Syntheses of (±)-α-Isokainic Acid and (±)-α-Dihydroallokainic Acid Using a Decarboxylative Ramberg-Bäcklund Reaction

Abstract

Total syntheses of (±)-α-isokainic acid and (±)-α-dihydroallokainic acid have been achieved via tandem radical addition-homoallylic rearrangement and a decarboxylative Ramberg-­Bäcklund reaction as the key steps.

Key words

total synthesis - stereoselective - kainoids - radical rearrangement - Ramberg-Bäcklund reaction

References

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11

Only a trace of the epimeric adduct (1:13) arising from addition to the less accessible endo face of 7-azabicycle 12 was detected.

14

2-Azabicycle 14 (270 mg, 0.711 mmol) was dissolved in CH₂Cl₂ (200 mL), and the temperature was lowered to
-78 °C. A mixture of O₃/O₂ was bubbled through the solution until it turned blue, followed by O₂ until the solution became colorless. Then, Ar was passed through the solution for 5 min, and Me₂S (5 mL, 68 mmol) was added dropwise. The mixture was warmed to 20 °C and stirred for 1 h. The mixture was then concentrated in vacuo and the residue dissolved in Et₂O (50 mL, the dissolution aided by small amount of CH₂Cl₂). This solution was washed with H₂O (2 × 30 mL), dried (MgSO₄), and concentrated in vacuo to give a crude mixture of lactols 15 and 16 as a white foam. This crude mixture was dissolved in MeCN-H₂O (17 mL, 1:1 MeCN-H₂O), and the temperature was lowered to 0 °C. 4-Acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl (14 mg, 0.066 mmol) was added, followed by aq KOH (7.5 M) until the pH was 11.5. A mixture of Br₂ (0.21 mL, 4.10 mmol) and MeCN (6 mL) was added dropwise over 30 min, together with aq KOH (7.5 M) to maintain the pH at 11.5. Residual Br₂ was washed into the reaction using MeCN-H₂O (6 mL, 1:1 MeCN-H₂O), and the reaction was further stirred at pH 11.5 and 0 °C for 2 h. Na₂S₂O₅ (1.35 g, 7.10 mmol) was then added and the mixture stirred vigorously until it turned colorless; aq KOH (6 mL, 7.5 M, 45.0 mmol) was then added and the temperature was raised to 95 °C for 2 h. The mixture was cooled to 20 °C and acidified to pH 1 with aq HCl (2.0 M). The aqueous layer was extracted with EtOAc (4 × 20 mL), and the combined organic extracts were washed with brine (100 mL), dried (MgSO₄), and concentrated in vacuo. The residue was dissolved in PhMe-MeOH (18 mL, 7:2 PhMe-MeOH), and(trimethylsilyl)diazomethane (5 mL, 2.0 M in hexane, 10.0 mmol) was added and the mixture stirred at 20 °C for 16 h. AcOH (0.6 mL) was then added and the mixture was concentrated in vacuo. Purification of the residue by column chromatography (25% Et₂O-pentane) gave protected a-isokainic acid 17 (174 mg, 72% over 3 steps) as a colorless oil; R _f = 0.3 (25% Et₂O-pentane). IR: ν_max = 2976, 1742, 1706, 1394, 1256, 1175, 1104, 1108, 897 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 4.33, 4.23 [1 H, s, C(2)H], 4.09-3.85 [2 H, m, C(5)H₂], 3.67, 3.64 (3 H, s, OMe), 3.67, 3.64 (3 H, s, OMe′), 3.27 [1 H, dd, J = 9.4 Hz, J = 5.5 Hz, C(3)H], 2.45-2.32 (2 H, m, CH₂CO₂), 1.60 (3 H, s, Me), 1.56 (3 H, s, Me′), 1.43, 1.37 (9 H, s, CMe₃). ¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 172.3 (CO₂Me), 172.0, 171.8 (C′O₂Me), 155.1, 154.6 (NCO₂), 130.0, 129.1 (=C), 126.4, 126.3 (=C′), 80.2, 80.2 (CMe₃), 64.4, 63.9 (C2), 52.4, 52.3 (OMe), 51.9, 51.9 (OMe′), 48.6 (C5), 42.7, 41.9 (C3), 38.5 (CH₂CO₂), 28.5, 28.3 (CMe ₃), 21.1, 21.1 (Me), 20.5, 20.5 (Me′). MS (ES): m/z (%) = 705 (14) [2 M + Na⁺], 364 (100) [M + Na⁺], 308 (22), 242 (39) [M - Boc + H⁺]. Anal. Calcd for C₁₇H₂₈NO₆ [M]: 342.1917; found [M + H⁺]: 342.1927.

15

a-Isokainic acid (3): mp 240-245 °C (dec.) [lit.⁵ 237-240 °C (dec.)]. IR: ν_max = 2927, 2361, 2342, 1564, 1557, 1373, 1297, 1043, 859 cm^-1. ¹H NMR (250 MHz, D₂O): δ = 4.15 [1 H, d, J = 1.2 Hz, C(2)H], 4.06 [1 H, d, J = 14.9 Hz, C(5)H], 3.94 [1 H, d, J = 14.9, C(5)H′], 3.55 [1 H, td, J = 6.8 Hz, J = 1.2 Hz, C(3)H], 2.54 (1 H, dd, J = 14.8 Hz, J = 6.8 Hz, CHCO₂), 2.46 (1 H, dd, J = 14.8 Hz, J = 6.8 Hz, CH′CO₂), 1.71 (3 H, s, Me), 1.62 (3 H, s, Me′). ¹³C NMR (126 MHz, D₂O): δ = 178.1 (CO₂), 174.1 (CO₂), 131.0 (=C), 126.0 (=C′), 66.7 (C2), 47.4 (C5), 42.2 (C3), 39.8 (C6), 21.2 (Me), 20.9 (Me′). MS (ES): m/z (%) = 212 (100) [M - H⁺], 168 (35). Anal. Calcd for C₁₀H₁₆NO₄ [M]: 214.1079; found: [M + H⁺]: 214.1074.