Catalysis

Enantioselective synthesis

Natural product

Molecule

Stereoisomerism

Stereochemistry

Combinatorial chemistry

Organic chemistry

Absolute configuration

Aldimine

Stereoselectivity

Chemistry

Selectivity

Stereocenter

Nature Synthesis

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.

Catalytic stereodivergent total synthesis of amathaspiramide D