New and Facile Synthesis of Aminobicyclo[2.2.1]heptane-2-carboxylic Acids

Abstract

A facile approach for the stereoselective synthesis of a- and b-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is described. Substrate-controlled α-carboxylation of norbonene monoester delivered the asymmetric diester intermediate with high diastereoselectivity (up to 35:1). Sequential chemoselective ester cleavage, Curtius rearrangement, and hydrolysis gave the a- and b-isomers of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, respectively.

Key words

carbocycles - amino acids - bicyclic compounds - diastereoselectivity - carbonylation

• References and Notes

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For the α-enolate alkylation of norbonene, see:
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• 12 Representative procedure for the preparation of a,b-(±)-BCH. (endo,exo)-Methyl Bicyclo[2.2.1]hept-5-ene-2-carboxylate (1a) To a solution of 5-norbornene-2-carboxylic acid (50.67 mmol, 7.00 g; predominantly endo mixture) in anhydrous CH₂Cl₂ (150 ml), oxalyl chloride (5.2 mL, 60.80 mmol) and DMF (390 μL, 5.07 mmol) were added at 0 °C under inert conditions. The reaction slowly warm to r.t. and stirred for 12 h at ambient temperature. The resulting solution was maintained at 0 °C and then anhydrous MeOH (4.10 mL, 101.33 mmol) and Et₃N (10.6 mL, 76.00 mmol) were added at 0 °C. The reaction mixture was allowed to ambient temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was diluted with CH₂Cl₂ (1000 mL), washed with H₂O (700 mL), dried over MgSO₄, filtered, and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (hexanes–EtOAc, 20:1) to give ester compound (5.92 g, 77%) as a colorless oil. endo-1a (major): ¹H NMR (600 MHz, CDCl₃): δ = 6.20–6.19 (dd, J = 3.6, 6.0 Hz, 1 H), 5.94–5.92 (dd, J = 6.0, 3.0 Hz, 1 H), 3.63 (s, 3 H), 3.20–3.20 (d, J = 0.6 Hz, 1 H), 2.97–2.94 (td, J = 3.6, 9.6 Hz, 1 H), 2.91 (s, 1 H), 1.94–1.89 (m, 1 H), 1.44–1.41 (m, 2 H), 1.28–1.27 (d, J = 8.4 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 175.28, 137.75, 132.37, 51.48, 49.61, 45.66, 43.17, 42.51, 29.25 ppm. exo-1a (minor): ¹H NMR (600 MHz, CDCl₃): δ = 6.15–6.13 (dd, J = 5.4, 5.4 Hz, 1 H), 6.11–6.10 (dd, J = 5.4, 5.4 Hz, 1 H), 3.69 (s, 3 H), 3.04–3.04 (d, J = 0.6 Hz, 1 H), 2.92 (s, 1 H), 2.24–2.22, (dd, J = 4.8, 10.8 Hz, 1 H), 1.94–1.91 (m, 1 H), 1.54–1.52 (d, J = 9 Hz, 1 H), 1.39–1.35 (m, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 176.76, 138.05, 135.73, 51.71, 46.57, 46.36, 42.98, 41.62, 29.25 ppm. 2-Benzyl 2-Methyl Bicyclo[2.2.1]hept-5-ene-2,2-dicarboxylate (2a) To a solution of (endo/exo)-1a (8.39 g, 55.13 mmol) in anhydrous THF (150 mL), LDA (2.0 M solution in THF, 28.9 mL, 57.88 mmol) and benzyl chloroformate (8.26 mL, 57.88 mmol) was slowly added at –78 °C and then stirred for 72 h. The reaction mixture was quenched with sat. NH₄Cl and slowly warmed to r.t. The solvent was removed in vacuo and the residue was diluted with EtOAc (1000 mL), washed with H₂O (700 mL), dried over MgSO₄ and filtered. The residue was purified by flash column chromatography (hexanes–EtOAc, 100:1) to give diester compound 2a (14.02 g, 89%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃): δ = 7.38–7.30 (m, 5 H), 6.27–6.26 (dd, J = 3.0, 5.4 Hz, 1 H), 5.99–5.98 (dd, J = 3.0, 5.4 Hz, 1 H), 5.23–5.21 (d, J = 12.6 Hz, 1 H), 5.16–5.14 (d, J = 12.6 Hz, 1 H), 3.60 (s, 3 H), 3.42–3.42 (d, J = 0.6 Hz, 1 H), 2.92 (s, 1 H) 2.14–2.12 (dd, J = 3.6, 12.6 Hz, 1 H), 2.03–2.00 (dd, J = 3.0, 12.6 Hz, 1 H), 1.65–1.64 (d, J = 9.0 Hz, 1 H), 1.52–1.51 (dd, J = 1.2, 9.0 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 172.29, 171.31, 139.82, 135.71, 133.45, 128.51, 128.21, 127.84, 66.96, 60.30, 52.28, 49.80, 48.80, 48.77, 42.03, 35.86 ppm. 2-(Methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid (5a) To a solution of diester compound 2a (300 mg, 1.05 mmol) in EtOAc (5 mL), 10% Pd/C (30 mg, 10 wt.%) was added under an inert atmosphere and the mixture was hydrogenated at 1 atm for 3 h. After completion of the reaction, the catalyst was removed by filtration through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes–EtOAc, 20:1 to 1:1) to give desired compound 5a (205 mg, 99%) as a white solid. ¹H NMR (600 MHz, CDCl₃): δ = 3.75 (s, 3H), 2.86–2.84 (d, J = 3.6 Hz, 1 H), 2.31–2.29 (dd, J = 3.0, 13.2 Hz, 2 H), 1.93–1.90 (m, 1 H), 1.66–1.65 (m, 1 H), 1.56–1.46 (m, 2 H), 1.41–1.38 (m, 1 H), 1.31–1.27 (m, 1 H), 1.15–1.11 (m, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 176.81, 171.50, 61.17, 52.68, 43.94, 39.40, 38.55, 36.35, 27.61, 25.23 ppm. Methyl 2-(Azidocarbonyl)bicyclo[2.2.1]heptane-2-carboxylate (6a) To a solution of acid compound 5a (205mg, 1.03 mmol) in CH₂Cl₂ (5 mL), diphenylphosphoryl azide (268 μL, 1.24 mmol) and Et₃N (173 μL, 1.24 mmol) were added at ambient temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was diluted with CH₂Cl₂ (120 mL), washed with H₂O (80 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexanes–EtOAc, 50:1) to give the desired acyl azide 6a (216 g, 94%) as a colorless oil. ¹H NMR (600 MHz, CDCl₃): δ = 3.75 (s, 3 H), 2.89–2.89 (d, J = 3.0 Hz, 1 H), 2.32–2.31 (t, J = 3.9 Hz, 1 H), 2.26–2.23 (dd, J = 3.0, 13.2 Hz, 1 H), 1.83–1.80 (m, 1 H), 1.56–1.46 (m, 3 H), 1.41–1.38 (m, 1 H), 1.30–1.26 (m, 1 H), 1.13–1.09 (m, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 178.98, 170.74, 63.29, 52.77, 43.46, 39.49, 38.76, 36.55, 27.61, 25.09 ppm. Methyl 2-[(tert-Butoxycarbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (7a) The acyl azide compound 6a (202 mg, 1.02 mmol) was diluted with anhydrous toluene (4 mL) and refluxed for 1 h. After completion of the reaction, solvent was removed under reduced pressure. The isocyanate intermediate was used in the next step without further purification. To a solution of isocyanate compound in t-BuOH (4 mL), NaOt-Bu (147 mg, 1.53 mmol) was added and stirred for 30 min at ambient temperature. After completion of the reaction, the reaction mixture was quenched with sat. NH₄Cl solution, and concentrated in vacuo. The reaction mixture was diluted with EtOAc (100 mL), washed with brine (70 mL), dried over MgSO₄, filtered, and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (hexanes–EtOAc, 10:1) to give the desired N-Boc amino ester compound 7a (198 mg, 72% over 2 steps) as a white solid. ¹H NMR (600 MHz, CDCl₃): δ = 4.96 (s, 1 H), 3.71 (s, 3 H), 2.45–2.42 (d, J = 12.6 Hz, 1 H), 2.34 (s, 1 H), 2.15–2.15 (d, J = 3.0 Hz, 1 H), 1.81–1.79 (m, 1 H), 1.69–1.67 (d, J = 14.4 Hz, 1 H), 1.53–1.47 (m, 1 H), 1.43–1.37 (m, 1 H), 1.40 (s, 9 H), 1.35–1.30 (m, 2 H), 1.21–1.18 (m, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 173.86, 154.87, 79.91, 66.50, 52.07, 47.14, 42.82, 38.28, 37.21, 28.24, 27.23, 24.23 ppm. (±)-2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid (a-(±)-BCH) To a solution of amino ester compound 7a in H₂O (5 mL), solid KOH (79 mg, 1.41) was added at ambient temperature and then heated to reflux for 12 h. After cooling the reaction mixture to ambient temperature, the reaction mixture was concentrated in vacuo, treated with 4 M HCl in 1,4-dioxane (5 mL), and stirred at ambient temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated in vacuo, purified by DOWEX®-50WX8 ion-exchange resin column chromatography to give the desired amino acid compound a-BCH (90 mg, 81% over 2 steps) as an ivory solid. ¹H NMR (600 MHz, D₂O): δ = 2.32 (s, 2 H), 2.06–2.04 (dd, J = 1.2, 13.2 Hz, 1 H), 1.59–1.57 (d, J = 10.8 Hz, 1 H), 1.48–1.35 (m, 4 H), 1.29–1.25 (m, 1 H), 1.19–1.15 (m, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 175.87, 68.10, 45.55, 38.77, 37.04, 37.02, 26.15, 23.88 ppm.
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