Koizumi Toru

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 2 Ph) 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 3 COOH 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 t OCO) 2 N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 2 NCHFCOOCH 2 Ph, under several kinds of neutral conditions, were also attempted.

Synthesis and optical resolution of α-fluoro-α-nitro-α-(arylthio)-acetates

Abstract As a part of synthetic studies for the multifunctional carbon compounds, some tri- and tetrafunctional α-nitroacetates(2 and 3) have been prepared. The first optical resolution of the tetrafunctionalized carbon structure has also succeeded. Reaction of nitroacetates(1) with arylsulfenyl chlorides gave α-nitro- α-(arylthio)acetates(2) in excellent yields. The acetates(2) were easily converted into their potassium salts, which were fluorinated with perchloryl fluoride to produce α-fluoro-α-nitro-α-(arylthio)acetates(3) in moderate yields. The fluoroacetates(3) were also prepared by reaction of potassium salts of the α-fluoro-α-nitroacetates(4) with arylsulfenyl chlorides in good yields. The novel trifunctional(2) and tetrafunctional(3) carbon compounds obtained here are not yet known despite of their structural simplicity. The fluorinated derivatives(3) seem to be potent candidates for serving as building blocks for synthesizing fluorine-containing organic compounds. Ethyl α-fluoro-α-nitro-α-(arylthio)acetate(3a: R=Et, R′=Ph) was then converted into the phenylethyl ester(5) by treatment with (+)-α-phenylethyl alcohol and Ti(OPr i ) 4 in high yield. The diastereomeric isomers(5a and 5b) were separated, and each isomer could be transformed to the optically active ethyl ester by treatment with EtOH and Ti(OEt) 4 in excellent yield.