Abstract:
This thesis describes synthetic efforts towards the griseusin family of anticancer agents, specifically griseusin A 40 and griseusin B 41. A flexible strategy for synthesis of the griseusins A 40 and B 41 was developed, the key step involving a Hauser-Kraus (HK) annulation between phthalide 153 and a suitably substituted enone. Initially, model griseusin A 204 was targeted to establish the conditions required for the key HK annulation step. Enone 206 was prepared via Horner-Wadsworth-Emmons (HWE) reaction between phosphonate 207 and lactone aldehyde 208. The stereochemistry in lactone aldehyde 208 was installed using a Sharpless asymmetric dihydroxylation. Unfortunately, the key HK annulation between enone 206 and phthalide 153 was unsuccessful. Enone 247 for the griseusin B model synthesis was prepared in high yields from phosphonate 207 and known aldehyde 248. The conditions employed for the HK annulation serendipitously resulted in the formation of spiroketal 254 in good yield. Subsequent side-chain manipulation followed by oxidative demethylation gave model griseusin B 245. Attention then concentrated on synthesis of the natural product griseusin B 41. The diol in phosphonate 202 was installed using a Sharpless asymmetric cis-dihydroxylation. HWE reaction between phosphonate 202 and aldehyde 248 afforded enone 265. Spiroketal 291 could be accessed by a one-pot annulation-methylation between enone 265 and phthalide 153 followed by a deprotectionspirocyclisation step. Elaboration to the spiroketal diol 296 was accomplished; however the synthesis of the natural product 42 was ultimately unsuccessful as oxidative demethylation could not be achieved.