Catalytic stereodivergent total synthesis of amathaspiramide D

Abstract

The configuration of biologically active molecules typically alters their physiological properties, which highlights the importance of preparing and fully characterizing all possible stereoisomers of a lead candidate or a given natural product. However, despite many advances in asymmetric synthesis, it remains challenging to completely control both the absolute and relative configuration in catalyst-mediated asymmetric reactions in which contiguous stereogenic centres are created in a single chemical transformation. Here we report a target-oriented stereodivergent propargylic substitution reaction to access four stereoisomers of amathaspiramide D and its analogues. By combining nickel and copper-catalysed stereodivergent propargylation, the key substituted 2-pyrrolidone intermediate was synthesized with excellent selectivity. The scope of the stereoselective propargylation process was demonstrated across a range of propargylic carbonate and aldimine ester substrates. The synthetic utility of the chiral propargylated α-amino ester products was shown through reductive and cyclization transformations. Making many stereogenic centres in a single step remains a challenge. Now, a combined nickel and copper-catalysed stereodivergent propargylic substitution process has been developed to access four stereoisomers of amathaspiramide D. The scope of the reaction is shown across a range of propargylic carbonate and aldimine ester substrates to generate a number of chiral propargylated α-amino ester products.