A Synthesis of (–)-cis-2-Aminomethylcyclopropanecarboxylic Acid [(–)-CAMP]

Abstract

An enantioselective synthesis of (–)-cis-2-aminomethylcyclopropanecarboxylic acid [(–)-CAMP] has been achieved in 2.5% total yield over ten steps starting from 2-furaldehyde. The synthesis features diastereoselective cyclopropane formation via diazene, followed by oxime formation and the reduction, for construction of the γ-aminobutyric acid (GABA) motif.

Key words

amino acids - cycloaddition - photochemistry - ring contraction - stereoselective synthesis

• References and Notes

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• 10 Spectroscopic data for diazene 4: [α]_D ^20.1 –57.2 (c = 0.94, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 5.05 (d, J = 6.8 Hz, 1 H), 4.41 (d, J = 2.0 Hz, 1 H), 3.95 (m, 1 H), 3.79 (m, 1 H), 3.35 (td, J = 10.6, 4.3 Hz, 1 H), 2.34 (m, 1 H), 1.95 (m, 1 H), 1.70 (m, 1 H), 1.52–1.57 (m, 2 H), 1.25 (m, 1 H), 1.10 (br, 1 H), 0.99–1.01 (m, 6 H), 0.85–0.95 (m, 4 H), 0.69–0.79 (m, 2 H). ¹³C NMR (100 MHz, C₆D₆): δ = 167.0, 104.3, 93.5, 83.1, 77.7, 48.1, 39.9, 39.1, 34.3, 31.3, 25.7, 23.2, 22.3, 21.0, 15.9.
• 11 Spectroscopic data for cyclopropane 2: [α]_D ^20.3 +137.0 (c = 1.07, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.41 (s, 1 H), 3.53 (td, J = 10.8, 4.11 Hz, 1 H), 2.01–2.19 (m, 4 H), 1.61–1.66 (m, 2 H), 1.37 (m, 1 H), 1.15–1.25 (m, 2 H), 0.77–1.04 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.4, 99.8, 77.5, 47.7, 40.2, 34.2, 31.4, 25.3, 23.1 (2 ×), 22.1, 20.9, 17.1, 15.6, 11.8.
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• 14 A suspension of protected CAMP 9 (13.0 mg, 0.053 mmol) in hydrochloric acid (6 M, 0.200 mL) was stirred at 90 °C for 8 h. The reaction mixture was then concentrated under reduced pressure and subjected to ion-exchange chromatography (Dowex 1-X8, 1.0 × 5 cm, H₂O) to give (–)-CAMP hydrochloride (8.2 mg, 100%) as a colorless solid; [α]_D ^20.3 –35.9 (c = 0.50, H₂O). IR (KBr): 3430, 3105, 1706, 1600, 1428, 1194, 861 cm^–1. ¹H NMR (400 MHz, D₂O): δ = 3.08–3.19 (m, 2 H), 1.80 (m 1 H), 1.53 (m, 1 H), 1.20 (m, 1 H), 0.94 (m, 1 H). ¹³C NMR (100 MHz, D₂O): δ = 176.5, 37.9, 17.7, 17.4, 12.8.