Synthesis of rac-2′-(trimethylsilyl)isovaline: A novel silicon-containing α,α-dialkylated α-amino acid

Falgner, Steffen; Buchner, Ginka; Tacke, Reinhold

doi:10.1016/j.jorganchem.2010.08.027

Cited by 7 publications

(3 citation statements)

References 19 publications

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“…Another racemic synthesis of 83a,b was obtained by an alkylation step on silyl malonate derivative 50, providing the corresponding dialkyl derivative 89 in 95% yield. 56 Finally, β-silyl α,α′disubstituted amino acids 83a,b were prepared in 11% and 28% overall yields, respectively (Scheme 24). 4.4.3.…”

Section: Racemic Synthesis Bymentioning

confidence: 99%

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

et al. 2016

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Unnatural α-amino acids form a family of essential molecules used for, among other applications, the synthesis of modified peptides, to improve resistance to proteolytic enzyme degradation, and to modulate physico- and biochemical properties of bioactive peptides as well as chiral inducers in asymmetric synthesis. Among them, silicon-containing unnatural amino acids are becoming an interesting new class of building blocks. The replacement of carbon atoms in bioactive substances with silicon is becoming increasingly popular. Peptides containing silyl amino acids hold great promise for maintaining or reinforcing the biological activity of active compounds, while they simultaneously enhance their resistance to enzyme degradation. In addition, the lipophilicity of the silicon atom facilitates their membrane crossing and their bioavailability. Nowadays, the interest of the pharmaceutical industry in peptide- and protein-based therapies is increasing. In this respect, silicon-containing amino acids and peptides are likely to be a significant part of future innovations in this area, and more generally in the area of biomolecules. In this process, commercial availability of silicon-containing amino acids is necessary: new syntheses have been developed, and work in this area is ongoing. This review aims to be a comprehensive and general summary of the different methods used to prepare silicon-containing amino acids and their implications on conformational structures and biological applications when they are incorporated into bioactive molecules.

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Section: Racemic Synthesis Bymentioning

confidence: 99%

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

et al. 2016

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“…53 Substituting heavier Group 14 elements into organic molecules of biological interest is an area of research in synthetic and structural chemistry that has, over the years, given rise to important insights and developments. This year, advances have been made in the synthesis of the silicon-containing a,a-dialkylated a-amino acid rac-2 0 -trimethylsilyl isovaline, 54 of (2-F-) and (2-Cl-5-pyridyl)dimethyloxiran-2-ylmethyl silane, potential building blocks for silicon-containing medicinal chemistry 55 and of silatrifluoroperidol. 56 The silicon-containing version of haloperidol does not give rise to the pyridinium metabolite, seen in the case of the all-carbon version and which is believed to be responsible for the side effects, in microsomal incubations.…”

Section: M(14)-groupmentioning

confidence: 99%

Carbon, silicon, germanium, tin and lead

Parr

2011

Annu. Rep. Prog. Chem., Sect. A: Inorg. Chem.

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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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Synthesis of rac-2′-(trimethylsilyl)isovaline: A novel silicon-containing α,α-dialkylated α-amino acid

Cited by 7 publications

References 19 publications

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides

Carbon, silicon, germanium, tin and lead

Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

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