Synthetic studies on the α-fluoro-α-amino acid derivatives

Abstract

Syntheses of α-fluoro-α-amino acid derivatives have been attempted from the viewpoints of their structural and biological interests. α-Amino esters were diazotized with i-AmONO or NaNO 2 to produce the corresponding diazo esters, which were treated with NBS and HF/pyridine to yield the α-bromo-α-fluoro esters(RCFBrCOOEt, 1a∼c). Introduction of nitrogenous functionality was undertaken by reaction of 1b(RMe) and 1c (RCH 2Ph) with potassium phthalimide to produce the undesired elimination products. Reaction of 1a(RH) with the potassium salts of phthalimide or iminodicarboxylates gave the α-fluoroglycine derivatives(R′R″NCHFCOOEt, 2a:R′R″phthalyl, 2b:R′COOMe, R″COOBu t, 2c:R′R″COOBu t). Removal of the phthalyl group of 2a under various conditions was unsuccessful. Acid treatment of 2b produced the unstable fluoro ester, MeOCONHCHFCOOEt, which was easily hydrolyzed during workup to give the hydroxy derivative, MeOCONHCH(OH)COOEt. On the other hand, reaction of 2c with CF 3COOH resulted in complete decomposition, probably via the imine(HNCHCOOEt) formation. Then, the alkaline hydrolysis of 2c was first carried out to yield successfully the N-protected fluoroglycine((Bu tOCO) 2NCHFCOOH, 3). However, the deprotection of the t-butoxycarbonyl group of 3 under acidic condition did not produce the ‘free’ α-fluoroglycine, presumably owing to the acid labile property of the α-fluoro-α-amino acid structure. Reductions of the novel trifunctional carbon compounds, N 3-CHF-COOR and O 2NCHFCOOCH 2Ph, under several kinds of neutral conditions, were also attempted.