Moore A*, Chugg A, Kawamoto EM, Jacobsen MT
The reaction of primary amines with acetyl dimedones has been used to create the well-established Dde (N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) protecting group in solid-phase peptide synthesis (SPPS). We recently utilized this reaction to introduce solubilizing groups (“Helping Hands”) onto Lys side chains of difficult peptides with the Fmoc-Ddae-OH linker. Helping Hands can be cleaved with a nucleophile, usually hydrazine, to restore the primary amine. In the first part of this presentation, we present advice on the scope of acetyl dimedone incorporation and removal kinetics in a diversity of SPPS contexts.
Acetyl dimedones and its analogs are generally prepared in a one-pot, two-step reaction involving a carboxylic acid and dimedone. During the course of developing new acetyl dimedone derivatives, we recognized that the key synthetic intermediate, dimedone ester, is an easy-to-prepare, useful, and highly-solubilizing group for peptide synthesis. In contrast to the acetyl dimedone, the dimedone ester (“Helping Handcuff”) creates a non-cleavable amide bond with peptide amines. In the second part of this presentation, we showcase the versatility of dimedone esters; in particular, we note their significant solubilizing benefit under SPPS conditions (e.g., 10-30x greater solubility compared to the corresponding NHS ester). Finally, we demonstrate the overall utility of both Fmoc and biotin-dimedone esters for general peptide synthesis.