Studies in the synthesis of prenylated aromatics: Schweinfurthins, arieianal, and montadial

The schweinfurthins are diprenylated stilbenes isolated by Beutler et al. at the National Cancer Institute from the African plant Macaranga schweinfurthii. Schweinfurthins A, B, and D display significant and selective cytotoxicity in the NCI 60-cell line assay and based on their profile of activity, these compounds potentially represent a new type of anticancer agent. The low and variable quantities of these compounds obtained from the natural source strongly suggest the need for their synthetic preparation.;The general retrosynthetic approach to the schweinfurthins involves disconnection at the stilbene olefin via a Horner-Wadsworth-Emmons condensation. The left half aldehyde component for schweinfurthin C was prepared in 8 steps from vanillin employing a key halogen-metal exchange reaction. Condensation of this aldehyde with the phosphonate representing the right half of the natural product and global deprotection gave synthetic schweinfurthin C in 10 linear steps.;Two routes for synthesis of the tricyclic left half of schweinfurthin B were developed. A convergent route provided the intermediate 3-bromomethyl-2,2,4-trimethylcyclohex-3-enone ethylene ketal in six steps and 14% yield. Unexpected chelation effects of aluminum reagents to the ketal in both hydrocyanation and reduction reactions were encountered. While coupling of this bromide with aryllithium or arylstannane reagents was unsuccessful, coupling of an aldehyde precursor with an aryllithium reagent provided an advanced bicyclic intermediate.;A second approach to the tricyclic aldehyde was based upon a Lewis acid catalyzed cyclization of a beta-hydroxyselenide intermediate. A racemic hydroxyselenide was prepared via epoxidation of a geranylated arene, and the key cyclization step afforded a single xanthene diastereomer in 21% yield. Approaches to allow attachment of a chiral hydroxyselenide unit to the arene were explored.;Preparation of dideoxyschweinfurthin was investigated through both the cyclohexenyl pathway and by a tin catalyzed cyclization.;Arieianal, a new prenylated benzoic acid, was isolated from Piper arieianium and the structure was assigned by spectral methods. Synthetic endeavors towards arieianal have led to preparation of two cyano(homoprenyl)phosphonates. Methods for alkylation of the aromatic core also were explored. Synthesis of the closely related natural product montadial was undertaken, and a Claisen-rearrangement of O-allyl vanillin followed by oxidative cleavage has provided an advanced intermediate.