Supporting Information for. Total Synthesis of (±)-Perophoramidine via an Indol-2-one Intermediate. James R. Fuchs and Raymond L.

Transcription

1 Supporting Information for Total Synthesis of (±)-Perophoramidine via an Indol-2-one Intermediate James R. Fuchs and Raymond L. Funk* 8 3-omo-3-methyl-2-indolinone (8). omoindolinone 8 was prepared via a modification of the procedure of inman and Bauman. 1 -omosuccinimide (BS) (5.42 g, mmol) was dissolved in cold TF (100 ml). The resulting TF solution was then added dropwise via addition funnel to a stirring solution of 3-methylindole (10, 2.00 g, mmol) in t-bu (100 ml) and 2 (1 ml) at room temperature over a period of one hour. After stirring for an additional hour, the solution was concentrated under reduced pressure and the crude material was directly purified by silica gel column chromatography (EtAc-hexanes 1:4) to give 3-bromo-3-methyl-2-indolinone (8) as a pale yellow solid (2.52 g, 73%), mp C (lit C) 1 : 1 MR (CD 3, 400 Mz) δ 2.06 (s, 3), 6.96 (br d, J = 7.8 z, 1), 7.10 (dt, J = 1.0, 7.6 z, 1), 7.28 (dt, J = 1.2, 7.8 z, 1), 7.43 (br d, J = 7.6 z, 1), 9.29 (s, 1); 13 C MR (CD 3, 100 Mz) δ 26.2, 52.9, 110.9, 123.4, 124.4, 130.1, 132.0, 139.0, 177.5; IR (neat) 3253, 1723 cm -1 ; RMS (M + ) calcd for C , found Indolenine omo-3-methyl-2-indolinone (8, 307 mg, 1.36 mmol) was dissolved in a solution of C 2 2 (7 ml). The resulting solution was then added via addition funnel to a stirring solution of 3-methylindole (10, 267 mg, 2.04 mmol) and cesium carbonate (1.11 g, 3.40 mmol) in C 2 2 (7 ml) at room temperature over a period of thirty minutes. The solution was stirred for 24 hours or until TLC showed complete S-1

2 consumption of the 3-bromoindolinone. The reaction mixture was then filtered through a pad of Celite, washed thoroughly with C 2 2, and concentrated. The crude material was purified by silica gel column chromatography (EtAc-hexanes, 1:1) to give a 95:5 mixture of the indolenines 13 as a yellow foam (285 mg, 76%). The two diastereomers were then separated through further purification: (minor isomer, R f = 0.3, EtAchexanes, 2:1) 1 MR (CD 3, 400 Mz) δ 1.42 (s, 3), 1.45 (s, 3), 6.76 (d, J = 7.4 z, 1), 6.90 (dt, J = 1.0, 7.6 z, 1), (m, 3), 7.26 (dt, J = 1.1, 7.6 z, 1), 7.34 (d, J = 7.4 z, 1), 7.51 (d, J = 7.7 z, 1), 8.58 (s, 1), 8.66 (s, 1); 13 C MR (CD 3, 100 Mz) δ 14.9, 19.4, 51.3, 60.9, 109.5, 121.1, 121.9, 122.7, 124.2, 125.8, 128.3, 128.4, 131.2, 140.1, 140.2, 155.0, 176.0, 180.6; IR (neat) 3212, 1708 cm -1 ; (major isomer, R f = 0.2, EtAc-hexanes, 2:1) 1 MR (CD 3, 400 Mz) δ 1.52 (s, 3), 1.57, (s, 3), 6.76 (br d, J = 7.4 z, 1), 6.85 (d, J = 7.8 z, 1), 6.91 (t, J = 7.6 z, 1), 6.97 (br d, J = 7.3 z, 1), 7.13 (t, J = 7.5 z, 1), 7.21 (dt, J = 1.2, 7.7 z, 1), 7.31 (dt, J = 1.2, 7.7 z, 1), 7.51 (d, J = 7.7 z, 1), 8.16 (s, 1), 8.37 (s, 1); 13 C MR (CD 3, 100 Mz) δ 15.4, 18.8, 51.3, 60.3, 110.0, 120.7, 121.7, 122.8, 123.9, 125.9, 128.1, 128.5, 131.3, 140.3, 140.8, 154.6, 175.9, 180.2; IR (neat) 3204, 1713 cm -1 ; RMS (M + ) calcd for C , found Ts Tosylimide 14. Indolenine 13 (88 mg, 0.32 mmol) was dissolved in TF (3.2 ml) and cooled to 0 C in an ice bath. Sodium hydride (19 mg, 0.48 mmol) was added and the solution was stirred for ten minutes before the addition of tosyl chloride (92 mg, 0.48 mmol). The resulting solution was warmed to room temperature and stirred for one hour. The reaction was quenched with water and extracted three times with EtAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:2) to afford the imide 14 as a pale yellow foam (108 mg, 78%): 1 MR (CD 3, 400 Mz) δ 1.37 (s, 3), 1.49 (s, 3), 2.42 (s, 3), 6.79 (d, J = 7.2 z, 1), 6.83 (br d, J = 7.8 z, S-2

3 1), (m, 2), 7.25 (d, J = 8.1 z, 2), (m, 1), 7.35 (t, J = 7.8 z, 1), 7.42 (d, J = 7.6 z, 1), 7.80 (d, J = 8.1 z, 2), 7.88 (s, 1), 7.92 (d, J = 8.2 z, 1); 13 C MR (CD 3, 100 Mz) δ 15.5, 19.4, 21.6, 51.2, 61.1, 113.6, 121.4, 122.8, 124.3, 126.0, 127.6, 127.8, 128.6, 129.3, 129.7, 130.7, 134.8, 138.7, 139.4, 145.4, 154.9, 174.5, 175.9; IR (neat) 1750, 1602, 1461 cm -1 ; RMS (M + ) calcd for C S , found Ts Ts 16 Aminal 16. Cesium carbonate (76 mg, 0.23 mmol) was added to a stirring solution of imide 14 (50 mg, 0.12 mmol) in methanol (1.5 ml) and TF (1.5 ml). The resulting solution was then stirred at room temperature for 12 hours. The reaction mixture was concentrated and then taken up in water and extracted three times with C 2 2. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:4) to afford the aminal 16 as a white foam (35 mg, 65 %): 1 MR (CD 3, 400 Mz) δ 1.81 (s, 3), 2.02 (s, 3), 2.40 (s, 3), 3.23 (s, 3), 4.68 (s, 1), 6.02 (s, 1), 6.41 (m, 2), 6.79 (dt, J = 1.0, 7.6 z, 1), 6.88 (d, J = 7.9 z, 1), 6.97 (dt, J = 1.4, 7.5 z, 1), 7.01 (dt, J = 1.7, 7.5 z, 1), 7.18 (dd, J = 1.7, 7.5 z, 1), 7.28 (d, J = 8.1 z, 2), 7.60 (dd, J = 1.4, 7.9 z, 1), 7.77 (d, J = 8.1 z, 2); 13 C MR (CD 3, 50 Mz) δ 17.7, 21.4, 22.4, 50.3, 51.8, 56.8, 80.5, 108.6, 118.5, 122.1, 123.1, 124.6, 124.8, 127.1, 127.3, 127.6, 129.5, 133.0, 135.2, 135.9, 137.4, 143.7, 147.5, 174.1; IR (neat) 3413, 1731, 1608, 1484 cm -1 ; RMS (M + ) calcd for C S , found omotryptophol. xalyl chloride (2.28 ml, mmol) was added dropwise to a solution of 6-bromoindole (4.13 g, mmol) in ether (42 ml) at 0 C. The solution S-3

4 was warmed to room temperature over a period of one hour. Methanol (4.27 ml, mmol) was then added and stirring continued at that temperature for 24 hours. The solution was filtered and washed thoroughly with water and cold ether. The resulting yellow solid was dried under vacuum to give the (6-bromoindol-3-yl)oxoacetic acid methyl ester which was used without further purification. A suspension of the methyl ester (4.41 g, mmol) in TF (45 ml) was treated with B 3 DMS (2.0 M in TF, ml, mmol) and heated at reflux for 4 hours. The solution was then cooled and treated with water followed by a 2 C 3 (sat). The aqueous solution was then extracted four times with ether. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:2) to give 6- bromotryptophol as a white solid (3.45 g, 65%), mp C: 1 MR (CD 3, 400 Mz) δ 1.63 (br s, 1), 3.00 (dt, J = 0.7, 6.3 z, 2), 3.89 (t, J = 6.3 z, 2), 7.04 (br s, 1), 7.22 (dd, J = 1.7, 8.5 z, 1), 7.47 (d, J = 8.5 z, 1), 7.50 (d, J = 1.7 z, 1), 8.12 (br s, 1); 13 C MR (CD 3, 100 Mz) δ 28.5, 62.6, 112.6, 114.1, 115.7, 120.1, 122.7, 123.0, 126.3, 137.1; IR (neat) 3421 (br), 2937 cm -1 ; RMS (M + ) calcd for C , found I 6-omo-3-(2-iodoethyl)indole. Imidazole (1.15 g, mmol), triphenylphosphine (4.06 g, mmol), and iodine (3.93 g, mmol) were added sequentially to a rapidly stirring solution of 6-bromotryptophol (3.38 g, mmol) in benzene (230 ml) at room temperature. After 3 hours at room temperature, the reaction was quenched with a 1:1 mixture of ac 3 and a 2 S 2 3. The aqueous mixture was then extracted three times with ether. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography (EtAc-hexanes, 1:5) to give the iodide as a white solid (4.17 g, 85%), mp C: 1 MR (CD 3, 360 Mz) δ 3.31 (m, 1), 3.33 (d, J = 6.8 z, 1), 3.40 (d, J = 6.9 z, S-4

5 1), 3.43 (dd, J = 1.9, 6.9 z, 1), 7.06 (d, J = 2.4 z, 1), 7.24 (dd, J = 1.7, 8.5 z, 1), 7.44 (d, J = 8.5 z, 1), 8.10 (br s, 1); 13 C MR (CD 3, 90 Mz) δ 5.8, 29.9, 114.1, 115.6, 115.7, 119.7, 122.4, 122.8, 125.7, 136.8; IR (neat) 3427 cm -1 ; LRMS (M + ) calcd for C I 349.9, found I 3 6-omo-3-(2-azidoethyl)indole. Sodium azide (1.25 g, mmol) was added to a solution of the iodoethylindole (3.36 g, 9.60 mmol) in DMF (20 ml) at room temperature. The resulting solution was warmed to 50 C in an oil bath and maintained at that temperature for 2 hours. The solution was then cooled, poured into water and extracted four times with ether. The combined organic phases were washed successively with a (sat) and water, dried over sodium sulfate, and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes 1:5) to give the azide as a thick oil (2.39 g, 94%): 1 MR (CD 3, 400 Mz) δ 3.04 (dt, J = 0.4, 7.0 z, 2), 3.56 (t, J = 7.0 z, 2), 7.04 (d, J = 2.4 z, 1), 7.25 (dd, J = 1.7, 8.4 z, 1), 7.46 (d, J = 8.4 z, 1), 7.50 (d, J = 1.7 z, 1), 8.02 (br s, 1); 13 C MR (CD 3, 100 Mz) δ 24.7, 51.4, 112.4, 114.0, 115.5, 119.7, 122.6, 122.8, 125.9, 136.8; IR (neat) 3432, 2100 cm -1 ; LRMS (M + ) calcd for C , found (2-Azidoethyl)-3,6-dibromo-1,3-dihydroindol-2-one 18. BS (4.92 g, mmol) was dissolved in cold TF (92 ml). The resulting TF solution was then added dropwise via addition funnel to a stirring solution of alkyl azide (3.66 g, mmol) in t-bu (92 ml) and 2 (0.92 ml) at room temperature over a period of one hour. After stirring for an additional hour, the solution was concentrated under reduced pressure and the crude material was directly purified by silica gel column S-5

6 chromatography (EtAc-hexanes 1:4) to give the 3-bromo-2-indolinone 18 as a pale yellow solid (4.58 g, 92%), mp C (dec): 1 MR (CD 3, 400 Mz) δ 2.59 (ddd, J = 5.1, 7.5, 14.3 z, 1), 2.77 (dt, J = 7.7, 14.3 z, 1), 3.22 (dt, J = 7.5, 12.6 z, 1), 3.37 (ddd, J = 5.1, 7.7, 12.6 z, 1), 7.18 (d, J = 1.5 z, 1), 7.25 (d, J = 8.1 z, 1), 7.28 (dd, J = 1.5, 8.1 z, 1); 13 C MR (CD 3, 100 Mz) δ 37.8, 47.6, 53.3, 114.7, 124.3, 125.9, 126.6, 128.0, 140.7, 176.1; IR (neat) 3250, 2103, 1727 cm -1 ; RMS (M + ) calcd for C , found TIPS Indolenine omo-indolinone 18 (4.08 g, mmol) was dissolved in C 2 2 (58 ml). The resulting solution was then added via addition funnel to a stirring solution of 3-(2-triisopropylsilyloxyethyl)indole 2 (17) (5.39 g, mmol) and cesium carbonate (12.94 g, mmol) in C 2 2 (58 ml) at room temperature over a period of thirty minutes. The solution was stirred for 48 hours at room temperature. The reaction mixture was then filtered through a pad of Celite, washed thoroughly with C 2 2, and concentrated. The crude material was purified by silica gel column chromatography (EtAc-hexanes, 1:3) to give the indolenine 19 as a yellow foam (6.00 g, 89%): 1 MR (CD 3, 400 Mz) δ 0.90 (m, 21), 2.24 (br dt, J = 6.1, 12.8 z, 1), 2.33 (ddd, J = 4.8, 6.2, 13.1 z, 1), 2.48 (dt, J = 7.9, 13.5 z, 1), (m, 3), (m, 2), 6.39 (br s, 1), 7.03 (br d, J = 8.0 z, 1), 7.08 (d, J = 1.7 z, 1), 7.25 (br t, J = 6.9 z, 1), 7.38 (br t, J = 8.2 z, 1), 7.53 (d, J = 7.7 z, 1), 8.14 (s, 1), 9.23 (s, 1); 13 C MR (CD 3, 100 Mz) δ 11.5, 17.6, 31.0, 32.6, 47.2, 54.4, 58.6, 63.5, 113.7, 121.1, 122.6, 123.5, 124.8, 125.5, 126.0, 126.2, 129.2, 137.2, 142.7, 155.9, 174.2, 178.9; IR (neat) 3192, 2943, 2100, 1714, 1609 cm -1 ; RMS (M + ) calcd for C Si , found S-6

7 3 3 TIPS TIPS BC 19 Protection of lactam 19. Indolenine 19 (5.70 g, 9.56 mmol) was dissolved in TF (96 ml) and cooled to 0 C in an ice bath. Sodium hydride (573 mg, mmol) was added and the solution was stirred for ten minutes before the addition of di-t-butyl-dicarbonate (3.13 g, mmol). The resulting solution was warmed to room temperature and stirred for one hour. The reaction was quenched with water and extracted three times with EtAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:4) to afford the imide 14 as a pale yellow foam (6.12 g, 92%): 1 MR (CD 3, 400 Mz) δ 0.86 (m, 21), 1.53 (s, 9), (m, 2), 2.48 (dt, J = 8.1, 13.6 z, 1), 2.71 (br dt, J = 7.6, 13.2 z, 1), (m, 3), 3.02 (ddd, J = 4.5, 7.2, 10.2 z, 1), 6.50 (br s, 1), 7.05 (v br s, 1), 7.14 (d, J = 8.0 z, 1), 7.18 (t, J = 7.4 z, 1), 7.35 (dt, J = 0.9, 7.7 z, 1), 7.51 (d, J = 7.7 z, 1), 8.03 (d, J = 1.8 z, 1), 8.08 (s, 1); 13 C MR (CD 3, 100 Mz) δ 11.5, 17.7, 31.3, 32.6, 47.3, 54.7, 58.6, 64.3, 84.9, 118.6, 121.3, 121.7, 123.1, 124.3, 125.3, 126.2, 126.9, 129.1, 136.6, 141.1, 148.3, 156.2, 173.4, 173.8; IR (neat) 2942, 2100, 1769, 1736, 1598 cm -1 ; RMS (M + ) calcd for C Si , found TIPS 3 TIPS BC 20 BC Aminal 20. Triphenylphosphine (2.52 g, 9.60 mmol) was added to a stirring solution of imide 14 (3.34 g, 4.80 mmol) in TF (48 ml) and water (12 ml) at room temperature. The resulting solution was then heated at 50 C for five hours. The solution was cooled to room temperature and treated with ac 3 (aq) and extracted three times with EtAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc- S-7

8 hexanes, 1:4) to afford the aminal 20 as a white foam (2.85 g, 89%): 1 MR (CD 3, 400 Mz) δ 0.90 (m, 21), 1.58 (s, 9), 2.33 (m, 1), (m, 3), 3.08 (m, 1), 3.46 (m, 1), 3.67 (m, 1), 5.10 (v br s, 1), 6.14 (s, 1), 6.57 (d, J = 7.7 z, 1), 6.67 (t, J = 6.9 z, 1), 6.68 (br s, 1), (m, 3); 13 C MR (CD 3, 100 Mz) δ 12.2, 18.4, 28.8, 31.2, 36.3, 39.3, 53.8, 55.9, 60.5, 77.7, 82.6, 109.4, 119.6, 120.8, 124.6, 126.8, 127.0, 127.5, 129.0, 130.7, 132.5, 138.5, 149.6, 154.2, 177.0; IR (neat) 3214, 2942, 1698 cm -1 ; RMS (M + ) calcd for C Si , found TIPS BC 20 TIPS BC Chlorination of aminal 20. -Chlorosuccinimide (1.12 g, 8.42 mmol) was added to a stirring solution of aminal 20 (1.41 g, 2.10 mmol) in acetic acid at room temperature. The solution was allowed to stir at room temperature for 24 hours. The reaction was then quenched with a 2 S 2 3 and extracted with C 2 2. The resulting organic layers were then washed with ac 3 (aq). The aqueous layer was then extracted again with C 2 2. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAchexanes, 1:4) to afford the chlorinated aminal (1.34 g, 89%) as a white foam: 1 MR (CD 3, 400 Mz) δ 0.91 (m, 21), 1.59 (s, 9), 2.39 (m, 1), 2.56 (m, 1), 2.81 (m, 1), 2.99 (m, 1), 3.13 (m, 1), 3.50 (m, 1), 3.69 (m, 1), 5.26 (br s, 1), 6.22 (s, 1), 6.52 (s, 1), 6.92 (d, J = 1.7 z, 1), 7.02 (d, J = 8.3 z, 1), 7.07 (d, J = 1.7 z, 1), 7.16 (dd, J = 1.9, 8.3 z, 1), 7.72 (br s, 1); 13 C MR (CD 3, 100 Mz) δ 11.7, 17.6, 28.3, 30.6, 35.7, 38.9, 53.4, 57.0, 59.9, 82.4, 114.4, 120.8, 123.0, 123.5, 126.4, 126.8, 127.4, 127.9, 129.4, 131.6, 137.9, 145.1, 153.2, 176.2; IR (neat) 3214, 2942, 1698 cm -1 ; RMS (M + ) calcd for C Si , found S-8

9 TIPS BC TIPS s BC 21 4-osylimide 21. The chlorinated lactam (1.34 g, 1.81 mmol) was dissolved in TF (18 ml) and cooled to -78 C. amds (1.0 M in TF, 1.99 ml) was then added dropwise to the solution. After fifteen minutes, 4-nitrophenylsulphonyl chloride (482 mg, 2.17 mmol) was added and the solution was warmed to room temperature over one hour. The reaction was quenched with water and extracted three times with EtAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:9) to afford the nosyl imide 21 (1.35 g, 81%) as a yellow foam: 1 MR (CD 3 C, 400 Mz) δ 0.93 (m, 21), 1.53 (s, 9), 1.97 (m, 1), 2.21 (m, 1), 2.66 (dd, J = 6.1, 13.4 z, 1), 6.28 (br s, 1), 6.82 (d, J = 1.3 z, 1), 6.92 (d, J = 8.6 z, 1), 6.93 (d, J = 1.3 z, 1), 7.04 (dd, J = 2.0, 8.6 z, 1) 7.41 (s, 1), 7.91 (br s, 2), 8.18 (br d, J = 8.0 z, 2); 13 C MR (CD 3 C, 100 Mz) δ 12.6, 18.4, 25.9, 28.6, 38.9, 45.3, 56.3, 60.2, 60.5, 76.5, 82.5, 114.2, 122.2, 122.8, 124.1, 125.2, 127.6, 128.6, 129.9, 130.6, 131.7, 140.1, 142.8, 146.9, 151.7, 153.0, 171.7; IR (neat) 3416, 2943, 1714, 1535 cm -1 ; RMS (M + ) calcd for C SiS , found TIPS s s 21 BC BC Desilylation of ether 21. osylimide 21 (1.18 g, 1.28 mmol) was dissolved in TF (13 ml). Acetic acid (580 µl, mmol) and TBAF (1.0 M in TF, 5.12 ml) were added sequentially to the solution at room temperature. The reaction mixture was heated at 40 C in an oil bath for 24 hours. The reaction was then cooled and poured into 4 (aq) and extracted four times with EtAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel S-9

10 column chromatography (EtAc-hexanes, 1:2) to afford the primary alcohol (970 mg, 98%) as a yellow foam: 1 MR (CD 3, 400 Mz) δ 1.58 (s, 9), 1.85 (ddd, J = 3.3, 6.5, 14.8 z, 1), (m, 1), 2.51 (dt, J = 8.7, 15.4 z, 1), 2.60 (dt, J = 6.3, 14.8 z, 1), (m, 1), 3.05 (m, 1), (m, 1), 4.50 (ddd, J = 3.1, 7.9, 11.7 z, 1), 5.12 (br s, 1), 5.16 (t, J = 6.1 z, 1), 5.95 (br s, 1), 6.84 (d, J = 8.3 z, 1), 6.89 (d, J = 1.8 z, 1), 7.07 (d, J = 1.8 z, 1), 7.17 (dd, J = 2.0, 8.3 z, 1), 7.72 (br s, 1), 7.92 (d, J = 8.9 z, 2), 8.31 (d, J = 8.9 z, 2); 13 C MR (CD 3, 100 Mz) δ 28.1, 29.6, 31.5, 40.0, 52.3, 64.6, 77.3, 83.7, 114.7, 121.9, 122.7, 123.8, 124.3, 127.2, 128.0, 128.1, 128.4, 128.8, 129.0, 130.7, 137.5, 144.3, 145.6, 149.9, 152.4, 172.1; IR (neat) 3416, 2943, 1714, 1535 cm -1 ; LRMS (M + ) calcd for C S , found s 3 s BC 22 BC Azide 22. The primary alcohol (417 mg, 0.54 mmol) was dissolved in TF (6 ml) and cooled to 0 C. Triphenylphosphine (213 mg, 0.81 mmol), DPPA (175 µl, 0.81 mmol), and DIAD (160 µl, 0.81 mmol) were added sequentially to the TF solution. The reaction was allowed to gradually warm to room temperature over 1 hour. The solution was then stirred for another three hours at room temperature. The reaction mixture was then concentrated and the crude material was directly purified by silica gel column chromatography (EtAc-hexanes 1:9) to give the azide 22 as a yellow solid (344 mg, 80%): 1 MR (CD 3, 400 Mz) δ 1.59 (s, 9), 1.60 (m, 1), (m, 3), 3.00 (ddd, J = 5.7, 8.8, 12.2 z, 1), 3.19 (br ddd, J = 7.2, 8.5, 12.8 z, 1), 3.67 (m, 1), 3.85 (m, 1), 5.18 (v br s, 1), 5.87 (br s, 1), 6.54 (br s, 1), 6.74 (d, J = 8.3 z, 1), 7.02 (d, J = 1.6 z, 1), 7.10 (br d, J = 7.9 z, 1), 7.61 (br s, 1), 8.09 (br s, 2), 8.34 (br d, J = 7.3 z, 2); 13 C MR (CD 3, 100 Mz) δ 28.7, 28.8, 44.3, 47.8, 55.7, 57.5, 76.5, 83.9, 115.4, 122.5, 122.7, 124.2, 124.8, 126.0, 127.9, 128.1, 129.3, 129.5, 129.6, 138.0, 143.0, 145.2, 151.4, 153.3, 171.9; IR (neat) 3400, 2099, 1705 cm -1. S-10

11 3 s BC 22 s BC Transamidation of nosylimide 22. Trimethylphosphine (1.0 M in TF, 950 µl) was added to a solution of azide 22 (303 mg, 0.38 mmol) in TF (4 ml) at room temperature. The solution was stirred for one hour and then concentrated. The crude material was directly purified by silica gel column chromatography (EtAc-hexanes 1:1) to give the nosylamide as a yellow foam (251 mg, 86%): 1 MR (CD 3, 400 Mz) δ 1.42 (s, 9), 1.95 (br d, J = 12.6 z, 1), 2.49 (br d, J = 10.8 z, 1), (m, 2), (m, 2), (m, 2), 4.76 (br s, 1), 6.17 (br s, 1), 6.70 (d, J = 8.4 z, 1), 6.91 (d, J = 1.7 z, 1), 6.95 (br s, 1), 7.08 (dd, J = 1.4, 8.4 z, 1), 7.51 (br s, 1), 7.94 (d, J = 8.8 z, 2), 8.21 (d, J = 8.8 z, 2); 13 C MR (CD 3, 100 Mz) δ 28.1, 29.0, 31.0, 37.4, 39.3, 50.0, 60.3, 75.0, 82.2, 113.6, 120.8, 122.5, 123.3, 124.1, 127.0, 127.9, 128.1, 128.3, 129.3, 130.9, 138.3, 144.7, 145.2, 149.8, 152.1, 173.4; IR (neat) 3359, 1698, 1660 cm -1 ; LRMS (M + ) calcd for C S , found s s BC BC 23 Methylation of nosylamide 23. Cesium carbonate (248 mg, 0.76 mmol) was added to a solution of nosylamide 23 (530 mg, 0.69 mmol) in acetonitrile (7 ml) at room temperature. After 15 minutes, iodomethane (130 µl, 2.08 mmol) was added and stirring was continued for six hours. C 2 2 (30 ml) was then added and the resulting solution was filtered through a pad of Celite. The sovent was removed under vacuum and the crude material was directly purified by silica gel column chromatography (EtAchexanes 1:1) to give the methylated nosylamide 23 as a yellow foam (497 mg, 92%): 1 MR (CD 3, 400 Mz) δ 1.53 (br s, 9), 1.88 (m, 1), (m, 2), 2.50 (m, 1), 2.81 (br s, 3), 3.15 (m, 2), 3.58 (m, 2), 5.01 (v br s, 1), 5.84 (br s, 1), 6.03 (v br s, S-11

12 1), 6.93 (d, J = 1.6 z, 1), 7.02 (d, J = 8.4 z, 1), 7.03 (br s, 1), 7.22 (dd, J = 1.9, 8.4 z, 1), 7.54 (br s, 1), 7.88 (d, J = 8.7 z, 2), 8.32 (d, J = 8.7 z, 2); 13 C MR (CD 3, 50 Mz) δ 28.2, 29.6, 29.7, 35.5, 37.8, 48.5, 51.2, 58.2, 76.4, 82.3, 114.3, 121.3, 123.0, 123.3, 124.3, 127.7, 128.2, 128.3, 128.5, 130.9, 137.4, 143.7, 144.5, 149.9, 152.8, 171.9; IR (neat) 3391, 1699, 1669 cm -1 ; LRMS (M + ) calcd for C S , found s BC s Me Cyclic imidate 24. DIPEA (61 µl, 0.35 mmol) and trimethyloxonium tetrafluoroborate (99 mg, 0.67 mmol) were added sequentially to a solution of lactam 23 (249 mg, 0.32 mmol) in C 2 2 (2.5 ml) at room temperature. The flask was sealed with a glass stopper and allowed to stir for 48 hours during which time a white precipitate formed. The reaction mixture was then poured into a solution of ac 3 (aq) and extracted three times with C 2 2. The combined organic layers were dried over sodium sulfate and concentrated. The crude material was then purified by silica gel column chromatography (EtAc-hexanes, 1:2) to afford the cyclic imidate (150 mg, 68%) as a yellow foam: 1 MR (DMS, 400 Mz) δ (m, 2), 1.59 (dd, J = 6.1, 13.4 z, 1), 2.13 (br dt, J = 3.7, 12.4 z, 1), 2.27 (br t, J = 10.8 z, 1), 2.51 (s, 3), 2.95 (ddd, J = 5.5, 11.3, 13.5 z, 1), 3.52 (br dd, J = 7.2, 16.3 z, 1), (m, 1), 3.70 (s, 3), 4.94 (t, J = 4.0 z, 1), 6.50 (d, J = 4.0 z, 1), 6.61 (d, J = 4.0 z, 1), 6.62 (d, J = 2.0 z, 1), 6.64 (d, J = 8.2 z, 1), 6.79 (dd, J = 2.0, 8.2 z, 1), 7.08 (d, J = 2.0 z, 1), 7.14 (d, J = 2.0 z, 1), 7.80 (d, J = 8.9 z, 1), 8.36 (d, J = 8.9 z, 1); 13 C MR (DMS, 100 Mz) δ 26.2, 31.6, 34.3, 42.1, 47.3, 48.5, 51.0, 52.5, 76.4, 113.4, 117.1, 120.3, 120.8, 121.3, 123.0, 123.1, 124.6, 127.4, 128.2, 128.6, 133.4, 142.8, 143.4, 146.1, 149.6, 162.2; IR (neat) 3370, 1675, 1595 cm -1 ; RMS (M + ) calcd for C S , found S-12

13 s Me 24 11,12-Dihydroperophoramidine. Cesium carbonate (315 mg, 0.97 mmol) was added to a solution of nosylamide 24 (112 mg, 0.16 mmol) in DMF (2 ml). Thiophenol (50 µl, 0.48 mmol) was then added and the resulting solution was heated at 45 C for 24 hours. The solvent was removed under vacuum to give a residue which was taken up in C Me (99:1) and filtered through a fritted glass filter. The resulting filtrate was concentrated and purified by silica gel column chromatography ( 4 -Me-C 2 2, 1:2:97) to afford the amidine (54 mg, 68%) as a white solid: 1 MR (CD 2 2, 360 Mz) δ (m, 2), 1.61 (ddd, J = 1.4, 7.8, 13.9 z, 1), 1.71 (dd, J = 5.5, 12.3 z, 1), 2.88 (br t, J = 8.6 z, 1), 3.00 (s, 3), 3.04 (ddd, J = 5.7, 9.6, 9.6 z, 1), 3.55 (br dd, J = 6.9, 16.6 z, 1), 3.80 (dt, J = 8.4, 16.6 z, 1), 4.75 (m, 1), 5.06 (br t, J = 5.4 z, 1), 6.57 (d, J = 8.6 z, 1), (m, 2), 6.91 (d, J = 1.9 z, 1), 7.13 (d, J = 1.9 z, 1); 13 C MR (DMS, 50 Mz) δ 28.5, 30.2, 30.5, 43.2, 46.1, 46.6, 46.8, 76.2, 113.2, 116.1, 119.3, 120.3, 121.5, 122.4, 123.0, 127.2, 134.5, 142.5, 145.8, 160.8; RMS (M + ) calcd for C , found Perophoramidine. Active Mn 2 (150 mg) was added to a rapidly stirring solution of dihydroperophoramidine (51 mg, 0.11 mmol) in C 2 2 (2 ml). The solution was stirred for thirty minutes and filtered through a fritted glass filter. The crude material was directly purified by silica gel column chromatography (C 3 -Me, 96:4) to give perophoramidine as a white amorphous solid (33 mg, 65%). The white residue was then dissolved in Me and concentrated prior to MR analysis. The 1 and C13 spectral characteristics were identical to those previously published 3 : 1 MR (CD 3, 400 Mz) S-13

14 δ (dd, J = 5.9, 13.8 z, 1), 1.71 (dd, J = 5.7, 12.1 z, 1), 1.79 (br dt, J = 9.4, 12.0 z, 1), 2.21 (ddd, J = 7.8, 10.2, 13.6 z, 1), 3.13 (br t, J = 9.0 z, 1), 3.18 (br s, 3), 3.30 (ddd, J = 6.0, 9.7, 9.7 z, 1), 3.64 (ddd, J = 6.5, 10.2, 16.7 z, 1), 3.72 (br dd, J= 7.8, 16.7 z, 1), 6.72 (d, J = 8.2 z, 1), 6.95 (d, J = 1.9 z, 1), 7.10 (dd, J = 1.9, 8.2 z, 1), 7.24 (d, J = 1.9 z, 1), 7.27 (d, J = 1.9 z, 1); 13 C MR (CD 3, 75 Mz) δ 25.1, 29.9, 31.1, 42.8, 45.6, 46.4, 52.2, 120.4, 121.9, 122.5, 122.9, 125.5, 126.9, 127.3, 128.3, 129.0, 135.6, 138.5, 147.6, 159.6, 172.2; IR (neat) 1653, 1561 cm -1 ; RMS (M + ) calcd for C , found References 1. inman, R. L.; Bauman, C. P. J. Am. Chem. Soc. 1964, Fukuda, T.; Maeda, R.; Iwao, M. Tetrahedron, 1999, 55, Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. rg. Chem. 2002, 67, S-14