives 6a 8c. a Cmpd Solubility b BBBP c Absorption d CYP2D6 e Hepatotox. f PPB g a b a b c a b c a b c a Acquired from Discovery Studio 3.5 program (Accelrys, Inc., San Diego, CA) for prediction of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. b It predicts the level of the solubility of each compound in water at 25 o C: high, ++; medium, +; low, ; very low, 0. c It predicts the level of blood-brain barrier penetration (BBBP) after oral administration of each compound: high penetration, ++; medium, +; low, ; undefined,. d It predicts the human intestinal absorption level of each compound: high, ++; medium, +; low, ; very low, 0. e It predicts cytochrome P450 2D6 enzyme inhibition by each compound: none, 0. f It predicts the occurrence of dose-dependent human hepatotoxicity by each compound: none, 0. g Plasma protein binding (PPB) predicts likelihood that a compound will be bound to carrier proteins in the blood: low,. S2

3 (A) (B) (C) (D) Figure S1. Structures of peramivir 5 and phosphono-peramivir 6a: (A) molecular modeling structure of 5 in the active site of NA (N1 subtype, PDB code: 2HU4) 6, (B) structure of 5 in the 5 NA complex (PDB: 1L7F), 20 (C) molecular modeling of 6a in the active site of NA (N1 subtype, PDB code: 2HU4) 6, (D) X-ray structure of 6a. The root-mean-square deviation (RMSD) is 0.01Å. S3

4 Figure S2. Overlay of the molecular modeling structures in the NA active site (N1 subtype, PDB code: 2HU4) 6 : peramivir 5 (light pink), phosphono-peramivir 6a (blue) and dehydration derivative 7a (yellow), in comparison with the structure of 5 (purple) in the 5 NA complex (PDB: 1L7F). 20 S4

5 S5

6 Figure S3. Stability test of phosphonate monoethyl ester 7b in PBS (1 mm, ph 7.4) at 37 o C by HPLC and MS analyses at intervals of 24, 48, 72 and 96 h. HPLC conditions: HC-C18 column (Merck Chromolith, mm i.d., 2 µm particle size); eluent, MeOH/(0.1%TFA aqueous solution) = 3:7; flow rate, 1 ml/min; detection at 214 nm wavelength. The protonated ion [M + H] + (C 16 H 32 N 4 O 4 P calculated m/z ) and sodiated molecular ion [M + Na] + (C 16 H 31 N 4 NaO 4 P calculated m/z ) were observed in the ESI HRMS spectra. No MS signals for phosphonic acid 7a appeared. S6

7 S7

8 Figure S4. Stability test of phosphonate monoethyl ester 7b in acetate buffer (1 mm, ph 4.0) at 37 o C by HPLC and MS analyses at intervals of 24, 48, 72 and 96 h. HPLC conditions: HC-C18 column (Merck Chromolith, mm i.d., 2 µm particle size); eluent, MeOH/(0.1%TFA aqueous solution) = 3:7; flow rate, 1 ml/min; detection at 214 nm wavelength. The protonated ion [M + H] + (C 16 H 32 N 4 O 4 P calculated m/z ) and sodiated molecular ion [M + Na] + (C 16 H 31 N 4 NaO 4 P calculated m/z ) were observed in the ESI HRMS spectra. No MS signals for phosphonic acid 7a appeared. S8

9 S9

10 Figure S5. Stability test of phosphonate monoethyl ester 7b in HCl buffer (1 mm, ph 2.0) at 37 o C by HPLC and MS analyses at intervals of 24, 48, 72 and 96 h. HPLC conditions: HC-C18 column (Merck Chromolith, mm i.d., 2 µm particle size); eluent, MeOH/(0.1%TFA aqueous solution) = 3:7; flow rate, 1 ml/min; detection at 214 nm wavelength. The protonated ion [M + H] + (C 16 H 32 N 4 O 4 P calculated m/z ) and sodiated molecular ion [M + Na] + (C 16 H 31 N 4 NaO 4 P calculated m/z ) were observed in the ESI HRMS spectra. No MS signals for phosphonic acid 7a appeared. S10

11 S11

12 S12

13 Figure S6. Stability test of phosphonate monoethyl ester 7b in rabbit serum (1 mm) at 37 o C by HPLC and MS analyses at intervals of 24, 48, 72 and 96 h. HPLC conditions: HC-C18 column (Merck Chromolith, mm i.d., 2 µm particle size); eluent, MeOH/(0.1%TFA aqueous solution) = 3:7; flow rate, 1 ml/min; detection at 214 nm wavelength. The protonated ion [M + H] + (C 16 H 32 N 4 O 4 P calculated m/z ) and sodiated molecular ion [M + Na] + (C 16 H 31 N 4 NaO 4 P calculated m/z ) were observed in the ESI HRMS spectra. No MS signals for phosphonic acid 7a appeared. S13

14 1 H NMR spectrum of compound 6a (500 MHz, in D 2 O) 13 C NMR spectrum of compound 6a (100 MHz, in D 2 O) S14

15 31 P NMR spectrum of compound 6a (162 MHz, in D 2 O) HPLC diagram of phosphonic acid 6a. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 5.5 min [MeOH/(0.5%TFA aqueous solution) = 2:3] at a flow rate of 0.5 ml/min. S15

16 ORTEP drawing of phosphonic acid 6a (IC16071, deposit CCDC ); thermal ellipsoids drawn at the 50% probability level. S16

17 Table S2A. Crystal data and structure refinement of phosphonic acid 6a. Identification code ic16071 Empirical formula C15 H37 N4 O8 P Formula weight Temperature 200(2) K Wavelength Å Crystal system Monoclinic Space group C2 Unit cell dimensions a = (5) Å a= 90. b = (4) Å b= (4). c = (8) Å g = 90. Volume (16) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 936 Crystal size 0.20 x 0.10 x 0.02 mm 3 Theta range for data collection 5.28 to Index ranges -15<=h<=15, -12<=k<=6, -14<=l<=20 Reflections collected 4359 Independent reflections 2718 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2718 / 20 / 296 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.01(4) Largest diff. peak and hole and e.å -3 S17

18 Table S2B. Atomic coordinates ( 10 4 ) and equivalent isotropic displacement parameters (Å ) of phosphonic acid 6a. U (eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) P(1) 8522(1) 1126(1) 4352(1) 29(1) O(1) 7737(2) 123(3) 4123(2) 42(1) O(2) 8651(2) 1239(4) 5288(2) 38(1) O(3) 9567(2) 885(4) 4026(2) 36(1) O(4) 6718(2) 2926(3) 2953(2) 35(1) O(5) 7083(3) 7072(5) 1763(3) 62(1) N(1) 8500(3) 5842(4) 1939(2) 38(1) N(2) 9194(3) 5880(4) 3673(2) 36(1) N(3) 9796(3) 7962(5) 3775(3) 42(1) N(4) 8131(3) 7541(5) 4030(3) 43(1) C(1) 8014(3) 2689(5) 4042(2) 31(1) C(2) 7810(3) 2794(4) 3125(3) 30(1) C(3) 8403(3) 4007(4) 2881(3) 30(1) C(4) 8437(3) 4835(4) 3651(3) 33(1) C(5) 8661(4) 3849(5) 4302(3) 37(1) C(6) 9028(4) 7103(5) 3829(3) 32(1) C(7) 7975(3) 4630(5) 2098(3) 36(1) C(8) 8019(4) 3703(6) 1390(3) 41(1) C(9) 9122(4) 3373(7) 1182(3) 50(1) C(10) 9180(20) 2240(40) 675(19) 62(5) C(10') 9226(13) 1870(20) 983(18) 69(5) C(11) 7397(5) 4179(7) 651(3) 55(2) C(12) 6230(4) 4200(8) 732(4) 66(2) C(13) 8024(4) 6961(6) 1790(3) 47(1) C(14) 8707(5) 8111(7) 1645(4) 63(2) O(6) 5911(3) 1061(5) 1828(2) 53(1) C(15) 6346(5) 463(8) 1158(4) 67(2) O(7) 6056(3) -260(4) 3187(3) 48(1) O(8) 5668(4) 7238(5) 2895(4) 70(1) S18

19 Table S2C. Bond lengths [Å ] and angles [ ] of phosphonic acid 6a. P(1)-O(1) 1.492(3) P(1)-O(3) 1.522(3) P(1)-O(2) 1.575(3) P(1)-C(1) 1.811(5) O(4)-C(2) 1.442(5) O(5)-C(13) 1.233(7) N(1)-C(13) 1.330(7) N(1)-C(7) 1.461(6) N(2)-C(6) 1.313(7) N(2)-C(4) 1.463(6) N(3)-C(6) 1.347(7) N(4)-C(6) 1.319(6) C(1)-C(5) 1.516(6) C(1)-C(2) 1.550(6) C(2)-C(3) 1.542(6) C(3)-C(7) 1.537(6) C(3)-C(4) 1.549(6) C(4)-C(5) 1.510(7) C(7)-C(8) 1.531(7) C(8)-C(11) 1.523(7) C(8)-C(9) 1.541(7) C(9)-C(10) 1.46(3) C(9)-C(10') 1.60(2) C(11)-C(12) 1.538(8) C(13)-C(14) 1.515(9) O(6)-C(15) 1.432(8) O(1)-P(1)-O(3) 114.2(2) O(1)-P(1)-O(2) 109.8(2) O(3)-P(1)-O(2) (15) O(1)-P(1)-C(1) 108.2(2) O(3)-P(1)-C(1) (19) O(2)-P(1)-C(1) 103.6(2) C(13)-N(1)-C(7) 124.2(4) C(6)-N(2)-C(4) 126.6(4) C(5)-C(1)-C(2) 106.8(3) S19

20 C(5)-C(1)-P(1) 115.9(3) C(2)-C(1)-P(1) 112.7(3) O(4)-C(2)-C(3) 112.1(3) O(4)-C(2)-C(1) 108.2(3) C(3)-C(2)-C(1) 105.2(3) C(7)-C(3)-C(2) 113.9(4) C(7)-C(3)-C(4) 118.1(4) C(2)-C(3)-C(4) 102.6(3) N(2)-C(4)-C(5) 112.3(4) N(2)-C(4)-C(3) 114.5(3) C(5)-C(4)-C(3) 103.0(4) C(4)-C(5)-C(1) 104.3(4) N(2)-C(6)-N(4) 122.9(4) N(2)-C(6)-N(3) 119.3(4) N(4)-C(6)-N(3) 117.8(5) N(1)-C(7)-C(8) 110.8(4) N(1)-C(7)-C(3) 111.5(4) C(8)-C(7)-C(3) 111.8(4) C(11)-C(8)-C(7) 112.8(5) C(11)-C(8)-C(9) 110.2(4) C(7)-C(8)-C(9) 113.3(4) C(10)-C(9)-C(8) 113.4(12) C(10)-C(9)-C(10') 23.7(9) C(8)-C(9)-C(10') 110.9(8) C(8)-C(11)-C(12) 114.4(4) O(5)-C(13)-N(1) 122.8(5) O(5)-C(13)-C(14) 121.1(6) N(1)-C(13)-C(14) 116.2(5) Symmetry transformations used to generate equivalent atoms: S20

21 Table S2D. Anisotropic displacement parameters (Å ) of phosphonic acid 6a. The anisotropic displacement factor exponent takes the form : 2p 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 P(1) 20(1) 25(1) 42(1) 1(1) -1(1) 1(1) O(1) 33(2) 24(2) 67(2) 1(2) -8(1) 0(1) O(2) 18(1) 47(2) 50(2) 6(2) 4(1) 11(2) O(3) 29(2) 41(2) 39(1) -5(1) -2(1) 3(1) O(4) 20(2) 38(2) 46(2) -2(2) -2(1) -2(1) O(5) 42(2) 48(2) 97(3) 19(2) 14(2) 9(2) N(1) 24(2) 38(2) 52(2) 8(2) -1(2) -1(2) N(2) 21(2) 35(2) 52(2) -5(2) 5(1) 0(2) N(3) 25(2) 31(2) 71(3) -7(2) 9(2) -3(2) N(4) 29(2) 31(2) 69(3) -4(2) 12(2) -6(2) C(1) 24(2) 29(2) 39(2) -1(2) 1(2) 1(2) C(2) 23(2) 26(2) 40(2) 1(2) 2(2) 0(2) C(3) 17(2) 27(2) 44(2) 0(2) 0(2) 0(2) C(4) 25(2) 25(2) 49(2) -2(2) 4(2) -2(2) C(5) 34(2) 33(3) 43(2) -8(2) 1(2) -6(2) C(6) 29(2) 27(2) 40(2) 0(2) 0(2) -1(2) C(7) 25(2) 36(3) 49(2) 9(2) 0(2) -2(2) C(8) 30(2) 49(3) 44(2) 5(2) -2(2) -5(2) C(9) 39(3) 67(4) 43(3) -5(3) 4(2) -3(3) C(10) 49(8) 88(13) 50(10) 3(10) 11(8) 14(9) C(10') 56(6) 74(10) 75(10) -14(7) 6(7) 11(6) C(11) 54(3) 64(4) 45(3) 12(3) -6(2) -12(3) C(12) 40(3) 83(5) 71(4) 11(4) -26(3) -1(3) C(13) 41(3) 42(3) 59(3) 19(3) 8(2) 2(2) C(14) 58(4) 45(4) 84(4) 20(3) -2(3) -1(3) O(6) 46(2) 50(2) 61(2) -5(2) -2(2) -3(2) C(15) 49(3) 71(5) 81(4) -11(4) 4(3) -12(3) O(7) 23(2) 48(3) 72(2) -3(2) -11(2) 2(2) O(8) 81(3) 51(3) 81(3) 0(3) 30(3) -4(3) S21

22 1 H NMR spectrum of compound 6b (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 6b (100 MHz, in CD 3 OD) S22

23 31 P NMR spectrum of compound 6b (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monoethyl ester 6b. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 12.2 min [MeOH/(0.5%TFA aqueous solution) = 3:7] at a flow rate of 0.5 ml/min. S23

24 1 H NMR spectrum of compound 6c (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 6c (100 MHz, in CD 3 OD) S24

25 31 P NMR spectrum of compound 6c (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monohexyl ester 6c. HC-C18 column (Merck, mm, 2 µm porosity), t R = 4.7 min [MeOH/(0.1%TFA aqueous solution) = 3:2] at a flow rate of 1.0 ml/min. S25

26 1 H NMR spectrum of compound 7a (400 MHz, in D 2 O) 13 C NMR spectrum of compound 7a (100 MHz, in D 2 O) S26

27 31 P NMR spectrum of compound 7a (162 MHz, in D 2 O) HPLC diagram of phosphonic acid 7a. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 9.8 min [MeOH/(0.5%TFA aqueous solution) = 3:7] at a flow rate of 0.5 ml/min. S27

28 1 H NMR spectrum of compound 7b (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 7b (100 MHz, in CD 3 OD) S28

29 31 P NMR spectrum of compound 7b (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monoethyl ester 7b. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 12.8 min [MeOH/(0.5%TFA aqueous solution) = 3:7] at a flow rate of 0.5 ml/min. S29

30 1 H NMR spectrum of compound 7c (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 7c (100 MHz, in CD 3 OD) S30

31 31 P NMR spectrum of compound 7c (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monohexyl ester 7c. HC-C18 column (Merck, mm, 2 µm porosity), t R = 11.4 min [MeOH/(0.1%TFA aqueous solution) = 1:1] at a flow rate of 1.0 ml/min. S31

32 1 H NMR spectrum of compound 8a (400 MHz, in D 2 O) 13 C NMR spectrum of compound 8a (100 MHz, in D 2 O) S32

33 31 P NMR spectrum of compound 8a (162 MHz, in D 2 O) HPLC diagram of phosphonic acid 8a. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 16.9 min [MeOH/(0.5%TFA aqueous solution) = 1:4] at a flow rate of 0.5 ml/min. S33

34 1 H NMR spectrum of compound 8b (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 8b (100 MHz, in CD 3 OD) S34

35 31 P NMR spectrum of compound 8b (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monoethyl ester 8b. HC-C18 column (Agilent, mm, 5 µm porosity), t R = 11.1 min [MeOH/(0.5%TFA aqueous solution) = 2:3] at a flow rate of 0.5 ml/min. S35

36 1 H NMR spectrum of compound 8c (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 8c (100 MHz, in CD 3 OD) S36

37 31 P NMR spectrum of compound 8c (162 MHz, in CD 3 OD) HPLC diagram of phosphonate monohexyl ester 8c. HC-C18 column (Merck, mm, 2 µm porosity), t R = 8.6 min [MeOH/(0.1%TFA aqueous solution) = 11:9 to 13:7] at a flow rate of 1.0 ml/min. S37

38 1 H NMR spectrum of compound 10a (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 10a (100 MHz, in CDCl 3 ) S38

39 1 H NMR spectrum of compound 11 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 11 (100 MHz, in CDCl 3 ) S39

40 ORTEP drawing of iodo compound 11 (IC15951, deposit CCDC ); thermal ellipsoids drawn at the 30% probability level. S40

41 Table S3A. Crystal data and structure refinement of iodo compound 11. Identification code ic15951 Empirical formula C24 H47 I N2 O4 Si Formula weight Temperature 295(2) K Wavelength Å Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = (8) Å a= 90. b = (15) Å b= (5). c = (7) Å g = 90. Volume (5) Å 3 Z 6 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1824 Crystal size 0.20 x 0.15 x 0.10 mm 3 Theta range for data collection 2.87 to Index ranges -17<=h<=15, -27<=k<=28, -18<=l<=20 Reflections collected Independent reflections [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters / 89 / 865 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.04(3) Largest diff. peak and hole and e.å -3 S41

42 Table S3B. Atomic coordinates ( 10 4 ) and equivalent isotropic displacement parameters (Å ) of iodo compound 11. U (eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) I(1) 1275(1) 7941(1) 3742(1) 192(1) Si(1) 1771(3) 7506(2) 650(2) 105(1) C(6) 1750(20) 6817(7) 1296(13) 248(14) C(7) 2835(12) 7489(13) 12(12) 230(13) C(8) 576(9) 7569(6) -87(7) 122(4) C(9) 483(18) 7042(12) -770(12) 256(13) C(10) -299(11) 7597(13) 366(11) 223(12) C(11) 590(20) 8176(10) -593(15) 280(17) O(1) 1934(5) 8098(3) 1271(3) 87(2) O(2) 4608(13) 10394(7) 2180(11) 226(7) O(3) 884(9) 10272(5) 1993(6) 157(4) O(4) 1932(7) 10637(4) 3141(4) 119(3) N(1) 4015(6) 9413(4) 2345(5) 91(2) N(2) 1995(7) 9701(4) 2808(5) 97(3) C(1) 1136(10) 8191(8) 2448(7) 120(5) C(2) 2130(7) 8124(5) 2165(6) 88(3) C(3) 2657(6) 8721(5) 2465(5) 74(2) C(4) 1822(7) 9166(5) 2242(6) 88(3) C(5) 815(10) 8835(10) 2248(10) 144(6) C(12) 3552(8) 8779(4) 2189(7) 93(3) C(13) 4209(8) 9860(6) 1812(7) 101(3) C(14) 4049(6) 9730(4) 1014(5) 66(2) C(15) 4452(9) 8336(5) 2376(8) 104(3) C(16) 4794(10) 8296(8) 3386(10) 141(6) C(17) 4810(30) 7697(14) 3728(15) 330(20) C(18) 5389(12) 8391(11) 2018(14) 183(8) C(19) 5246(15) 8324(10) 1109(12) 182(8) C(20) 1515(10) 10199(7) 2581(7) 121(5) C(21) 1631(14) 11248(8) 2971(9) 139(5) C(22) 599(19) 11370(10) 2995(15) 199(9) C(23) 1906(15) 11455(9) 2191(10) 169(7) C(24) 2332(14) 11589(7) 3702(10) 155(6) S42

43 I(2) 6413(1) 6957(1) -515(1) 142(1) Si(2) 8322(2) 6660(2) 2578(2) 95(1) O(5) 7364(5) 6272(3) 1996(4) 86(2) O(6) 5987(7) 4403(4) 2317(5) 117(3) O(7) 3425(6) 5605(6) 604(6) 160(5) O(8) 3450(6) 5071(5) -579(6) 145(4) N(3) 6425(6) 4583(4) 1047(5) 89(2) N(4) 4780(7) 5616(6) 145(6) 142(5) C(25) 6369(8) 6725(5) 779(6) 93(3) C(26) 7160(7) 6249(4) 1094(5) 77(3) C(27) 6622(6) 5653(4) 810(5) 69(2) C(28) 5526(7) 5749(5) 834(6) 85(3) C(29) 5387(9) 6439(6) 897(9) 112(4) C(30) 9564(9) 6342(8) 2478(10) 137(5) C(31) 8268(10) 7485(5) 2211(7) 111(4) C(32) 8096(11) 6594(7) 3664(8) 122(4) C(33) 8006(14) 5929(6) 3911(8) 144(6) C(34) 9023(13) 6892(9) 4296(8) 166(7) C(35) 7067(11) 6904(8) 3709(10) 135(5) C(36) 7069(7) 5102(4) 1313(6) 77(2) C(37) 5929(10) 4279(5) 1584(9) 103(3) C(38) 5258(13) 3763(6) 1131(10) 138(5) C(39) 8212(8) 4971(5) 1263(7) 92(3) C(40) 8351(9) 4884(7) 369(6) 105(4) C(41) 9382(14) 4980(15) 272(12) 220(11) C(42) 8632(11) 4478(9) 1848(9) 148(6) C(43) 8520(20) 4432(16) 2681(13) 271(16) C(44) 3873(9) 5419(7) 114(8) 107(4) C(45) 2351(11) 4942(10) -739(11) 148(6) C(46) 2119(16) 4562(12) -45(16) 215(10) C(47) 2198(13) 4562(12) -1499(13) 232(13) C(48) 1782(13) 5493(12) -838(16) 202(9) I(3) 7443(1) 8457(1) 7919(1) 220(1) Si(3) 8162(6) 9507(4) 5213(5) 251(4) C(54) 8546(17) 10232(12) 5745(19) 310(20) C(55) 9369(12) 8922(14) 5565(14) 310(20) C(56) 8169(15) 9517(11) 4132(12) 255(6) C(57) 7193(18) 9964(12) 3859(15) 257(7) S43

44 C(58) 9220(16) 9718(12) 3996(15) 240(6) C(59) 7977(18) 8841(11) 3830(15) 243(6) O(9) 7122(5) 9237(4) 5454(5) 109(2) O(10) 3659(6) 9536(4) 4318(4) 102(2) O(11) 4178(10) 7567(5) 5820(8) 164(5) O(12) 3462(9) 7857(5) 6884(6) 146(3) N(5) 4172(6) 9670(4) 5717(5) 84(2) N(6) 4661(8) 8407(5) 6546(6) 108(3) C(49) 7206(13) 8509(8) 6536(10) 145(6) C(50) 6951(8) 9188(7) 6277(7) 109(4) C(51) 5839(7) 9216(5) 6274(5) 86(3) C(52) 5410(8) 8574(5) 6009(7) 91(3) C(53) 6321(11) 8175(7) 6079(12) 139(5) C(60) 5237(8) 9731(4) 5722(5) 77(3) C(61) 3473(8) 9572(4) 5029(6) 82(3) C(62) 2402(9) 9455(7) 5173(8) 128(5) C(63) 5667(10) 10348(5) 5965(7) 103(3) C(64) 5549(11) 10545(6) 6886(7) 113(4) C(65) 6303(18) 10982(12) 7248(12) 227(12) C(66) 5002(14) 10825(7) 5373(10) 150(5) C(67) 5310(30) 10970(20) 4640(20) 390(30) C(68) 4112(12) 7920(8) 6350(9) 122(4) C(69) 2816(13) 7331(8) 6857(10) 133(5) C(70) 2140(20) 7322(15) 6042(15) 263(15) C(71) 3510(20) 6823(10) 7204(16) 231(12) C(72) 2250(30) 7480(12) 7510(17) 290(20) S44

45 Table S3C. Bond lengths [Å ] and angles [ ] of iodo compound 11. I(1)-C(1) 2.135(13) Si(1)-O(1) 1.641(7) Si(1)-C(8) 1.805(12) Si(1)-C(6) 1.853(17) Si(1)-C(7) 1.922(15) C(8)-C(10) 1.506(19) C(8)-C(11) 1.58(2) C(8)-C(9) 1.60(2) O(1)-C(2) 1.415(11) O(2)-C(13) 1.384(14) O(3)-C(20) 1.153(13) O(4)-C(20) 1.368(15) O(4)-C(21) 1.425(17) N(1)-C(13) 1.372(12) N(1)-C(12) 1.538(11) N(2)-C(20) 1.294(14) N(2)-C(4) 1.488(12) C(1)-C(2) 1.503(16) C(1)-C(5) 1.51(2) C(2)-C(3) 1.535(14) C(3)-C(12) 1.370(13) C(3)-C(4) 1.485(14) C(4)-C(5) 1.541(19) C(12)-C(15) 1.541(15) C(13)-C(14) 1.297(12) C(15)-C(18) 1.492(19) C(15)-C(16) 1.61(2) C(16)-C(17) 1.44(3) C(18)-C(19) 1.45(2) C(21)-C(22) 1.42(3) C(21)-C(23) 1.46(2) C(21)-C(24) 1.55(2) I(2)-C(25) 2.164(10) Si(2)-O(5) 1.674(7) Si(2)-C(32) 1.846(13) Si(2)-C(30) 1.849(14) S45

46 Si(2)-C(31) 1.919(12) O(5)-C(26) 1.429(11) O(6)-C(37) 1.202(13) O(7)-C(44) 1.161(13) O(8)-C(44) 1.385(15) O(8)-C(45) 1.476(17) N(3)-C(37) 1.371(15) N(3)-C(36) 1.453(13) N(4)-C(44) 1.287(14) N(4)-C(28) 1.374(11) C(25)-C(29) 1.510(16) C(25)-C(26) 1.512(14) C(26)-C(27) 1.533(13) C(27)-C(28) 1.497(13) C(27)-C(36) 1.525(13) C(28)-C(29) 1.547(16) C(32)-C(33) 1.54(2) C(32)-C(35) 1.56(2) C(32)-C(34) 1.589(18) C(36)-C(39) 1.583(14) C(37)-C(38) 1.549(18) C(39)-C(42) 1.482(18) C(39)-C(40) 1.505(14) C(40)-C(41) 1.44(2) C(42)-C(43) 1.39(2) C(45)-C(48) 1.43(3) C(45)-C(47) 1.47(2) C(45)-C(46) 1.48(3) I(3)-C(49) 2.194(16) Si(3)-O(9) 1.638(10) Si(3)-C(56) 1.748(17) Si(3)-C(54) 1.848(18) Si(3)-C(55) 2.067(18) C(56)-C(58) 1.54(2) C(56)-C(59) 1.58(2) C(56)-C(57) 1.63(2) O(9)-C(50) 1.398(14) O(10)-C(61) 1.226(12) S46

47 O(11)-C(68) 1.177(16) O(12)-C(68) 1.350(15) O(12)-C(69) 1.450(18) N(5)-C(61) 1.323(12) N(5)-C(60) 1.437(13) N(6)-C(68) 1.311(18) N(6)-C(52) 1.502(15) C(49)-C(53) 1.47(2) C(49)-C(50) 1.58(2) C(50)-C(51) 1.495(15) C(51)-C(52) 1.562(15) C(51)-C(60) 1.571(14) C(52)-C(53) 1.497(16) C(60)-C(63) 1.506(15) C(61)-C(62) 1.526(17) C(63)-C(66) 1.580(19) C(63)-C(64) 1.588(17) C(64)-C(65) 1.44(2) C(66)-C(67) 1.365(18) C(69)-C(70) 1.44(3) C(69)-C(72) 1.46(2) C(69)-C(71) 1.50(3) O(1)-Si(1)-C(8) 109.5(5) O(1)-Si(1)-C(6) 109.3(7) C(8)-Si(1)-C(6) 109.0(10) O(1)-Si(1)-C(7) 108.7(8) C(8)-Si(1)-C(7) 107.9(7) C(6)-Si(1)-C(7) 112.4(12) C(10)-C(8)-C(11) 107.8(16) C(10)-C(8)-C(9) 113.9(14) C(11)-C(8)-C(9) 106.0(14) C(10)-C(8)-Si(1) 111.2(9) C(11)-C(8)-Si(1) 108.1(11) C(9)-C(8)-Si(1) 109.6(11) C(2)-O(1)-Si(1) 129.2(7) C(20)-O(4)-C(21) 119.0(10) C(13)-N(1)-C(12) 132.8(8) S47

48 C(20)-N(2)-C(4) 119.9(8) C(2)-C(1)-C(5) 105.2(11) C(2)-C(1)-I(1) 111.3(10) C(5)-C(1)-I(1) 114.9(9) O(1)-C(2)-C(1) 108.6(8) O(1)-C(2)-C(3) 109.8(8) C(1)-C(2)-C(3) 101.6(9) C(12)-C(3)-C(4) 122.0(9) C(12)-C(3)-C(2) 111.0(8) C(4)-C(3)-C(2) 102.5(7) C(3)-C(4)-N(2) 111.3(7) C(3)-C(4)-C(5) 107.8(11) N(2)-C(4)-C(5) 114.0(9) C(1)-C(5)-C(4) 103.8(11) C(3)-C(12)-N(1) 112.6(8) C(3)-C(12)-C(15) 125.6(9) N(1)-C(12)-C(15) 105.9(8) C(14)-C(13)-N(1) 116.6(10) C(14)-C(13)-O(2) 126.2(12) N(1)-C(13)-O(2) 117.1(11) C(18)-C(15)-C(12) 124.2(13) C(18)-C(15)-C(16) 107.7(12) C(12)-C(15)-C(16) 106.9(9) C(17)-C(16)-C(15) 114.9(14) C(19)-C(18)-C(15) 115.6(15) O(3)-C(20)-N(2) 126.7(13) O(3)-C(20)-O(4) 125.6(13) N(2)-C(20)-O(4) 107.6(9) C(22)-C(21)-O(4) 114.7(17) C(22)-C(21)-C(23) 112.4(16) O(4)-C(21)-C(23) 110.8(13) C(22)-C(21)-C(24) 109.5(15) O(4)-C(21)-C(24) 102.2(11) C(23)-C(21)-C(24) 106.4(17) O(5)-Si(2)-C(32) 103.8(5) O(5)-Si(2)-C(30) 111.3(6) C(32)-Si(2)-C(30) 112.0(7) O(5)-Si(2)-C(31) 109.9(5) S48

49 C(32)-Si(2)-C(31) 111.4(6) C(30)-Si(2)-C(31) 108.4(7) C(26)-O(5)-Si(2) 124.0(6) C(44)-O(8)-C(45) 119.0(9) C(37)-N(3)-C(36) 122.4(9) C(44)-N(4)-C(28) 129.6(11) C(29)-C(25)-C(26) 103.8(9) C(29)-C(25)-I(2) 114.5(7) C(26)-C(25)-I(2) 109.7(7) O(5)-C(26)-C(25) 107.3(8) O(5)-C(26)-C(27) 108.6(7) C(25)-C(26)-C(27) 104.0(7) C(28)-C(27)-C(36) 112.7(8) C(28)-C(27)-C(26) 106.2(7) C(36)-C(27)-C(26) 114.8(7) N(4)-C(28)-C(27) 120.8(9) N(4)-C(28)-C(29) 100.9(9) C(27)-C(28)-C(29) 105.9(9) C(25)-C(29)-C(28) 106.7(9) C(33)-C(32)-C(35) 107.2(12) C(33)-C(32)-C(34) 108.9(12) C(35)-C(32)-C(34) 112.1(13) C(33)-C(32)-Si(2) 111.0(10) C(35)-C(32)-Si(2) 108.9(10) C(34)-C(32)-Si(2) 108.7(9) N(3)-C(36)-C(27) 109.2(7) N(3)-C(36)-C(39) 111.6(8) C(27)-C(36)-C(39) 113.7(8) O(6)-C(37)-N(3) 124.5(12) O(6)-C(37)-C(38) 123.5(12) N(3)-C(37)-C(38) 112.0(11) C(42)-C(39)-C(40) 114.3(11) C(42)-C(39)-C(36) 110.6(10) C(40)-C(39)-C(36) 112.4(8) C(41)-C(40)-C(39) 112.9(11) C(43)-C(42)-C(39) 124.8(17) O(7)-C(44)-N(4) 118.1(13) O(7)-C(44)-O(8) 124.3(11) S49

50 N(4)-C(44)-O(8) 116.9(11) C(48)-C(45)-C(47) 114.5(19) C(48)-C(45)-O(8) 110.4(17) C(47)-C(45)-O(8) 103.0(13) C(48)-C(45)-C(46) 112.4(19) C(47)-C(45)-C(46) 107(2) O(8)-C(45)-C(46) 109.3(15) O(9)-Si(3)-C(56) 114.6(8) O(9)-Si(3)-C(54) 112.3(8) C(56)-Si(3)-C(54) 113.4(13) O(9)-Si(3)-C(55) 111.5(10) C(56)-Si(3)-C(55) 97.0(10) C(54)-Si(3)-C(55) 106.7(12) C(58)-C(56)-C(59) 109.1(16) C(58)-C(56)-C(57) 119.8(19) C(59)-C(56)-C(57) 114.8(17) C(58)-C(56)-Si(3) 109.5(13) C(59)-C(56)-Si(3) 105.2(14) C(57)-C(56)-Si(3) 96.5(13) C(50)-O(9)-Si(3) 124.4(7) C(68)-O(12)-C(69) 121.6(12) C(61)-N(5)-C(60) 124.1(8) C(68)-N(6)-C(52) 118.3(10) C(53)-C(49)-C(50) 103.6(11) C(53)-C(49)-I(3) 115.1(12) C(50)-C(49)-I(3) 107.4(10) O(9)-C(50)-C(51) 110.3(8) O(9)-C(50)-C(49) 104.9(10) C(51)-C(50)-C(49) 101.8(11) C(50)-C(51)-C(52) 106.1(9) C(50)-C(51)-C(60) 115.7(9) C(52)-C(51)-C(60) 112.7(7) C(53)-C(52)-N(6) 116.3(10) C(53)-C(52)-C(51) 105.5(10) N(6)-C(52)-C(51) 108.7(9) C(49)-C(53)-C(52) 107.9(12) N(5)-C(60)-C(63) 114.6(9) N(5)-C(60)-C(51) 109.6(7) S50

51 C(63)-C(60)-C(51) 112.6(8) O(10)-C(61)-N(5) 123.7(10) O(10)-C(61)-C(62) 120.4(9) N(5)-C(61)-C(62) 115.7(10) C(60)-C(63)-C(66) 108.0(10) C(60)-C(63)-C(64) 112.9(9) C(66)-C(63)-C(64) 103.4(11) C(65)-C(64)-C(63) 111.9(13) C(67)-C(66)-C(63) 116.3(18) O(11)-C(68)-N(6) 127.1(13) O(11)-C(68)-O(12) 123.2(16) N(6)-C(68)-O(12) 109.7(14) C(70)-C(69)-O(12) 107.7(15) C(70)-C(69)-C(72) 110(2) O(12)-C(69)-C(72) 101.2(13) C(70)-C(69)-C(71) 124(2) O(12)-C(69)-C(71) 105.4(15) C(72)-C(69)-C(71) 106(2) Symmetry transformations used to generate equivalent atoms: S51

52 Table S3D. Anisotropic displacement parameters (Å ) of iodo compound 11. The anisotropic displacement factor exponent takes the form : 2p 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 I(1) 205(1) 285(2) 101(1) -53(1) 66(1) -145(1) Si(1) 109(2) 118(2) 82(2) -22(2) 6(2) 13(2) C(6) 410(40) 109(13) 194(19) -29(12) -30(20) 53(17) C(7) 117(12) 410(40) 171(16) -130(20) 47(11) -5(17) C(8) 110(9) 150(11) 100(8) -43(8) 6(7) -21(8) C(9) 260(20) 340(30) 150(16) -130(20) 2(15) -120(20) C(10) 98(12) 390(40) 163(15) 5(19) -20(11) -60(16) C(11) 310(30) 200(20) 250(30) 110(20) -130(20) -20(20) O(1) 82(4) 118(5) 59(3) -20(3) 6(3) -1(4) O(2) 218(15) 195(14) 254(17) 45(12) 24(12) -30(12) O(3) 177(9) 161(8) 103(6) -21(5) -42(6) 76(7) O(4) 153(7) 118(6) 76(5) 7(4) -2(4) 42(6) N(1) 77(5) 123(7) 69(4) 9(5) 7(4) -16(5) N(2) 106(6) 107(7) 65(4) -16(4) -18(4) 23(5) C(1) 106(9) 165(14) 98(8) -45(8) 42(6) -71(9) C(2) 81(7) 114(8) 69(6) -9(5) 13(4) -7(6) C(3) 44(5) 121(8) 59(5) 8(5) 14(4) -18(5) C(4) 68(6) 114(8) 77(6) -31(5) 1(4) 12(6) C(5) 78(9) 208(19) 143(12) -54(12) 14(7) -15(10) C(12) 79(7) 85(7) 102(7) -25(5) -16(6) 5(6) C(13) 68(7) 110(9) 123(10) -5(8) 17(6) -13(6) C(14) 49(4) 94(6) 54(5) 22(4) 6(3) -11(4) C(15) 99(8) 87(7) 133(10) -13(6) 38(7) 8(6) C(16) 87(8) 169(14) 144(12) -32(11) -25(7) 40(9) C(17) 600(70) 210(30) 124(16) -10(17) -30(30) -50(30) C(18) 92(10) 270(20) 200(20) -15(17) 61(11) -6(12) C(19) 178(17) 240(20) 135(14) 2(13) 45(11) -48(15) C(20) 116(9) 157(12) 71(7) -24(7) -27(7) 60(9) C(21) 166(14) 158(14) 97(9) 12(9) 35(9) 53(11) C(22) 200(20) 190(20) 220(20) -35(16) 89(17) 37(16) C(23) 189(16) 202(17) 124(11) 78(12) 48(11) 48(13) C(24) 198(16) 112(10) 142(12) -29(9) 7(11) 41(10) S52

53 I(2) 177(1) 148(1) 96(1) 25(1) 16(1) 21(1) Si(2) 88(2) 111(2) 82(2) -3(2) 9(1) -17(2) O(5) 88(4) 97(5) 71(4) -3(3) 10(3) -17(3) O(6) 159(7) 119(6) 84(5) 4(4) 52(5) 8(5) O(7) 75(5) 274(14) 137(7) -101(8) 35(5) -16(6) O(8) 58(5) 229(11) 147(8) -71(7) 18(5) -7(5) N(3) 98(6) 100(6) 74(5) -6(4) 26(4) 1(5) N(4) 77(7) 252(14) 87(6) 24(7) -8(5) -46(8) C(25) 87(7) 110(8) 78(6) -6(5) 4(5) 12(6) C(26) 72(6) 89(7) 69(5) 12(5) 11(4) -12(5) C(27) 58(5) 92(7) 62(5) -3(4) 21(4) 6(5) C(28) 74(7) 91(8) 84(6) -14(5) 2(5) 17(5) C(29) 82(8) 137(11) 117(9) -4(7) 20(6) 11(7) C(30) 77(8) 191(15) 147(12) -7(10) 32(7) -12(8) C(31) 141(10) 109(8) 90(7) -2(6) 36(6) -47(8) C(32) 136(11) 140(11) 89(7) -9(7) 21(7) -30(9) C(33) 203(15) 117(10) 99(9) 26(7) 0(9) -49(10) C(34) 195(15) 208(16) 87(8) -6(9) 8(8) -115(14) C(35) 125(11) 144(11) 151(11) -27(10) 63(9) -14(9) C(36) 81(6) 82(6) 68(5) 3(5) 15(4) 17(5) C(37) 116(9) 91(8) 107(9) 3(7) 39(7) 15(7) C(38) 175(14) 111(10) 140(11) -14(8) 58(10) -37(10) C(39) 68(6) 118(8) 89(7) 2(6) 11(5) 23(6) C(40) 89(8) 155(11) 73(6) -6(6) 22(5) 7(7) C(41) 132(15) 390(40) 141(15) -38(17) 45(11) -57(18) C(42) 114(10) 210(16) 117(9) 42(10) 18(8) 67(11) C(43) 280(30) 400(40) 124(12) 60(20) 29(15) 100(30) C(44) 60(7) 167(12) 93(8) -13(8) 17(6) -4(7) C(45) 90(10) 217(18) 132(12) -66(12) 7(8) -15(11) C(46) 165(18) 270(30) 200(20) -20(20) 33(15) -101(19) C(47) 121(12) 360(30) 197(19) -160(20) 2(12) -57(16) C(48) 93(11) 240(20) 250(20) -26(18) -10(13) 20(14) I(3) 181(1) 334(2) 131(1) 73(1) -6(1) 95(1) Si(3) 203(6) 344(9) 244(6) -136(7) 138(5) -150(6) C(54) 200(20) 370(40) 380(40) -260(40) 150(30) -180(30) C(55) 85(11) 600(60) 220(20) 40(30) -27(12) 140(20) C(56) 220(9) 331(12) 250(10) -126(10) 137(9) -130(10) C(57) 215(11) 343(14) 249(12) -95(12) 136(10) -90(11) S53

54 C(58) 199(10) 333(14) 232(11) -99(11) 151(9) -113(11) C(59) 213(11) 315(13) 233(11) -138(11) 121(10) -109(11) O(9) 79(5) 154(7) 97(5) -8(5) 24(4) 1(4) O(10) 103(5) 129(6) 63(4) -13(4) -7(3) 14(4) O(11) 235(12) 133(8) 151(8) -46(7) 103(8) -61(8) O(12) 199(10) 149(8) 109(6) -18(6) 76(6) -38(8) N(5) 77(6) 101(6) 70(5) -15(4) 1(4) 7(4) N(6) 139(8) 107(7) 85(6) -13(5) 36(5) -4(7) C(49) 129(12) 165(14) 146(12) 31(10) 41(9) 88(12) C(50) 63(7) 166(12) 91(7) -15(7) 1(5) 6(7) C(51) 75(7) 127(9) 56(5) 15(5) 11(4) 7(6) C(52) 85(7) 91(7) 98(7) 2(6) 22(5) 3(6) C(53) 92(9) 132(11) 189(14) 20(10) 18(9) 39(9) C(60) 94(7) 93(7) 45(4) 1(4) 11(4) -7(5) C(61) 85(7) 78(6) 73(6) -3(5) -4(5) 25(5) C(62) 87(9) 169(13) 119(9) -37(9) -1(7) 9(8) C(63) 128(9) 94(8) 83(7) 4(6) 13(6) -18(7) C(64) 141(11) 98(8) 93(8) -13(6) 4(7) -16(7) C(65) 240(20) 310(30) 135(14) -91(17) 37(14) -110(20) C(66) 185(15) 104(10) 153(12) 27(9) 12(11) -14(9) C(67) 290(40) 610(80) 270(30) 290(50) 70(30) 110(40) C(68) 165(13) 119(12) 96(8) 6(9) 55(8) -7(11) C(69) 164(13) 130(12) 126(9) 10(9) 78(8) -30(11) C(70) 230(30) 390(40) 167(16) 20(20) 35(13) -130(30) C(71) 360(40) 151(19) 210(20) 28(16) 110(20) -40(20) C(72) 440(50) 240(30) 240(30) -110(20) 220(30) -190(30) S54

55 1 H NMR spectrum of compound 12 (400 MHz, in CD 3 OD) 13 C NMR spectrum of compound 12 (100 MHz, in CD 3 OD) S55

56 ORTEP drawing of epoxide 12 (IC15953, deposit CCDC ); thermal ellipsoids drawn at the 30% probability level. S56

57 Table S4A. Crystal data and structure refinement of epoxide 12. Identification code ic15953 Empirical formula C18 H32.50 N2 O4.25 Formula weight Temperature 295(2) K Wavelength Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = (7) Å a= 90. b = (8) Å b= 90. c = (14) Å g = 90. Volume (4) Å 3 Z 8 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1508 Crystal size 0.25 x 0.20 x 0.15 mm 3 Theta range for data collection 2.89 to Index ranges -10<=h<=12, -22<=k<=22, -29<=l<=25 Reflections collected Independent reflections 9226 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 9226 / 21 / 460 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.5(13) Largest diff. peak and hole and e.å -3 S57

58 Table S4B. Atomic coordinates ( 10 4 ) and equivalent isotropic displacement parameters (Å ) of epoxide 12. U (eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) O(1) 4214(2) 8525(1) 970(1) 75(1) O(2) 3243(3) 7400(1) 798(1) 84(1) O(3) -837(2) 7031(1) 1967(1) 82(1) O(4) 3895(2) 5977(1) 2015(1) 70(1) N(1) 2530(3) 8185(1) 1502(1) 60(1) N(2) 3375(2) 7062(1) 2468(1) 53(1) C(1) 1380(3) 7745(1) 1663(1) 53(1) C(2) 96(3) 8115(2) 1462(2) 72(1) C(3) -902(3) 7836(2) 1875(2) 78(1) C(4) -250(3) 7535(2) 2384(2) 66(1) C(5) 1212(3) 7605(1) 2321(1) 50(1) C(6) 3315(3) 7981(2) 1064(1) 58(1) C(7) 5125(4) 8479(2) 475(2) 75(1) C(8) 5816(5) 9241(3) 496(2) 117(2) C(9) 4374(5) 8403(2) -79(2) 103(1) C(10) 6080(5) 7830(3) 565(2) 124(2) C(11) 1977(3) 6918(1) 2550(1) 53(1) C(12) 4205(3) 6611(1) 2192(1) 54(1) C(13) 5560(3) 6917(2) 2103(2) 68(1) C(14) 1659(3) 6699(2) 3179(1) 67(1) C(15) 2106(5) 7300(2) 3615(2) 96(1) C(16) 1637(6) 7204(3) 4228(2) 133(2) C(17) 2214(4) 5923(2) 3338(2) 87(1) C(18) 1469(5) 5284(2) 3175(4) 163(3) O(5) 7820(2) 6033(1) 3118(1) 70(1) O(6) 7619(3) 4755(1) 3044(1) 87(1) O(7) 9189(4) 3998(2) 951(2) 156(2) O(8) 5900(3) 3506(1) 2106(1) 84(1) N(3) 8248(3) 5485(1) 2291(1) 63(1) N(4) 5642(3) 4688(1) 1771(1) 58(1) C(19) 8502(3) 4890(2) 1870(2) 68(1) C(20) 9979(5) 4852(2) 1704(2) 110(2) S58

59 C(21) 9962(7) 4649(3) 1068(3) 142(2) C(22) 8684(7) 4739(3) 836(2) 124(2) C(23) 7755(4) 5004(2) 1303(1) 76(1) C(24) 7872(3) 5366(2) 2835(1) 58(1) C(25) 7289(4) 6101(2) 3703(1) 81(1) C(26) 8073(6) 5642(3) 4121(2) 137(2) C(27) 7460(6) 6930(3) 3818(2) 122(2) C(28) 5858(5) 5888(4) 3690(2) 132(2) C(29) 6458(4) 4581(2) 1261(1) 64(1) C(30) 5379(3) 4129(2) 2146(1) 59(1) C(31) 4427(4) 4291(2) 2623(2) 73(1) C(32) 5691(5) 4741(2) 701(2) 89(1) C(33) 4577(6) 4174(3) 619(2) 126(2) C(34) 4953(8) 3391(3) 579(3) 173(3) C(35) 5254(7) 5561(2) 641(2) 131(2) C(36) 4865(7) 5788(3) 28(2) 153(3) O(9) 2125(6) 5956(3) 992(3) 99(2) S59

60 Table S4C. Bond lengths [Å ] and angles [ ] of epoxide 12. O(1)-C(6) 1.345(3) O(1)-C(7) 1.471(4) O(2)-C(6) 1.200(3) O(3)-C(4) 1.439(4) O(3)-C(3) 1.442(4) O(4)-C(12) 1.234(3) N(1)-C(6) 1.335(4) N(1)-C(1) 1.454(4) N(2)-C(12) 1.325(4) N(2)-C(11) 1.458(4) C(1)-C(2) 1.533(4) C(1)-C(5) 1.544(4) C(2)-C(3) 1.477(5) C(3)-C(4) 1.447(5) C(4)-C(5) 1.500(4) C(5)-C(11) 1.536(4) C(7)-C(9) 1.490(5) C(7)-C(10) 1.519(6) C(7)-C(8) 1.521(5) C(11)-C(14) 1.533(4) C(12)-C(13) 1.496(4) C(14)-C(17) 1.528(4) C(14)-C(15) 1.531(5) C(15)-C(16) 1.499(5) C(17)-C(18) 1.412(6) O(5)-C(24) 1.349(4) O(5)-C(25) 1.455(4) O(6)-C(24) 1.211(3) O(7)-C(21) 1.421(6) O(7)-C(22) 1.433(7) O(8)-C(30) 1.226(3) N(3)-C(24) 1.326(4) N(3)-C(19) 1.455(4) N(4)-C(30) 1.340(3) N(4)-C(29) 1.449(4) C(19)-C(23) 1.522(5) S60

61 C(19)-C(20) 1.551(6) C(20)-C(21) 1.506(8) C(21)-C(22) 1.415(9) C(22)-C(23) 1.506(6) C(23)-C(29) 1.521(5) C(25)-C(26) 1.490(6) C(25)-C(27) 1.501(6) C(25)-C(28) 1.504(6) C(29)-C(32) 1.532(5) C(30)-C(31) 1.491(4) C(32)-C(33) 1.525(7) C(32)-C(35) 1.525(5) C(33)-C(34) 1.440(7) C(35)-C(36) 1.520(6) C(6)-O(1)-C(7) 120.9(2) C(4)-O(3)-C(3) 60.3(2) C(6)-N(1)-C(1) 122.0(2) C(12)-N(2)-C(11) 125.3(2) N(1)-C(1)-C(2) 112.3(2) N(1)-C(1)-C(5) 115.2(2) C(2)-C(1)-C(5) 105.7(2) C(3)-C(2)-C(1) 104.4(2) O(3)-C(3)-C(4) 59.8(2) O(3)-C(3)-C(2) 113.2(3) C(4)-C(3)-C(2) 109.2(3) O(3)-C(4)-C(3) 59.9(2) O(3)-C(4)-C(5) 113.5(3) C(3)-C(4)-C(5) 110.3(3) C(4)-C(5)-C(11) 113.8(2) C(4)-C(5)-C(1) 102.6(2) C(11)-C(5)-C(1) 114.0(2) O(2)-C(6)-N(1) 125.4(3) O(2)-C(6)-O(1) 125.0(3) N(1)-C(6)-O(1) 109.6(2) O(1)-C(7)-C(9) 110.1(3) O(1)-C(7)-C(10) 109.8(3) C(9)-C(7)-C(10) 112.1(4) S61

62 O(1)-C(7)-C(8) 102.6(3) C(9)-C(7)-C(8) 110.2(3) C(10)-C(7)-C(8) 111.7(4) N(2)-C(11)-C(14) 111.8(3) N(2)-C(11)-C(5) 108.2(2) C(14)-C(11)-C(5) 114.7(2) O(4)-C(12)-N(2) 123.0(3) O(4)-C(12)-C(13) 121.3(3) N(2)-C(12)-C(13) 115.7(2) C(17)-C(14)-C(15) 111.0(3) C(17)-C(14)-C(11) 112.1(3) C(15)-C(14)-C(11) 112.3(2) C(16)-C(15)-C(14) 116.3(3) C(18)-C(17)-C(14) 117.2(3) C(24)-O(5)-C(25) 122.1(2) C(21)-O(7)-C(22) 59.5(4) C(24)-N(3)-C(19) 124.4(2) C(30)-N(4)-C(29) 122.7(2) N(3)-C(19)-C(23) 112.7(2) N(3)-C(19)-C(20) 111.5(3) C(23)-C(19)-C(20) 106.2(3) C(21)-C(20)-C(19) 103.8(4) C(22)-C(21)-O(7) 60.7(4) C(22)-C(21)-C(20) 110.5(5) O(7)-C(21)-C(20) 112.6(4) C(21)-C(22)-O(7) 59.8(4) C(21)-C(22)-C(23) 110.0(5) O(7)-C(22)-C(23) 112.2(4) C(22)-C(23)-C(29) 110.2(3) C(22)-C(23)-C(19) 104.9(4) C(29)-C(23)-C(19) 115.0(2) O(6)-C(24)-N(3) 125.3(3) O(6)-C(24)-O(5) 125.6(3) N(3)-C(24)-O(5) 109.1(2) O(5)-C(25)-C(26) 110.7(4) O(5)-C(25)-C(27) 101.5(3) C(26)-C(25)-C(27) 111.0(4) O(5)-C(25)-C(28) 108.7(3) S62

63 C(26)-C(25)-C(28) 113.2(4) C(27)-C(25)-C(28) 111.1(4) N(4)-C(29)-C(23) 112.4(2) N(4)-C(29)-C(32) 111.3(3) C(23)-C(29)-C(32) 113.9(3) O(8)-C(30)-N(4) 121.9(3) O(8)-C(30)-C(31) 120.6(2) N(4)-C(30)-C(31) 117.5(2) C(33)-C(32)-C(35) 113.5(5) C(33)-C(32)-C(29) 111.3(3) C(35)-C(32)-C(29) 113.6(3) C(34)-C(33)-C(32) 116.3(5) C(36)-C(35)-C(32) 114.3(3) Symmetry transformations used to generate equivalent atoms: S63

64 Table S4D. Anisotropic displacement parameters (Å ) of epoxide 12. The anisotropic displacement factor exponent takes the form: 2p 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 O(1) 73(2) 87(1) 65(1) -10(1) 24(1) -26(1) O(2) 99(2) 68(1) 85(2) -14(1) 37(1) -10(1) O(3) 63(1) 76(1) 108(2) 24(1) -6(1) -18(1) O(4) 82(2) 48(1) 81(1) -9(1) 9(1) 10(1) N(1) 66(2) 56(1) 58(2) -7(1) 20(1) -16(1) N(2) 48(1) 45(1) 66(2) -5(1) 4(1) 1(1) C(1) 55(2) 46(1) 57(2) 2(1) 10(1) -7(1) C(2) 71(2) 66(2) 78(2) 14(2) -2(2) -6(2) C(3) 54(2) 72(2) 107(3) 25(2) 3(2) 2(2) C(4) 56(2) 66(2) 74(2) 14(2) 14(2) 7(1) C(5) 50(2) 46(1) 55(2) -2(1) 8(1) -1(1) C(6) 61(2) 57(2) 57(2) 4(1) 9(2) -4(1) C(7) 73(2) 91(2) 61(2) 5(2) 23(2) -9(2) C(8) 107(4) 143(4) 100(3) -8(3) 40(3) -56(3) C(9) 117(4) 123(3) 68(2) 14(2) 13(2) -27(3) C(10) 87(3) 165(4) 120(4) 34(3) 32(3) 25(3) C(11) 48(2) 43(1) 68(2) 2(1) 5(1) -3(1) C(12) 61(2) 48(1) 53(2) 7(1) -3(1) 13(1) C(13) 54(2) 74(2) 77(2) 7(2) 7(2) 11(1) C(14) 60(2) 63(2) 78(2) 18(2) 11(2) 0(1) C(15) 134(4) 91(2) 62(2) 4(2) 23(2) -13(2) C(16) 179(6) 156(4) 64(3) 6(3) 23(3) -36(4) C(17) 74(2) 81(2) 107(3) 36(2) -1(2) -2(2) C(18) 76(3) 63(2) 350(9) 33(3) -34(4) -4(2) O(5) 76(2) 77(1) 56(1) 4(1) 4(1) -2(1) O(6) 103(2) 73(1) 86(2) 28(1) 12(2) -8(1) O(7) 153(3) 104(2) 211(4) -72(2) 99(3) -26(2) O(8) 111(2) 59(1) 82(2) 21(1) 29(1) 26(1) N(3) 74(2) 49(1) 65(2) 7(1) 9(1) -6(1) N(4) 76(2) 47(1) 50(1) 5(1) 9(1) 9(1) C(19) 73(2) 53(2) 79(2) 3(1) 21(2) -2(1) C(20) 81(3) 99(3) 148(5) -10(3) 37(3) -2(2) C(21) 135(5) 110(3) 180(6) -55(3) 91(5) -46(3) S64

65 C(22) 148(5) 128(4) 96(3) -27(3) 67(4) -66(4) C(23) 114(3) 54(2) 60(2) 5(1) 27(2) -7(2) C(24) 49(2) 64(2) 61(2) 13(2) 0(2) 0(1) C(25) 73(3) 117(3) 54(2) 2(2) -1(2) -8(2) C(26) 145(5) 196(5) 69(3) 25(3) -29(3) 3(4) C(27) 142(5) 135(4) 88(3) -38(3) 14(3) 4(3) C(28) 83(3) 225(5) 89(3) -18(3) 22(3) -34(4) C(29) 93(2) 52(1) 46(2) 2(1) 11(2) 3(2) C(30) 67(2) 53(2) 56(2) 4(1) 5(2) 5(1) C(31) 70(2) 75(2) 75(2) 7(2) 18(2) 6(2) C(32) 140(4) 78(2) 49(2) 1(2) -1(2) 20(2) C(33) 158(5) 135(4) 84(3) 5(3) -42(3) -10(3) C(34) 235(7) 137(4) 148(5) 37(4) -79(5) -82(5) C(35) 231(7) 101(3) 62(2) 3(2) -16(3) 67(3) C(36) 273(8) 114(3) 72(3) 9(2) -25(4) 76(4) O(9) 97(4) 79(3) 120(4) -3(3) -15(3) -13(3) S65

66 1 H NMR spectrum of compound 13 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 13 (100 MHz, in CDCl 3 ) S66

67 31 P NMR spectrum of compound 13 (162 MHz, in CDCl 3 ) COSY NMR spectrum of compound 13 (400 MHz, in CDCl 3 ) S67

68 NOESY NMR spectrum of compound 13 (400 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 13-isomer (400 MHz, in CDCl 3 ) S68

69 13 C NMR spectrum of compound 13-isomer (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 13-isomer (162 MHz, in CDCl 3 ) S69

70 COSY NMR spectrum of compound 13-isomer (400 MHz, in CDCl 3 ) NOESY NMR spectrum of compound 13-isomer (400 MHz, in CDCl 3 ) S70

71 1 H NMR spectrum of compound 14 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 14 (100 MHz, in CDCl 3 ) S71

72 31 P NMR spectrum of compound 14 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 15 (400 MHz, in CDCl 3 ) S72

73 13 C NMR spectrum of compound 15 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 15 (162 MHz, in CDCl 3 ) S73

74 1 H NMR spectrum of compound 16 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 16 (100 MHz, in CDCl 3 ) S74

75 31 P NMR spectrum of compound 16 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 17 (400 MHz, in CDCl 3 ) S75

76 13 C NMR spectrum of compound 17 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 17 (162 MHz, in CDCl 3 ) S76

77 1 H NMR spectrum of compound 18 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 18 (100 MHz, in CDCl 3 ) S77

78 31 P NMR spectrum of compound 18 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 19 (400 MHz, in CDCl 3 ) S78

79 13 C NMR spectrum of compound 19 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 19 (162 MHz, in CDCl 3 ) S79

80 1 H NMR spectrum of compound 20 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 20 (100 MHz, in CDCl 3 ) S80

81 31 P NMR spectrum of compound 20 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 21 (400 MHz, in CDCl 3 ) S81

82 13 C NMR spectrum of compound 21 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 21 (162 MHz, in CDCl 3 ) S82

83 1 H NMR spectrum of compound 22 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 22 (100 MHz, in CDCl 3 ) S83

84 31 P NMR spectrum of compound 22 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 23 (400 MHz, in CDCl 3 ) S84

85 13 C NMR spectrum of compound 23 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 23 (162 MHz, in CDCl 3 ) S85

86 1 H NMR spectrum of compound 24 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 24 (100 MHz, in CDCl 3 ) S86

87 31 P NMR spectrum of compound 24 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 25 (400 MHz, in CDCl 3 ) S87

88 13 C NMR spectrum of compound 25 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 25 (162 MHz, in CDCl 3 ) S88

89 1 H NMR spectrum of compound 26 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 26 (100 MHz, in CDCl 3 ) S89

90 31 P NMR spectrum of compound 26 (162 MHz, in CDCl 3 ) 1 H NMR spectrum of compound 27 (400 MHz, in CDCl 3 ) S90

91 13 C NMR spectrum of compound 27 (100 MHz, in CDCl 3 ) 31 P NMR spectrum of compound 27 (162 MHz, in CDCl 3 ) S91

92 1 H NMR spectrum of compound 28 (400 MHz, in CDCl 3 ) 13 C NMR spectrum of compound 28 (100 MHz, in CDCl 3 ) S92

93 31 P NMR spectrum of compound 28 (162 MHz, in CDCl 3 ) S93