Spiroligomers are a class of rigid, shape-programmable spirocyclic peptidomimetics that are both stereochemically and functionally diverse. They are assembled from 4-Hydroxyproline derived bis-amino acids that are chiral, cyclic building blocks containing two alpha-amino acids on two stereocenters through pairs of amide bonds. A new large-scale synthesis of bis-amino acid intermediates, 1-benzyl 2-(<i>tert</i>-butyl)-4-oxopyrrolidine-1,2-dicarboxylate is presented here. It allows the manufacturing of kilogram-scale stereochemically pure S- and R- intermediates in a more efficient and environment-friendly way that eliminates the use of highly toxic Jones reagent and explosive isobutylene in previous methods. To facilitate solid phase synthesis of spiroligomers, we developed a selective Fmoc protection of functionalized bis-amino acid building blocks using temporary Cu<sup>2+</sup> complexation strategy and successfully applied it to all four stereoisomers. The Fmoc-protected monomers were pre-activated by forming pentafluorophenyl ester. Then a small library of four tetramers consisting of arbitrary combinations of four monomers with different stereochemical configuration and side group were constructed on solid support. Higher purity and yields were observed when compared to previous synthesis using para-nitrobenzyl carbamate (pNZ) protecting group. The structures of spiroligomers were validated with high-resolution mass spectrometry. Two-dimensional NMR confirmed the intended connectivity of spiroligomers. NOESY and ROESY correlations were used to verify their stereochemistry and determine the conformational preference of scaffolds and side chains. This research laid the foundation for the high throughput synthesis of functionalized spiroligomers using automated solid phase peptide synthesizer based on prevalent Fmoc chemistry. It will enable the development of various applications as sensors, catalysts and therapeutics.

An upscaled synthesis of Fmoc-protected bis-amino acids for highly functionalized spiroligomers

ACS Spring 2022

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