Automated synthesis of highly functionalized spiroligomers
Abstract
"We report the fluorenylmethoxycarbonyl (Fmoc) protection of functionalized bis-amino acid building blocks using a temporary Cu2+ complexation strategy, together with an efficient multikilogram-scale synthesis of bis-amino acid precursors. This allows the synthesis of stereochemically and functionally diverse spiroligomers utilizing solid-phase Fmoc/tBu chemistry to facilitate the development of applications. Four tetramers were assembled on a semiautomated microwave peptide synthesizer."
Scaling Complexity
The synthesis of complex spiroligomers has traditionally been hindered by the difficulty of producing monomeric building blocks at scale. In this work, we developed a route to synthesize key bis-amino acid intermediates at the tens of kilograms scale, increasing production by three orders of magnitude while replacing toxic Jones reagent with greener alternatives.
A critical innovation was the development of a temporary Cu2+ complexation strategy. This allowed us to selectively install the Fmoc protecting group on the proline nitrogen, enabling compatibility with standard solid-phase peptide synthesis (SPPS). Using this method, we successfully assembled highly functionalized tetramers (T1-T4) on a microwave-assisted peptide synthesizer.