Methods for the synthesis of peptoids using green solvents

A method of synthesizing a peptoid, the method comprising

• a) reacting a solid support comprising a terminal amine group, with a haloacetic acid (HA) in the presence of a HA activating agent in an acylation solvent, to obtain a solid support resin comprising an acylated amino group;
• b) washing the solid support comprising the acylated amino group with an acylation wash solvent to obtain a washed solid support resin comprising the acylated amino group;
• c) reacting the washed solid support comprising the acylated amino group with a primary amine in a displacement solvent, to obtain a washed solid support comprising an acylated resin-bound amide;
• d) washing the solid support comprising the acylated resin-bound amide, with a displacement wash solvent, to obtain an attached peptoid monomer comprising an amine group;
• e) repeating steps a)-d) at least once, where the amine group is the terminal amine group in step a) to obtain a peptoid;
• wherein the acylation solvent, and the displacement solvent, are polar aprotic solvents that are non-reactive to secondary amines and optionally the acylation solvent provides for a resin swelling of at least 1.25, 1.3, 1.35, 1.4, 1.45 or 1.5 and/or the acylation wash solvent is able to solubilize 1,3-diisopropylurea;
• or
• wherein the acylation solvent is selected from EtOAc, or a DMSO and EtOAc mixture, or
• wherein the acylation wash solvent is selected from DMSO, EtOAc, or a mixture thereof, and
• wherein when the acylation solvent is EtOAc, the acylation wash solvent is not EtOAc, and when the acylation wash solvent is DMSO, the acylation solvent is not DMSO.