Syntheses of?-fluoro-?-amino acids

Abstract

Methods for the synthesis of racemic and optically active title compounds are presented. Key step of these four-step procedures is the alkylation with 1-bromo-2-fluoroalkanes of glycine-ester-derived imines in anhydrous medium using lithium diisopropylamide as a base at low temperature or phase transfer catalyzed alkylation with 50% NaOH and triethylbenzylammoniumchloride as the phase transfer catalyst, respectively. Subsequent three-step deprotection gave the free acids in 13-33% overall yield. Deracemization ofγ-fluoro-α-aminobutyric acid methyl and ethyl esters withα-chymotrypsin was shown to give the (-)-enantiomers of the esters and (+)-γ-fluoro-α-aminobutyric acid in >98% ee, while from thetert-butylester the opposite stereochemical result was observed giving the (-)-acid with 88% ee. Optically activeγ-fluoro-α-amino acids were synthesized alternatively by phase transfer catalysis with N-benzyl-cinchonium chloride or using an auxiliary-directed asymmetric alkylation of the imine derived from (R)-(+)-camphor or (R)-(+)-2-hydroxypinan-3-one. These processes gave different enantiomers ofγ-fluoro-α-aminobutyric acid via a monomeric lithium enolate in the first or a dimeric lithium enolate in the second case, respectively. The enantiomeric excess can be improved by lithium/magnesium exchange.

Synthesis and Physicochemical Properties of 3‐Fluorocyclobutylamines

“…Having both isomers of the fluorinated cyclobutanes cis / trans ‐ 6 and cis / trans ‐ 13b , c in hand, we wanted to study the influence of fluorine on the basicity of the NH 2 group. Well‐studied involvement of fluorine in weak bonds, which are considered as charge–dipole interactions10d,15 or hydrogen bonds,16 often lead to significant change of p K a values 10a–10d. In the case of compounds 6 and 13 , we expected to observe this kind of interaction for trans isomers, for which fluorine and NH 3 + are in cis ‐orientation to each other 12.…”

Stereoselective Synthesis of γ-Fluorinated α-Amino Acids Using 2-Hydroxy-3-pinanone as an Auxiliary

“…[7] Most of them were prepared by substitution of a γ-hydroxy group or a γ-halogen atom by a fluorine atom in the corresponding amino acids, or by amination of γ-fluorinated α-halocarboxylic acids. [8,9] We became interested in the application of easily accessible fluorinated building blocks such as 1-bromo-2-fluoroalkanes [10] or 3-3737 wise deprotection was used. The selectivity of the alkylation increased by lithium/magnesium exchange or for 1b also by addition of DMPU.…”

Gallium (III) triflate catalyzed efficient Strecker reaction of ketones and their fluorinated analogs

“…However, successful three component Strecker reactions using ketones and fluorinated ketones are rare (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Fluorinated amino acids are becoming increasingly important in pharmaceuticals and other biological applications (15)(16)(17)(18)(19)(20)(21), such as the development of anticancer drugs for the control of tumor growth and drugs for the control of blood pressure and allergies (22). They have been shown as irreversible inhibitors of pyridoxal phosphate-dependent enzymes (23).…”