Solution-, solid-phase, and fluorous synthesis of beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives: a comparative study.
The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.
Fustero
Santos
S
Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Valencia, Spain. santos.fustero@uv.es
Sánchez-Roselló
María
M
Rodrigo
Vanessa
V
Sanz-Cervera
Juan F
JF
Piera
Julio
J
Simón-Fuentes
Antonio
A
del Pozo
Carlos
C
D000586:Amination; D000598:Amino Acids, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D007097:Imines / Q000737:chemistry; D015394:Molecular Structure; D011522:Protons; D012996:Solutions; D013237:Stereoisomerism
D000598:Amino Acids, Cyclic; D004952:Esters; D017611:Fluorine Compounds; D007097:Imines; D011522:Protons; D012996:Solutions