Abstract
The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp2 hybridization in the urea as well as a high barrier for sp3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.
Highlights
Chiral nitrogen has typically a low isomerization barrier [1]
In the interest of further exploring the adaptive chirality of nitrogen in an aza-peptide analog, we selected to make an aza-analog of the sugar substitute aspartame, because earlier studies had demonstrated that the S,S- and R,S-diastereomers (Figure 4) exhibited sweet and bitter tastes, respectively [7]
Aza-aspartame 9 was synthesized starting from tert-butylcarbazate (10) and tert-butyl bromoacetate (Scheme 1)
Summary
Chiral nitrogen has typically a low isomerization barrier [1]. Substitution of a chiral carbon by nitrogen can create a dynamic chiral center in a molecule possessing properties of both enantiomers of its carbon counterpart. Potential to adopt receptor requirements for recognition can give an aza-analog with potency similar to that of the more potent enantiomer. Such was the case when the chiral carbon at position-3 of pilocarpine (3) was replaced by nitrogen [3]. In the interest of further exploring the adaptive chirality of nitrogen in an aza-peptide analog, we selected to make an aza-analog of the sugar substitute aspartame, because earlier studies had demonstrated that the S,S- and R,S-diastereomers (Figure 4) exhibited sweet and bitter tastes, respectively [7]. The synthesis and author’s tasting of aza-aspartame 9 is presented; crystals of 9 were obtained and examined by X-ray analysis, which has provided additional structural information on the character of the nitrogen center in aza-amino acid residues
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