Toward a Stable α-Cycloalkyl Amino Acid with a Photoswitchable Cationic Side Chain

The N-alkylated indanylidenepyrroline (NAIP) Schiff base 3 is an unnatural α-amino acid precursor potentially
useful for the preparation of semisynthetic peptides and proteins
incorporating charged side chains whose structure can be modulated
via Z/E photoisomerization. Here
we report that the heteroallylic protons of 3 led to
partial loss of ethanol accompanied by formation of the novel heterocyclic
system 4 during attempted deprotection. We also show
that the same protons catalyze the thermal isomerization of 3, making the light-driven conformational control concept
ineffective for times longer than a few hours. These problems are
not present in the previously unreported compound 5 where
the acidic methyl group is replaced by an H atom. Therefore, 5, rather than 3, constitutes a promising prototype
for the design of building blocks capable to modulate the electrostatic
potential of a protein in specific locations via light irradiation.