Synthesis of Amaminol B

Abstract

The synthesis of the cytotoxic marine natural product amaminol B is described. Key steps include an organocatalytic intramolecular Diels-Alder reaction, an HWE olefination and a dia­stereoselective ketone reduction.

Key words

natural products - Diels-Alder reactions - total synthesis - amino alcohols - asymmetric catalysis

References and Notes

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32

(3a R ,4 S ,5 R ,7a S )-5-[( E )-But-1-enyl]-2,3,3a,4,5,7a-hexahydro-1 H -indene-4-carbaldehyde (4): [α]_D -283.8 (c = 1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 9.62 (d, J = 2.7 Hz, 1 H), 5.88 (d, J = 9.9 Hz, 1 H), 5.53 (dt, J = 6.3, 15.1 Hz, 1 H), 5.41 (m, 1 H), 5.35 (dd, J = 8.8, 15.1 Hz, 1 H), 3.31 (m, 1 H), 2.52 (ddd, J = 2.7, 6.3, 9.1 Hz, 1 H), 1.98 (dq, J = 6.3, 7.4 Hz, 2 H), 1.83 (m, 3 H), 1.69 (m, 3 H), 1.13 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.7, 135.3, 129.7, 129.3, 127.7, 56.2, 45.1, 41.3, 39.7, 28.5, 27.6, 25.6, 22.5, 13.8. IR (film): 3017, 2960, 2876, 1712, 1217, 970, 758 cm^-1. MS (EI): m/z (%) = 204 (40) [M⁺], 175 (60), 157 (25), 147 (37), 134 (92), 119 (71), 105 (62), 91 (100), 79 (56), 67 (20), 55 (16). HRMS: m/z calcd for C₁₄H₂₀O: 204.1514; found: 204.1514.
Methyl 3-{(3a R ,4 S ,5 R ,7a S )-5-[( E )-But-1-enyl]-2,3,3a,4,5,7a-hexahydro-1 H -inden-4-yl}propanoate (15): [α]_D -56.6 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.77 (d, J = 9.9 Hz, 1 H), 5.45 (dt, J = 6.3, 15.1 Hz, 1 H), 5.36 (ddd, J = 2.4, 5.2, 9.6 Hz, 1 H), 5.23 (dd, J = 9.0, 15.4 Hz, 1 H), 3.62 (s, 3 H), 2.85 (m, 1 H), 2.37 (m, 1 H), 2.19 (m, 1 H), 1.98 (dq, J = 6.3, 7.4 Hz, 2 H), 1.70 (m, 6 H), 1.54 (m, 2 H), 1.12 (m, 3 H), 0.93 (t, J = 7.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.3, 133.8, 130.7, 129.2, 128.1, 51.2, 46.0, 44.5, 42.9, 41.9, 31.3, 29.1, 27.7, 26.1, 25.5, 22.0, 13.8. IR (film): 3014, 2952, 2867, 1739, 1438, 1168, 970, 719 cm^-1. MS (EI): m/z (%) = 262 (100) [M⁺], 231 (48), 218 (56), 201 (73), 175 (89), 159 (84), 145 (46), 131 (73), 119 (97), 105 (54), 91 (98), 79 (68), 67 (27), 55 (27). HRMS: m/z calcd for C₁₇H₂₆O₂: 262.1933; found: 262.1933.
(2 R ,3 S ,3a R ,5a S ,8a R ,8b S )-Methyl-3-propyl-1,2,3,3a,5a,6,7,8,8a,8b-decahydro- as -indacene-2-carboxylate (16): [α]_D -78.2 (c = 1, CH₃Cl). ¹H NMR (500 MHz, CDCl₃): δ = 5.88 (d, J = 9.8 Hz, 1 H), 5.62 (dt, J = 3.1, 9.8 Hz, 1 H), 3.66 (s, 3 H), 2.98 (ddd, J = 3.7, 7.6, 14.9 Hz, 1 H), 2.45 (m, 1 H), 2.21 (m, 1 H), 2.15 (m, 1 H), 1.86 (m, 1 H), 1.79 (m, 3 H), 1.69 (m, 2 H), 1.57 (m, 1 H), 1.48 (m, 2 H), 1.31 (m, 1 H), 1.13 (m, 3 H), 1.01 (m, 1 H), 0.89 (t, J = 7.4 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 176.1, 130.9, 129.6, 51.1, 49.1, 48.4, 46.7, 45.4, 43.9, 42.3, 33.7, 32.9, 29.4, 28.8, 22.4, 21.4, 14.4. IR (film): 3015, 2952, 2867, 1734, 1455, 1376, 1193, 1166, 710 cm^-1. MS (EI): m/z (%) = 262 (27) [M⁺], 230 (18), 219 (22), 202 (100), 187 (10), 173 (15), 159 (61), 147 (6), 134 (20), 119 (21), 105 (13), 91 (35), 87 (20), 79 (23), 67 (9), 55 (12). HRMS: m/z calcd for C₁₇H₂₆O₂: 262.1933; found: 262.1933.
(3 S ,4 S )-1-{(3a R ,4 S ,5 R ,7a S )-5-[( E )-But-1-enyl]-2,3,3a,4,5,7a-hexahydro-1 H -inden-4-yl}-4-nitropentan-3-ol (17): [α]_D -123.1 (c = 1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.82 (d, J = 9.6 Hz, 1 H), 5.46 (dt, J = 6.6, 15.1 Hz, 1 H), 5.39 (ddd, J = 2.5, 4.4, 9.3 Hz, 1 H), 5.27 (dd, J = 9.3, 15.1 Hz, 1 H), 4.52 (q, J = 6.9 Hz, 1 H), 4.10 (br s, 1 H), 3.80 (m, 1 H), 2.85 (m, 1 H), 2.02 (dq, J = 6.3, 7.4 Hz, 2 H), 1.81 (m, 2 H), 1.69 (m, 3 H), 1.55 (m, 7 H), 1.28 (m, 2 H), 1.15 (m, 2 H), 0.97 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 133.7, 130.8, 129.4, 128.5, 87.5, 73.7, 46.3, 44.9, 43.6, 42.7, 30.5, 29.4, 28.1, 27.0, 25.8, 22.3, 14.2, 12.3. IR (film): 3382, 2955, 2870, 1550, 1454, 1389, 1362, 972, 756 cm^-1. MS (EI): m/z (%) = 307 (47) [M⁺], 236 (21), 223 (35), 201 (33), 185 (48), 175 (49), 159 (45), 145 (69), 131 (99), 119 (86), 105 (65), 91 (100), 79 (98), 67 (48), 57 (50). HRMS: m/z calcd for C₁₈H₂₉NO₃: 307.2147; found: 307.2147.
tert -Butyl ( R , E )-5-{(3a R ,4 S ,5 R ,7a S )-5-[( E )-But-1-enyl]-2,3,3a,4,5,7a-hexahydro-1 H -inden-4-yl}-3-oxopent-4-en-2-ylcarbamate (19): [α]_D -88.1 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 6.82 (dd, J = 9.4, 15.8 Hz, 1 H), 6.10 (d, J = 15.6 Hz, 1 H), 5.84 (d, J = 9.9 Hz, 1 H), 5.39 (m, 1 H), 5.32 (ddd, J = 6.2, 15.6 Hz, 1 H), 5.25 (dd, J = 8.2, 14.8 Hz, 1 H), 4.54 (q, J = 7.2 Hz, 1 H), 2.92 (m, 1 H), 2.44 (ddd, J = 4.4, 6.2, 10.6 Hz, 1 H), 1.96 (q, J = 6.9, 7.4 Hz, 2 H), 1.80 (m, 2 H), 1.62 (m, 2 H), 1.56 (m, 3 H), 1.37 (s, 9 H), 1.25 (d, J = 6.9 Hz, 3 H), 1.16 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 198.2, 155.1, 152.0, 135.1, 129.9, 129.5, 128.1, 126.1, 79.4, 53.1, 47.9, 45.4, 44.9, 42.7, 28.9, 28.3, 27.9, 25.6, 22.1, 19.1, 13.9. IR (film): 3386, 3333, 2965, 2875, 1712, 1629, 1495, 1451, 1366, 1247, 1169, 1047, 983, 733 cm^-1. MS (EI): m/z (%) = 373 (1) [M⁺], 318 (12), 317 (50), 300(5), 273 (4), 256 (6), 236 (7), 229 (23), 201 (14), 186 (8), 174 (3), 159 (4), 145 (10), 144 (67), 131 (9), 119 (11), 107 (8), 95 (15), 88 (70), 79 (12), 67 (8), 57 (100). HRMS: m/z [M - C₄H₈] calcd for C₁₉H₂₇NO₃: 317.1991; found: 317.1991.
tert -Butyl (2 R ,3 S )-5-{(3a R ,4 S ,5 R ,7a S )-5-[( E )-But-1-enyl]-2,3,3a,4,5,7a-hexahydro-1 H -inden-4-yl}-3-hy­-droxy­pentan-2-ylcarbamate (20): [α]_D -28.3 (c = 1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.75 (d, J = 9.6 Hz, 1 H), 5.40 (dt, J = 6.3, 15.1 Hz, 1 H), 5.34 (ddd, J = 2.5, 4.4, 9.6 Hz, 1 H), 5.23 (dd, J = 8.8, 15.1 Hz, 1 H), 4.76 (m, 1 H), 3.61 (m, 1 H), 3.52 (m, 1 H), 2.80 (m, 1 H), 1.95 (dq, J = 6.3, 7.4 Hz, 2 H), 1.74 (m, 2 H), 1.63 (m, 3 H), 1.50 (m, 3 H), 1.37 (s, 9 H), 1.18 (m, 6 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.90 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.9, 133.5, 130.9, 129.2, 128.6, 79.4, 74.7, 50.8, 46.4, 44.8, 43.3, 42.5, 30.5, 29.4, 28.5, 28.1, 27.4, 25.8, 22.3, 14.6, 14.2. IR (CHCl₃): 3438, 3011, 2961, 2869, 1692, 1507, 1453, 1391, 1369, 1247, 1170, 1054, 972, 758, 667 cm^-1. MS (EI): m/z (%) = 377 (1) [M⁺], 321 (29), 303 (3), 276 (2), 260 (5), 233 (12), 215 (14), 190 (14), 159 (8), 145 (18), 144 (26), 134 (30), 119 (11), 105 (11), 91 (15), 88 (75), 79 (17), 67 (10), 57 (100). HRMS: m/z [M - C₄H₈] calcd for C₁₉H₃₁NO₃: 321.2304; found: 321.2304.