Synthesis of Fluorinated Cyclopropyl Amino Acid Analogues: Toward the Synthesis of Original Fluorinated Peptidomimetics.

Abstract

A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.

Synthesis of complex unnatural fluorine-containing amino acids

“…The synthesis of α-amino-β-fluorocyclopropanecarboxylic acids was disclosed by Jubault and co-workers in 2012 as part of a study into their agonistic behaviour towards metabotropic glutamate receptor 4 ( Scheme 35 ) [ 127 ]. To begin their synthesis, a Michael induced ring closure reaction between the dibromofluoroacetate 165 and the amino acrylate 166 in the presence of Et 2 Zn was carried out to give the fluorocyclopropane 167 in 63 % yield and a dr of 2:1 [ 128 ]. The ethyl ester could be regio- and diastereoselectively saponified to give a separable mixture of the carboxylic acid 169 and ethyl ester 168 .…”

Synthesis and Applications of Fluorocyclopropanes

“…This methodology was also applied to the synthesis of biorelevant fluorocyclopropanes, such as amino acid analogues. 26 Mimetics of methionine, leucine, arginine, and lysine were readily synthetized after functional group manipulations from a common fluorocyclopropane bearing a protected amino acid function (Scheme 12). Ester and carbamate selective deprotections were also performed and allowed the use of these amino acids in peptide synthesis.…”

Titanium-Mediated Cyclopropanation of Nitriles with Unsaturated Grignard Reagents: Application to the Synthesis of Constrained Lysine Derivatives

“…22 Using the 2nd generation Hoveyda-Grubbs catalyst in di-chloromethane, the metathesis led to the expected alkene cis-27 in 79% yield. The mixture was directly subjected to various reduction conditions inspired from recent Jubault's work on similar structures, 23 but it was not possible to remove the benzyl protecting group or to reduce the nitrile. 24 In the unique case of nitrile reduction [Pd(OH) 2 /C, 30 bar H 2 ], ammonia as well as a condensation product were formed, as already observed by Maschmeyer.…”

“…Nitriles 1 and 4, as well as MeTi(Oi-Pr) 3 , were prepared according to known procedures. 15,23,26 Analytical TLC were performed on Alugram SIL G/UV254 silica gel sheets (Macherey-Nagel) by using 5% ethanolic vanillin solution as stated. Column chromatography was carried out using silica gel 60 (0.040-0.063 mm) from Merck.…”