Enantiodivergent synthesis of cytotoxic styryl lactones from d-xylose. The first total synthesis of (+)- and (−)-crassalactone C

Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from d-xylose. The key steps of the synthesis of 7-epi-(+)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected dialdose, and a stereospecific furano-lactone ring formation by reaction of a related hemiacetal derivative with Meldrum's acid. Synthesis of both (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was then applied to the synthesis of the unnatural (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, as well as two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone. Their in vitro antiproliferative activities against a number of human tumour cell lines were recorded and compared with those observed for the parent natural products.