Asymmetric Organocatalytic Cyclopropanation on Chiral Menthyl Acrylate for the Synthesis of (–)-trans-2-Aminomethylcyclopropanecarboxylic Acid [(–)-TAMP]

Abstract

An enantioselective synthesis of (–)-trans-2-aminomethylcyclopropanecarboxylic acid [(–)-TAMP], a partial agonist for GABAc receptor, has been achieved as the hydrochloride salt in 3.9% overall yield for total eight steps from l-menthol. The synthesis features double asymmetric cyclopropanation that employs cinchona alkaloid derived organocatalyst and l-menthyl chiral auxiliary.

Key words

amino acids - asymmetric catalysis - carbocycles - chiral auxiliaries - diastereoselectivity

• References and Notes

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• 7 To a stirred solution of quinidine derivative 5 (585 mg, 1.73 mmol) and Cs₂CO₃ (3.38 g, 10.4 mmol) in MeCN (20 mL) were added a solution of tert-butyl bromoacetate (1.26 mL, 8.65 mmol) and l-menthyl acrylate (2, 2.00 g, 9.51 mmol) in MeCN (15 mL). After stirring at 80 °C for 24 h, the reaction mixture was poured into CH₂Cl₂ (20 mL) and washed with sat. aq NH₄Cl (20 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (70 g, Et₂O–hexane = 1:9) to give cyclopropane 3 (1.20 g, 42%) as a colorless oil. Unreacted acrylate 2 was also recovered (1.13 g, 57%). Diastereomeric purity of 3 was determined to be 50% de from chiral HPLC analysis (CHIRALPAK ID-3, 0.46 × 25 cm, H₂O– MeCN = 40:60). Spectroscopic Data for Cyclopropane 3 (50% de) [α]_D ^23.2 –83.8 (c 2.43, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.64 (ddd, J = 12.0, 12.0, 4.4 Hz, 1 H), 2.05–2.01 (m, 2 H), 1.93 (m, 1 H), 1.82 (m, 1 H), 1.62 (m, 2 H), 1.43 (m, 1 H), 1.40 (s, 9 H), 1.36–1.26 (m, 3 H), 1.02–0.90 (m, 2 H), 0.86–0.84 (m, 7 H), 0.72–0.70 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.6, 171.0, 128.4, 81.3, 47.0, 40.9, 34.3, 31.4, 28.1 (3×), 26.3, 23.4, 23.2, 22.3, 22.1, 20.9, 16.4, 15.4.

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• 12 A suspension of 11 (48.8 mg, 0.138 mmol) in HCl (6 M, 0.200 mL) was stirred at 60 °C for 15 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography on reversed-phase silica gel (500 mg, H₂O) to give HCl salt of (–)-TAMP (1, 20.9 mg, quant.) as a colorless solid: [α]_D ^22.0 –65.4 (c 0.15, 1 M HCl). ¹H NMR (400 MHz, D₂O): δ = 2.98 (dd, J = 12.0, 8.0 Hz, 1 H), 2.87 (dd, J = 12.0, 8.0 Hz, 1 H), 1.68–1.60 (m, 2 H), 1.23 (m, 1 H), 1.02 (m, 1 H). ¹³C NMR (100 MHz, D₂O): δ = 181.6, 42.8, 21.9, 17.4, 12.2.

For our related studies, see:
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