Synthesis of aza-derivatives of tetrahydrofuran lignan natural products

Abstract

The synthesis of novel aza-derivatives of THF lignan natural products has been achieved. This synthesis originates in the use of a highly selective acyl-Claisen reaction to provide a syn morpholine amide which ultimately determines a trans relationship at the 3- and 4-positions on the central ring. Initial attempts at the synthesis resulted in premature cyclisation, producing either dihydro-pyrrole or tetrahydrofuran structures. Later stage introduction of the amine functionality resulted in successful synthesis of aza-lignans. This synthesis allows for several variations in the aza-lignan structure, including the substitution on the aromatic ring and the amine that can be incorporated, resulting in the synthesis of a range of aza-analogues of fragransin A2 and galbelgin. Furthermore, these analogues have been tested for their anti-proliferative properties against various human cancer cell lines, along with their naturally occurring THF counterparts. Results show that for most cases, aza-derivatives are more active than the corresponding THF compound, with the most active compound, the aza-derivative of fragransin A2, IC50 5.1 μM against a human breast cancer cell line.