Crystal-to-Crystal Synthesis of Triazole-Linked Pseudo-proteins via Topochemical Azide–Alkyne Cycloaddition Reaction

Isosteric
replacement of amide bond(s) of peptides with surrogate
groups is an important strategy for the synthesis of peptidomimetics
(pseudo-peptides). Triazole is a well-recognized bio-isostere for
peptide bonds, and peptides with one or more triazole units are of
great interest for different applications. We have used a catalyst-free
and solvent-free method, viz., topochemical azide–alkyne cycloaddition
(TAAC) reaction, to synthesize pseudo-proteins with repeating sequences.
A designed β-sheet-forming l-Ala-l-Val dipeptide
containing azide and alkyne at its termini (N3-Ala-Val-NHCH2CCH, 1) was synthesized. Single-crystal
XRD analysis of the dipeptide 1 showed parallel β-sheet
arrangement along the b-direction and head-to-tail
arrangement of such β-sheets along the c-direction.
This head-to-tail arrangement along the c-direction
places the complementary reacting motifs, viz., azide and alkyne,
of adjacent molecules in proximity. The crystals of dipeptide 1, upon heating at 85 °C, underwent crystal-to-crystal
polymerization, giving 1,4-triazole-linked pseudo-proteins. This TAAC
polymerization was investigated by various time-dependent techniques,
such as NMR, IR, DSC, and PXRD. The crystal-to-crystal nature of this
transformation was revealed from polarizing microscopy and PXRD experiments,
and the regiospecificity of triazole formation was evidenced from
various NMR techniques. The MALDI-TOF spectrum showed the presence
of pseudo-proteins >7 kDa.