Designing Silylated l‐Amino Acids using a Wittig Strategy: Synthesis of Peptide Derivatives and ¹⁸F‐Labelling

Abstract

An efficient semisynthesis of silylated l‐amino acids by reaction of silylated benzaldehydes with a phosphonium l‐amino acid used as a Wittig reagent is described. The efficiency of the silylated l‐amino acids in peptide synthesis was investigated by coupling both the carboxylic acid and the amino moiety with l‐alanine and phenylalanine derivatives, respectively. The silylated derivatives were treated with KF or tetrabutylammonium fluoride to give the corresponding fluorosilyl derivatives without racemization. The hydrolysis of the fluorosilylated derivatives in phosphate buffer at pH 7.2 was checked. Finally, the 18F‐labelling of di‐tert‐butylsilylated saturated and unsaturated dipeptides was achieved in hot DMSO with a mixture of K[18F]/cryptand (K2.2.2) and acetic acid. The 18F‐labelled dipeptides were obtained with radiochemical yields and molar activities of up to 31 % and 410 GBq/µmol, respectively. Consequently, this semisynthesis involving a Wittig reaction offers a new and efficient route for the design and 18F‐labelling of Si‐based amino acids and peptide derivatives, which may find applications in PET imaging.

Silicon switch: Carbon–silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug‐like properties in anticancer pharmacophores

“…Some of the emerging applications of silicon switch not discussed in this review include the incorporation of silicon into peptides either to mimic the active tetrahedral intermediates in protease inhibitors, to modify the peptide's lipophilicity or conformation, as well as to increase their resistance to degradation and to stabilize their secondary structures (Cavelier et al, 2008;Rugeri et al, 2017;Soto-Cairoli et al, 2008). These applications extend beyond the realm of small molecule therapeutics to include their implementation in positron emission tomography (PET) imaging, bettercontrolled drug release strategies, and structural probes for the direct detection of drug-protein-binding interactions (Hiscock et al, 2012a(Hiscock et al, , 2012bMu et al, 2010;Schirrmacher et al, 2006).…”

Phosphorus-containing amino acids with a P–C bond in the side chain or a P–O, P–S or P–N bond: from synthesis to applications

“…The amino acids 176 and 177, bearing aryl boronate and silylated moieties on the side chains, were also obtained under these conditions and they are potentially useful for further functionalization or for 18 F-labeling (Scheme 44). 62,63 Ortho-boronato-phenylphosphonium amino acids were also prepared according to this strategy via the quaternization of ortho-boronato-diphenylphosphine 180 with the g-iodoamino ester 179. Then, saponication led to compound 182 with a free carboxylic acid and the deprotection of the amine was performed via acidolysis into the corresponding ammonium salt 183 (Scheme 45).…”