, eq.) and phenyl selenoester (1.5 eq.) in chlorobenzene (0.1 M) were added Bu3SnH (1.3 eq.) and AIBN (0.1 eq.). The reaction mixture was cooled-20°C and stirred under sun lamp irradiation
, Synthesized according to the general procedure F from a mixture of ethyl 2-(((tertbutyldiphenylsilyl)oxy)(phenyl)methyl)acrylate 203a (523 mg, 1.18 mmol) and AcSePh (352 mg, 1.77 mmol), Bu3SnH (412 µL, 1.53 mmol) and AIBN (2 x 19 mg, 2 x 0.12 mmol) in benzene (12 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil, tert-butyldiphenylsilyl)oxy)(phenyl)methyl)-4-oxopentanoate 197b
, )oxy)(phenyl)methyl)acrylate 203a (105 mg, 0.24 mmol) and AcSePh (70 mg, 0.35 mmol), TTMSH (110 µL, 0.35 mmol) and DTBHN (2 x 4 mg, 2 x 0.024 mmol) in benzene (2.3 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer syn is described below
, H-NMR (300 MHz, CDCl3) ? (ppm) = 7.65-7.54 (m, 2H), 7.47-7.11 (m, 13H), 5.05 (d, J = 5.1 Hz, 1H, H6), 3.93-3.77 (m, 1H, H2), 3.73-3.58 (m, 1H, H2), vol.1, 1065.
, HRMS (ESI) : Calcd. for C30H36O4NaSi [M+Na] + 511.2275, found 511, 2276.
, oxopropyl)heptanoate 197c: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylideneheptanoate 203b (100 mg, 0.24 mmol) and AcSePh (70 mg, 0.35mmol), TTMSH (109 µL, 0.35 mmol) and DTBHN (2 x 4 mg, 2 x 0.024 mmol) in benzene (2.4 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer syn is described below
, , pp.61-63
, H-NMR (300 MHz, CDCl3) ? (ppm) = 7.68-7.59 (m, 4H), 7.467.33 (m, 6H), vol.1, 1075.
, HRMS (ESI) : Calcd. for C28H40O4NaSi [M+Na] + 491.2588, found 491, 2591.
, (triisopropylsilyl)oxy) hexanoate 197d: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylidene-6-{[tris(propan-2-yl)silyl]oxy}hexanoate 203c (200 mg, 0.34 mmol), AcSePh (102 mg, 0.51 mmol), TTMSH (160 µL, 0.51 mmol) and DTBHN (2 x 6 mg, 2 x 0.034 mmol) in benzene (4 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer syn is described below
, HNMR (300 MHz, CDCl3) ? (ppm) = 7.70-7.59 (m, 4H), vol.1, 1019.
, CDCl3) ? (ppm) = 207.6 (C7), 173.6 (C3), 136.0, 135.9, vol.134
, HRMS (ESI) : Calcd. for C36H58O5NaSi2 [M+Na] + 649.3715, found 649, p.3702
, oxo-2-phenylethyl)hexanoate 197e: Synthesized according to the general procedure F from a mixture of ethyl 3-((tertbutyldiphenylsilyl)oxy)-5-methyl-2-methylenehexanoate 191e (100 mg, 0.24 mmol) and BzSePh (92 mg, 0.35 mmol), Bu3SnH (82 µL, 0.31 mmol) and AIBN (2 x 3.9 mg, 2 x 0.024 mmol) in benzene (2.5 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil, tert-butyldiphenylsilyl)oxy)-5-methyl-2, vol.3
, )oxy)-5-methyl-2-methylenehexanoate 191e (200 mg, 0.47 mmol) and BzSePh (184 mg, 0.71 mmol), TTMSH (219 µL, 0.71 mmol) and DTBHN (2 x 8.2 mg, 2 x 0.047 mmol) in benzene (5 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer syn is described below
, CDCl3) ? (ppm) = 8.14-7.91 (m, 2H)
, HRMS (ESI) : Calcd. for C33H42O4NaSi [M+Na] + 553.2744, found 553, 2759.
, Synthesized according to the general procedure E from a mixture of ethyl 2-(((tertbutyldiphenylsilyl)oxy)(phenyl)methyl)acrylate 203a (115 mg, 0.26 mmol) and BzSePh (135 mg, 0.52 mmol), TTMSH (121 µL, 0.39 mmol) and DTBHN (2 x 4.5 mg, 2 x 0.026 mmol) in benzene (2.6 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 95/5) afforded the title compound as a mixture of two diastereoisomers as a colorless oil, tert-butyldiphenylsilyl)oxy)(phenyl)methyl)-4-oxo-4-phenylbutanoate 197f
, H-NMR (300 MHz, CDCl3) ? (ppm) = 7.81-7.16 (m, 20H, M+m), 5.16 (d, J = 6.6 Hz, 0.2H, m, H6), 5.08 (d, J = 6.0 Hz, 0.8H, M, H6, vol.1, 1090.
, HRMS (ESI) : Calcd. for C35H38O4NaSi [M+Na] + 573.2431, found 573, 2431.
, phenylethyl)heptanoate 197g: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylideneheptanoate 203b (100 mg, 0.24 mmol) and BzSePh (123 mg, 0.47 mmol), TTMSH (109 µL, 0.35 mmol) and DTBHN (2 x 4 mg, 2 x 0.024 mmol) in benzene (2.4 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil, tert-butyldiphenylsilyl)oxy)-2, vol.3
, Both compounds were separable and only major diastereoisomer syn is described below
, H-NMR (300 MHz, CDCl3) ? (ppm) = 8.02-7.94 (m, 2H), 7.73-7.31 (m, 13H), vol.1, 1026.
,
,
, HRMS (ESI) : Calcd. for C33H42O4NaSi [M+Na] + 553.2744, found 553, 2748.
, (triisopropylsilyl)oxy) hexanoate 197h: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylidene-6-{[tris(propan-2-yl)silyl]oxy}hexanoate 203c (200 mg, 0.34 mmol), BzSePh (134 mg, 0.51 mmol), TTMSH (160 µL, 0.51 mmol) and DTBHN (2 x 6 mg, 2 x 0.034 mmol) in benzene (4 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer syn is described below
, CDCl3) ? (ppm) = 8.01-7.93 (m, 2H), 7.73-7.31 (m, 13H)
, (tert-butyldiphenylsilyl)oxy)-3-methylbutyl)-4-oxoheptanedioate 197i: Synthesized according to the general procedure E from a mixture of ethyl 3-((tertbutyldiphenylsilyl)oxy)-5-methyl-2-methylenehexanoate 191e (2100 mg, 4.95 mmol) and methyl 4oxo-4-(phenylselanyl)butanoate 200 (1609 mg, 5.93 mmol), TTMSH (2.31 mL, 7.42mmol) and DTBHN (2 x 43 mg, 2 x 0.25 mmol) in benzene (50 mL). Purification by flash chromatography over silica gel, HRMS
, Both compounds were separable and only major diastereoisomer syn is described below
, IR (ATR) ?max (cm-1 ) = 2955, 2858, 1735, 1720, 1105, 1073; 1 H-NMR (300 MHz, CDCl3) ? (ppm) = 7.71-7.55 (m, 4H), 7.48-7.29 (m, 6H), 4.38-4.27 (m, 1H, H6)
, tert-butyldiphenylsilyl)oxy)(phenyl)methyl)-4-oxoheptanedioate 197j: Synthesized according to the general procedure F from a mixture of ethyl 2-{[(tertbutyldiphenylsilyl)oxy](phenyl)methyl}prop-2-enoate 203a (500 mg, 1.12 mmol) and methyl 4-oxo4-(phenylselanyl)butanoate 200 (457 mg, 1.69 mmol), Bu3SnH (394 µL, 1.46 mmol) and AIBN (2 x 18 mg, 2 x 0.11 mmol) in benzene (11 mL). Purification by flash chromatography over silica gel, HRMS (ESI) : Calcd. for C31H44O6NaSi
, mmol) and methyl 4-oxo4-(phenylselanyl)butanoate 200 (192 mg, 0.71 mmol), TTMSH (220 µL, 0.71 mmol) and DTBHN (2 x 8.2 mg, 2 x 0.0.47 mmol) in benzene (5 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer syn is described below
, 92-3.78 (m, 1H, H2), 3.74-3.56 (m, 4H, H2 and H11), 3.21-3.06 (m, 1H, H4), 2.97 (dd, J = 17.6, 11.1 Hz, 1H, H5), 300 MHz, CDCl3) ? (ppm) = 7.65-7.56 (m, 2H), 7.48-7.13 (m, 13H), 5.08 (d, J = 5.1 Hz, 1H, H6), vol.3
, HRMS (ESI) : Calcd. for C33H40O6NaSi [M+Na] + 583.2486, found 583, 2492.
, Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylideneheptanoate 203b (200 mg, 0.47 mmol) and methyl 4-oxo-4(phenylselanyl)butanoate 200 (192 mg, 0.71 mmol), TTMSH (220 µL, 0.71 mmol) and DTBHN (2 x 8 mg, 2 x 0.047 mmol) in benzene (4.8 mL). Purification by flash chromatography over silica gel, tert-butyldiphenylsilyl)oxy)pentyl)-4-oxoheptanedioate 197k
, Both compounds were separable and only major diastereoisomer syn is described below
, 67 (s, 3H, H14), 3.21 (dd, J = 17.1, 10.5 Hz, 1H, H4), 3.08 (dt, 300 MHz, CDCl3) ? (ppm) = 7.70-7.56 (m, 4H), 7.48-7.30 (m, 6H), 4.29-4.18 (m, 1H, H6), 4.13-3.86 (m, 2H, H2), vol.1, pp.45-46, 1076.
, 3-diphenyl-4,9-dioxa-3,10disiladodecan-5-yl)-4-oxoheptanedioate 197l: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylidene-6-{[tris(propan-2-yl)silyl]oxy}hexanoate 203c (519 mg, 0.89 mmol) and methyl 4-oxo-4-(phenylselanyl)butanoate 200 (161 mg, 0.59 mmol), TTMSH (277 µL, 0.89 mmol) and DTBHN (2 x 10 mg, 2 x 0.059 mmol) in benzene (7 mL). Purification by flash chromatography over silica gel, HRMS (ESI) : Calcd. for C31H44O6NaSi [M+Na] + 563.2799, found 563.2814. 1-Ethyl 7-methyl, vol.2, pp.11-14
, Both compounds were separable and only major diastereoisomer syn is described below
, 68 (s, 3H, H14), 3.34 (t, J = 6.3 Hz, 2H, H10), 3.26-3.03 (m, 2H, H4 and H5, CDCl3) ? (ppm) = 7.70-7.56 (m, 4H), 7.47-7.32 (m, 6H), 4.27-4.18 (m, 1H, H6), 4.11-3.83 (m, 2H, H2), vol.3
, HRMS (ESI) : Calcd. for C39H62O7NaSi2 [M+Na] + 721.3926, found 721, p.3937
, 47 mmol) and ethyl 2-(((tertbutyldiphenylsilyl)oxy)(phenyl)methyl)acrylate 203a (105 mg, 0.23 mmol) in dioxane (2 mL) were added tert-dodecylmercaptan (11 µL, 0.047 mmol) and DTBHN (4.1 mg, 0.023 mmol). The reaction mixture was stirred for 6h at 60°C. Thiol and DTBHN were added again after 2h and 4h (same quantities). Dioxane was removed under reduced pressure. The crude product was purified by flash chromatography over silica gel, tert-butyldiphenylsilyl)oxy)(phenyl)methyl)-4-oxooctanoate 204: To a solution of valeraldehyde (50 µL
, IR (ATR) ?max (cm-1 ), 1065.
, 300 MHz, CDCl3) ? (ppm) = 7.75-7.58 (m, 4H), 7.47-7.15 (m, 11H)
, m, 1.5H, H5), 2.42-2.22 (m, 2H, H8), 1.50-1.38 (m, 2H, H9), 1.31-1.20 (m, 2H, H10), 1.16 (t, J = 7.1 Hz, 1.5H, H1), 1.03 (s, 9H), 0.97-0.81 (m, 4.5H, H1 and H11); 13 C-NMR (75 MHz, CDCl3) ? 209.7 (C7), 209.2 (C7), 172.7 (C3), 172.7 (C3, vol.42
, HRMS (ESI) : Calcd. for C33H42O4NaSi [M+Na] + 553.2744, found 553, 2744.
, Synthesized according to the general procedure D from a mixture of 3-[hydroxy(phenyl)methyl]but3-en-2-one 205 (2.00 g, 11.35 mmol), TBDPSCl (4.42 mL, 17.02 mmol) and imidazole (1.16 g, 17.02 mmol) in CH2Cl2 (40 mL). The crude product was purified by flash chromatography over silica gel, (((tert-butyldiphenylsilyl)oxy)(phenyl)methyl)but-3-en-2-one, vol.206
, HNMR (300 MHz, CDCl3) ? (ppm) = 7.64-7.56 (m, 2H), 7.46-7.13 (m, 13H), vol.1, pp.51-57, 1063.
, HRMS (ESI) : Calcd. for C26H36O3NaSi, vol.437, p.436, 1907.
, 33 mmol) and BF3.Et2O (21 µL, 0.16 mmol. in MeCN (0.8 mL). Purification by flash chromatography over silica gel (Pentane/Et2O 95/5) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, IR (ATR) ?max (cm-1 ) = 2971, 1028.
, 300 MHz, CDCl3) ? (ppm) = 7.46-7.23 (m, 5H), 5.02 (d, J = 7.2 Hz, 1H, H1), 4.354.11 (m, 3H, H2 and H6), 2.97 (ddd, J = 9, vol.9
, HRMS (ESI) : Calcd. for C14H18O3Na [M+Na] + 257.1148, found 257, 1140.
, Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-(2-oxopropyl)heptanoate 197c (55 mg, 0.12 mmol), TTMSH (146 µL, 0.47 mmol) and BF3.Et2O (30 µL, 0.23 mmol) in MeCN (1.2 mL). Purification by flash chromatography over silica gel (Pentane/Et2O 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, IR (ATR) ?max (cm-1 ) = 3456, 3072, 1181.
, 300 MHz, CDCl3) ? (ppm) = 4.21-3.97 (m, 3H, H1 and H3)
, MHz, CDCl3) ? (ppm) = 174.4 (C5), 82.5 (C1), 75.1 (C2), 60.8 (C6), 49.7 (C3), vol.37
, HRMS (ESI) : Calcd. for C12H22O3Na [M+Na] + 237.1461, found 237, 1467.
, Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-(2-oxopropyl)-6-{[tris(propan-2-yl)silyl]oxy}hexanoate 197d (59 mg, 0.094 mmol), TTMSH (117 µL, 0.38 mmol) and BF3.Et2O (24 µL, 0.19 mmol) in MeCN (1 mL). Purification by flash chromatography over silica gel
, Experimental Part Both compounds were separable and only major diastereoisomer cis is described below
, IR (ATR) ?max (cm-1 ) = 3418, 1057.
, 300 MHz, CDCl3) ? (ppm) = 4.19-4.02 (m, 3H, H1 and H6), 3.97-3.87 (m, 1H, H2), 3.73-3.57 (m, 2H, H11), vol.1
, HRMS (ESI) : Calcd. for C11H20O4Na
, Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-5-methyl-2-(2-oxo-2-phenylethyl)hexanoate 197e (78 mg, 0.15 mmol), TTMSH (183µL, 0.59 mmol) and BF3.Et2O (37 µL, 0.29 mmol) in MeCN (1.5 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 97/3) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, IR (ATR) ?max (cm-1 ) = 2958, 1024.
, 77 (ddd, J = 9, 300 MHz, CDCl3) ? (ppm) = 7.42-7.19 (m, 5H), 4.99 (dd, J = 8.1, 6.9 Hz, 1H, H2), 4.27-4.11 (m, 3H, H1 and H6), vol.2
, CDCl3) ? (ppm) = 174.1 (C5), 142.2, 128.5, 127.6, 125.9, C1 or C2), vol.81
, HRMS (ESI) : Calcd. for C17H24O3Na [M+Na] + 299.1617, found 299, 1605.
, Synthesized according to the general procedure G from a mixture of ethyl 2-{[(tertbutyldiphenylsilyl)oxy](phenyl)methyl}-4-oxo-4-phenylbutanoate 197f (31 mg, 0.056 mmol), TTMSH (70 µL, 0.22 mmol) and BF3.Et2O (14 µL, 0.11 mmol) in MeCN (0.6 mL). Purification by flash chromatography over silica gel (Pentane/Et2O 95/5) afforded the title compound as a mixture of two diastereoisomers as a colorless oil, Ethyl, vol.2, pp.5-8
, Both compounds were separable and only major diastereoisomer cis is described below
, HNMR (300 MHz, CDCl3) ? (ppm) = 7.52-7.27 (m, 10H), 5.23-5.11 (m, 2H, H1 and H2, vol.1, 1025.
, HRMS (ESI) : Calcd. for C19H20O3Na, p.319, 1307.
, Synthesized according to the general procedure G from a mixture of 3-[(tert-butyldiphenylsilyl)oxy]2-(2-oxo-2-phenylethyl)heptanoate 197g (45 mg, 0.085 mmol), TTMSH (105 µL, 0.34 mmol) and BF3.Et2O (21 µL, 0.17 mmol) in MeCN (0.9 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 97/3) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, HNMR (300 MHz, CDCl3) ? (ppm) = 7.39-7.23 (m, 5H), vol.1, 1026.
, HRMS (ESI) : Calcd. for C17H24O3Na [M+Na] + 299.1617, found 299, 1617.
, Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-(2-oxo-2-phenylethyl)-6-{[tris(propan-2-yl)silyl]oxy}hexanoate 197h (78 mg, 0.11 mmol), TTMSH (141 µL, 0.45 mmol) and BF3.Et2O (29 µL, 0.23 mmol) in MeCN (1.2 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 60/40) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, H-NMR (300 MHz, CDCl3) ? (ppm) = 7.37-7.24 (m, 5H), vol.1, 1024.
, 1.98-1.87 (m, 1H, H8), 1.87-1.71 (m, 3H, H8 and H9), vol.1
, MHz, CDCl3) ? (ppm) = 173.7 (C5)
, HRMS (ESI) : Calcd. for C16H22O4Na, p.301, 1397.
, Synthesized according to the general procedure G from a mixture of 1-ethyl 7-methyl 2-(1-((tertbutyldiphenylsilyl)oxy)-3-methylbutyl)-4-oxoheptanedioate 197i (139 mg, 0.26 mmol), TTMSH (319 µL, 1.03 mmol) and BF3.Et2O (65 µL, 0.51 mmol) in MeCN (2.6 mL). Purification by flash chromatography over silica gel (Pentane/EtOAc 90/10) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, Both compounds were separable and only major diastereoisomer cis is described below
, 98-3.85 (m, 2H, H6), 3.64 (s, 3H, H14), 2.58 (ddd, J = 9, 300 MHz, CDCl3) ? (ppm) = 4.18-4.06 (m, 2H, H1 and H2), vol.1, 1081.
, HRMS (ESI) : Calcd. for C15H26O5Na [M+Na] + 309.1672, found 309, 1684.
, Synthesized according to the general procedure G from a mixture of 1-ethyl 7-methyl 2-{[(tertbutyldiphenylsilyl)oxy](phenyl)methyl}-4-oxoheptanedioate 197j (124 mg, 0.22 mmol), TTMSH (275 µL, 0.88 mmol) and BF3.Et2O (56 µL, 0.44 mmol). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer cis is described below
, 67 (s, 3H, H11), 2.92 (ddd, J = 9, HNMR (300 MHz, CDCl3) ? (ppm) = 7.39-7.23 (m, 5H), 5.00 (d, J = 7.2 Hz, 1H, H1), 4.21-4.08 (m, 3H, H2 and H6), vol.1, 1026.
, HRMS (ESI) : Calcd. for C17H22O5Na [M+Na] + 329.1359, found 329, 1344.
, Synthesized according to the general procedure G from a mixture of 1-ethyl 7-methyl 2-{1-[(tertbutyldiphenylsilyl)oxy]pentyl}-4-oxoheptanedioate 197k (35 mg, 0.065 mmol), TTMSH (80 µL, 0.26 mmol) and BF3.Et2O (16 µL, 0.16 mmol) in MeCN (0.6 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer cis is described below
, IR (ATR) ?max (cm-1 ) = 2955, 1178.
, 66 (s, 3H, H15), 2.64 (ddd, J = 9, 300 MHz, CDCl3) ? (ppm) = 4.22-4.08 (m, 2H, H1 and H2), 3.99-3.84 (m, 2H, H6), vol.3
, C4 or C13), 30.8 (C12 or C8), CDCl3) ? (ppm) = 174.1 (C5 or C14), 174.0 (C5 or C14), 82.4 (C1), vol.77
, HRMS (ESI) : Calcd. for C15H26O5Na
, Synthetized according to the general procedure G from a mixture of 1-ethyl 7-methyl 4-oxo-2[2,2,11-trimethyl-3,3-diphenyl-10,10-bis(propan-2-yl)-4,9-dioxa-3,10-disiladodecan-5yl]heptanedioate 197l (123 mg, 0.18 mmol), TTMSH (219 µL, 0.70 mmol) and BF3.Et2O (44 µL, 0.35 mmol) in MeCN (1.8 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer cis is described below: ethyl (2R,3R,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-(4-methoxyphenoxy)-2-(2oxopropyl, vol.292
, 2methylenepentanoate 291f (78 mg, 0.15 mmol) and AcSePh (45 mg, 0.23 mmol) in benzene (2 mL) were added Bu3SnH (81 mg, 0.23 mmol) and AIBN (2 mg, 0.015 mmol). The reaction mixture was cooled to 0°C and stirred at this temperature for 4h under sun lamp irradiation. Concentration under reduced pressure and chromatography over silica gel, 3R,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-(4-methoxyphenoxy
, Both compounds were separable and only major diastereoisomer syn is described below
, IR (ATR) ?max (cm-1 ) = 3049, 1110.
, 300 MHz, CDCl3) ? (ppm) : 7.76-7.32 (m, 10H), 6.80-6.62 (m, 4H)
, 13 C NMR (76 MHz, CDCl3) ? 207.4 (C10), 173.8 (C3)
, HRMS (ESI) : Calcd. for C33H42O6NaSi [M+Na] + =585.2642, found 585, 2638.
, Synthesized according to the general procedure G from a mixture of ethyl (2R,3R,4S)-3-((tertbutyldiphenylsilyl)oxy)-4-(4-methoxyphenoxy)-2-(2-oxopropyl)pentanoate 292f (31 mg, 0.056 mmol), TTMSH (70 µL, 0.24 mmol) and BF3.Et2O (16 µL, 0.12 mmol) in MeCN (1 mL). Purification by flash chromatography over silica gel
, Both compounds were separable and only major diastereoisomer cis is described below
, H NMR (200 MHz, CDCl3) ? (ppm) : 6.93-6.75 (m, 4H), vol.1, 1038.
, Ethyl 3-((tert-butyldiphenylsilyl)oxy)-2-methylenepent-4-ynoate 296: Synthesized according to the general procedure D from a mixture of ethyl 3-hydroxy-2methylidenepent-4-ynoate 301 (2500 mg, 16.22 mmol), TBDPSCl (6.31 mL, 24.32 mmol) and imidazole (1655 mg, 24.32 mmol) in CH2Cl2 (40 mL). The crude product was purified by flash chromatography over silica gel, HRMS (ESI) : Calcd. for C17H24O5Na [M+Na] + =331.1515, found 331.1521
, HNMR (300 MHz, CDCl3) ? (ppm) = 7.83-7.61 (m, 4H), 7.50-7.28 (m, 6H), 6.37-6.28 (m, 1H, H5), vol.1, pp.27-33, 1112.
, HRMS (ESI) : Calcd. for C24H28O3NaSi [M+Na] + 415.1699, found 415, 1704.
, Synthesized according to the general procedure C from a mixture of ethyl acrylate (4.01 mL, 36.9 mmol), 3-(trimethylsilyl)prop-2-ynal 298 (5.17 g, 24.6 mmol) and DABCO (551 mg, 4.9 mmol). Chromatography over silica gel
, MHz, CDCl3) ? (ppm) = 6.28 (s, 1H, H5), 6.12 (s, 1H, H5), 5.23 (d, J = 6, IR (ATR) ?max (cm-1 ), vol.1, 0200.
, HRMS (ESI) : Calcd. for C17H30O3NaSi [M+Na] + 333.1856, found 333, 1843.
, Synthesized according to the general procedure D from a mixture of ethyl 3-hydroxy-2-methylidene5-[tris(propan-2-yl)silyl]pent-4-ynoate 299 (347 mg, 1.17 mmol), TBDPSCl (0.39 mL, 1.52 mmol) and imidazole (104 mg, 1.52 mmol) in CH2Cl2 (5 mL). The crude product was purified by flash chromatography over silica gel
, MHz, CDCl3) ? (ppm) = 7.83-7.62 (m, 4H), pp.1075-1076, 0200.
, 13 C NMR (50 MHz, CDCl3) ? (ppm) = 165.5 (C3), vol.1
, HRMS (ESI) : Calcd. for C33H48O3NaSi2 [M+Na] + 571.3034, found 571, vol.3048
, To a solution of ethyl 3-hydroxy-2-methylene-5-(triisopropylsilyl)pent-4-ynoate 299 (100 mg, 0.32 mmol) in THF (2.5 mL) was added TBAF (1M in THF, 0.64 mL, 0.64 mmol). The mixture was stirred for 4h at room temperature and quenched with water. The aqueous layer was extracted with Et2O (2 x 10 mL) and combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was then purified by flash chromatography over silica gel
, MHz, CDCl3) ? (ppm) = 6.34 (s, 1H, H5), 6.14-6.12 (m, 1H, H5), IR (ATR) ?max (cm-1 ) = 3445, vol.1, 0200.
, HRMS (ESI) : Calcd. for C8H10O3Na
, oxopropyl)pent-4-ynoate 302a: Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylidenepent-4-ynoate 296 (1.86 g, 4.74 mmol), AcSePh (1.23g, 6.16 mmol), TTMSH (2.21 mL, 7.11 mmol) and DTBHN (2 x 45 mg, 2 x 0.26 mmol) in benzene (40 mL). The crude product was purified by flash chromatography over silica gel
, MHz, CDCl3) ? (ppm) = 7.76-7.30 (m, 10H), vol.1, 0200.
, 13 C-NMR (50 MHz, CDCl3) ? (ppm) = 207.1 (C9), vol.171
, HRMS (ESI) : Calcd. for C26H32O4NaSi [M+Na] + 459, p.459, 1957.
, Synthesized according to the general procedure E from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-methylidene-5-[tris(propan-2-yl)silyl]pent-4-ynoate 300 (514 mg, 0.94 mmol), AcSePh (224 mg, 1.12 mmol), TTMSH (437 µL, 1.40 mmol) and DTBHN (2 x 16 mg, 2 x 0.094 mmol) in benzene (10mL). Purification by flash chromatography over silica gel, tert-butyldiphenylsilyl)oxy)-2-(2-oxopropyl)-5-(triisopropylsilyl)pent-4-ynoate 302b, vol.3
, Both compounds were separable and only major diastereoisomer syn is described below
, IR (ATR) ?max (cm-1 ) = 2943, 1079.
, 300 MHz, CDCl3) ? (ppm) = 7.74-7.62 (m, 4H), 7.56-7.27 (m, 6H)
, HRMS (ESI) : Calcd. for C35H52O4NaSi2 [M+Na] + 615, vol.3296, p.615
, Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-(2-oxopropyl)pent-4-ynoate 302a (38 mg, 0.087 mmol), TTMSH (108 µL, 0.35 mmol) and BF3.Et2O (22 µL, 0.17 mmol) in MeCN (1 mL). Purification by flash chromatography over silica gel (Pentane/Et2O 85/15) afforded the title compound as a mixture of two diastereoisomers as a colorless oil
, H NMR (600 MHz, CDCl3) ? (ppm) = 7.73-7.70 (m, TBDPSOH), vol.1, 1112.
, 07 (s, TBDPSOH), C NMR (151 MHz, CDCl3) (ppm) = 172.5 (m, C5), 172.2 (M, C5), 134.8 (TBDPSOH), 129.6 (TBDPSOH), 127.7 (TBDPSOH), 82.8 (M, C9), 82.2 (m, C9), 76.1 (m, C10), 75.6 (M, C10), 73.6 (m, C1), vol.6, p.9
, HRMS (ESI) : Calcd. for C10H14O3Na
, )ethynyl)tetrahydrofuran-3-carboxylate 303b: Synthesized according to the general procedure G from a mixture of ethyl 3-[(tertbutyldiphenylsilyl)oxy]-2-(2-oxopropyl)-5-[tris(propan-2-yl)silyl]pent-4-ynoate 302b (30 mg, 0.051 mmol), TTMSH (63 µL, 0.20 mmol) and BF3.Et2O (22 µL, 0.10 mmol)
, IR (ATR) ?max (cm-1 ) = 2962, 1022.
,
, HRMS (ESI) : Calcd. for C19H34O3NaSi [M+Na] + 361.2169, found 361, 2178.
, Deionized water (6.2 µL, 0.34 mmol) was then added and the mixture was heated at 100°C for 12h. The reaction mixture was filtered over a pad of silica/Na2SO4 (1/1) and the crude oil was purified by chromatography over silica gel (Pentane/EtOAc 70/30) to afford, vol.3
, Rf = 0.4 (Pentane/EtOAc 70/30)
, 3.80Experimental Part methyl 3-((2R,3aS,6S,6aR)-6-methyl-4-oxohexahydrofuro[3,4-b]furan-2-yl)propanoate 323: To a 0°C solution of 1-ethyl 7-methyl (2S)-2-[(1R,2S)-2-(tert-butoxy)-1-hydroxypropyl]-4oxoheptanedioate 320a (60 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added Et3SiH (84 µL, 0.52 mmol) followed by TMSOTf (31 µL, 0.17 mmol). The mixture was stirred for 30min at this temperature and quenched by water (2 mL). Aqueous layer was extracted with CH2Cl2 (3 x 5 mL) and combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was then purified by chromatography (Pentane/EtOAc 75/25) over silica, MHz, CDCl3) ? 7.87-7.29 (m, 10H), 4.59-4.50 (m, 1H, H6), 4.18-3.96 (m, 1H, H9)
, Both compounds were separable and only major diastereoisomer is described below
, CHCl3
, IR (ATR) ?max (cm-1 ) = 3529, vol.1, 1067.
, 75 MHz, CDCl3) ? (ppm) 178.6 (C5 or C10), vol.173
, (R)-2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-4-oxopentanoate 344a: To a solution of Bailys-Hillman adduct 337-anti (550 mg, 2.31 mmol) in benzene (20 mL) was added Et2BOMe (1M in THF, 2.31 mL, 2.31 mmol) and the reaction mixture was stirred at 25°C for 5min. AcSePh (690 mg, 3.47 mmol), TTMSH (1.08 mL, 3.47 mmol) and DTBHN (40 mg, 0.23 mmol) were then added and the solution was heated to 45°C and stirred at this temperature for 3h. Concentration under reduced pressure and chromatography over silica gel, HRMS (ESI) : Calcd. for C8H12O3Na, p.251
, Hydroxyketone : Rf = 0.3 (Pentane/EtOAc 60/40)
, IR (ATR) ?max (cm
, H NMR (300 MHz, CDCl3) ? (ppm) 4.083.86 (m, 4H, H7 and H5 and H6), vol.3460, 1066.
, 13 C NMR (76 MHz, CDCl3) ? (ppm) 206.8 (C10), 174.1 (C2), 109.6 (C8), 76.7 (C5), vol.72
, Calcd. for C12H20O6Na, p.283, 1153.
, A solution of Baylis-Hillman adduct 337-anti (325 mg, 1.50 mmol) and HCl (1M, 1.50 mL, 1.50 mmol) in MeOH (10 mL) was stirred at 25°C for 16h. Volatils were removed under reduced pressure and the crude mixture was dissolved in DMF, cooled to 0°C and collidine (1.19 mL, 9.00 mmol) followed by TESOTf (850 µL, 3.76 mmol) were added. The reaction mixture was stirred for 18h at 25°C and saturated aqueous NH4Cl (10 mL) was added. Aqueous layer was extracted with Et2O (3 x 20 mL). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography over silica gel, vol.348
, CHCl3, issue.86
, MHz, CDCl3) ? (ppm) 6.34 (d, J = 2.2 Hz, 1H, H1), IR (ATR) ?max (cm-1 ), vol.1, 0200.
, (triethylsilyl)oxy)methyl) dihydrofuran2(3H)-one 355: To a solution of methylene lactone 348 (32 mg, 0.086 mmol) and AcSePh (34 mg, 0.17 mmol) in benzene (1 mL) were added TTMSH (40 µL, 0.13 mmol) and DTBHN (1.5 mg, 0.009 mmol). The reaction mixture was heated to 45°C and stirred for 4h. DTBHN (1.5 mg, 0.009 mmol) was added and the reaction mixture was stirred at this temperature for an additional 12h. The reaction mixture was concentrated under reduced pressure and purified by chromatography over silica gel, HRMS (ESI) : Calcd. for C18H36O4NaSi2, vol.4
, Both compounds were separable and only major diastereoisomer is described below
, CHCl3, p.1
, H NMR (600 MHz, CDCl3) ? (ppm) 4.32 (dd, J = 7.0, 5.6 Hz, 1H, H4), vol.1, 1105.
, oxopropyl)dihydrofuran-2(3H)-one 356: A mixture of compound 355 (20 mg, 0.048 mmol) and (+) CSA (5.6 mg, 0.024 mmol) in MeCN (1.5 mL) was stirred at 25°C for 24h. The crude mixture was concentrated under reduced pressure and purified by chromatography over silica gel, HRMS (ESI) : Calcd. for C20H40O5NaSi2 [M+Na]+ 439.2306, found 439.2305. (3S,4S,5R
, , vol.46
, , pp.86-90
, IR (ATR) ?max (cm
, = 3405, 1038.
, )methyl)-2-methoxydihydrofuran-3(2H)-one 368: To a 0°C solution of alcohol 367 (3 g, 8.71 mmol) in CH2Cl2 (80 mL) was added Dess-Martin Periodinane (4.43 g, 10.45 mmol) by portions over 5 minutes. The mixture was stirred at 25°C for 18h. Et2O (50 mL) was added and the salts were filtered off. Organic layer was washed with a saturated solution of NaHCO3, brine and then dried over Na2SO4, 4S,5R)-4-(benzyloxy)-5-((benzyloxy
, CHCl3, vol.56, p.1
, m, 3H, OMe, C NMR (75 MHz, CDCl3) ? (ppm) 206.7 (C2), 205.8 (C2), 137.9, vol.1, 1049.
, To a-78°C solution of phosphonium salt (617 mg, 1.52 mmol) in THF (25 mL) was added dropwise n-BuLi (2M in hexanes, 0.76 mL, 1.52 mmol). The reaction mixture was stirred at this temperature for 15min and at 25°C for 15min. The mixture was cooled to-78°C and a solution of ketone 368 (400 mg, 1.17 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at-78°C for 2h and at 25°C for an additional 2h. Acetone (2 mL) was added to quench the excess of phosphonium ylide and water (20 mL) was added. The mixture was extracted with Et2O (3 x 20 mL). Combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by chromatography over silica gel, HRMS (ESI) : Calcd. for C20H22O5Na [M+Na] + 365.1359, found 365.1369. (2R,3R)-3-(benzyloxy)-2-((benzyloxy)methyl)-5-methoxy-4-methylenetetrahydrofuran, vol.369
, CHCl3, issue.23, p.1
, H NMR (300 MHz, CDCl3) ? (ppm) 7.38-7.23 (m, 10H), 5.53-5.34 (m, 3H, H1 and H6, vol.3030, 1041.
, 5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-methylenedihydrofuran-2(3H)-one 370: To a 0°C solution of alkene 369 (1.27 g, 3.73 mmol) in acetone (150 mL) was added dropwise Jones reagent (0.72 M, 15.5 mL, 11.2 mmol). The mixture was stirred at 25°C for 3h. Salts were filtered off and the filtrate was concentrated under reduced pressure. The crude was dissolved in Et2O (50 mL), washed with a saturated solution of NaHCO3 and brine, HRMS
, CHCl3, vol.88, p.1
, H NMR (300 MHz, CDCl3) ? (ppm) 7.40-7.25 (m, 10H), 6.45-6.40 (m, 1H, H6), 5.87-5.82 (m, 1H, H6), 4.69-4.43 (m, 6H, H3, H4 and 2 x OCH2Ar, vol.1, 1091.
, HRMS (ESI) : Calcd. for C20H20O4Na, p.347, 1243.
, To a solution of lactone 370 (73 mg, 0.225 mmol) and AcSePh (224 mg, 1.125 mmol) in benzene (2.5 mL) were added TTMSH (77 µL, 0.247 mmol) and DTBHN (4 mg, 0.022 mmol). The mixture was stirred for 4h at 45°C and DTBHN (4 mg, 0.022 mmol) was added. The reaction mixture was heated to 45°C for an additional 12h. After concentration under reduced pressure the crude mixture was purified by chromatography over silica gel (Pentane/EtOAc 70/30) to afford the desired product as a colorless oil, vol.371
, Rf = 0.4 (Pentane/EtOAc 70/30)
, CHCl3, p.1
, IR (ATR) ?max (cm-1 ) = 2950, 1750, 1708, 1350, 1042; 1 H NMR (600 MHz, CDCl3) ? (ppm) 7.38-7.28 (m, 8H), 7.21-7.16 (m, 2H), vol.73
, HRMS (ESI) : Calcd. for C22H24O5Na
, 44 mmol) in benzene (3 mL) were added TTMSH (182 µL, 0.586 mmol) and DTBHN (5 mg, 0.029 mmol). The mixture was stirred for 4h at 45°C and DTBHN (5 mg, 0.029 mmol) was added. The reaction mixture was heated to 45°C for an additional 12h. After concentration under reduced pressure the crude mixture was purified by chromatography over silica gel (Pentane/EtOAc 95/5 to 70/30) to afford the side product 372 as a colorless oil, To a solution of lactone 370 (95 mg, 0.293 mmol) and AcSePh (87 mg, vol.372
, 2106A: To a solution of ketone 371 (77 mg, 0.21 mmol) in MeOH (5 mL) was added Pd (10% on charcoal, 22 mg, 0.021 mmol). The reaction mixture was stirred for 72h at 25°C under an atmosphere of H2, H NMR (300 MHz, CDCl3) ? 7.40-7.23 (m, 10H), 4.74-4.44 (m, 5H, H4 and 2 x OCH2Ph), 4.18 (dd, J = 5.0, 3.0 Hz, 0.4H, H5), 3.97 (t, J = 5.3 Hz, 0.6H, H5), 3.83 (d, J = 6.6 Hz, 0.8H, H6), vol.1, 1123.
, CHCl3, vol.32
, Mp = 115-117°C (EtOAc)
, EXPERIMENTAL PART FOR CHAPTER IV SYNTHESIS OF PHENYL SELENOESTERS : methyl 5-oxo-5-(phenylselanyl)pentanoate 421: Synthesized according to the general procedure B from a mixture of diphenyldiselenide (3.39 g, 10.9 mmol), sodium metal (0.50 g, 21.7 mmol) and acyl chloride 420 (3.00 mL, 21.7 mmol) in tetrahydrofuran (20 mL), H NMR (600 MHz, CDCl3) ? (ppm) = 5.13-5.09 (m, 1H), 4.88 (ddd, J = 7.9, 1.8, 0.8 Hz, 1H), 3.91 (dd, J = 12, vol.1, 1040.
, IR (ATR) ?max (cm-1 ) = 3058, vol.1, 1212.
, 2H, H6); 13 C NMR (50 MHz, CDCl3) ? 199.9 (C3), vol.173
, Calcd. for C12H14O3NaSe
, 07 g, 17.8 mmol) and (PhSe)2 (6.68 g, 21.4mmol) in CH2Cl2 (40 mL) was added PBu3 (5.30 mL, 21.7 mmol). The reaction mixture was stirred at 25°C for 12h and water (20 mL) was added. Aqueous layer was extracted twice with CH2Cl2 (2 x 20 mL) and combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Chromatography over silica gel, To a 0°C solution of carboxylic acid, vol.435
, H NMR (300 MHz, CDCl3) ? 7.55-7.48 (m, 2H), vol.1, 1162.
, 18 (s, 3H, H1), vol.2
, 13 C NMR (76 MHz, CDCl3) ? 205.9 (C2), vol.199
, HRMS (CI) : Calcd. for C11H13O2Se, p.251, 1381.
, To a 0°C solution of carboxylic acid (2.00 mL, 16.9 mmol) and (PhSe)2 (6.33 g, vol.436
, 3 mmol). The reaction mixture was stirred at 25°C for 12h and water (20 mL) was added. Aqueous layer was extracted twice with CH2Cl2 (2 x 20 mL) and combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, CH2Cl2 (40 mL) was added PBu3 (5.00 mL, vol.20
, 71 (s, 1H, NH), H NMR (300 MHz, CDCl3) ? 6.18 (d, J = 1.1 Hz, 1H, H4), vol.1, 1170.
, )carbonyl)amino)-2-methyleneheptanoate 406b: Prepared according to the general procedure H from a mixture of corresponding ?-amidosulfone 404b (1.76g g, 5.14 mmol), sulfonyl acetate 407 (2.00 g, 7.72 mmol), TBAB (83 mg, 0.26 mmol) and aqueous K3PO4 (50% w /w, 5.68 g, 13.36 mmol) in toluene (50 mL), HRMS (ESI) : Calcd. for C14H25NO4Na
, IR (ATR) ?max (cm-1 ) = 3341, vol.1, 1242.
, m, 2H, OCH2Ph), 4.51-4.37 (m, 1H, H5), 3.76 (s, 3H, H1), 1.71-1.58 (m, 2H, H6), 1.39-1.18 (m, 4H, H7 and H8
, benzyloxy)carbonyl)amino)-2-methylene-5-(phenylthio)pentanoate 406c: Prepared according to the general procedure H from a mixture of corresponding ?-amidosulfone 404c (2.32 g, 5.09 mmol), sulfonyl acetate 407 (1.98 g, 7.64 mmol), TBAB (82 mg, 0.25 mmol) and aqueous K3PO4 (50% w /w, 5.60 g, 13.16 mmol) in toluene (50 mL, HRMS (ESI) : Calcd. for C17H23NO4Na
, 24 (br s, 1H, H4), 5.80 (s, 1H, H4), 5.59 (d, J = 9, H NMR (300 MHz, CDCl3) ? 7.39-7.15 (m, 10H), vol.1, 1438.
, Experimental Part methyl 2-((((benzyloxy)carbonyl)amino)(furan-2-yl)methyl)acrylate 406d: To a mixture of corresponding ?-amidosulfone 404d (2.60 g, 6.75 mmol) and methyl acrylate (2.45 mL, 27.0 mmol was added DABCO (757 mg, 6.75 mmol). The reaction mixture was stirred at room temperature for 36h and excess methyl acrylate was removed under vacuum. The crude oil was purified by chromatography over silica gel, HRMS (ESI) : Calcd. for C21H23NO4NaS
, 39-6.35 (m, 1H, furane), 6.30 (dd, J = 3.3, 1.8 Hz, 1H, furane), 6.18 (d, J = 3.3 Hz, 1H, furane), 5.92 (br s, 1H, H4), 5.81 (br s, 2H, H4 and NH), H NMR (300 MHz, CDCl3) ? 7.42-7.30 (m, 5H), vol.1, 1240.
, HRMS (ESI) : Calcd. for C17H17NO5Na, p.338, 1008.
, Michael acceptor (1 eq.) and TTMSH (1.5 eq.) in benzene (0.1 M) was added DTBHN (0.1 eq.). The reaction mixture was heated at 45°c and stirred for 4h. DTBHN was added (0.1 eq.) and the mixture was stirred for an additional 12h at this temperature. The reaction mixture was concentrated under reduced pressure and the crude was purified by chromatography on silica gel. methyl-3-(((benzyloxy)carbonyl)amino)-2-(2-oxopropyl)-5-phenylthio)pentanoate 412c: Prepared according to the general procedure E from a mixture of AcSePh (159 mg, 0.80 mmol), Michael acceptor 406c (257 mg, 0.67 mmol), TTMSH (311 µL, 1.00 mmol) and DTBHN (2 x 12 mg, Chromatography over silica gel
, Rf = 0.3 (Pentane/EtOAc 70/30)
, H NMR (300 MHz, CDCl3) ? 7.42-7.13 (m, 10H), 5.42-5.24 (m, 1H, NH), 5.14-5.04 (m, 2H, OCH2Ph), 4.12-3.94 (m, 1H, H5), 3.65-3.43 (m, 3H, H1), 3.12-2.73 (m, 4H, H3 and H4 and H7), vol.1, 1163.
, (benzyloxy)carbonyl)amino)(furan-2-yl)methyl)-4-oxopentanoate 412d: Prepared according to the general procedure E from a mixture of AcSePh (189 mg, 0.95 mmol), Michael acceptor 406d (250 mg, 0.79 mmol), TTMSH (370 µL, 1.19 mmol) and DTBHN (2 x 14 mg, 2 x 0.08 mmol) in benzene (8 mL). Chromatography over silica gel (Pentane/EtOAc 70/30) afford the desired product as a pale yellow oil, HRMS (ESI) : Calcd. for C23H27NO5NaS
, Both compounds were separable and only major diastereoisomer syn is described below
, Rf = 0.4 (Pentane/EtOAc 70/30)
, IR (ATR) ?max (cm-1 ) = 3340, 1166.
, 29 (dd, J = 3.3, 1.8 Hz, 1H, furane), 6.18 (d, J = 3.2 Hz, 1H, furane), 5.76-5.64 (m, 1H, NH), 300 MHz, Chloroform-d) ? 7.38-7.29 (m, 6H), vol.6
, 13 (s, 3H, H7), vol.2
, 13 C NMR (75 MHz, CDCl3) ? 206.0 (C6), 172.6 (C2), vol.155
, (tert-butoxycarbonyl)amino)(phenyl)methyl)-4-oxopentanoate 413 and 414: Prepared according to the general procedure E from a mixture of AcSePh (104 mg, 0.52 mmol), Michael acceptor 405a (127 mg, 0.44 mmol), TTMSH (204 µL, 0.65 mmol) and DTBHN (2 x 8 mg, 2 x 0.044 mmol) in benzene (4.5 mL). Chromatography over silica gel, HRMS (ESI) : Calcd. for C19H21NO6Na
,
, H NMR (600 MHz, CDCl3) ? 7.36-7.18 (m, 5H), 5.68-5.31 (m, 1H, NH), vol.1, 1166.
, tert-butoxycarbonyl)amino)(phenyl)methyl)-4-oxooctanedioate 422: Prepared according to the general procedure E from a mixture of selenoester 421 (404 mg, 1.42 mmol), Michael acceptor 405a (344 mg, 1.18 mmol), TTMSH (551 µL, 1.77 mmol) and DTBHN (2 x 21 mg, 2 x 0.12 mmol) in benzene (12 mL). Chromatography over silica gel (Pentane/EtOAc 70/30) afford the desired product as a pale yellow oil (420 mg, 84% of major, HRMS (ESI) : Calcd. for C18H25NO5Na
, Rf = 0.3 (Pentane/EtOAc 70/30)
, IR (ATR) ?max (cm-1 ) = 3374, 1249.
, 51 (s, 3H, H1 or H11), 3.44 (s, 3H, H1 or H11), 3.32-3.19 (m, 1H, H3), 2.79-2.57 (m, 1H, H4), 2.392.26 (m, 3H, H4 and H7), 2.19-2.08 (m, 2H, H9), 1.78-1.66 (m, 2H, H8), 1.27 (s, 9H, Boc); 13 C NMR (75 MHz, CDCl3), 300 MHz, CDCl3) ? 7.24-7.03 (m, 5H), 5.32-5.16 (m, 1H, NH), 4.97-4.81 (m, 1H, H5), vol.3
, )carbonyl)amino)(phenyl)methyl)-4,7-dioxooctanoate 437: Prepared according to the general procedure E from a mixture of selenoester 435 (536 mg, 2.10 mmol), Michael acceptor 406a (620 mg, 1.91 mmol), TTMSH (890 µL, 2.86 mmol) and DTBHN (2 x 33 mg, 2 x 0.19 mmol) in benzene (15 mL). Chromatography over silica gel (Pentane/EtOAc 50/50) afford the desired product as a pale yellow oil (720 mg, 80% of major, HRMS (ESI) : Calcd. for C22H31NO7Na
, 54 (s, 3H, H1), 3.47-3.40 (m, 1H, H3), 2.86 (dd, J = 17.6, 8.7 Hz, 1H, H4), 2.70-2.55 (m, 5H, H4 and H7 and H8), 2.12 (s, 3H, H10), H NMR (600 MHz, CDCl3, 60°C) ? 7.37-7.19 (m, 10H), 5.68 (d, J = 8.9 Hz, 1H, NH), 5.145.02 (m, 3H, H5 and OCH2Ph), vol.1, 1173.
, (benzyloxy)carbonyl)amino)(phenyl)methyl)-4,8-dioxononanoate 438: Prepared according to the general procedure E from a mixture of selenoester 435 (298 mg, 1.11 mmol), Michael acceptor 406a (300 mg, 0.92 mmol), TTMSH (430 µL, 1.38 mmol) and DTBHN (2 x 16 mg, 2 x 0.092 mmol) in benzene (15 mL). Chromatography over silica gel (Pentane/EtOAc 50/50) afford the desired product as a pale yellow oil (305 mg, HRMS (ESI) : Calcd. for C24H27NO6Na
, Both compounds were separable and only major diastereoisomer syn is described below
, 55 (s, 3H, H1), 3.49-3.40 (m, 1H, H3), 2.79 (dd, H NMR (600 MHz, CDCl3) ? 7.37-7.20 (m, 10H), 5.70-5.61 (m, 1H, NH), 5.15-5.01 (m, 3H, H5 and OCH2Ph), vol.1, 1172.
, tert-butoxycarbonyl)amino)(phenyl)methyl)-4,7-dioxooctanoate 442: Prepared according to the general procedure E from a mixture of selenoester 436 (391 mg, 1.45 mmol), Michael acceptor 405a (354 mg, 1.21 mmol), TTMSH (564 µL, 1.82 mmol) and DTBHN (2 x 21 mg, 2 x 0.12 mmol) in benzene (12 mL). Chromatography over silica gel (Pentane/EtOAc 65/35) afford the desired product as a pale yellow oil (390 mg, HRMS (ESI) : Calcd. for C25H29NO6Na
, Both compounds were separable and only major diastereoisomer syn is described below
, 64 (s, 3H, H1), 3.53-3.36 (m, 1H, H3), 3.01-2.79 (m, 1H, H4), 2.58-2.43 (m, 5H, H4, H7 and H9), 2.17 (s, 3H, H11), 1.93-1.79 (m, 2H, H8), 1.47 (s, 9H, Boc), H NMR (300 MHz, CDCl3) ? 7.44-7.22 (m, 5H), 5.48 (d, J = 9.1 Hz, 1H, NH), 5.18-4.80 (m, H5), vol.1, 1169.
, Prepared according to the general procedure E from a mixture of selenoester 421 (123 mg, 0.43 mmol), Michael acceptor 406a (117 mg, 0.36 mmol), TTMSH (169 µL, 0.54 mmol) and DTBHN (2 x 6.3 mg, 2 x 0.036 mmol) in benzene (3.6 mL). Chromatography over silica gel (Pentane/EtOAc 70/30) afford the desired product as a pale yellow oil (126 mg, 77% of major, benzyloxy)carbonyl)amino)(phenyl)methyl)-4-oxooctanedioate
, Rf = 0.3 (Pentane/EtOAc 70/30)
, IR (ATR) ?max (cm-1 ) = 3353, 1243.
, 300 MHz, CDCl3) ? 7.40-7.15 (m, 10H), 5.78 (d, J = 9.0 Hz, 1H, NH), 5.15-4.98 (m, 3H, H5 and OCH2Ph)
, m, 3H, H4 and H7), 2.28 (t, J = 7.2 Hz, 2H, H9), 1.91-1.76 (m, 2H, H8); 13 C NMR (76 MHz, CDCl3) ? 207.7 (C6, vol.173
, HRMS (ESI) : Calcd. for C25H29NO7Na [M+Na] + 478.1836, found 478, 1831.
, Michael acceptor (1 eq.) and TTMSH (1.5 eq.) in benzene (0.1 M) was added DTBHN (0.1 eq.). The reaction mixture was heated at 45°c and stirred for 4h. DTBHN was added (0.1 eq.) and the mixture was stirred for an additional 12h at this temperature. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in MeCN (1M). BF3.Et2O (2 eq.) was added and the reaction mixture was stirred at 25°C for 12h and quenched by addition of a saturated solution of NaHCO3. Aqueous layer was extracted twice with EtOAc and combined organic layers were dried over Na2SO4
, Prepared according to the general procedure H from a mixture of AcSePh (94 mg, 0.47 mmol), Michael acceptor 405a (106 mg, 0.36 mmol), TTMSH (170 µL, 0.55 mmol) and DTBHN (2 x 6.3 mg, 2 x 0.036 mmol) in benzene (4 mL)
, Both compounds were separable and only major diastereoisomer is described below
, H NMR (300 MHz, CDCl3) ? 7.29-7.11 (m, 5H), vol.1, 1379.
, found 218.1177. methyl 2-butyl-5-methyl-3,4-dihydro-2H-pyrrole-3-carboxylate 415b: Prepared according to the general procedure H from a mixture of AcSePh (330 mg, 1.66 mmol), Michael acceptor 405b (300 mg, 1.11 mmol), TTMSH (1.18 mL, 1.66 mmol) and DTBHN (2 x 19 mg, 2 x 0.11 mmol) in benzene (11 mL). After completion and concentration, were added MeCN (11 mL) and BF3.Et2O (270 µL, 2.21 mmol). Chromatography over silica gel, HRMS
, Both compounds were separable and only major diastereoisomer is described below
, 70 (s, 3H, H6), 2.97-2.69 (m, 3H, H3 and H4, H NMR (300 MHz, CDCl3) ? 4.16-4.06 (m, 1H, H1), vol.1, 1204.
, Prepared according to the general procedure H from a mixture of selenoester 421 (165 mg, 0.58 mmol), Michael acceptor 405a (140 mg, 0.48 mmol), TTMSH (224 µL, 0.72 mmol) and DTBHN (2 x 8.4 mg, 2 x 0.048 mmol) in benzene (5 mL), HRMS
, Both compounds were separable and only major diastereoisomer is described below
, IR (ATR) ?max (cm-1 ) = 3029, 1360.
, 76 (s, 3H, H6 or H11), 3.69 (s, 3H, H6 or H11), 3.16-2.87 (m, 3H, H3 and H4), 2.60-2.39 (m, 4H, H7 and H9), 2.17-1.96 (m, 2H, H8); 13 C NMR (50 MHz, CDCl3) ? 176.2 (C2 or C5 or C10), MHz, CDCl3) ? 7.44-7.18 (m, 5H), 5.39-5.29 (m, 1H, H1), vol.3
, HRMS (ESI) : Calcd. for C17H21NO4Na, p.326, 1374.
, Prepared according to the general procedure H from a mixture of selenoester 200 (151 mg, 0.56 mmol), Michael acceptor 405a (135 mg, 0.46 mmol), TTMSH (216 µL, 0.70 mmol) and DTBHN (2 x 8.1 mg, 2 x 0.046 mmol) in benzene (5 mL)
, Both compounds were separable and only major diastereoisomer is described below
, IR (ATR) ?max (cm-1 ) = 3029, 1240.
, 75 (s, 3H, H6 or H10), 3.70 (s, 3H, H6 or H10), 3.09-2.64 (m, 7H, H3, H4, H7 and H8); 13 C NMR (75 MHz, CDCl3) ? 175.4 (C2 or C5 or C9), 300 MHz, CDCl3) ? 7.36-7.19 (m, 5H), 5.37-5.28 (m, 1H, H1), vol.3
, Prepared according to the general procedure H from a mixture of selenoester 421 (223 mg, 0.83 mmol), Michael acceptor 405b (173 mg, 0.64 mmol), TTMSH (298 µL, 0.96 mmol) and DTBHN (2 x 11 mg, 2 x 0.06 mmol) in benzene (6 mL). After completion and concentration, were added MeCN (6 mL) and BF3.Et2O (118 µL, 0.96 mmol). Chromatography over silica gel (Pentane/EtOAc 50/50) afford the desired product as a colorless oil (111 mg, 61% of major, HRMS (ESI) : Calcd. for C16H19NO4Na
, 69 (s, 3H, H6 or H11), 3.66 (s, 3H, H6 or H11), 2.95-2.81 (m, 1H, H3), 2.80-2.67 (m, 2H, H4), 2.43-2.31 (m, 4H, H7 and H9, 2H, H12), 1.53-1.22 (m, 6H, H8 and H13 and H14), vol.1, 1175.
, Prepared according to the general procedure H from a mixture of selenoester 435 (196 mg, 0.77 mmol), Michael acceptor 405a (204 mg, 0.70 mmol), TTMSH (326 µL, 1.05 mmol) and DTBHN (2 x 12 mg, 2 x 0.07 mmol) in benzene (7 mL), HRMS (ESI) : Calcd. for C15H25NO4Na
, Both compounds were separable and only major diastereoisomer is described below
, Rf = 0.45 (Pentane/EtOAc 30/70)
, 73 (s, 3H, H6), 3.12-2.50 (m, 7H, H3, H4, H7 and H8), 2.19 (s, 3H, H10), H NMR (300 MHz, CDCl3) ? 7.38-7.11 (m, 5H), 5.33-5.21 (m, 1H, H1), vol.1, 1381.
, Prepared according to the general procedure H from a mixture of selenoester 436 (207 mg, 0.77 mmol), Michael acceptor 405a (204 mg, 0.70 mmol), TTMSH (326 µL, 1.05 mmol) and DTBHN (2 x 12 mg, 2 x 0.07 mmol) in benzene (7 mL), HRMS (ESI) : Calcd. for C16H19NO3Na [M+Na] + 296.1257, found 296.1262. methyl-5-(4-oxopentyl
, Both compounds were separable and only major diastereoisomer is described below
, Rf = 0.4 (Pentane/EtOAc 30/70)
, 72 (s, 3H, H6), 3.10-2.85 (m, 3H, H3 and H4), 2.61-2.36 (m, 4H, H7 and H9), 2.14 (s, 3H, H11), H NMR (300 MHz, CDCl3) ? 7.41-7.16 (m, 5H), 5.34-5.25 (m, 1H, H1), vol.1, 1028.
, The reaction mixture was heated at 45°C and stirred for 4h. DTBHN was added (0.1 eq.) and the mixture was stirred for an additional 12h at this temperature. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in MeCN (0.1 M). TTMSH (3 eq.) was added followed by BF3.Et2O (1.5 eq.). The reaction mixture was stirred at 25°C for 12h and quenched by addition of a saturated aqueous solution of NaHCO3. Aqueous layer was extracted twice with EtOAc and combined organic layers were dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on silica gel. ethyl-5-methyl-2-phenyl-1-tosylpyrrolidine-3-carboxylate 408: Prepared according to the general procedure I from a mixture of AcSePh (58 mg, 0.29 mmol), Michael acceptor 402 (80 mg, 0.22 mmol), TTMSH (104 µL, 0.33 mmol) and DTBHN (2 x 3.8 mg, 2 x 0.022 mmol) in benzene (2.5 mL). After completion and concentration, HRMS (ESI) : Calcd. for C17H21NO3Na [M+Na] + 310.1413, found 310.1421. Experimental Part GENERAL PROCEDURE I FOR THE SYNTHESIS OF PROTECTED PYRROLIDINES To a mixture of phenyl selenoester (1.2 eq.), Michael acceptor (1 eq.) and TTMSH (1.5 eq.) in benzene (0.1 M) was added DTBHN (0.1 eq.)
, Mp = 126-128 °C (EtOAc)
, 45 (s, 3H, tosyle), 2.22-1.72 (m, 2H, H4), 1.67 (d, J = 6.1 Hz, 0.3H, H8), 1.54 (d, J = 6.4 Hz, 2.7H, H8), 1.17 (t, J = 7.1 Hz, 2.7H, H7), 0.99 (t, J = 7.1 Hz, 0.3H, H7), C NMR (50 MHz, CDCl3) ? 171.9 (M, C5), 169.4 (m, C5), 143.6 (m), 143.5 (M), 141.8 (M), 139.0 (m), 135.1 (m), 134.8 (M), 129.7 (m), 129.6 (M), 128.5 (M), 128.0 (m), 127.8 (M), 127.6 (m), 127.4 (m), 126.3 (M), 67.3 (M, C1), 65.9 (m, C1), 61.1 (M, C6), 60.7 (m, C6), 57.0 (M, C2), 56.7 (m, C2), 52.1 (M, C3), vol.1, 1164.
, 1-benzyl 3-methyl-5-methyl-2-phenylpyrrolidine-1,3-dicarboxylate 410a: Prepared according to the general procedure I from a mixture of AcSePh (109 mg, 0.55 mmol), Michael acceptor 406a (149 mg, 0.46 mmol), TTMSH (214 µL, 0.69 mmol) and DTBHN (2 x 8 mg, 2 x 0.046 mmol) in benzene (5 mL), HRMS (ESI) : Calcd. for C21H25NO4NaS [M+Na] + 410.1396, found 410.1387
, Both compounds were separable and only major diastereoisomer is described below
, H NMR (400 MHz, CDCl3, 60°C) ? 7.35-6.94 (m, 10H), 5.24 (d, J = 6.2 Hz, 1H, H1), vol.1, 1205.
, 1513. methyl-5-methyl-2-phenylpyrrolidine-3-carboxylate 411: To a solution of protected pyrrolidine 410 (15 mg, 0.042 mmol) in MeOH (2 mL) was added Pd/C (10% on charcoal, 4.5 mg, 0.0042 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite, HRMS (ESI) : Calcd. for C21H23NO4Na, vol.376
, H NMR (300 MHz, CDCl3) ? 7.447.21 (m, 5H), vol.1, 1168.
, (phenylthio)ethyl)pyrrolidine-1,3-dicarboxylate 410c: To a solution of 412c (82 mg, 0.19 mmol) in MeCN (2 mL) were added TTMSH (78 µL, 0.57 mmol) and BF3.Et2O (35 µL, 0.29 mmol). Chromatography over silica gel (Pentane/EtOAc 85/15) afford the desired product as a colorless oil as a mixture of diastereoisomers, HRMS, issue.2
, ) : Calcd. for C23H27NO4NaS [M+Na] + 436.1553, found 436.1552. 1-benzyl 3-methyl-2-(furan-2-yl)-5-methylpyrrolidine-1,3-dicarboxylate 410d: To a solution of 412d (155 mg, 0.43 mmol) in MeCN (5 mL) were added TTMSH (402 µL, 1.29 mmol) and BF3, MHz, CDCl3) ? 7.40-7.16 (m, 10H), 5.21-5.11 (m, 2H, D1+D2+D3, Cbz
, Both compounds were separable and only major diastereoisomer is described below
, 18 (br s, 1H, furane), 5.39-5.35 (m, 1H, H1), H NMR (600 MHz, CDCl3) ? 7.35-7.24 (m, 6H), 6.29-6.26 (m, 1H, furane), vol.1, 1178.
, 1320. methyl-5-methyl-2-phenylpyrrolidine-3-carboxylate 416a: To a solution of imine 415a (30 mg, 0.14 mmol) in MeOH (3 mL) was added PtO2 (3.1 mg, 0.014 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure afforded the pure product as a colorless oil as mixture of diastereoisomers, HRMS (ESI) : Calcd. for C19H21NO5Na, vol.366
, The mixture of diastereoisomers is described below
, 68 (s, 2.4H, H6), 3.65 (s, 0.6H, H6), 3.61-3.39 (m, 1H, H2), 3.02 (ddd, J = 9, 142.7 (m), 128.6 (M), 128.6 (m), 127.5 (m), 127.2 (M), 126.9 (m), 126.4 (M), 66.6 (m, C1), 65.0 (M, C1), 54.7 (M, C2), vol.1, 1169.
, 1331. methyl-2-butyl-5-methylpyrrolidine-3-carboxylate 416b: To a solution of imine 415b (76 mg, 0.38 mmol) in MeOH (9 mL) was added PtO2 (4 mg, 0.019 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite and concentrated under reduced pressure. Chromatography over silica gel (DCM/MeOH 90/10) afforded the pure product as a colorless oil as mixture of diastereoisomers, HRMS, vol.220
, The mixture of diastereoisomers is described below
, IR (ATR) ?max (cm-1 ), 1169.
, 300 MHz, CDCl3) ? 3.72-3.66 (m, 3H, H6), 3.46-3.10 (m, 2H, H1 and H2)
, Experimental Part 1-benzyl 3-methyl-5-(3-methoxy-3-oxopropyl)-2-phenylpyrrolidine-1,3-dicarboxylate 432: Prepared according to the general procedure I from a mixture of selenoester 200 (222 mg, 0.82 mmol), Michael acceptor 406a (222 mg, 0.68 mmol), TTMSH (318 µL, 1.02 mmol) and DTBHN (2 x 12 mg, 2 x 0.068 mmol) in benzene (7 mL), HRMS, pp.80-90
, IR (ATR) ?max (cm-1 ) = 3032, 1207.
, 76 (s, 1H, H6 or H10), 3.68 (s, 5H, H6 and H10), 3.13 (dt, J = 9, Hz, 0.66H, H3), 2.91-2.82 (m, 0.33H, H3), 2.54-2.16 (m, 4H, H4 and H8), 2.05-1.82 (m, 1H, H7), 1.71-1.55 (m, 1H, H7); 13 C NMR (151 MHz, CDCl3) ? 173.2 (C5 or C9), vol.3
, methoxy-4-oxobutyl)-2-phenylpyrrolidine-1,3-dicarboxylate 433: Prepared according to the general procedure I from a mixture of selenoester 421 (285 mg, 1.00 mmol), Michael acceptor 406a (270 mg, 0.83 mmol), TTMSH (387 µL, 1.25 mmol) and DTBHN (2 x 14 mg, 2 x 0.083 mmol) in benzene (8 mL), HRMS (ESI) : Calcd. for C24H27NO6Na [M+Na] + 448.1730, found 448.1725. 1-benzyl 3-methyl-5
, Rf = 0.45 (Pentane/EtOAc 70/30)
, H NMR (600 MHz, CDCl3) ? 7.33-7.20 (m, 8H), 7.15-7.00 (m, 2H), 5.22 (d, J = 6.8 Hz, 1H, H1), vol.1, 1347.
, C3 or C6 or C11), 51.5 (C3 or C6 or C11), vol.35
, SYNTHESIS OF INDOLIZIDINONES methyl-5-oxo-3-phenyloctahydroindolizine-2-carboxylate 425: To a solution of protected pyrrolidine 433 (174 mg, 0.40 mmol) in MeOH (10 mL) was added Pd/C (10% on charcoal, 42 mg, 0.04 mmol). The mixture was stirred for 30 min under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure afforded an oil which was dissolved in toluene (10 mL). Et3N (56 µL, 0.40 mmol) was added and the mixture was stirred for 12h at 80°C. The reaction mixture was concentrated under reduced pressure and purified by chromatography over silica gel, HRMS (ESI) : Calcd. for C25H29NO6Na [M+Na] + 462.1887, found 462.1878
, Mp = 100-102 °C (EtOAc)
, 38 (br s, 1H, H1), 3.80-3.71 (m, 4H, H2 and H6, H NMR (600 MHz, CDCl3) ? 7.31-7.25 (m, 2H), 7.21-7.13 (m, 3H), vol.1, 1168.
, To a solution of imine 423 (100 mg, 0.33 mmol) in MeOH (3 mL) was added PtO2 (3.7 mg, 0.016 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure afforded an oil which was dissolved in toluene (3 mL). Et3N (46 µL, 0.33 mmol) was added and the mixture was stirred for 12h at 80°C. The reaction mixture was concentrated under reduced pressure and purified by chromatography over silica gel (EtOAc) affording the desired product as a colorless oil, HRMS (ESI) : Calcd. for C16H19NO3Na
, Both compounds were separable and only major diastereoisomer is described below
, H NMR (300 MHz, CDCl3) ? 7.40-7.16 (m, 5H), 5.47 (d, J = 7.6 Hz, 1H, H1), 3.97-3.83 (m, 1H, H2), 3.73 (s, 3H, H6), 3.05 (dt, J = 11.2, 7.4 Hz, 1H, H3), 2.57-2.17 (m, 4H, H4 and H9), 2.08-1.70 (m, 3H, H7 and H8, vol.1, 1270.
, HRMS (ESI) : Calcd. for C16H19NO3Na
, ) : Calcd. for C16H21NO3Na [M+Na] + 298.1413, found 298.1417. methyl-3-butyl-5-oxooctahydroindolizine-2-carboxylate 431: To a solution of imine 428 (29 mg, 0.102 mmol) in MeOH (3 mL) was added PtO2 (1.2 mg, 0.005 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure afforded an oil which was dissolved in toluene (6 mL). Et3N (14 µL, 0.102 mmol) was added and the mixture was stirred for 12h at 120°C with DeanStark apparitus. The reaction mixture was concentrated under, H NMR (600 MHz, CDCl3) ? 7.31-7.08 (m, 5H), 6.15 (br s, 1H, NH), 3.60 (s, 3H, H6), vol.1, 1165.
, IR (ATR) ?max (cm-1 ) = 2953, 1413.
, m, 2H), 1.93-1.84 (m, 2H), 1.78-1.61 (m, 2H), 1.38-1.19 (m, 8H), 0.91-0.83 (m, 3H, H14, C NMR (151 MHz, CDCl3) ? 174.5 (m, C5), 174.2 (M, C5), 169.6 (m, C10), 168.4 (M, C10), 61.0 (m), 60.0 (M), 58.5 (M), vol.13
, HRMS (ESI) : Calcd. for C14H23NO3Na
, To a solution of compound 437 (27 mg, 0.063 mmol) in MeOH (2 mL) was added PtO2 (0.7 mg, 0.003 mmol) and Pd/C (10% on charcoal, 3.2 mg, 0.003 mmol). The mixture was stirred for 2h under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure and chromatography over silica gel (Pentane/EtOAc 50/50) afforded the desired product as a colorless oil (12 mg, 73% of major, Compounds were separable and only major diastereoisomer is described below
, H NMR (600 MHz, CDCl3) ? 7.43-7.39 (m, 2H), 7.31-7.27 (m, 2H), vol.1, 1166.
,
, 13 C NMR (151 MHz, CDCl3) ? 174.3 (C5)
, To a solution of imine 443 (90 mg, 0.31 mmol) in MeOH (10 mL) was added PtO2 (3.6 mg, 0.016 mmol). The mixture was stirred for 12h under an H2 atmosphere (balloon) and filtered through a pad of Celite. Concentration under reduced pressure and chromatography over silica gel (Pentane/EtOAc 90/10 to 80/20) afforded the desired product as a colorless oil as a mixture of diastereoisomers (51 mg, 60% combined). Three diastereoisomers were separated, HRMS
, D1
, 69 (s, 3H, H6), 2.64 (ddd, J = 10.2, 5.3, 1.8 Hz, 1H, H3), 2.44-2.38 (m, 1H, H2), 2.37-2.30 (m, 1H, H10), 2.06 (ddd, J = 12.2, 5.2, 1.8 Hz, H NMR (600 MHz, CDCl3) ? 7.45-7.40 (m, 2H), 7.30-7.25 (m, 2H), 7.21-7.17 (m, 1H), 3.82 (d, J = 5.3 Hz, 1H, H1), vol.1, 1167.
, HRMS (ESI) : Calcd. for C17H24NO2 [M+H] + 274.1801, found 274, 1799.
, D2 (444c) : Rf = 0.3 (Pentane/EtOAc 90/10)
, 64 (s, 3H, H6), 3.57-3.51 (m, 1H, H2), 2.83 (ddd, J = 11.6, 8.1, 5.8 Hz, 1H, H3), 2.79-2.75 (m, 1H, H10), 2.38 (ddd, H NMR (600 MHz, CDCl3) ? 7.39-7.35 (m, 2H), 7.34-7.29 (m, 2H), 7.27-7.22 (m, 1H), 4.37 (d, J = 8.1 Hz, 1H, H1), vol.1, 1167.
, HRMS (ESI) : Calcd
, D3 (444a) : Rf = 0.2 (Pentane/EtOAc 90/10)
, H NMR (600 MHz, CDCl3) ? 7.34-7.21 (m, 5H), vol.1, 1172.
, HRMS (ESI) : Calcd