Semi-synthetic transformation of 6β-acetoxyvouacapane via cascade organocatalytic reactions through trienamine activation

This work presents the progress in the semi-synthetic transformation of 6β-acetoxyvouacapane, a cassane-type diterpene isolated from Coulteria platyloba, using an organocatalytic strategy based on trienamine activation. C. platyloba is a plant of ethnopharmacological interest, with several traditional medicinal uses and a rich content of biologically relevant diterpenes.

The methodology involved the maceration of 1 Kg of dried leaves, yielding 77 g of dichloromethane extract. From this, 8.13 g of 6β-acetoxyvouacapane were successfully isolated through silica gel column chromatography. The semi-synthetic strategy includes: an oxidative aromatization of ring C to obtain an aromatic derivative, furan ring opening to generate a salicylaldehyde fragment, and then the formation of a coumarin core through a Knoevenagel condensation with diethyl malonate. From this intermediate, a nucleophilic substitution with a primary amine will be performed to obtain an amide derivative. Subsequently, this amide will undergo an organocatalytic cascade with various α,β,γ,δ-unsaturated aldehydes under trienamine activation.

As part of the preliminary studies, a Diels–Alder cycloaddition with dienals was successfully performed using the coumarin intermediate, confirming the feasibility of this step under trienamine catalysis, albeit outside of a cascade sequence. All compounds have been fully characterized by NMR and MS spectroscopy.

The first three transformations have been successfully achieved with good yields and purity. These results establish the viability of the proposed methodology for future cascade reactions aimed at generating novel scaffolds through efficient, sustainable, and stereocontrolled approaches aligned with Diversity-Oriented Synthesis (DOS) and ApDOS principles.