Abstract
In this study, we address the challenge of regioselective Boc protection in the more
sterically hindered amide NH of unsymmetrical 2,5-diketopiperazines (DKPs) formed
from glycine and various amino acids. Our research introduces a novel technique utilizing
cost-effective triisobutylaluminium and trimethoxysilane. Notably, trimethoxysilane
selectively reacts with the less hindered amide NH, facilitating the regioselective
Boc protection of the more congested amide NH in DKPs. The primary objective of our
work is to develop a straightforward and scalable approach for the synthesis of Boc-protected
DKPs, with a focus on addressing the steric challenges presented by these compounds.
We successfully demonstrate the scalability of this method, enabling the synthesis
of a variety of mono-Fmoc-, Cbz-, Alloc-, and EtOCO-protected DKPs. Furthermore, we
extend the applicability of this strategy by employing it in the construction of pentapeptides
through a twofold peptide-elongation process. Our findings reveal the versatility
and efficiency of this regioselective Boc-protection method. Overall, this research
introduces a valuable solution to the regioselective Boc-protection challenge in DKPs
and demonstrates its applicability in peptide synthesis, showcasing its potential
for further advancements in the field.
Key words triisobutylaluminium - mono-Boc-DKPs - trimethoxysilane - peptide elongation - regioselective
protection
