Synthesis of Molecularly Encoded Oligomers Using a Chemoselective "AB + CD" Iterative Approach

A library of eight sequence‐defined model oligomers, whose sequence is based on a (0,1) binary code, is prepared through chemoselective repeating cycles of amidification and copper‐assisted alkyne‐azide cycloaddition reactions from a non‐modified Wang resin. This library is constructed from two AB (A = acid, B = alkyne) building blocks, i.e., 4‐pentynoic acid and 2‐methyl‐4‐pentynoic acid acting, respectively, as non‐coding (0) and coding (1) monomer, and 1‐amino‐11‐azido‐3,6,9‐trioxaundecane as complementary CD (C = amine, D = azide) spacer building block. In particular, encoded triads are synthesized by consecutive covalent attachment of five building blocks (i.e., three coding/non‐coding monomers and two spacers). In this communication, optimal protocols for the synthesis of the targeted oligomers are reported along with their full characterization by 1H NMR, MALDI‐TOF mass spectrometry, and size‐exclusion chromatography. It is found that all possible encoded triads (i.e., eight possibilities) could be synthesized using this approach. Indeed, monodisperse sequence‐defined oligomers are prepared and characterized in all cases. The synthesis of sequence‐controlled oligomers based on an “AB‐CD” chemoselective approach is described. The methodology employs an iterative strategy from a solid support and does not require the use of protecting groups. In the present communication, the relevance of this technique to encode oligomer chains is demonstrated.