New Access to Kainic Acid via Intramolecular Palladium-Catalyzed Allylic Alkylation

Abstract

The formal synthesis of kainic acid was carried out in eleven steps. The key cyclization step was accomplished through an intramolecular palladium-catalyzed allylic alkylation of an allylic sulfone. Further functionalization of the resulting pyrrolidone ­featured, inter alia, a N-heterocyclic carbene-copper hydride (NHC-CuH)-mediated stereoconvergent conjugate reduction.

Key words

kainic acid - synthesis - palladium - allylic alkylation - ring closure

References and Notes

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17

Procedure for the Palladium-Catalyzed Cyclization Reaction: To a solution of tetrabutylammonium bromide (10 mol%) in CH₂Cl₂ (1 mL) were added in this order allylpalladium chloride dimer (5 mol%) and dppe (12.5 mol%). After 5 min stirring, to the thus formed catalytic system were added successively a CH₂Cl₂ (5 mL) solution of 6 (795 mg, 1.6 mmol), H₂O (6.0 mL), and a 50% aq KOH solution (6.4 mmol). The resulting biphasic system was stirred vigorously at r.t. for 16 h. The aqueous phase was extracted with CH₂Cl₂ (3 ×). The collected organic phases were dried over MgSO₄ and the solvent was removed in vacuo. The crude product was purified by flash chromatography to afford 7 in quantitative yield as an oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.19 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.78 (br s, 2 H), 4.46 (d, J = 14.6 Hz, 1 H), 4.40 (d, J = 14.6 Hz, 1 H), 3.87 (d, J = 10.8 Hz, 3 H), 3.81 (d, J = 10.8 Hz, 3 H), 3.80 (s, 3 H), 3.55 (dd, J = 8.3, 9.6 Hz, 1 H), 3.20-3.32 (m, 1 H), 2.98-3.07 (m, 1 H), 2.94 (dd, J = 4.5, 22.8 Hz, 1 H), 1.63 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 159.2, 144.3, 129.6, 127.4, 114.1, 112.3, 55.3, 53.5 (J = 100 Hz), 50.1, 46.4, 46.0 (J = 140 Hz), 39.7, 19.2. IR: 2955, 2360, 1688, 1514, 1247, 1031 cm^-1. MS (ESI⁺): m/z = 392 [M + K⁺], 376 [M + Na⁺], 354 [M + H⁺].

20

Procedure for the Hydride Conjugate Addition: An oven-dried flask under an argon atmosphere was charged with IPr-CuCl (2 mol%), t-BuONa (10 mol%) and anhydrous toluene (1 mL). After 10 min stirring at r.t., PMHS (90 µL) was added and the resulting orange solution was stirred at r.t. for 5 min. Then toluene (1 mL), and further PMHS (270 µL) were added. A solution of 8 (1:1 E/Z mixture) (508 mg, 1.54 mmol) in toluene (8 mL) was added via cannula to the thus generated reducing system and the reaction mixture was stirred at r.t. for 16 h. H₂O was added, the aqueous phase was extracted with EtOAc (3 ×). The collected organic phases were washed with brine, dried over MgSO₄ and the solvents were removed in vacuo. The crude product was purified by flash chromatography to afford pure 9 as an oil (72%). ¹H NMR (400 MHz, CDCl₃): δ = 7.16 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 4.74 (br s, 1 H), 4.65 (br s, 1 H), 4.39 (d, J = 14.2 Hz, 1 H), 4.35 (d, J = 14.2 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.77 (s, 3 H), 3.36-3.42 (m, 1 H), 3.10-3.15 (m, 2 H), 3.03 (dd, J = 1.3, 10.1 Hz, 1 H), 2.83 (dd, J = 3.5, 17.2 Hz, 1 H), 2.21-2.32 (m, 1 H), 1.42 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.1, 172.5, 159.2, 143.1, 130.0, 128.1, 114.9, 114.0, 60.6, 55.3, 49.0, 46.3, 42.0, 41.6, 31.0, 19.8, 14.3. IR: 2936, 1731, 1687, 1513, 1246, 1175, 1032 cm^-1.