Synthesis of the decalin core of codinaeopsin via an intramolecular Diels–Alder reaction

Abstract

We describe the synthesis of the decalin core of codinaeopsin (1), a tryptophan-polyketide hybrid natural product with promising antimalarial activity (IC₅₀ 4.7 μM, against Plasmodium falciparum), via an intramolecular Diels–Alder (IMDA) reaction. A convergent synthesis was developed to prepare the precursors for the IMDA reaction in 10 steps. The exo cycloadducts were derived from thermal, IMDA reactions of the substrates containing a Weinreb amide or ester conjugated dienophile, and the endo adducts were from Lewis acid promoted reactions of the substrates with a formyl group. Both exo and endo products of the IMDA were exclusively isolated and characterized by NMR spectroscopy. One endo cycloadduct was further confirmed with X-ray crystallography. Theoretical calculations reveal the influence of the substituents of the decalin core on the IMDA process.