A Novel Four-Component Synthesis of N-Substituted Amino Acid Esters

Abstract

A library of N-substituted amino acid esters was synthesized using a solid phase bound organic isocyanide that provides a C1 synthon to the final molecule. This novel four-component, one-pot reaction delivers the final products in acceptable yields with high purities of the crude reaction products, facilitating the final purification. The preparation of the isocyano resin is also described the intermediates being controlled by ATR-spectroscopy.

Key words

multi-component reaction - amino acids - polymer-supported synthesis - combinatorial chemistry - Lewis acids

References

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10

Synthesis of N -(4-Methoxyphenyl)-( R , S )-valine methylester: 0.044 mL Isobutyraldehyde (0.48 mmol) and 60 mg p-anisidine (0.48 mmol) were dissolved in 2 mL dry dichloromethane and 50 mg molecular sieves (0.4 nm) was added. The reaction mixture was stirred at room temperature for one hour. The molecular sieve was filtered off and 0.195 mL dry methanol (4.8 mmol), 0.183 mL boron trifluoride etherate (1.44 mmol) and 400 mg isocyanomethyl polystyrene (0.24 mmol) were added together with 2 mL dry dichloromethane. The reaction mixture was shaken at room temperature for two hours. The resin was filtered off and washed twice with dry dichloromethane and dry acetone. The cleavage was performed by shaking the resin with a mixture of acetone/water = 4:1 for 4 h at room temperature. The resin was filtered off and washed several times with acetone. The combined filtrates were combined and the solvent was evaporated, yielding 22.8 mg N-(4-methoxyphenyl)-(R,S)-valine methylester as a yellow oil (40% yield, calculated based on the loading of the resin). Satisfactory analytical data were obtained. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ(ppm) 1.00 [d, ³ J(H,H) = 6.3 Hz, 3 H, CH ₃CH], 1.09 [d, ³ J(H,H) = 6.3 Hz, 3 H, CH ₃CH], 2.33 (m, 1 H, CH₃CHCH₃), 3.72 (s, 3 H, CH₃O), 3.79 (s, 3 H, CH₃O), 4.06 (m, 1 H, CHNH), 6.88 [d, ³ J(H,H) = 8.6 Hz, 2 H, ArH], 7.43 [d, ³ J(H,H) = 8.6 Hz, 2 H, ArH]. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ(ppm) 16.3 CH₃CH), 19.5 (CH₃CH), 28.4 (CH₃ CH), 53.1 (CH₃O), 55.5 (CH₃O), 71.4 (CHNH), 115.2 (m-CAr), 124.7 (i-CAr), 125.6 (o-CAr), 160.5 (p-CAr), 167.0 (CO).