Chemistry of Silicon‐Containing Amino Acids

Qi, Yingmei; Sieburth, Scott McN.

doi:10.1002/9783527631780.ch6

Cited by 2 publications

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“…In light of our systematic investigations on silicon-containing α-amino acids and their application in the synthesis of silicon-containing peptidic drugs, , and inspired by Weidmann’s finding that phenylalanine ( 1 ) and β-(trimethylsilyl)alanine ( 2 ) can behave as bioisosteric building blocks in biologically active peptides, we have been interested in the design of silicon-based dipeptidic sweeteners (Scheme ) (for recent reviews dealing with silicon-containing α-amino acids and peptides, see ref ). Previous work, in which α-methyl-phenylalanine ( 3 ) was used for the development of artificial sweeteners, inspired us to incorporate the α-methylated α-amino acids ( R )- and ( S )-α-[(trimethylsilyl)methyl]alanine (( R )- 4 and ( S )- 4 ) , into several dipeptides ( 5 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

et al. 2012

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8) was prepared in multistep syntheses, starting from the enantiopure silicon-containing α-methylated α-amino acids (R)-or (S)-α-[(trimethylsilyl)methyl]alanine ((R)-4 or (S)-4). For the preparation of (R)-4 and (S)-4, a robust synthesis on a multigram scale was developed, using an enzymecatalyzed stereoselective ester hydrolysis as the key step. Coupling of (R)-4 and (S)-4 with different S-configured aspartate residues yielded a series of dipeptides that can be best described as silicon analogues of the artificial sweeteners aspartame and neotame. The identity of these dipeptides was established by elemental analyses and NMR spectroscopic studies ( 1 H, 13 C, 15 N, 29 Si). Some of the title compounds and some of their precursors were structurally characterized by single-crystal X-ray diffraction. The silicon-containing dipeptides were shown to display attractive ADME properties, including good solubility and plasma protein binding capabilities, no CYP inhibition, and no metabolic stability liabilities. Thus, the silicon-containing α-amino acids (R)-4 and (S)-4 proved to be promising building blocks for the design of biologically active peptides. Attempts to characterize the title compounds for their T1R2/R3 activating properties by testing their ability to induce GLP-1 secretion from the intestinal endocrine cell line STC-1 failed for unknown reasons. Sensory evaluation of the silicon-containing dipeptides demonstrated the aspartame analogue (S,R)-5 and the neotame analogue (S,R)-8 to be very potent artificial sweeteners, whereas the corresponding diastereomers tasted bitter. The silicon compounds (S,R)-5 and (S,R)-8 are approximately 50 and 600 times, respectively, as sweet as sucrose on a weight basis.

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Section: Introductionmentioning

confidence: 99%

Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

et al. 2012

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“…Despite their attractiveness, they are still rare and limited in diversity (Figure ). Some of them have been successfully used for the preparation of biological active compounds …”

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Access to α,α-Disubstituted Disilylated Amino Acids and Their Use in Solid-Phase Peptide Synthesis

et al. 2015

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A concise synthetic pathway yielding to hydrophobic α,α-disubstituted disilylated amino acids based on a hydrosilylation reaction is described. As a first example of utilization in solid-phase peptide synthesis, TESDpg was introduced in replacement of Aib in an alamethicin sequence, leading to analogues with modified physicochemical properties and conserved helical structures. This study highlights the potential of these new amino acids as tools for peptide modulation.

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Chemistry of Silicon‐Containing Amino Acids

Cited by 2 publications

References 49 publications

Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

Access to α,α-Disubstituted Disilylated Amino Acids and Their Use in Solid-Phase Peptide Synthesis

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