Fluorinated amino acid derivatives

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Virginia Polytechnic Institute and State University

A new approach in the syntheses of 3-bromo-2-butanone and 2-bromo-3-fluorobutane has been developed. All attempts to alkylate the sodium salt of diethyl malonate, ethyl acetoacetate, or diethyl acetamidomalonate with 2-bromo-3-fluorobutane failed.

New phosphonoacetates, tert-butyl and benzyl diethylphosphono-acetates were prepared as very versatile intermediates in the syntheses of carboxylic acids.

Methyl-, ethyl-, tert-butyl-, and benzyl 4-fluoro-3-methyl-2-pentenoates were synthesized in high yields by the Horner-Emmons reaction.

The reaction is stereoselective and gave E and Z form in 75:25 ratio as determined from proton and fluorine nmr spectra.

A long-range coupling was observed in fluorine nmr spectrum of 3-fluoro-2-butanone.

From the ethyl 4-fluoro-3-methyl-2-pentenoate, ethyl 2-bromo-4-fluoro-3-methyl-2-pentenoate was prepared, but the latter could not be reduced under the conditions of catalytic hydrogenation.

Ethyl 2-chloro-4-fluoro-3-methyl-2-pentenoate was prepared from 3-fluoro-2-butanone and ethyl diethylphosphonochloroacetate, but could not be reduced.

Catalytic hydrogenation of alky 4-fluoro-3-methyl-2-pentenoates gave the corresponding saturated esters in high yields.

Treatment of alkyl 4-fluoro-3-methylpentanoates with lithium diisopropylamide and bromine at -78° yielded the corresponding 2-bromoderivatives.

Methyl-, ethyl-, and tert-butyl 2-bromo-4-fluoro-3-methyl-pentanoates were treated with sodium azide to give the corresponding 2-azido derivatives which were further reduced into methyl-, ethyl-, and tert-butyl 2-amino-4-fluoro-3-methylpentanoates.