Design and Synthesis of Histone Deacetylase Inhibitors by Side Chain Modification of 2-Amino-(n-1)-alkenoic Acids

Introduction Enantiomerically pure aliphatic amino acids having easily modifiable functional groups at the end of the side chain on α-carbon atom are highly interesting synthetic targets as the terminal functional groups can be changed to the required groups which provide a series of non-poteinogenic amino acids [1]. As the double bond is a masked functional group and is stable to most acidic and basic reaction conditions, the classical reactivity of alkenes towards addition, oxidation, etc., can be used for the side chain modification. So it is worthy to synthesize α-amino acids containing side chains with a terminal double bond, 2-amino-(n-1)-alkenoic acids (Aens). As a precursor, it can be easily converted to various amino acids having different side chain functionality. In fact several methods are available for the synthesis of specific ω-unsaturated α-amino acids [2,3]. Here we report a convenient method, for the synthesis of Boc-2-amino-(n-1)-alkenoic acids (Boc-Aen-OH, n = 5-9) from commercially available reagents, diethyl Boc-aminomalonate and ω-bromoalkenes. We also explored the possibility of their use in the synthesis of some new zinc ligands for chlamydocin type cyclic tetrapeptide scaffold in order to develop histone deacetylase inhibitors as anti-cancer agents with optimized pharmacokinetic properties.