Reactivity of Steroidal 1-Azadienes Toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids. Supporting Information

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1 Reactivity of Steroidal 1-Azadienes Toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids Susana M. M. Lopes, a Clara S. B. Gomes, b Teresa M. V. D. Pinho e Melo a,* a CQC and Department of Chemistry, University of Coimbra, Coimbra, Portugal. b Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisboa, Portugal Supporting Information Table of Contents 1. General information.....,...s2 2. Synthesis and characterization of new steroids..... S2 3. Copies of NMR spectra of all new compounds....s10 4. X-Ray Crystallographic data for compound 4a...S33 5. References....S52

2 1. General information 1 H and 13 C NMR spectra were recorded with a Bruker Avance III instrument operating at 400 and 100 MHz, respectively. The solvent was deuteriochloroform except where indicated otherwise. Chemical shifts are expressed in ppm relative to TMS, and coupling constants (J) are in Hz. Infrared spectra (IR) were recorded with an Agilent Technologies Carey 630 FTIR spectrometer with ATR. High-resolution mass spectra (HMRS) were obtained with a TOF VG Autospect M spectrometer with electrospray ionization (ESI) or electronic impact (EI). Melting points were determined using a Melting Point Device Falc R (open capillary method). Elemental analyses were carried out with an Elemental Vario Micro Cube analyser. Thin-layer chromatography (TLC) analyses were performed using precoated silica gel plates Macherey-Nagel Xtra SIL G/UV254. Flash column chromatography was performed with silica gel 60 ( mm) provided by Acros Organics, as the stationary phase. 3β-Acetoxy-5,16-pregnadien-20-oxime (2) 1 and 1-(1-p-Chlorophenyl-1H-1,2,3- triazol-4-yl)ethanone (6) 2 were prepared as described in the literature. 2. Procedures and characterization data of new steroids 3β-Acetoxy-5,16-pregnadien-20-tosylimine (1): A solution of oxime 2 (6.07 g, 16.4 mmol) in CCl 4 (112 ml), at 0 ºC and under N 2, was treated sequentially with triethylamine (2.74 ml, 19.7 mmol) and freshly prepared p-toluenesulfinyl chloride 18 (3.17 g, 18.0 mmol). The reaction mixture was stirred at 0 ºC for 15 minutes. After this time, the trimethylamine hydrochloride was filtered and washed with CCl 4 (10 ml). The resulting filtrate was stirred at room temperature overnight. The solvent was evaporated and the product purified by flash chromatography [ethyl acetate/hexane (1:4)]. Compound 1 was obtained as a white solid in 42% yield (3.51 g; 6.89 mmol). mp S2

3 ºC (from ethyl acetate/hexane). [α] D +10 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 989, 1030, 1086, 1152, 1243, 1559 and 1732 cm H NMR δ = 0.87 (s, 3H, H-18), (m, 1H), 1.01 (s, 3H, H-19), (m, 1H), (m, 1H), (m, 3H), (m, 3H), (m, 2H), (m, 1H), 2.03 (s, 3H, H-32), (m, 1H), (m, 1H), (m, 3H), 2.44 (s, 3H, H-30), 2.66 (s, 3H, H-21), (m, 1H, H-3), 5.37 (br d, J = 5.2 Hz, 1H, H-6), 6.83 (br dd, J = 3.2 and 2.0 Hz, 1H, H-16), 7.31 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 15.5 (C-18), 19.2 (C-19), 20.7, 21.0, 21.4, 21.6, 27.7, 30.1, 31.4, 32.5, 34.6, 36.7, 36.8, 38.1, 46.8, 50.1, 56.5, 73.8 (C-3), (C-6), 126.8, 129.3, 139.1, 140.2, 143.1, (C-16), (C-17), (C-31), (C-20). HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 30 H 40 NO 4 S ; found General procedure for the synthesis of hexacyclic steroids using commercial enamines 3: A solution of 1-azadiene 1 (0.153 g, 0.3 mmol) and 1-pyrrolidino-1-cyclohexene (3a) or 1-pyrrolidino-1-cyclopentene (3b) (0.45 mmol) in dry dichloromethane (1 ml) was irradiated in a microwave reactor at 50 ºC for 10 minutes. After cooling to room temperature, the solvent was evaporated and the product purified by flash chromatography. Hexacyclic steroid 4a: Obtained from 1-pyrrolidino-1-cyclohexene (3a). Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4a as a white solid (119 mg, 67%): mp C (from ethyl acetate/hexane). 25 [α] D +110 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1031, 1090, 1146, 1241, 1300, 1560, 1598 and 1729 cm H NMR δ = 0.80 (s, 3H), (m, 1H), 1.00 (s, 3H), (m, 4H), (m, 10H), (m, 5H), 2.03 (s, 3H), (m, 5H), (m, 2H), 2.43 (s, 3H), (m, 1H), (m, 1H), 5.35 (br d, J = 4.4 Hz, 1H), 6.93 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 11.9, 19.3, 20.3, 21.4, 21.6, 25.2, 26.7, 26.9, 27.7, 31.4, 31.6, 32.9, 35.7, 36.7, 36.9, 37.3, 38.1, S3

4 41.4, 44.1, 46.8, 50.4, 55.6, 60.1, 73.8, 120.3, 122.1, 126.7, 129.3, 139.5, 140.0, 142.8, 167.9, 170.5, HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 36 H 48 NO 4 S ; found Hexacyclic steroid 4b: Obtained from 1-pyrrolidino-1-cyclopentene (3b). Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4b as a white solid (83.3 mg, 48%). mp C (from ethyl 25 acetate/hexane). [α] D +15 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1028, 1090, 1151, 1240, 1313, 1561, 1615 and 1726 cm H NMR δ = 0.80 (s, 3H, H-18), (m, 1H), 1.00 (s, 3H, H-19), (m, 4H), (m, 7H), (m, 1H), (m, 4H), 2.03 (s, 3H), (m, 4H), (m, 2H), 2.43 (s, 3H), (m, 1H), 2.54 (dd, J = 19.6 and 9.2 Hz, 1H), 2.69 (dd, J = 19.6 and 9.6 Hz, 1H), (m, 1H, H-3), 5.35 (br d, J = 4.8 Hz, 1H, H-6), 7.07 (br d, J = 2.0 Hz, 1H, H-21), 7.29 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 12.1 (C-18), 19.3 (C-19), 20.4, 21.4, 21.6, 23.6, 27.5, 27.7, 31.49, 31.55, 31.61, 32.3, 36.7, 36.9, 37.2, 38.1, 41.6, 46.1, 50.4, 52.4, 55.9, 61.6, 73.9 (C-3), (C-21) (C-6), 126.7, 129.3, 139.5, 140.0, 142.8, 170.6, 176.6, (C-20). HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 35 H 46 NO 4 S ; found General procedure for the synthesis of hexacyclic and pentacyclic steroids for enamines generated in situ: Method A: A solution of 1-azadiene 1 (0.153 g, 0.3 mmol), appropriate ketone (1.5 mmol) and pyrrolidine (5 μl, 0.06 mmol, 20 mol%) in dry toluene (15 ml) was refluxed, with a Dean-Stark apparatus, for hours. After cooling to room temperature, the solvent was evaporated and the product purified by flash chromatography. S4

5 Method B: A solution of 1-azadiene 1 (0.153 g, 0.3 mmol), appropriate ketone (0.45 mmol) and pyrrolidine (5 μl, 0.06 mmol, 20 mol%) in dry toluene (1 ml) was irradiated in a microwave reactor at 140 ºC for 10 minutes. After cooling to room temperature, the solvent was evaporated and the product purified by flash chromatography. Hexacyclic steroid 4a: Obtained from cyclohexanone. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4a (Method A: mg, 70%; Method B: mg, 65%). Compound 4a was identified by comparison with the specimen previously isolated (see above). Hexacyclic steroid 4b: Obtained from cyclopentanone. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4b (Method A: mg, 71%; Method B: mg, 62%). Compound 4b was identified by comparison with the specimen previously isolated (see above). Hexacyclic steroid 4c: Obtained from cycloheptanone. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4c as a white solid (Method B: 90.3 mg, 50%): mp C (from ethyl acetate/hexane). 25 [α] D +100 (c 0.5 in CH 2 Cl 2 ). IR (ATR) 1033, 1091, 1143, 1244, 1298, 1552, 1593, 1593 and 1729 cm H NMR δ = 0.79 and 0.81 (s, 3H), (m, 1H), 0.99 and 1.00 (s, 3H), (m, 3H), (m, 9H), (m, 9H), 2.03 (s, 3H), (m, 5H), 2.43 (s, 3H), (m, 3H), (m, 1H), 5.35 (br d, J = 3.2 Hz, 1H), 6.94 and 7.01 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H). 13 C NMR δ 12.1, 19.3, 20.4, 21.4, 25.4, 26.3, 27.6, 27.7, 28.5, 31.5, 31.6, 36.7, 36.9, 37.7, 38.1, 41.3, 42.0, 42.7, 43.5, 50.3, 54.3, 55.5, 56.4, 73.8, 121.4, 122.1, 126.7, 129.3, 139.6, 139.9, 142.7, 170.6, 174.0, Anal. Calcd for C 37 H 49 NO 4 S: C, 73.59; H, 8.14; N, Found: C, 73.45; H, 8.34; N, Duplication of signals corresponding to protons H-21, H-18 and H-19 is observed in the 1 H NMR spectrum of steroid 4c. The 13 C NMR spectrum shows also duplication of S5

6 some signals (Figure 8). This can be explained considering conformational isomerism since steroid 4c was isolated as a single compound as indicated by the observed narrow melting range. Hexacyclic steroid 4d: Obtained from cyclooctanone. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4d as a white 25 solid (Method B: 52.3 mg, 28%): mp C (from ethyl acetate/hexane). [α] D +95 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1031, 1088, 1155, 1238, 1311, 1578 and 1729 cm H NMR δ = 0.84 (s, 3H), (m, 1H), 1.00 (s, 3H), (m, 15H), (m, 5H), (m, 2H), 2.02 (s, 3H), (m, 8H), 2.42 (s, 3H), (m, 1H), (m, 1H), 5.35 (bd, J = 4.8 Hz, 1H), 7.01 (bd, J = 2.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 12.1, 19.3, 20.3, 21.4, 21.5, 23.9, 25.0, 25.4, 26.0, 26.8, 27.7, 31.4, 31.6, 33.4, 33.9, 36.7, 36.9, 37.3, 38.1, 41.7, 42.0, 48.1, 50.4, 55.5, 61.3, 73.9, 122.1, 122.9, 126.7, 129.3, 139.7, 140.0, 142.7, 170.5, 175.2, HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 38 H 52 NO 4 S ; found Hexacyclic steroid 4e: Obtained from tetrahydro-4h-pyran-4-one. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:2)] gave compound 4e as a white solid (Method B: 78.8 mg, 44%): mp C (from ethyl 25 acetate/hexane). [α] D +110 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1030, 1091, 1144, 1258, 1300, 1562, 1607 and 1725 cm H NMR δ = 0.79 (s, 3H), (m, 1H), 1.00 (s, 3H), (m, 3H), (m, 7H), (m, 4H), 2.03 (s, 3H), (m, 1H), 2.09 (sl, 1H), (m, 2H), 2.44 (s, 3H), 2.47 (sl, 1H), (m, 2H), 3.06 (br t, J = 11.0 Hz, 1H), (m, 1H), 4.14 (ddd, J = 18.0, 11.6 and 6.4 Hz, 2H), (m, 1H), 5.35 (br d, J = 4.8 Hz, 1H), 7.03 (s, 1H), 7.31 (d, J = 8.0 Hz, S6

7 2H), 7.85 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 11.8, 19.3, 20.3, 21.4, 21.6, 26.6, 27.7, 31.4, 31.5, 35.1, 36.7, 36.9, 37.2, 38.1, 39.3, 41.2, 46.3, 50.3, 55.8, 59.6, 68.0, 71.9, 73.8, 120.9, 122.0, 126.7, 129.3, 139.2, 140.0, 143.1, 162.0, 170.5, HRMS (ESI- TOF) m/z: [M+H + ] Calcd. for C 35 H 46 NO 5 S ; found Hexacyclic steroid 4f: Obtained from tetrahydro-4h-thiopyran-4-one. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 4f as a white solid (Method B: mg, 67%): mp C (from ethyl 25 acetate/hexane). [α] D +110 (c 0.5 in CH 2 Cl 2 ). IR (ATR) 1027, 1091, 1148, 1261, 1302, 1567, 1600 and 1721 cm H NMR δ = 0.79 (s, 3H), (m, 1H), 0.99 (s, 3H), (m, 3H), (m, 8H), (m, 3H), 2.03 (s, 3H), (m, 2H), (m, 2H), 2.44 (s, 3H), (m, 7H), (m, 1H), 5.35 (br d, J = 4.8 Hz, 1H), 6.99 and 7.01 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H). 13 C NMR δ 11.8, 19.3, 20.3, 21.4, 21.6, 26.9, 27.7, 29.1, 31.3, 31.5, 33.7, 36.7, 36.9, 37.2, 37.4, 38.1, 41.5, 43.1, 48.1, 50.3, 55.5, 59.9, 73.8, 122.0, 122.5, 126.7, 129.3, 139.1, 140.0, 143.1, 162.9, 170.5, Anal. Calcd for C 35 H 45 NO 4 S 2 : C, 69.16; H, 7.46; N, Found: C, 68.91; H, 7.42; N, Duplication of signals corresponding to protons H-21 is observed in the 1 H NMR spectrum of steroid 4f. The 13 C NMR spectrum shows also duplication of some signals (Figure 11). This can be explained considering conformational isomerism since steroid 4f was isolated as a single compound as indicated by the observed narrow melting range. The chemical shift and appearance of proton H-21 depends on the deuterium solvent (DMSO-d 6 or CDCl 3 ) and on the temperature used to record the spectrum (Figures 12 and 13). S7

8 Hexacyclic steroid 4g: Obtained from N-methyl-4-piperidone. Purification of the crude product by flash chromatography [ethyl acetate (100%) and ethyl acetate/methanol (95:5)] gave compound 4g as a yellow solid (Method B: mg, 60%): mp C (from ethyl acetate/hexane). [α] D +90 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1033, 1088, 1146, 1238, 1298, 1567, 1597 and 1735 cm H NMR δ = 0.80 (s, 3H), (m, 1H), 1.00 (s, 3H), (m, 3H), (m, 7H), (m, 1H), (m, 4H), 2.03 (s, 3H), (m, 4H), (m, 1H), 2.33 (s, 3H), 2.43 (s, 3H), (m, 3H), (m, 1H), 3.08 (dd, J = 10.4 and 5.2 Hz, 1H), (m, 1H), 5.35 (approx. d, J = 4.4 Hz, 1H), 6.99 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H). 13 C NMR δ = 11.9, 19.3, 20.3, 21.4, 21.6, 26.8, 27.7, 31.4, 31.5, 34.8, 36.7, 36.9, 37.2, 38.1, 41.4, 41.5, 45.87, 45.91, 50.3, 55.4, 55.6, 59.8, 60.9, 73.8, 120.6, 122.8, 126.7, 129.3, 139.3, 140.0, 143.0, 163.4, 170.5, HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 36 H 49 N 2 O 4 S ; found Pentacyclic steroids 7a and 7b: Obtained from 1-(1-p-chlorophenyl-1H-1,2,3-triazol-4- yl)ethanone 6. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave, in order of elution, compound 7a as a white solid (Method B: 68.0 mg, 32%) and compound 7b as a white solid (Method B: 50.6 mg, 24%). 25 Compound 7a: mp C (from ethyl acetate/hexane). [α] D +65 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1020, 1026, 1091, 1152, 1248, 1300, 1500, 1569, 1592 and 1717 cm H NMR δ = 0.85 (s, 3H, H-18), (m, 1H), 1.02 (s, 3H, H-19), (m, 4H), (m, 5H), (m, 1H), (m, 2H), (m, 1H), 2.03 (s, 3H, H-42), (m, 1H), 2.16 (d, J = 12.8 Hz, 1H, H-17), (m, 2H), 2.45 (s, 3H), (m, 1H, H-16), (m, 1H, H-23), 3.56 (dd, J = 17.6 and 3.6 Hz, 1H, H-23), (m, 1H, H-3), 5.38 (br d, J = 4.8 Hz, 1H, H-6), 7.33 (d, J = 8.0 Hz, 2H), (m, 2H), 7.69 (br d, J = 2.0 Hz, 1H, H-21), (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 8.33 (s, 1H, H-25). 13 C NMR δ = 12.0 (C-18), 19.3 (C- 19), 20.3, 21.4, 21.6, 27.7, 28.5, 31.4, 31.5, 35.6, 36.7, 37.0, 37.3, 38.1, 38.6, 41.6, 50.4, 55.5, 61.1 (C-17), 73.8 (C-3), (C-25), (C-21), 121.8, 122.2, 126.8, 129.4, S8

9 130.1, 135.0, 135.2, 139.1, 139.9, 143.2, 147.4, 150.0, (C-42), (C-20). HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 40 H 46 ClN 4 O 4 S ; found Compound 7b: mp C (from ethyl acetate/hexane). [α] D -40 (c 0.5 in CH 2 Cl 2 ). IR (ATR) 1026, 1091, 1152, 1238, 1249, 1298, 1499, 1587 and 1720 cm H NMR δ = 0.74 (s, 3H, H-18), (m, 1H), 0.99 (s, 3H, H-19), (m, 2H), (m, 8H), (m, 4H), 2.04 (s, 3H, H-42), (m, 3H), 2.43 (s, 3H), (m, 2H, H-23), (m, 1H, H-3), 5.35 (br d, J = 4.4 Hz, 1H, H- 6), 5.88 (s, 1H, H-32), 6.56 (br d, J = 2.8 Hz, 1H, H-21), 7.31 (d, J = 8.4 Hz, 2H), (m, 2H), (m, 4H), 7.97 (s, 1H, H-25). 13 C NMR δ = 16.2 (C-18), 19.3 (C- 19), 20.7, 21.4, 21.6, 27.7, 29.9, 30.8, 31.3, 31.8, 35.8, 36.5, 36.9, 37.9, 38.0, 44.6, 49.8, 56.3, 73.7 (C-3), (C-25), 120.7, 121.6, (C-6), (C-21), 126.9, 129.5, 130.0, 130.1, 134.5, 135.5, 139.6, 143.8, (C-20), (C-24), (C-41). HRMS (ESI-TOF) m/z: [M+H + ] Calcd. for C 40 H 46 ClN 4 O 4 S ; found Bis-steroid 8: A solution of 1-azadiene 1 (0.153 g, 0.3 mmol) and pyrrolidine (5 μl, 0.06 mmol, 20 mol%) in dry toluene (1 ml) was irradiated in a microwave reactor at 140 ºC for 10 minutes. After cooling to room temperature, the solvent was evaporated. Purification of the crude product by flash chromatography [ethyl acetate/hexane (1:4)] gave compound 8 as a white solid (66.5 mg, 52%): mp C (from ethyl 25 acetate/hexane). [α] D +55 (c 1.0 in CH 2 Cl 2 ). IR (ATR) 1037, 1091, 1235, 1244, 1296, 1540, 1578 and 1731 cm H NMR δ = 0.82 (s, 3H), (m, 1H), 1.00 (s, 3H), 1.03 (s, 3H), 1.06 (s, 3H), (m, 5H), (m, 8H), (m, 14H), 2.03 (s, 3H), 2.04 (s, 3H), (m, 1H), (m, 7H), 2.43 (s, 3H), 2.47 (br s, 1H), 2.79 (br d, J = 12.8 Hz, 1H), (m, 2H), 5.36 (br d, J = 4.8 Hz, 1H), 5.39 (br d, J = 4.8 Hz, 1H), 6.27 (br s, 1H, H-16 ), 7.29 (d, J = 8.0 Hz, 2H), 7.35 (s, 1H, H-21), 7.85 (d, J = 8.0 Hz, 2H). 13 C NMR δ 12.1, 16.1, 19.2, 19.3, 20.3, 21.1, 21.4, 21.6, 27.7, 28.7, 30.2, 31.4, 31.5, 31.6, 32.1, 35.2, 36.7, 36.8, 37.0, 37.3, 38.1, S9

10 38.9, 41.6, 47.0, 50.2, 50.4, 55.5, 57.1, 61.3, 73.8, 73.9, (C-21), , , 126.7, 129.3, (C-16 ), 139.6, 140.0, 140.3, 142.8, 155.0, 155.2, 170.6, (C- 20). Anal. Calcd for C 53 H 69 NO 6 S: C, 75.05; H, 8.20; N, Found: C, 75.13; H, 7.90; N, 73. S10

11 3. Copies of NMR spectra of all new compounds Figure 1. 1 H and 13 C NMR spectra of compound 1 (CDCl 3 ). S11

12 Figure 2. COSY and NOESY spectra of compound 1 (CDCl 3 ). S12

13 Figure 3. HSQC and HMBC spectra of compound 1 (CDCl 3 ). S13

14 Figure 4. 1 H and 13 C NMR spectra of compound 4a (CDCl 3 ). S14

15 Figure 5. 1 H and 13 C NMR spectra of compound 4b (CDCl 3 ). S15

16 Figure 6. COSY and NOESY spectra of compound 4b (CDCl 3 ). S16

17 Figure 7. HSQC and HMBC spectra of compound 4b (CDCl 3 ). S17

18 Figure 8. 1 H and 13 C NMR spectra of compound 4c (CDCl 3 ). S18

19 Figure 9. 1 H and 13 C NMR spectra of compound 4d (CDCl 3 ). S19

20 Figure H and 13 C NMR spectra of compound 4e (CDCl 3 ). S20

21 Figure H and 13 C NMR spectra of compound 4f (CDCl 3 ). S21

22 Figure 12. Expansion of 1 H NMR spectra of compound 4f, in CDCl 3 and DMSO-d 6. Figure 13. Chemical behavior of the H-21 proton, in the 1 H NMR spectra of compound 4f with increasing temperature (DMSO-d 6 ). S22

23 Figure H and 13 C NMR spectra of compound 4g (CDCl 3 ). S23

24 Figure H and 13 C NMR spectra of compound 7a (CDCl 3 ). S24

25 Figure 16. COSY and NOESY spectra of compound 7a (CDCl 3 ). S25

26 Figure 17. HSQC and HMBC spectra of compound 7a (CDCl 3 ). S26

27 Figure H and 13 C NMR spectra of compound 7b (CDCl 3 ). S27

28 Figure 19. COSY and NOESY spectra of compound 7b (CDCl 3 ). S28

29 Figure 20. HSQC and HMBC spectra of compound 7b (CDCl 3 ). S29

30 Figure H and 13 C NMR spectra of compound 8 (CDCl 3 ). S30

31 Figure 22. COSY and NOESY spectra of compound 8 (CDCl 3 ). S31

32 Figure 23. HSQC and HMBC spectra of compound 8 (CDCl 3 ). S32

33 4. X-Ray Crystallographic data for compound 4a. X-ray Diffraction. Crystals of compound 4a was selected, covered with polyfluoroether oil, and mounted on a nylon loop. Crystallographic data for this compound was collected at the IST using graphite monochromated Mo-Kα radiation (λ= å) on a Bruker AXS-KAPPA APEX II diffractometer equipped with an Oxford Cryosystem open-flow nitrogen cryostat, at 150 K. Cell parameters were retrieved using Bruker SMART software and refined using Bruker SAINT on all observed reflections. Absorption corrections were applied using SADABS. 3 Structure solution and refinement were performed using direct methods with the programs SIR included in the package of programs WINGX-Version and SHELXL. 6 The crystal showed the presence of disordered solvent molecules, the PLATON/SQUEEZE 7 routine being applied, since a good disorder model was impossible to attain. All hydrogen atoms were inserted in idealised positions and allowed to refine riding on the parent carbon atom, with C H distances of 0.93 Å, 0.96 Å, 0.97 Å, and 0.99 Å for aromatic, methyl, methylene and methine H atoms, respectively, and with U iso (H) = 1.2U eq (C). The figures of the molecular structure were generated using ORTEP-III. CCDC (for 4a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via S33

34 Table 1. Crystallographic data and details about refinement for structure 4a. 4a Formula C 36 H 47 N O 4 S M (Å) T (K) 150(2) crystal system Orthorhombic space group P a (Å) (9) b (Å) (3) c (Å) (6) ( ) 90 ( ) 90 ( ) 90 V (Å 3 ) (10) Z 4 calc (g.cm -3 ) µ (mm -1 ) Crystal size Crystal colour Colourless Crystal description Needle max ( ) total data unique data 6870 R int R [I>2 (I)] R w Goodness of fit min max S34

35 Figure 24. ORTEP-3 diagram of compound 4a, using 30% probability level ellipsoids. Selected bond lengths (Å): C1 C2, 1.531(7); C5 C6, 1.321(7); C8 C14, 1.520(7); C15 C16, 1.535(7); C21 C22, 1.333(7); N28 C20, 1.303(6); S29 N28, 1.658(4); S29 O3, 1.440(4); S29 O4, 1.445(4); C3 O1, 1.461(6); Selected bond angles (º): C19 C10 C (4); C18 C13 C (4); C20 N28 S29, 118.2(4); C2 C3 O1, 106.2(4). S35

36 Table 2. Crystal data and structure refinement for 4a. Identification code Empirical formula Formula weight Temperature Wavelength Crystal system 4a C36 H47 N O4 S 293(2) K Å Orthorhombic Space group P Unit cell dimensions a = (9) Å = 90. b = (3) Å = 90. c = (6) Å = 90. Volume (10) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1272 Crystal size x x mm 3 Theta range for data collection to Index ranges Reflections collected <=h<=5, -21<=k<=19, -39<=l<=39 Independent reflections 6870 [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 6870 / 0 / 383 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter -0.04(9) Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S36

37 Table 3. Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for 4a. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) S(29) 6507(2) 6596(1) 8016(1) 47(1) O(3) 5064(7) 6218(2) 7733(1) 65(1) O(1) 12134(7) 3349(2) 11460(1) 67(1) N(28) 7633(6) 5971(2) 8340(1) 42(1) O(4) 8126(6) 7103(2) 7846(1) 61(1) C(14) 11505(8) 4245(3) 9034(2) 40(1) C(8) 12302(8) 4199(3) 9477(2) 40(1) C(13) 10203(8) 4990(3) 8939(2) 39(1) C(31) 2889(8) 7333(3) 8250(2) 47(1) C(16) 12130(8) 4634(3) 8323(2) 42(1) C(9) 10407(8) 4250(3) 9783(2) 43(1) C(17) 9867(8) 4856(3) 8474(2) 39(1) C(5) 12879(9) 3661(3) 10312(2) 44(1) C(7) 13489(9) 3436(3) 9556(2) 53(2) C(21) 9393(9) 5317(3) 7748(2) 50(2) C(20) 8896(8) 5440(3) 8189(2) 43(1) C(10) 11179(8) 4276(3) 10238(2) 41(1) C(6) 13849(9) 3289(3) 10008(2) 53(2) C(4) 13467(9) 3497(4) 10756(2) 59(2) C(27) 12100(8) 4272(3) 7891(2) 48(2) O(2) 12820(9) 2084(3) 11439(1) 95(2) C(18) 11483(9) 5741(3) 9018(2) 53(2) C(11) 8847(8) 4915(3) 9676(2) 51(2) C(30) 4978(8) 7171(3) 8360(2) 43(1) C(32) 1746(10) 7881(3) 8466(2) 56(2) C(22) 10735(9) 4771(4) 7613(2) 53(2) C(15) 13099(8) 4161(3) 8680(2) 53(2) C(3) 11513(10) 3348(3) 11024(2) 54(2) C(12) 8220(8) 4961(3) 9215(2) 48(1) C(35) 5916(10) 7542(4) 8687(2) 60(2) C(33) 2652(10) 8269(4) 8789(2) 58(2) C(1) 9271(9) 4083(4) 10521(2) 57(2) S37

38 C(2) 9851(10) 3980(4) 10977(2) 62(2) C(25) 14470(11) 3977(4) 7270(2) 74(2) C(37) 12751(11) 2681(5) 11633(2) 69(2) C(26) 14380(9) 4194(4) 7725(2) 63(2) C(19) 12100(11) 5081(3) 10351(2) 68(2) C(34) 4733(11) 8093(4) 8902(2) 72(2) C(23) 10926(11) 4619(5) 7155(2) 80(2) C(38) 13353(13) 2786(4) 12072(2) 93(2) C(24) 13271(12) 4569(4) 7016(2) 84(2) C(36) 1406(13) 8904(4) 9013(2) 104(3) S38

39 Table 4. Bond lengths [Å] and angles [ ] for 4a. S(29)-O(3) 1.440(4) S(29)-O(4) 1.445(4) S(29)-N(28) 1.658(4) S(29)-C(30) 1.769(5) O(1)-C(37) 1.333(7) O(1)-C(3) 1.461(6) N(28)-C(20) 1.303(6) C(14)-C(8) 1.520(7) C(14)-C(15) 1.526(7) C(14)-C(13) 1.547(7) C(14)-H(14) C(8)-C(7) 1.527(7) C(8)-C(9) 1.549(7) C(8)-H(8) C(13)-C(12) 1.530(7) C(13)-C(17) 1.536(7) C(13)-C(18) 1.540(7) C(31)-C(32) 1.374(7) C(31)-C(30) 1.384(7) C(31)-H(31) C(16)-C(27) 1.530(7) C(16)-C(15) 1.535(7) C(16)-C(17) 1.547(7) C(16)-H(16) C(9)-C(11) 1.544(7) C(9)-C(10) 1.548(7) C(9)-H(9) C(17)-C(20) 1.492(7) C(17)-H(17) C(5)-C(6) 1.321(7) C(5)-C(4) 1.507(7) C(5)-C(10) 1.520(7) C(7)-C(6) 1.500(7) C(7)-H(7A) C(7)-H(7B) C(21)-C(22) 1.333(7) S39

40 C(21)-C(20) 1.473(7) C(21)-H(21) C(10)-C(19) 1.540(8) C(10)-C(1) 1.541(7) C(6)-H(6) C(4)-C(3) 1.522(8) C(4)-H(4A) C(4)-H(4B) C(27)-C(22) 1.507(8) C(27)-C(26) 1.530(8) C(27)-H(27) O(2)-C(37) 1.204(8) C(18)-H(18A) C(18)-H(18B) C(18)-H(18C) C(11)-C(12) 1.544(7) C(11)-H(11A) C(11)-H(11B) C(30)-C(35) 1.368(7) C(32)-C(33) 1.363(8) C(32)-H(32) C(22)-C(23) 1.510(8) C(15)-H(15A) C(15)-H(15B) C(3)-C(2) 1.512(8) C(3)-H(3) C(12)-H(12A) C(12)-H(12B) C(35)-C(34) 1.387(8) C(35)-H(35) C(33)-C(34) 1.387(9) C(33)-C(36) 1.524(8) C(1)-C(2) 1.531(7) C(1)-H(1A) C(1)-H(1B) C(2)-H(2A) C(2)-H(2B) C(25)-C(24) 1.508(9) S40

41 C(25)-C(26) 1.519(8) C(25)-H(25A) C(25)-H(25B) C(37)-C(38) 1.480(8) C(26)-H(26B) C(26)-H(26A) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(34)-H(34) C(23)-C(24) 1.538(10) C(23)-H(23B) C(23)-H(23A) C(38)-H(38A) C(38)-H(38B) C(38)-H(38C) C(24)-H(24A) C(24)-H(24B) C(36)-H(36A) C(36)-H(36B) C(36)-H(36C) O(3)-S(29)-O(4) 118.0(3) O(3)-S(29)-N(28) 112.2(2) O(4)-S(29)-N(28) 109.4(2) O(3)-S(29)-C(30) 108.2(3) O(4)-S(29)-C(30) 106.4(2) N(28)-S(29)-C(30) 101.2(2) C(37)-O(1)-C(3) 118.7(5) C(20)-N(28)-S(29) 118.2(4) C(8)-C(14)-C(15) 119.1(4) C(8)-C(14)-C(13) 113.8(4) C(15)-C(14)-C(13) 106.0(4) C(8)-C(14)-H(14) C(15)-C(14)-H(14) C(13)-C(14)-H(14) C(14)-C(8)-C(7) 111.3(4) C(14)-C(8)-C(9) 110.4(4) S41

42 C(7)-C(8)-C(9) 108.3(4) C(14)-C(8)-H(8) C(7)-C(8)-H(8) C(9)-C(8)-H(8) C(12)-C(13)-C(17) 117.1(4) C(12)-C(13)-C(18) 110.7(4) C(17)-C(13)-C(18) 111.0(4) C(12)-C(13)-C(14) 106.6(4) C(17)-C(13)-C(14) 98.2(4) C(18)-C(13)-C(14) 112.6(4) C(32)-C(31)-C(30) 120.0(6) C(32)-C(31)-H(31) C(30)-C(31)-H(31) C(27)-C(16)-C(15) 118.5(4) C(27)-C(16)-C(17) 112.2(4) C(15)-C(16)-C(17) 104.8(4) C(27)-C(16)-H(16) C(15)-C(16)-H(16) C(17)-C(16)-H(16) C(11)-C(9)-C(10) 112.9(4) C(11)-C(9)-C(8) 112.5(4) C(10)-C(9)-C(8) 111.7(4) C(11)-C(9)-H(9) C(10)-C(9)-H(9) C(8)-C(9)-H(9) C(20)-C(17)-C(13) 124.1(4) C(20)-C(17)-C(16) 110.1(4) C(13)-C(17)-C(16) 102.7(4) C(20)-C(17)-H(17) C(13)-C(17)-H(17) C(16)-C(17)-H(17) C(6)-C(5)-C(4) 120.4(5) C(6)-C(5)-C(10) 122.7(5) C(4)-C(5)-C(10) 116.9(5) C(6)-C(7)-C(8) 112.4(5) C(6)-C(7)-H(7A) C(8)-C(7)-H(7A) C(6)-C(7)-H(7B) S42

43 C(8)-C(7)-H(7B) H(7A)-C(7)-H(7B) C(22)-C(21)-C(20) 123.5(6) C(22)-C(21)-H(21) C(20)-C(21)-H(21) N(28)-C(20)-C(21) 126.4(5) N(28)-C(20)-C(17) 119.0(5) C(21)-C(20)-C(17) 114.5(5) C(5)-C(10)-C(19) 108.9(4) C(5)-C(10)-C(1) 107.4(4) C(19)-C(10)-C(1) 110.1(5) C(5)-C(10)-C(9) 110.4(4) C(19)-C(10)-C(9) 111.6(4) C(1)-C(10)-C(9) 108.4(4) C(5)-C(6)-C(7) 125.2(5) C(5)-C(6)-H(6) C(7)-C(6)-H(6) C(5)-C(4)-C(3) 112.2(5) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(5)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(22)-C(27)-C(16) 108.7(4) C(22)-C(27)-C(26) 111.8(5) C(16)-C(27)-C(26) 110.1(4) C(22)-C(27)-H(27) C(16)-C(27)-H(27) C(26)-C(27)-H(27) C(13)-C(18)-H(18A) C(13)-C(18)-H(18B) H(18A)-C(18)-H(18B) C(13)-C(18)-H(18C) H(18A)-C(18)-H(18C) H(18B)-C(18)-H(18C) C(12)-C(11)-C(9) 114.6(4) C(12)-C(11)-H(11A) C(9)-C(11)-H(11A) S43

44 C(12)-C(11)-H(11B) C(9)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(35)-C(30)-C(31) 120.7(5) C(35)-C(30)-S(29) 120.9(4) C(31)-C(30)-S(29) 117.5(4) C(33)-C(32)-C(31) 120.5(6) C(33)-C(32)-H(32) C(31)-C(32)-H(32) C(21)-C(22)-C(27) 124.2(5) C(21)-C(22)-C(23) 119.6(6) C(27)-C(22)-C(23) 116.2(5) C(14)-C(15)-C(16) 104.8(4) C(14)-C(15)-H(15A) C(16)-C(15)-H(15A) C(14)-C(15)-H(15B) C(16)-C(15)-H(15B) H(15A)-C(15)-H(15B) O(1)-C(3)-C(2) 106.2(4) O(1)-C(3)-C(4) 109.6(5) C(2)-C(3)-C(4) 112.0(5) O(1)-C(3)-H(3) C(2)-C(3)-H(3) C(4)-C(3)-H(3) C(13)-C(12)-C(11) 111.0(4) C(13)-C(12)-H(12A) C(11)-C(12)-H(12A) C(13)-C(12)-H(12B) C(11)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(30)-C(35)-C(34) 118.4(6) C(30)-C(35)-H(35) C(34)-C(35)-H(35) C(32)-C(33)-C(34) 119.1(6) C(32)-C(33)-C(36) 120.1(6) C(34)-C(33)-C(36) 120.8(7) C(2)-C(1)-C(10) 114.4(5) C(2)-C(1)-H(1A) S44

45 C(10)-C(1)-H(1A) C(2)-C(1)-H(1B) C(10)-C(1)-H(1B) H(1A)-C(1)-H(1B) C(3)-C(2)-C(1) 110.1(5) C(3)-C(2)-H(2A) C(1)-C(2)-H(2A) C(3)-C(2)-H(2B) C(1)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(24)-C(25)-C(26) 110.1(5) C(24)-C(25)-H(25A) C(26)-C(25)-H(25A) C(24)-C(25)-H(25B) C(26)-C(25)-H(25B) H(25A)-C(25)-H(25B) O(2)-C(37)-O(1) 121.6(6) O(2)-C(37)-C(38) 126.5(7) O(1)-C(37)-C(38) 111.8(6) C(25)-C(26)-C(27) 113.3(5) C(25)-C(26)-H(26B) C(27)-C(26)-H(26B) C(25)-C(26)-H(26A) C(27)-C(26)-H(26A) H(26B)-C(26)-H(26A) C(10)-C(19)-H(19A) C(10)-C(19)-H(19B) H(19A)-C(19)-H(19B) C(10)-C(19)-H(19C) H(19A)-C(19)-H(19C) H(19B)-C(19)-H(19C) C(35)-C(34)-C(33) 121.2(6) C(35)-C(34)-H(34) C(33)-C(34)-H(34) C(22)-C(23)-C(24) 111.7(6) C(22)-C(23)-H(23B) C(24)-C(23)-H(23B) C(22)-C(23)-H(23A) S45

46 C(24)-C(23)-H(23A) H(23B)-C(23)-H(23A) C(37)-C(38)-H(38A) C(37)-C(38)-H(38B) H(38A)-C(38)-H(38B) C(37)-C(38)-H(38C) H(38A)-C(38)-H(38C) H(38B)-C(38)-H(38C) C(25)-C(24)-C(23) 110.8(7) C(25)-C(24)-H(24A) C(23)-C(24)-H(24A) C(25)-C(24)-H(24B) C(23)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(33)-C(36)-H(36A) C(33)-C(36)-H(36B) H(36A)-C(36)-H(36B) C(33)-C(36)-H(36C) H(36A)-C(36)-H(36C) H(36B)-C(36)-H(36C) Symmetry transformations used to generate equivalent atoms. S46

47 Table 5. Anisotropic displacement parameters (Å 2 x 10 3 )for 4a. The anisotropic displacement factor exponent takes the form: -2 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 S(29) 49(1) 51(1) 41(1) 4(1) 1(1) 7(1) O(3) 67(3) 70(3) 58(3) -18(2) -23(2) 18(2) O(1) 98(3) 59(3) 42(2) -4(2) -23(2) 11(3) N(28) 40(2) 51(3) 37(3) 3(2) -3(2) 8(2) O(4) 58(2) 62(3) 63(3) 14(2) 20(2) 5(2) C(14) 33(3) 41(3) 47(3) 4(3) -3(3) 0(3) C(8) 34(3) 34(3) 51(3) 3(3) -6(3) 1(2) C(13) 36(3) 41(3) 41(3) -1(3) -6(3) 4(3) C(31) 39(3) 54(4) 49(4) 4(3) 2(3) -1(3) C(16) 34(3) 44(3) 48(3) -6(3) 5(3) 7(2) C(9) 40(3) 43(3) 45(3) 3(3) -1(3) -3(3) C(17) 36(3) 40(3) 41(3) -4(3) 4(3) -2(3) C(5) 44(3) 46(3) 42(3) -1(3) -8(3) -4(3) C(7) 48(3) 57(4) 55(4) 0(3) 3(3) 12(3) C(21) 55(4) 56(4) 40(4) 1(3) 0(3) 6(3) C(20) 34(3) 49(3) 47(3) 0(3) -2(3) -7(3) C(10) 38(3) 44(3) 42(3) -2(3) -7(3) -5(3) C(6) 47(4) 55(4) 58(4) 11(3) -8(3) 10(3) C(4) 59(4) 67(4) 50(4) 5(3) -18(3) 13(4) C(27) 54(4) 36(3) 52(4) -10(3) 4(3) 2(3) O(2) 153(5) 67(3) 66(3) -2(3) -10(3) 21(3) C(18) 58(4) 52(3) 49(4) -1(3) -1(3) -11(3) C(11) 43(3) 60(4) 49(4) 8(3) 0(3) 15(3) C(30) 39(3) 49(4) 40(3) 9(3) 7(3) 4(3) C(32) 42(3) 58(4) 68(4) 7(3) 6(3) 6(3) C(22) 53(4) 59(4) 48(4) -15(3) 0(3) 2(3) C(15) 39(3) 70(4) 51(4) -5(3) 3(3) 16(3) C(3) 72(4) 50(3) 40(3) -1(3) -5(3) 1(4) C(12) 38(3) 59(4) 46(3) 3(3) -1(3) 11(3) C(35) 50(4) 79(5) 51(4) -14(4) -6(3) 0(3) C(33) 54(4) 59(4) 59(4) -1(3) 19(3) 6(3) C(1) 48(4) 77(4) 45(4) 1(3) -8(3) 5(3) C(2) 65(4) 81(5) 40(4) 6(3) -2(3) 6(4) S47

48 C(25) 76(5) 76(5) 69(5) -30(4) 25(4) 8(4) C(37) 80(5) 71(5) 56(4) 5(4) 2(4) 9(4) C(26) 53(4) 68(4) 67(5) -10(4) 12(3) 10(3) C(19) 90(5) 53(4) 61(4) -6(3) -21(4) 1(4) C(34) 75(5) 80(5) 60(5) -23(4) 7(4) 2(4) C(23) 81(5) 107(6) 52(4) -21(4) 6(4) 18(4) C(38) 129(6) 111(6) 39(4) 0(4) -12(4) 46(5) C(24) 99(6) 94(5) 60(4) -15(4) 7(5) 14(5) C(36) 110(6) 90(5) 112(7) -26(5) 21(6) 32(5) S48

49 Table 6. Torsion angles [ ] for 4a. O(3)-S(29)-N(28)-C(20) 64.4(4) O(4)-S(29)-N(28)-C(20) -68.5(4) C(30)-S(29)-N(28)-C(20) 179.5(4) C(15)-C(14)-C(8)-C(7) -56.4(6) C(13)-C(14)-C(8)-C(7) 177.5(4) C(15)-C(14)-C(8)-C(9) (5) C(13)-C(14)-C(8)-C(9) 57.2(6) C(8)-C(14)-C(13)-C(12) -62.9(6) C(15)-C(14)-C(13)-C(12) 164.3(4) C(8)-C(14)-C(13)-C(17) 175.6(4) C(15)-C(14)-C(13)-C(17) 42.8(5) C(8)-C(14)-C(13)-C(18) 58.7(6) C(15)-C(14)-C(13)-C(18) -74.1(5) C(14)-C(8)-C(9)-C(11) -46.8(6) C(7)-C(8)-C(9)-C(11) (4) C(14)-C(8)-C(9)-C(10) (4) C(7)-C(8)-C(9)-C(10) 62.9(6) C(12)-C(13)-C(17)-C(20) 74.0(6) C(18)-C(13)-C(17)-C(20) -54.4(6) C(14)-C(13)-C(17)-C(20) (5) C(12)-C(13)-C(17)-C(16) (5) C(18)-C(13)-C(17)-C(16) 70.9(5) C(14)-C(13)-C(17)-C(16) -47.2(5) C(27)-C(16)-C(17)-C(20) -60.6(6) C(15)-C(16)-C(17)-C(20) 169.6(4) C(27)-C(16)-C(17)-C(13) 165.4(4) C(15)-C(16)-C(17)-C(13) 35.6(5) C(14)-C(8)-C(7)-C(6) (5) C(9)-C(8)-C(7)-C(6) -45.2(6) S(29)-N(28)-C(20)-C(21) -2.0(7) S(29)-N(28)-C(20)-C(17) (4) C(22)-C(21)-C(20)-N(28) 178.7(5) C(22)-C(21)-C(20)-C(17) -5.2(8) C(13)-C(17)-C(20)-N(28) -23.9(7) C(16)-C(17)-C(20)-N(28) (5) C(13)-C(17)-C(20)-C(21) 159.7(5) S49

50 C(16)-C(17)-C(20)-C(21) 37.6(6) C(6)-C(5)-C(10)-C(19) (6) C(4)-C(5)-C(10)-C(19) 69.5(6) C(6)-C(5)-C(10)-C(1) 131.6(5) C(4)-C(5)-C(10)-C(1) -49.7(6) C(6)-C(5)-C(10)-C(9) 13.7(7) C(4)-C(5)-C(10)-C(9) (5) C(11)-C(9)-C(10)-C(5) (4) C(8)-C(9)-C(10)-C(5) -46.1(6) C(11)-C(9)-C(10)-C(19) -52.9(6) C(8)-C(9)-C(10)-C(19) 75.1(6) C(11)-C(9)-C(10)-C(1) 68.5(6) C(8)-C(9)-C(10)-C(1) (4) C(4)-C(5)-C(6)-C(7) (5) C(10)-C(5)-C(6)-C(7) 2.4(9) C(8)-C(7)-C(6)-C(5) 14.5(8) C(6)-C(5)-C(4)-C(3) (6) C(10)-C(5)-C(4)-C(3) 50.4(7) C(15)-C(16)-C(27)-C(22) 169.8(4) C(17)-C(16)-C(27)-C(22) 47.5(6) C(15)-C(16)-C(27)-C(26) -67.5(6) C(17)-C(16)-C(27)-C(26) 170.2(5) C(10)-C(9)-C(11)-C(12) 174.0(5) C(8)-C(9)-C(11)-C(12) 46.4(6) C(32)-C(31)-C(30)-C(35) 1.2(8) C(32)-C(31)-C(30)-S(29) (4) O(3)-S(29)-C(30)-C(35) 174.0(5) O(4)-S(29)-C(30)-C(35) -58.2(5) N(28)-S(29)-C(30)-C(35) 56.0(5) O(3)-S(29)-C(30)-C(31) -16.0(5) O(4)-S(29)-C(30)-C(31) 111.7(4) N(28)-S(29)-C(30)-C(31) (4) C(30)-C(31)-C(32)-C(33) 0.0(9) C(20)-C(21)-C(22)-C(27) -7.2(9) C(20)-C(21)-C(22)-C(23) 172.0(5) C(16)-C(27)-C(22)-C(21) -14.7(7) C(26)-C(27)-C(22)-C(21) (6) C(16)-C(27)-C(22)-C(23) 166.1(5) S50

51 C(26)-C(27)-C(22)-C(23) 44.4(7) C(8)-C(14)-C(15)-C(16) (5) C(13)-C(14)-C(15)-C(16) -21.7(5) C(27)-C(16)-C(15)-C(14) (5) C(17)-C(16)-C(15)-C(14) -8.4(6) C(37)-O(1)-C(3)-C(2) 149.5(6) C(37)-O(1)-C(3)-C(4) -89.3(6) C(5)-C(4)-C(3)-O(1) (5) C(5)-C(4)-C(3)-C(2) -51.0(7) C(17)-C(13)-C(12)-C(11) 167.0(4) C(18)-C(13)-C(12)-C(11) -64.4(6) C(14)-C(13)-C(12)-C(11) 58.4(6) C(9)-C(11)-C(12)-C(13) -53.3(6) C(31)-C(30)-C(35)-C(34) -1.0(9) S(29)-C(30)-C(35)-C(34) 168.7(5) C(31)-C(32)-C(33)-C(34) -1.2(9) C(31)-C(32)-C(33)-C(36) 177.0(6) C(5)-C(10)-C(1)-C(2) 53.0(6) C(19)-C(10)-C(1)-C(2) -65.4(6) C(9)-C(10)-C(1)-C(2) 172.2(5) O(1)-C(3)-C(2)-C(1) 174.0(5) C(4)-C(3)-C(2)-C(1) 54.3(7) C(10)-C(1)-C(2)-C(3) -57.4(7) C(3)-O(1)-C(37)-O(2) 0.5(10) C(3)-O(1)-C(37)-C(38) 179.2(5) C(24)-C(25)-C(26)-C(27) 57.1(8) C(22)-C(27)-C(26)-C(25) -48.8(7) C(16)-C(27)-C(26)-C(25) (5) C(30)-C(35)-C(34)-C(33) -0.3(10) C(32)-C(33)-C(34)-C(35) 1.4(10) C(36)-C(33)-C(34)-C(35) (6) C(21)-C(22)-C(23)-C(24) 133.3(7) C(27)-C(22)-C(23)-C(24) -47.4(8) C(26)-C(25)-C(24)-C(23) -59.0(7) C(22)-C(23)-C(24)-C(25) 54.0(8) Symmetry transformations used to generate equivalent atoms. S51

52 5. References: 1. Li, H.; Liu, H.-M.; Ge, W.; Huang, L.; Shan, L. Steroids 2005, 70, Lopes, S. M. M.; Novais, J. S.; Costa, D. C. S.; Castro, H. C.; Figueiredo, A. M. S.; Ferreira, V. F.; Pinho e Melo, T. M. V. D.; da Silva, F. d. C. Eur. J. Med. Chem. 2018, 143, G. M. Sheldrick, SADABS, Program for Empirical Absorption Correction; University of Göttingen: Göttingen, Germany, M. C. Burla, R. Caliandro, B. Carrozzini, G. L. Cascarano, C. Giacovazzo, M. Mallamo, A. Mazzone, G. Polidori 2014, in preparation. 5. L. J. Farrugia, J. Appl. Crystallogr. 2012, 45, G. M. Sheldrick, (a) SHELX97 - Programs for Crystal Structure Analysis (Release 97-2), Institüt für Anorganische Chemie der Universität, Tammanstrasse 4, D-3400 Göttingen, Germany, 1998; (b) G. M. Sheldrick, Acta Crystallogr. 2008, A64, A. L. Spek, J. Appl. Crystallogr. 2003, 36, S52