Citric Acid → 5(S)-[1(S)-(Boc-Amino)-2-cyclohexylethyl]-3(R)-[(2,3,4-trimethoxyphenyl)-methyl]dihydrofuran-2-(3H)-one

Participants

Reaction Steps

A solution of 1.47 g (4.72 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-(3H)-one in 6 ml of abs. THF and 1 ml (1.65 equivalents) of DMPU is cooled down to -75° C., under argon, and treated dropwise, at an internal temperature of below -70° C. and over the space of approximately 20 min, with 9.44 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After a further 20 min at -75° C., a solution of 1.45 g (4.72 mmol) of 2,3,4-trimethoxybenzyl iodide [Example 47b)] in 3 ml of abs. THF is added dropwise to this mixture, within the space of approximately 10 min, and this mixture is allowed to react at -75° C. for a further 2.5 h. For the working up, the reaction mixture is treated with 1.76 ml of propionic acid, followed by 1.76 ml of water, and the temperature is allowed to rise to 0° C. The reaction mixture is diluted with approximately 70 ml of ethyl acetate and stirred up with 30 ml of (cold) 10% citric acid. The aqueous phase is separated off and the organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again. The combined aqueous phases are reextracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue which remains after removing the solvent is chromatographed on silica gel (toluene:ethyl acetate, 5:1). HPLC tRet =19.13 min (gradient II). FAB-MS (M+H)+ =491. IR(CH2Cl2)=inter alia 3429, 1766, 1711, 1602, 1495, 1165 und 1100 cm-1. 1H-NMR(CD3OD)=inter alia 6.86 (d, 1H); 6.70 (d, 1H); 4.37 (m, 1H); 3.87, 3.82 and 3.81 (each s, each 3H); 3.37 (m, 1H); 3.13 (dxd, 1H); 2.94 (m, 1H); 2.59 (dxd, 1H) and 1.40 (s, 9H).

Provenance & Evidence