Silicon-Containing Dipeptidic Aspartame and Neotame Analogues

A series of seven silicon-containing dipeptides ((S,R)-5, (S,S)-5, (S,R)-6, (S,R)-7, (S,S)-7, (S,R)-8, and (S,S)-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 enzyme-catalyzed 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
(1H, 13C, 15N, 29Si).
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.