On the Structure of Palau amine: Evidence for the Revised Relative Configuration from Chemical Synthesis

Transcription

1 n the Structure of Palau amine: Evidence for the Revised Relative Configuration from Chemical Synthesis Brian A. Lanman, Larry E. verman,* Ralph Paulini, and Nicole S. White Contribution from the Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California Supporting Information (70 pages) Part 1. Experimental procedures pages S1 S6 2D NMR data for compounds 3 and 4 pages S7 Experimentally determined and calculated pages S8 S10 interproton distances for 3 and 4. Molecular models of computed lowest-energy pages S11-S13 conformers 2D NMR data for compounds 15 and 16 pages S14 S17 Part 2. 1 H, 13 C, and 2D NMR spectra of new compounds pages S18 S70 Experimental procedures General methods. Commercial reagents were used as received unless otherwise specified. Reactions were monitored by thin-layer chromatography on precoated glass-backed plates (Kieselgel 60 F 254 ) and components were visualized using UV light and by treatment with KMn 4 /H 2 S 4 or anisaldehyde/h 2 S 4 and heat as developing agents. Flash chromatography was performed using silica gel (Merck, µm). Concentrations were done at reduced pressure using a rotary evaporator. RP-HPLC was carried out on an Agilent 1100 Series instrument. NMR chemical shifts are reported in ppm downfield of SiMe 4, using the residual signal of the solvent as an internal reference. Coupling constants (J) are given in Hz. The resonance multiplicity is described as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Infrared (IR) spectra were obtained using a ASI React IR module. Intermediate 7. A solution of 6 (150 mg, mmol) in THF/CH 3 H (9:1, 20 ml) was sparged with Ar for 20 min. Addition of a dark blue solution of SmI 2 in THF (ca M, 5.5 ml, 0.44 mmol) at room temperature resulted in a blue solution that changed color to yellow within ca. 5 min. This solution was stirred at room temperature for another 10 min., then Si 2 was added and S1

2 volatiles were removed in vacuo. Column chromatography (Si 2 ; hexanes/etac 3:2) yielded 119 mg (79%) of thiohydantoin 7 as a colorless, amorphous solid. 1 H NMR (500 MHz, CDCl 3 ) δ 8.17 (bs, 1 H), 6.69 (bs, 1 H), 5.80 (d, J = 10.9 Hz, 1 H), 5.27 (d, J = 10.9 Hz, 1 H), 4.47 (m, 1 H), 4.11 (t, J = 10.3 Hz, 1 H), 3.81 (s, 3 H), 3.72 (d, J = 10.0 Hz, 2 H), 3.37 (m, 2 H), 3.03 (q, J = 10.0 Hz, 1 H), 2.40 (m, 1 H), 2.28 (m, 1 H), 0.86 (m, 11 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 181.6, 173.6, 172.9, 160.5, 126.4, 117.7, 112.2, 99.9, 81.6, 75.6, 66.4, 66.1, 56.1, 55.6, 53.7, 52.9, 50.4, 25.7, 18.1, 17.9, 1.5, 4.7, 4.8; FTIR (film) 3288, 2954, 2931, 2860, 1773, 1737, 1642, 1499, 1428, 1372, 1250, 1219, 1094, 864, 837, 778 cm -1 ; HRMS (ESI) m/z calcd. for C 28 H 45 Br 2 N 5 Na 6 SSi 2 (M+Na): , found: Intermediate 8. MeI (84 mg, 37 µl, mmol) was added at room temperature to a suspension of thiohydantoin 7 (119 mg, mmol), DMAP (1.8 mg, mmol), and N,Ndiisopropylethylamine (97 mg, 130 µl, mmol) in CH 2 Cl 2 (5 ml), resulting in a clear, colorless solution after ca. 10 min. This solution was stirred at room temperature for 2 h, concentrated to a volume of ca. 1.5 ml and subjected to column chromatography (Si 2 ; hexanes/etac 3:2) providing 116 mg (96%) of S-methyl hydantoin 8 as a colorless foam. 1 H NMR (500 MHz, CDCl 3 ) δ 8.20 (s, 1 H), 6.72 (s, 1 H), 5.88 (d, J = 11.0 Hz, 1 H), 5.40 (d, J = 11.0 Hz, 1 H), 4.60 (t, J = 6.5 Hz, 1 H), 4.28 (t, J = 9.4 Hz, 1 H), 4.10 (t, J = 9.4 Hz, 1 H), 3.68 (s, 3 H), 3.57 (t, J = 9.9 Hz, 1 H), 3.45 (m, 2 H), 2.94 (dq, J = 1.7, 9.7 Hz, 1 H), 3.43 (s, 3 H), 2.34 (s, 2 H), 2.19 (dd, J = 6.8, 12.7 Hz, 1 H), 1.95 (dd, J = 7.8, 12.7 Hz, 1 H), 0.90 (m, 2H), 0.87 (s, 9H), 0.05 (s, 3 H), 0.03 (s, 3 H), 0.00 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 180.3, 176.5, 163.0, 160.3, 127.5, 117.2, 111.5, 99.8, 86.5, 77.3, 75.5, 66.3, 66.2, 57.4, 56.0, 52.5, 51.2, 50.3, 25.8, 18.1, 18.0, 12.3, 1.4, 4.7; FTIR (film) 3270, 2953, 2931, 2896, 2857, 1760, 1735, 1636, 1570, 1559, 1507, 1420, 1376, 1250, 1160, 1092, 1028, 861, 835, 777, 733 cm -1 ; HRMS (ESI) m/z calcd. for C 29 H 47 Br 2 N 5 Na 6 SSi 2 (M+Na): , found: Intermediate 9. 2-Trimethylsilylethyl chloroformate (0.9 M in toluene, 247 µl, mmol) and N,Ndiisopropylethylamine (48 mg, 64 µl, 0.37 mmol) were added to a solution of S-methyl hydantoin 8 (150 mg, mmol) in CH 2 Cl 2 (8 ml). The resulting clear, colorless solution was stirred at room temperature for 30 min., concentrated to a volume of ca. 1 ml and subjected to column chromatography (Si 2 ; hexanes/etac 4:1) providing 176 mg (quant.) of aminoester 9 as a colorless foam. 1 H NMR (500 MHz, CDCl 3 ) δ 6.73 (s, 1 H), 5.90 (d, J = 11.1 Hz, 1 H), 5.38 (d, J = 11.1 Hz, 1 H), 4.58 (t, J = 6.7 Hz, 1 H), 4.45 (dt, J = 2.8, 7.7 Hz, 2 H), 4.29 (t, J = 9.6 Hz, 1 H), 4.09 (t, J = 9.6 Hz, 1 H), 3.66 (s, 3 H), 3.52 (d, J = 9.6 Hz, 1 H), 3.41 (t, J = 9.0 Hz, 2 H), 2.95 (q, J = 9.6 Hz, 1 H), 2.32 (s, 3 H), 2.19 (dd, J = 6.7, 12.8 Hz, 1 H), 1.92 (dd, J = 7.7, 12.8 Hz, 1 H), 1.18 (dd, J = 7.7, 10.0 Hz, 2 H), 0.88 (m, 2 H), 0.85 (s, 9 H), 0.07 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H), 0.01 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) δ 176.0, 174.4, 163.5, 160.4, 149.5, 126.8, 117.5, 111.9, 99.8, 86.3, 75.2, 66.8, 66.1, 66.0, 57.2, 56.2, 52.5, 51.1, 50.4, 25.6, 18.0, 17.8, 17.4, 13.7, 1.59, 1.64, 4.85, 4.90; FTIR (film) 2954, 2933, 2898, 2860, 1798, 1742, 1632, 1567, 1428, 1378, 1301, 1252, 1229, 1202, 1094, 1028, 1003, 861, 837, 776 cm -1 ; HRMS (ESI) m/z calcd. for C 35 H 59 Br 2 N 5 Na 8 SSi 3 (M+Na): , found: Intermediate 10. Benzyloxycarbonyl isothiocyanate (11) (66 mg, 0.34 mmol) was added to a solution of aminoester 9 (216 mg, mmol) in CH 2 Cl 2 (6.5 ml) and the clear, colorless solution was stirred at 40 C for 1.5 h, concentrated to a volume of ca. 1 ml and subjected to column S2

3 chromatography (Si 2 ; hexanes/etac 4:1 7:3) yielding 239 mg (92%) of thiourea 10 as a colorless foam. 1 H NMR (500 MHz, CDCl 3 ) δ (bs, 1 H), 7.91 (s, 1 H), 7.39 (m, 5 H), 6.69 (bs, 1 H), 5.54 (bs, 2 H), 5.20 (d, J = 12.2 Hz, 1 H), 5.17 (d, J = 12.2 Hz, 1 H), 4.53 (m, 1H), 4.41 (t, J = 8.8 Hz, 2 H), 4.09 (dd, J = 8.1, 10.4 Hz, 1 H), 4.06 (m, 1 H), 3.88 (dd, J = 4.2, 10.4 Hz, 1 H), 3.71 (s, 3 H), 3.47 (dt, J = 6.8, 9.3 Hz, 2 H), 3.25 (m, 1 H), 2.96 (m, 1 H), 2.38 (dd, J = 5.1, 14.2 Hz, 1 H), 2.28 (s, 3 H), 1.17 (m, 2 H), 0.88 (m, 11 H), 0.06 (s, 3 H), 0.05 (s, 12 H), 0.00 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) δ 177.7, 172.2, 171.3, 164.1, 160.1, 152.5, 149.5, 134.4, 128.8, 128.7, 128.4, 127.0, 116.3, 111.0, 99.6, 86.0, 75.5, 74.8, 86.4, 67.9, 66.8, 66.1, 55.4, 52.9, 52.8, 52.6, 48.5, 25.7, 17.9, 17.8, 17.4, 13.9, 1.4, 1.6, 4.6, 4.7; FTIR (film) 3284, 3232, 2954, 2933, 2896, 2860, 1806, 1740, 1638, 1567, 1528, 1432, 1383, 1301, 1248, 1198, 1098, 1038, 861, 837, 774 cm -1 ; HRMS (ESI) m/z calcd. for C 44 H 66 Br 2 N 6 Na 10 S 2 Si 3 (M+Na): , found: Benzyloxycarbonyl isothiocyanate (11). Quinoline (50 mg, 45 µl, mmol) and KAc (52 mg, mmol) were added to a solution of KSCN (3g, mmol) in H 2 (3 ml), and the resulting emulsion was cooled to 0 C. Benzylchloroformate (1.96 g, 1.63 ml, mmol) was then added dropwise over the course of ca. 30 min, and the resulting yellow emulsion was stirred at 5-10 C for 4.5 h. The viscous, yellow emulsion was then partitioned between H 2 and CH 2 Cl 2, and the organic phase was dried over Na 2 S 4 and concentrated. The residue was purified by column chromatography (Si 2 ; hexanes/ch 2 Cl 2 17:3) to provide g (67%) of isothiocyanate 11 as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.40 (m, 5 H), 5.23 (s, 2 H); 13 C NMR (125 MHz, CDCl 3 ) δ 149.8, 147.3, 133.9, 129.0, 128.7, 128.6, 70.6; FTIR (film) 3070, 3037, 2964, 1935, 1744, 1455, 1376, 1212, 1063, 984, 907, 793, 745, 695 cm -1. Intermediate 12. EDC HCl (85 mg, mmol), 2-nitrobenzylamine hydrochloride (84 mg, mmol) and N,N-diisopropylethylamine (57 mg, 77 µl, mmol) were added to a solution of thiourea 10 (170 mg, mmol) in CH 2 Cl 2 (8 ml), and the resulting suspension was stirred at 40 C for 1.5 h. Another 1.5 equivalent of EDC HCl (43 mg, mmol) and of 2- nitrobenzylamine hydrochloride (42 mg, mmol) were added to the resulting yellow solution and stirring was continued at 40 C for 1 h. The yellow solution was concentrated to a volume of ca 1 ml and subjected to column chromatography (Si 2 ; hexanes/etac 4:1 7:3) providing 169 mg (93%) of spiroglycocyamidine 12 as a pale yellow, amorphous solid. 1 H NMR (500 MHz, CDCl 3 ) δ 9.20 (s, 1 H), 8.13 (dd, J = 1.1, 8.2 Hz, 1 H), 7.62 (td, J = 1.1, 7.6 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 2 H), 7.27 (m, 3 H), 7.08 (d, J = 7.8 Hz, 1 H), 6.96 (s, 1 H), 5.73 (d, J = 10.8 Hz, 1 H), 5.45 (d, J = 10.8 Hz, 1 H), 5.29 (d, J = 17.1 Hz, 1 H), 5.23 (d, J = 17.1 Hz, 1 H), 5.13 (d, J = 12.2 Hz, 1 H), 5.08 (d, J = 12.2 Hz, 1 H), 4.62 (td, J = 2.3, 6.8 Hz, 1 H), 4.44 (m, 2 H), 4.19 (m, 1 H), 3.77 (m, 1 H), 3.46 (m, 2 H), 3.27 (m, 2 H), 2.53 (dd, J = 7.5, 14.1 Hz, 1 H), 2.33 (m, 4 H), 1.18 (m, 2 H), 0.88 (m, 11 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.06 (s, 9 H), 0.02 (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 174.6, 173.8, 166.6, 163.8, 161.4, 161.2, 149.0, 147.7, 136.1, 134.0, 130.9, 128.7, 128.5, 128.3, 128.0, 127.1, 126.5, 125.5, 117.8, 112.1, 100.0, 86.1, 75.3, 75.2, 68.2, 67.7, 67.0, 66.2, 56.5, 54.1, 50.6, 48.5, 40.4, 25.6, 17.9, 17.8, 17.4, 14.0, 1.5, 1.7, 4.7, 4.8; FTIR (film) 3367, 2954, 2935, 2896, 2860, 1794, 1748, 1665, 1617, 1561, 1530, 1465, 1426, 1383, 1341, 1295, 1262, 1231, 1154, 1094, 963, 857, 837, 780, 727, 697 cm -1 ; HRMS (ESI) m/z calcd. for C 50 H 68 Br 2 N 8 Na 11 SSi 3 (M+Na): , found: S3

4 Intermediate 13. TFA (250 µl) was added to a solution of glycocyamidine 12 (74 mg, 0.06 mmol) in CH 2 Cl 2 (3.5 ml), and the yellowish solution was stirred at room temperature for 1 h, and then partitioned between saturated aqueous NH 4 Cl solution and EtAc. The organic phase was washed three times with saturated aqueous Na 2 C 3 solution, dried over Na 2 S 4, and concentrated. The residue was purified by column chromatography (Si 2 ; hexanes/etac/meh 7:3:0.1) to afford 54 mg (94%) of dibromopyrrole 13 as a colorless solid. Mp 260 C (dec.); 1 H NMR (500 MHz, CDCl 3 ) δ (s, 1 H), 9.50 (s, 1H), 8.60 (s, 1H), 8.05 (d, J = 7.9 Hz, 1 H), 7.55 (t, J = 7.9 Hz, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), (m, 5 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.62 (s, 1H), 5.23 (t, J = 17.9 Hz, 2 H), 5.07 (d, J = 12.5 Hz, 1 H), 5.03 (d, J = 12.5 Hz, 1 H), 4.90 (q, J = 7.6 Hz, 1 H), 4.03 (dd, J = 7.6, 9.7 Hz, 1 H), 3.92 (d, J = 8.8 Hz, 1 H), 3.32 (q, J = 6.6 Hz, 1 H), 3.11 (d, J = 7.6 Hz, 1 H), 2.50 (m, 4 H), 2.30 (dd, J = 6.8, 13.9 Hz, 1 H), 0.91 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H); 13 C NMR (125 MHz, CDCl 3 ) δ 179.7, 176.1, 167.0, 163.3, 160.3, 158.4, 147.7, 136.1, 134.0, 130.9, 128.4, 128.3, 128.0, 127.9, 127.1, 125.6, 125.3, 115.9, 107.2, 100.4, 87.1, 75.6, 67.8, 66.3, 56.3, 51.4, 51.2, 46.1, 40.2, 25.7, 17.9, 12.6, 4.5; FTIR (film) 3369, 3247, 2954, 2933, 2889, 2858, 1762, 1669, 1613, 1528, 1465, 1412, 1339, 1258, 1210, 1154, 1113, 980, 965, 878, 837, 780, 724, 699 cm -1 ; HRMS (ESI) m/z calcd. for C 38 H 42 Br 2 N 8 Na 8 SSi (M+Na): , found: Intermediate Trimethylsilylethyl chloroformate (0.9 M in toluene, 190 µl, mmol) and N,Ndiisopropylethylamine (25 mg, 34 µl, mmol) were added to a solution of dibromopyrrole 13 (125 mg, 0.13 mmol) in CH 2 Cl 2 (6 ml). The resulting clear, colorless solution was stirred at room temperature for 30 min., concentrated to a volume of ca. 1 ml and subjected to column chromatography (Si 2 ; hexanes/etac 4:1 7:3) yielding 130 mg (90%) of bis(spirocycle) 14 as a colorless solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ 9.46 (s, 1 H), 8.62 (s, 1H), 8.12 (d, J = 7.9 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.0 Hz, 2 H), 7.32 (t, J = 7.0 Hz, 2 H), 7.28 (t, J = 7.0 Hz, 1 H), 7.03 (d, J = 7.9 Hz, 1 H), 6.67 (d, J = 2.9 Hz, 1H), 5.23 (s, 2 H), 5.13 (d, J = 12.2 Hz, 1 H), 5.08 (d, J = 12.2 Hz, 1 H), 4.94 (q, J = 7.6 Hz, 1 H), 4.42 (dd, J = 8.8, 9.1 Hz, 2 H), 4.13 (dd, J = 7.2, 9.9 Hz, 1 H), 3.95 (dd, J = 2.0, 9.9 Hz, 1 H), 3.34 (qd, J = 2.0, 7.5 Hz, 1 H), 3.14 (d, J = 7.5 Hz, 1 H), 2.48 (s, 3 H), 2.44 (dd, J = 8.5, 14.0 Hz, 1 H), 2.32 (dd, J = 7.3, 14.0 Hz, 1 H), 1.16 (dd, J = 6.7, 10.0 Hz, 2 H), 0.91 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H), 0.02 (s, 9H); 13 C NMR (150 MHz, CDCl 3 ) δ 175.9, 173.0, 167.1, 163.2, 160.3, 158.2, 148.8, 147.8, 135.9, 134.0, 130.8, , , , 128.0, 127.1, 125.4, 125.2, 116.0, 107.1, 100.6, 86.5, 75.5, 67.7, 67.1, 65.7, 56.9, 51.4, 50.9, 46.2, 40.2, 25.7, 17.9, 17.3, 14.4, 1.7, 4.6; FTIR (film) 3365, 2956, 2931, 2898, 2858, 1748, 1671, 1617, 1530, 1465, 1412, 1339, 1297, 1260, 1189, 1152, 1129, 857, 837, 782, 754, 726 cm -1 ; HRMS (ESI) m/z calcd. for C 44 H 54 Br 2 N 8 Na 10 SSi 2 (M+Na): , found: Intermediates 15 and 16. NaBH 4 (107 mg, mmol) was added in one portion to a solution of bis(spirocycle) 14 (125 mg, mmol) in MeH/THF (2:1, 9 ml) at 0 C, and the resulting suspension was stirred at 0 C for 40 min., then partitioned between saturated aqueous NH 4 Cl solution and EtAc. The organic phase was dried over Na 2 S 4 and concentrated to give a mixture of two inseparable bis(hemiaminal) diastereoisomers. This mixture was redissolved in CH 2 Cl 2 (6 ml), and acetic anhydride (58 mg, 54 µl, mmol), pyridine (45 mg, 46 µl, mmmol), and N,N-dimethylaminopyridine (6.9 mg, mmol) were added to this solution at room temperature. The resulting solution was stirred at room temperature for 4 h, then S4

5 partitioned between saturated aqueous NH 4 Cl solution and EtAc. The organic phase was dried over Na 2 S 4 and concentrated. The residue was purified by column chromatography (Si 2 ; hexanes/etac/meh 7:3:0.1) to separately afford 68 mg (51%) of bis(spirocycle) 15 and 40 mg (29%) of the corresponding diastereoisomer 16 as colorless, non-crystalline solids. Data for 15: 1 H NMR (500 MHz, CDCl 3 ) δ 9.61 (s, 1 H), 8.36 (s, 1H), 8.03 (d, J = 8.2 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.35 (d, J = 7.3 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 2 H), 7.26 (d, J = 7.3 Hz, 1 H), 6.88 (s, 1H), 6.59 (d, J = 2.6 Hz, 1 H), 6.05 (s, 1 H), 5.16 (d, J = 17.0 Hz, 1 H), 5.13 (d, J = 12.0 Hz, 1 H), 5.06 (d, J = 12.0 Hz, 1 H), 4.94 (d, J = 17.0 Hz, 1 H), 4.56 (m, 1 H), 4.20 (m, 2 H), (m, 2 H), 2.83 (d, J = 7.1 Hz, 1 H), 2.73 (dd, J = 13.5, 7.1 Hz, 1 H), 2.69 (dd, J = 14.9, 9.4 Hz, 1 H), 2.49 (s, 3 H), 2.14 (dd, J = 14.9, 3.8 Hz, 1 H), 2.04 (s, 3 H), 1.71 (s, 3 H), (m, 2 H), 0.85 (s, 9 H), (s, 3 H), (s, 3 H), (s, 9 H); 13 C NMR (125 MHz, CDCl 3 ) δ 169.8, 169.3, 165.7, 163.8, 161.9, 158.7, 150.2, 148.1, 136.9, 133.2, 132.6, 129.7, , 128.2, 127.8, 126.7, 125.0, 115.6, 106.4, 100.4, 93.1, 87.1, 86.6, 75.8, 68.8, 67.0, 65.7, 53.8, 51.3, 50.1, 43.8, 41.4, 25.7, 20.7, 20.2, 17.8, 17.5, 15.3, 1.7, 4.5, 4.6; FTIR (film) 3375, 2956, 2931, 2900, 2858, 1737, 1661, 1605, 1528, 1397, 1343, 1293, 1258, 1225, 1154, 1121, 1044, 1013, 978, 857, 837, 777, 699 cm -1 ; HRMS (ESI) m/z calcd. for C 48 H 62 Br 2 N 8 Na 12 SSi 2 (M+Na): , found: Data for 16: 1 H NMR (500 MHz, CDCl 3 ) δ 9.59 (s, 1 H), 8.50 (s, 1H), 8.02 (d, J = 8.3 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), (m, 4 H), (m, 3 H), 6.82 (s, 1H), 6.56 (d, J = 2.7 Hz, 1 H), 6.15 (s, 1 H), 5.22 (d, J = 17.0 Hz, 1 H), 5.16 (d, J = 12.2 Hz, 1 H), 5.12 (d, J = 12.2 Hz, 1 H), 4.69 (d, J = 17.0 Hz, 1 H), 4.49 (m, 1 H), (m, 2 H), 4.03 (dd, J = 10.2, 8.9 Hz, 1 H), 3.87 (d, J = 10.2 Hz, 1 H), 3.03 (d, J = 8.6 Hz, 1 H), (m, 2 H), 2.47 (s, 3 H), 2.11 (s, 3 H), 2.05 (s, 3 H), 1.96 (dd, J = 14.0 Hz, 1 H), 1.07 (m, 2 H), 0.80 (s, 9 H), 0.06 (s, 9 H), 0.01 (s, 3 H), 0.02 (s, 3 H); 13 C NMR (125 MHz, CDCl 3 ) δ 170.0, 169.9, 166.2, 163.8, 162.2, 158.7, 150.5, 148.5, 137.0, 133.3, 132.5, 129.5, 128.9, 128.5, 128.2, 127.6, 126.7, 125.1, 115.8, 106.4, 100.3, 93.9, 87.4, 75.9, 68.4, 67.2, 65.8, 51.7, 50.9, 49.1, 48.4, 41.8, 25.6, 21.1, 20.4, 17.8, 17.5, 15.1, 1.6, 4.6, 4.7; FTIR (film) 3375, 3261, 2956, 2933, 2858, 1737, 1661, 1600, 1528, 1397, 1345, 1291, 1258, 1216, 1121, 1046, 1017, 980, 839, 782 cm -1 ; HRMS (ESI) m/z calcd. for C 48 H 62 Br 2 N 8 Na 12 SSi 2 (M+Na): , found: Intermediate 18. o-iodoxybenzoic acid (IBX, 56 mg, mmol) was added at room temperature to a solution of hemiaminal diastereoisomers 17 (55 mg, mmol) in DMS (3 ml), and the solution was stirred at room temperature for 4 h. The solution was then partitioned between H 2 and EtAc, and the organic phase was dried over Na 2 S 4 and concentrated. The residue was purified by column chromatography (Si 2 ; EtAc/MeH 19:1) to afford 52.8 mg (96%) of an inseparable mixture (1.8:1) of hemiaminal diastereoisomers 18 as a colorless, amorphous solid. 1 H NMR (500 MHz, CDCl 3 ) δ 8.17 (bs, 0.55 H), 7.87 (bs, 1.55 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 0.55 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.39 (m, 2.55 H), (m, 8.3 H), 6.88 (s, 1 H), 6.84 (s, 0.55 H), 6.47 (bs, 0.55 H), 6.24 (bs, 1 H), 6.15 (bs, 0.55 H), 5.78 (bs, 1 H), (m, 4.65 H), 4.80 (d, J = 12.2 Hz, 0.55 H), 4.68 (m, 2 H), 4.52 (d, J = 14.4 Hz, 0.55 H), 4.07 (t, J = 10.8 Hz, 1.55 H), 3.75 (d, J = 13.2 Hz, 0.55 H), 3.66 (d, J = 10.3 Hz, 1 H), 3.46 (m, 0.55 H), 3.21 (d, J = 19.5 Hz, 1 H), 2.81 (m, 0.55 H), 2.56 (m, 1 H), 2.7 (d, J = 19.5 Hz, 1 H), 2.42 (s, 4.65 H), 2.13 (d, J = 17.9 Hz, 0.55 H); 13 C NMR (125 MHz, CDCl 3 ) δ 212.0, 211.5, 167.2, 166.1, 163.7, 163.5, 153.6, 153.4, 148.1, 147.8, , , 133.9, 133.5, 132.9, 132.6, 129.4, , , , , , 124.9, 124.8, , , 116.1, 115.8, 106.8, 106.7, 103.0, 91.9, 91.5, 88.73, 87.7, 69.8, 69.6, 67.6, 64.2, 63.3, 59.1, 54.1, 49.7, 49.4, 48.8, 44.1, 42.6, 41.3, 29.6, 14.1, 13.8; FTIR (film) 3355, 3255, 2921, S5

6 1754, 1640, 1592, 1524, 1497, 1445, 1426, 1385, 1339, 1279, 1123, 1079, 980, 799, 733, 700 cm -1 ; HRMS (ESI) m/z calcd. for C 32 H 28 Br 2 N 8 Na 7 S (M+Na): , found: Intermediate 19. NaBH 4 (23 mg, 0.6 mmol) was added in one portion to a solution of hemiaminal diastereoisomers 18 (50 mg, mmol) in MeH (3 ml) at 0 C, and the resulting suspension was stirred at 0 C for 30 min., then partitioned between saturated aqueous NH 4 Cl solution and EtAc. The organic phase was dried over Na 2 S 4 and concentrated. The residue was purified by column chromatography (Si 2 ; EtAc/MeH 19:1) to afford 47 mg (94%) of an inseparable mixture (1:1) of hemiaminal diastereoisomers 19 as a colorless, amorphous solid. 1 H NMR (500 MHz, CD 3 D) δ 8.03 (d, J = 7.6 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), (m, 5 H), (m, 10 H), 6.95 (s, 2 H), 6.26 (s, 1 H), 5.87 (s, 1 H), (m, 6 H), 4.77 (m, 2 H), 4.66 (d, J = 16.4 Hz, 0.55 H), 4.60 (s, 1 H), 4.17 (m, 4 H), 3.82 (m, 2 H), 3.41 (d, J = 10.5 Hz, 1 H), 2.90 (m, 3 H), 2.65 (d, J = 9.5 Hz, 1 H), 2.53 (bs, 6 H), (m, 3 H); 13 C NMR (125 MHz, CD 3 D) δ 170.4, 170.1, , , 163.4, 162.8, 155.7, 155.5, 150.2, 149.9, 138.7, 138.5, 134.8, 134.5, 134.2, 133.5, 131.5, 130.4, 129.9, 129.6, 129.5, 129.2, , 129.0, 126.1, 126.0, 124.7, 124.6, , , 109.1, 103.7, 103.6, 92.0, 91.8, 89.3, 89.2, 71.8, 71.2, 70.3, 69.0, 68.5, 68.4, 68.3, 61.1, 55.5, 51.3, 46.0, 44.4, 43.9, 43.8, 43.5, 43.4, 41.7, 30.9, 14.1, 14.07; FTIR (film) 3361, 3249, 2919, 1636, 1590, 1524, 1426, 1383, 1337, 1285, 1121, 1079, 1027, 974, 940, 799, 733, 702 cm -1 ; HRMS (ESI) m/z calcd. for C 32 H 30 Br 2 N 8 Na 7 S (M+Na): , found: S6

7 H N N 6 HN NH HN NH 8 22 NH 2 NH 2 3 R 1 =H,R 2 =H 4 R 1 =H,R 2 =H R 1 R 2 Table S1. NMR data for 3 in D 2. Proton δ (mult, J [Hz]) CSY HMBC (dd, J = 4.0, 1.3) 4, 5 4, 2, (dd, J = 4.0, 2.7) 3, 5 2, 5, (dd, J = 2.7, 1.3) 3, 4 2, 3, (s) 2, 5, 8, 10, (d, J = 12.0) 12 6, 10, 12, 16, 17, 18, (dddd, J = 12.0, 10.1, 6.1, 4.1) 11, 13α, 13β, 18 13α 3.48 (dd, J = 12.3, 6.1) 12, 13β 12 13β 3.99 (dd, J = 12.3, 10.1) 12, 13α 10, 12, 15, 18 17α 1.99 (d, J = 14.3) 17β, 18 11, 12, 16, 18 17β 2.18 (dd, J = 14.3, 3.7) 17α, 18 16, 18, (m) 12, 17α, 17β (s) 16, 17, 22 Table S2. NMR data for 4 in D 2. Proton δ (mult, J [Hz]) CSY HMBC (dd, J = 4.0, 1.3) 4, 5 2, 4, (dd, J = 4.0, 2.7) 3, 5 2, (dd, J = 2.7, 1.3) 3, 4 3, 4, (s) 2, 5, 8, (d, J = 10.7) 12 6, 10, 12, 16, 17, 18, (dddd, J = 10.7, 9.9, 5.1, 4.6) 11, 13α, 13β, 18 13α 3.55 (dd, J = 12.3, 4.6) 12, 13β 12, 15 13β 3.90 (dd, J = 12.3, 9.9) 12, 13α 12, 15 17α 1.91 (dd, J = 15.4, 2.5) 17β, 18 12, 16, 18 17β 2.62 (dd, J = 15.4, 5.1) 17α, 18 16, (m) 12, 17α, 17β (s) 16, 22 S7

8 Table S3. Interproton distances (in pm) for compound 3 obtained from NESY spectra recorded at different mixing times (100, 150, 200 ms). Peaks from above and below the diagonal were evaluated. The intensity data were calibrated using the geminal protons at C13 (178 pm). Proton 200 ms 150 ms 100 ms a b above below above below above below average β β β α β Table S4. Interproton distances (in pm) for compound 4 obtained from NESY spectra recorded at different mixing times (100, 150, 200 ms). Peaks from above and below the diagonal were evaluated. The intensity data were calibrated using the geminal protons at C13 (178 pm). Proton 200 ms 150 ms 100 ms a b above below above below above below average β β β α β S8

9 Table S5. Comparison of interproton distances (in pm) obtained from volume integration of NESY spectra for compounds 3 and 4 with calculated values for 1, 2, 3, 4, trans-3, 1 trans-4, 2 and 5. Molecular modeling was performed using the software package Maestro with the AMBER* forcefield including solvation (H 2 ). Distances were obtained from evaluation of the respective global minima identified by conformational searches (MCMM method, 1000 steps). Protons 3 a 3 b 4 a 4 b 1 b trans- 3 b trans- 4 b 5 c 5 b 2 b 5/ / / /13β /17α n.o. 408 n.o /17β /18 n.o. 405 n.o / /13α 286 e e /13β 226 e e /17α n.o. 371 n.o /17β / /20 n.o α/13β α/ β/18 n.o. 349 n.o α/17β 178 e e α/ e e α/20 n.o. 296 n.o β/ e e β/ (a) Average distances from NESY spectra recorded at 100, 150 and 200 ms mixing times (Tables S3and S4). (b) Distances obtained from molecular modeling. (c) Data from: A. Grube, M. Köck Angew. Chem. 2007, 119, , Angew. Chem. Int. Ed. 2007, 46, (e) Average of distances obtained from NESY spectra recorded at 700, 750, and 800 ms mixing times (volume integrals from spectra recorded at shorter mixing times could not be used due to CSY artifacts). Peaks from above and below the diagonal were evaluated. The intensity data were calibrated using the geminal protons at C13 (178 pm). 1 Structures of trans-3 and trans-4 correspond to 3 and 4 with trans-configured azabicyclo[3.3.0]octane ring system. S9

10 Table S6. Comparison of interproton distances (in pm) obtained from volume integration of NESY spectra for compounds 3 and 4 with calculated values for 1, 2, 3, 4, trans-3, trans-4, and 5. Molecular modeling was performed using the software package SPARTAN 04. Low-energy conformations identified by conformational searches (AM1) were further energy-minimized (B3LYP 6-31G*). Distances were obtained from evaluation of the respective lowest-energy minima lacking intramolecular H-bonds. Protons 3 a 3 b 4 a 4 b 1 b trans-3 b trans-4 b 5 c 2 b 5/ / / /13β /17α n.o. 413 n.o /17β /18 n.o. 416 n.o / /13α 286 e e /13β 226 e e /17α n.o. 375 n.o /17β / /20 n.o α/13β α/ β/18 n.o. 361 n.o α/17β 178 e e α/ e e α/20 n.o. 316 n.o β/ e e β/ (a) Average distances from NESY spectra recorded at 100, 150 and 200 ms mixing times (Tables S3 and S4). (b) Distances obtained from molecular modeling. (c) Data from: A. Grube, M. Köck Angew. Chem. 2007, 119, , Angew. Chem. Int. Ed. 2007, 46, (e) Average distances obtained from NESY spectra recorded at 700, 750, and 800 ms mixing times (volume integrals from spectra recorded at shorter mixing times could not be used due to CSY artefacts). Peaks from above and below the diagonal were evaluated. The intensity data were calibrated using the geminal protons at C13 (178 pm). S10

11 Molecular Models Molecular modeling was performed using the software packages Maestro (AMBER* forcefield 3 including solvation (H 2 )) and SPARTAN 04 4 (B3LYP 6-31G*). 5 In all cases global minima were identified by carrying out conformational searches (Maestro: MCMM method, 1000 steps; SPARTAN: energy minima were first computed using a semiempirical method (AM1), and then further refined on DFT level (B3LYP 6-31G*)). Internally H-bonded minima obtained using SPARTAN were disregarded. 1. Molecular Mechanics (Maestro , AMBER* with solvation (H 2 )). 3 trans-3 E = kcal/mol E = kcal/mol 4 trans-4 E = kcal/mol E = kcal/mol 2 Schroeder, Inc.: Portland, R. 3 (a) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, (b) McDonald, D. Q.; Still, W. C. Tetrahedron Lett. 1992, 33, Spartan 04 for Macintosh; Wavefunction Inc.: Irvine, CA. 5 For information on the B3LYP functional, see: (a) Becke, A. D. J. Chem. Phys. 1993, 98, (b) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, (c) Becke,A. D. Phys. Rev. A 1988, 38, (d) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, (e) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, (f) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, S11

12 1 2 E = kcal/mol E = kcal/mol 5 E = kcal/mol S12

13 2. DFT (Spartan 04, B3LYP-6-31G*). 3 trans-3 E = hartrees E = hartrees 4 trans-4 E = hartrees E = hartrees 1 2 E = hartrees E = hartrees S13

14 47 Br HN N H N N 49 Si Br N SCH 3 HN Si H N 24b 24a N Table S7. NMR data for 15 in CDCl 3. No. 1 H, δ (mult, J [Hz]) 13 C CSY HMBC NESY (s) - 3, (d, J = 2.6 Hz) , 5, 15 13α, 13β (s) , 10, 11, 44, 48 11, (d, J = 7.1 Hz) , 12, 16, 17, 6, 12, 13β, 20, 18, 20 35, (dd, J = 13.5, , 13α/β, 18, , 13α, 13β 10, 11, 16, 18 Hz) 20, 24a/b, 49 13α, 13 β (m) , 11, 12, 18 3, 12, 24a/b α 2.69 (dd, J = 14.9, 9.4 Hz) 17β 2.14 (dd, J = 14.9, 3.8 Hz) β, 18 12, 16, 18, 20 17β, 18, 36, 43 17α, 18 11, 16, 18, (m) α, 17β 11, 13, (s) , a (s) b (s) , 17α, 24a/b, 26, 28 12, 17α, 17β, 13α/β, 24a/b, 26, 43 11, 12, 17β, 28, 29b, 35 12, 13α/β, 17β, 18, (s) , 25 24a/b S14

15 No. 1 H, δ (mult, J [Hz]) 13 C CSY HMBC NESY (s) β, 20, 24a/b, 26, 35, 49 29a 5.16 (d, J = 17.0 Hz) 29b 20, 22, 30, 31, 35 29b, 35, b 4.94 (d, J = 17.0 Hz) 29a 20, 22, 30, 31, 35 20, 29a, 35, (d, J = 8.2 Hz) , 34 29, 30, 31, (t, J = 7.5 Hz) , 34, 35 30, 32, 35 32, (t, J = 7.5 Hz) , 33, 35 30, 31, 32, 33 33, (d, J = 7.9 Hz) , 34 29, 30, 33, 34 11, 20, 28, 29a, 29b, 34, (s) - 16, 20 17α, a 5.13 (d, J = 12.0 Hz) 38b 37, 39, 40 38b, b 5.06 (d, J = 12.0 Hz) 38a 37, 39, 40 38a, (d, J = 7.3 Hz) , 42 38, 41, 42 38a, 38b, (t, J = 7.5 Hz) , 42 39, (d, J = 7.3 Hz) , 41 40, (s) α, 18, 36, 38b 45a/b 4.20 (m) , 46 46a/b, 47 46a/b (m) , 47 45a/b (s) a/b (s) , 28, 35, 29a, 29b, 40 S15

16 47 Br HN N H 10 6 N N 49 Si Br N SCH 3 HN Si H N b 24a N Table S8. NMR data for 16 in CDCl 3. No. 1 H, δ (mult, J [Hz]) (s) C CSY HMBC NESY (d, J = 2.7 Hz) , 5, 15 13α, 13β (s) , 10, 44, 48 11, (d, J = 8.6 Hz) , 12, 16, 17, 6, 12, 20, 28, 18, (m) , 13α, 13β, 11, 13β, 17β, 10, 11, 16, α 3.87 (d, J = 10.2 Hz) 12 10, 11, 12, 15, 18 3, 12, 13β, β 4.03 (dd, J = 10.2, Hz) 12 10, 11, 12, 18 3, 12, 13α α (m) 17β, 18 11, 12, 16, 20 17β, β 1.96 (dd, J = 14.0 Hz) 17α, 18 11, 18, 20 17α, (m) α, 17β 13 13α, 17α, 24a, 24b, (s) , 12, 17β, 26, 16, 17, 22, 27, 29 29a, 29b, a 0.01 (s) b 0.02 (s) (s) a, 24b S16

17 No. 1 H, δ (mult, J [Hz]) 13 C CSY HMBC NESY (s) , a 5.22 (d, J = 17.0 Hz) 29b 20, 22, 30, 31, 35 20, 29b, b 4.69 (d, J = 17.0 Hz) 29a 20, 22, 30, 31, 35 20, 29a, (d, J = 8.3 Hz) , 34 29, 30, 31, (m) , 34, 35 31, 35 32, (t, J = 7.5 Hz) , 33, 35 30, 32 33, (m) , 34 29, 31, (s) 16, 20, a 5.16 (d, J = 12.2 Hz) 38b 37, 39, b 5.12 (d, J = 12.2 Hz) 38a 37, 39, (m) , 42 38, (m) , 42 38, 39, (m) , (s) , 36, 38a/b a/b (m) , 47 46a/b 1.07 (m) , (s) (s) , 48 11, 29b S17