New strategy for the stereoselective synthesis of fluorinated beta-amino acids.
Racemic and chiral nonracemic alpha-substituted and alpha-unsubstituted beta-fluoroalkyl beta-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained gamma-fluorinated beta-enamino esters 4 by using ZnI(2)/NaBH(4) in a nonchelated aprotic medium (dry CH(2)Cl(2)) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral beta-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.
Fustero
Santos
S
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, 46100-Burjassot, Valencia, Spain. santos.fustero@uv.es
Pina
Belén
B
Salavert
Esther
E
Navarro
Antonio
A
Ramírez de Arellano
M Carmen
MC
Fuentes
Antonio Simón
AS
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
D000596:Amino Acids; D006845:Hydrocarbons, Fluorinated