TOTAL SYNTHESIS OF HEMIBREVETOXIN-B AND (7A-ALPHA)-EPI-HEMIBREVETOXIN-B

The total synthesis of hemibrevetoxin B (1) and (7aalpha)-epi-hemibrev etoxin B (2) is described. The synthesis of the epimer (2) was achieve d through a convergent approach involving coupling of the carboxylic a cid 17 carrying the bicyclic pyran system with the hydroxy compound 31 containing the monocyclic pyran system, thionation of the resulting d iester 32 to the dithionoester 33, photolytic closure to the oxepane e nol ether 34, and hydroxy ketone cyclization to the dioxepane system 4 0. The Z-diene system was established using a selenyl-Wittig reaction followed by syn elimination of the selenoxide to the diene. The alpha- vinyl functionality was installed using the Eschenmoser's salt methodo logy. The synthesis of hemibrevetoxin B (1) was achieved through a lin ear approach involving sequential formation of the oxepane rings (65 - -> 67 --> 73) using the method of thionolactone formation followed by nucleophilic addition and regio/stereoselective hydroboration (67 --> 68, 75 --> 76). Elaboration of the side chains was carried out in a si milar fashion as described for the epimer. The stereochemistry of the ring junctures in 1 and 2 and intermediates leading to them was establ ished by X-ray crystallographic analysis carried out on compounds 45 a nd 54. Biological studies with (7aalpha)-epi-hemibrevetoxin B (2) reve aled no binding for this molecule to the brevetoxin receptors.