6-Exo Cyclizations of 2-Indolylacyl Radicals: Access to the Uleine Alkaloid Skeleton

Abstract

A new straightforward approach to the bridged framework of uleine alkaloids, based on the 6-exo cyclization of selenoester-derived 3-(tetrahydro-2-pyridyl)-2-indolylacyl radicals under reductive conditions, is described.

Key words

indoles - radical reactions - cyclizations - metathesis - alkaloids

References and Notes

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• For reviews, see:
• 5a Joule JA. Indoles, The Monoterpenoid Indole Alkaloids, In The Chemistry of Heterocyclic Compounds   Vol. 25:  Weissberger A. Taylor EC. Wiley; New York: 1983. 
• 5b Alvarez M. Joule JA. Monoterpenoid Indole Alkaloids, In The Chemistry of Heterocyclic Compounds   Supplement to Vol. 25:  Taylor EC. Wiley; Chichester: 1994.  Part 4 Chap. 6.
• 5c Alvarez M. Joule JA. In The Alkaloids   Vol. 57:  Cordell GA. Academic Press; New York: 2001.  Chap. 4.
• For reviews, see:
• 6a Bosch J. Bonjoch J. In Studies in Natural Products Chemistry   . Elsevier; Amsterdam: 1988.  p.31-88  
• 6b Sapi J. Massiot G. Monoterpenoid Indole Alkaloids, In The Chemistry of Heterocyclic Compounds   Supplement to Vol. 25:  Taylor EC. Wiley; Chichester: 1994.  Part 4 Chap. 7.
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16

All attempts to carry out the amination-imine allylation sequence from an indole-3-carbaldehyde already incorporating a carboxylic acid or ester at the 2-position resulted in lactamization.

17

Removal of the Boc group under the usual acidic conditions (TFA, r.t.) resulted in decomposition.

18

Selenoester 5: mp 174-175 ºC. ¹H NMR (400 MHz, CDCl₃): δ = 2.48 (br d, J = 17.2 Hz, 1 H), 2.79 (m, 1 H), 3.59 (s, 3 H), 4.02 (d, J = 17.6 Hz, 1 H), 4.29 (d, J = 18.0 Hz, 1 H), 6.00 (m, 3 H), 7.10 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.44 (m, 3 H), 7.62 (m, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 8.74 (br s, 1 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 30.3 (CH₂), 42.4 (CH₂), 46.9 (CH), 52.7 (Me), 112.4 (CH), 121.1 (CH), 122.8 (CH), 124.9 (CH), 125.5 (C), 126.0 (C), 126.1 (2 × CH), 129.2 (CH), 129.4 (CH), 130.7 (C), 136.2 (CH), 136.8 (C), 156.6 (C), 183.4 (C); indole C-3 was not observed. Anal. Calcd for C₂₂H₂₀N₂O₃Se·H₂O: C, 57.77; H, 4.84; N, 6.12. Found: C, 57.92; H, 4.52; N, 5.92.

20

Selenoester 9: ¹H NMR (400 MHz, CDCl₃): δ = 1.65 (s, 9 H), 2.66 (dddd, J = 1.2, 5.4, 6.9, 18.3 Hz, 1 H), 2.83 (s, 3 H), 2.89 (dddd, J = 2.7, 3.0, 11.4, 18.6 Hz, 1 H), 5.14 (dd, J = 6.9, 11.4 Hz, 1 H), 6.08 (ddd, J = 0.9, 2.7, 9.6 Hz, 1 H), 6.56 (ddd, J = 3.0, 5.1, 9.9 Hz, 1 H), 7.29 (ddd, J = 0.9, 7.2, 8.1 Hz, 1 H), 7.43 (m, 3 H), 7.46 (ddd, J = 1.2, 7.5, 8.4 Hz, 1 H), 7.61 (m, 2 H), 7.75 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 28.0 (Me), 31.0 (CH₂), 31.9 (Me), 53.5 (CH), 86.2 (C), 115.8 (CH), 120.7 (C), 121.6 (CH), 124.0 (CH), 124.9 (CH), 125.9 (C), 126.2 (C), 127.1 (CH), 129.4 (CH), 129.6 (CH), 134.6 (C), 135.3 (CH), 136.3 (C), 138.1 (CH), 148.6 (C), 165.7 (C), 188.4 (C).

21

Typical Procedure for the Radical Cyclization: n-Bu₃SnH (0.13 mL, 0.50 mmol) and Et₃B (1 M in hexanes, 0.50 mL, 0.50 mmol) were added to a solution of the phenyl selenoester 5 or 9 (0.25 mmol, previously dried azeotropically with anhyd benzene) in anhyd benzene (7 mL). The reaction mixture was stirred at r.t. for 2-4 h with dry air constantly supplied by passing compressed air through a short tube of Drierite. The reaction mixture was concentrated. The residue was partitioned between hexanes (10 mL) and MeCN (10 mL), and the polar layer was washed with hexanes (3 × 10 mL). The MeCN solution was concentrated and the crude product was chromatographed (SiO₂, flash, hexanes-EtOAc, 7:3 or 8:2).
Methyl 6-Oxo-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3- b ]indole-2-carboxylate (10): yield: 60%. ¹H NMR (400 MHz, CDCl₃; assignment aided by HSQC and COSY, mixture of rotamers): δ = 2.02 (m, 2 H, 4-H), [2.22 (dt, J = 2.8, 2.8, 12.8 Hz) and 2.55 (br d, J = 10.8 Hz), 2 H, 12-H], [2.78 (br t, J = 12.8 Hz) and 3.80-4.00 (masked), 2 H, 3-H], 2.89 (s, 1 H, 5-H), 3.68, 3.88 (2 × s, 3 H, OMe), 5.78, 5.94 (2 × s, 1 H, 1-H), 7.18 (t, J = 7.2 Hz, 1 H, 10-H), 7.39 (t, J = 8.4 Hz, 1 H, 9-H), 7.48 (d, J = 8.0 Hz, 1 H, 8-H), [7.69 (br d, J = 6.8 Hz) and 7.91 (d, J = 7.6 Hz), 1 H, 11-H], 9.60, 9.64 (2 × s, 1 H, 7-H). ¹³C NMR (100.6 MHz, CDCl₃; assignment aided by HSQC and HMBC, mixture of rotamers): δ = 29.0 (C-4), 35.4 (C-12), 36.5 (C-3), 41.3 (C-5), 43.6, 44.1 (C-1), 52.7 (OMe), 112.5, 112.8 (C-8), 121.3 (C-10), 121.7, 122.7 (C-11), 124.3 (C-11a), 125.4 (C-11b), 127.5 (C-9), 132.6 (C-6a), 138.4 (C-7a), 155.9, 156.2 (CO₂), 193.3 (C-6). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₂: 285.1233; found: 285.1232.
Methyl 5-Oxo-2,3,4,5-tetrahydro-1,4-ethanoazepino[4,3- b ]-1 H -indole-2-carboxylate (11): yield: 10%. ¹H NMR (400 MHz, CDCl₃; assignment aided by HSQC and COSY, mixture of rotamers): δ = 1.90 (m, 2 H, 11-H, 12-H), 2.13 (m, 1 H, 12-H), 2.41 (m, 1 H, 11-H), [3.21 (t, J = 5.2 Hz) and 3.26 (br t), 1 H, 4-H], [3.51 (d, J = 12.8 Hz) and 3.65 (m), 2 H, 3-H], 3.64, 3.65 (2 × s, 3 H, OMe), [5.79 (dd, J = 2.4, 5.6 Hz)and 5.98 (dd, J = 2.0, 5.2 Hz), 1 H, 1-H], 7.22 (t, J = 7.6 Hz, 1 H, 9-H), 7.41 (m, 2 H, 7-H, 8-H), [7.79 (d, J = 8.0 Hz) and 7.91 (d, J = 7.6 Hz), 1 H, 10-H], 8.96, 8.99 (2 × s, 1 H, 6-H). ¹³C NMR (100.6 MHz, CDCl₃; assignment aided by HSQC and HMBC, mixture of rotamers): δ = 18.7 (C-12), 26.9, 27.0 (C-11), 42.3, 42.5 (C-3), 45.0, 45.5 (C-1), 46.5 (C-4), 52.6, 52.7 (MeO), 112.2, 112.4 (C-7), 120.7, 121.0 (C-10), 121.2 (C-9), 124.6, 124.8 (C-10a), 127.0, 127.2 (C-8), 130.7, 131.2 (C-10b), 132.8, 132.9 (C-5a), 137.2, 137.3 (C-6a), 155.6, 155.9 (CO₂), 194.0 (C-5). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₂: 285.1233; found: 285.1233.
tert -Butyl 2-Methyl-3,6-dioxo-1,2,3,4,5,6-hexahydro-1,5-methanoazocino[4,3- b ]indole-7-carboxylate (12): yield: 72%. ¹H NMR (400 MHz, CDCl₃; assignment aided by HSQC and COSY): δ = 1.62 (s, 9 H, Boc), 2.51 (dt, J = 3.2, 3.2, 13.2 Hz, 1 H, 12-H), 2.67 (dm, J = 13.2 Hz, 1 H, 12-H), 2.69 (d, J = 19.2 Hz, 1 H, 4-H), 2.93 (dd, J = 8.0, 18.4 Hz, 1 H, 4-H), 3.10 (s, 3 H, NMe), 3.17 (dt, J = 3.2, 3.2, 8.0 Hz, 1 H, 5-H), 4.79 (t, J = 3.2 Hz, 1 H, 1-H), 7.34 (t, J = 7.6 Hz, 1 H, 10-H), 7.51 (ddd, J = 1.2, 8, 8.8 Hz, 1 H, 9-H), 7.73 (d, J = 8.0 Hz, 1 H, 11-H), 8.08 (d, J = 8.8 Hz, 1 H, 8-H). ¹³C NMR (100.6 MHz, CDCl₃; assignment aided by HSQC and HMBC): δ = 27.6 (Me), 33.3 (C-12), 34.6 (NMe), 35.4 (C-4), 42.9 (C-5), 50.7 (C-1), 85.0 (C), 115.2 (C-8), 120.6 (C-11), 123.8 (C-10), 125.0 (C-11a), 129.3 (C-9), 130.3 (C-6a), 135.7 (C-11b), 139.1 (C-7a), 149.1 (CO₂), 167.8 (C-3), 188.8 (C-6). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₃N₂O₄: 355.1652; found: 355.1649. Anal. Calcd for C₂₀H₂₂N₂O₄·1/4H₂O: C, 66.94; H, 6.32; N, 7.80. Found: C, 66.64; H, 6.27; N, 7.56.

23

Tetracycle 13: ¹H NMR (300 MHz, CDCl₃): δ = 2.56 (dt, J = 3.3, 3.3, 13.2 Hz, 1 H, 12-H), 2.69 (m, 1 H, 12-H), 2.69 (m, 1 H, 4-H), 3.01 (dd, J = 8.4, 18.9 Hz, 1 H, 4-H), 3.11 (s, 3 H, NMe), 3.20 (dt, J = 3.0, 3.0, 8.4 Hz, 1 H, 5-H), 4.83 (t, J = 3.0 Hz, 1 H, 1-H), 7.21 (ddd, J = 0.9, 7.2, 8.4 Hz, 1 H, 10-H), 7.39 (ddd, J = 0.9, 6.6, 7.8 Hz, 1 H, 9-H), 7.49 (dt, J = 0.9, 0.9, 8.1 Hz, 1 H, 8-H), 7.75 (d, J = 8.1 Hz, 1 H, 11-H), 9.86 (br s, 1 H, 7-H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 34.3 (C-12), 34.4 (NMe), 35.4 (C-4), 42.0 (C-5), 50.9 (C-1), 113.2 (C-8), 120.7 (C-11), 121.7 (C-10), 124.5 (C-11a), 127.6 (C-9), 129.0 (C-11b), 129.6 (C-6a), 138.1 (C-7a), 168.0 (C-3), 192.1 (C-6). Anal. Calcd for C₁₅H₁₄N₂O₄·1/2H₂O: C, 68.43; H, 5.74; N, 10.64. Found: C, 68.49; H, 5.68; N, 10.30.