Asunto(s)
Catepsina B/antagonistas & inhibidores , Dipéptidos/síntesis química , Dipéptidos/farmacología , Diseño de Fármacos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Técnicas Químicas Combinatorias , Dipéptidos/química , Humanos , Hidrocarburos Fluorados/química , Estructura Molecular , Nitrilos/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Aminoácidos Cíclicos/síntesis química , Compuestos de Flúor/síntesis química , Aminación , Aminoácidos Cíclicos/química , Ésteres/química , Compuestos de Flúor/química , Iminas/química , Estructura Molecular , Protones , Soluciones , EstereoisomerismoRESUMEN
The scope of the transesterification reaction between beta-fluorinated alpha-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated alpha-imino esters.
RESUMEN
The synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated alpha-amino acids as single enantiomers.