Total Synthesis of Benthol A: Evidence for a Structure Revision

High Resolution Image Download MS PowerPoint Slide Benthol A, a dinoflagellate-derived polyol/polyether marine natural product endowed with potent antimalaria and appreciable antiviral activity, consists of a 72 C atom linear backbone featuring 35 stereogenic centers and four stereogenic alkenes. The constitution and configuration of this intriguing “super-carbon-chain compound” had been assigned by the isolation team by a combination of spectroscopic, chemical, and computational means. Outlined in this and the accompanying paper is the first total synthesis of this challenging target, which came along with a subtle structure revision. During the synthesis of the building blocks, a spectral irregularity was noticed in that the 13 C NMR chemical shifts as well as some of the 3 J H,H coupling constants of the synthetic samples deviated notably from the data reported for the entire C31–C41 region of benthol A corresponding to the tetrahydropyran E-ring and its vicinity. A systematic approach made it possible to narrow down the likely site of error to a single, incorrectly assigned stereocenter, i.e., the C40 position; interestingly, the configuration of this site had been determined by the isolation team solely by computational means. In chemical terms, our studies showed how the proper choice of a propargylic protecting group allows the regiochemical course of a gold-catalyzed spiroacetalization reaction to be steered. Moreover, carbonyl homologation by the addition of a highly functionalized but entirely unstabilized diazo derivative generated in situ to an equally highly functionalized aldehyde proved adequate for the coupling of elaborate building blocks (Buchner–Curtius–Schlotterbeck reaction).