Synthetic Studies Towards the Spiroindimicins

Abstract

This thesis describes synthetic efforts towards the spiroindimicins (135-138), a family of deep sea-derived natural products, which culminated in the total syntheses of (±)-spiroindimicins B (136) and C (137). Our initial efforts sought to construct all members of the family by conducting a dearomative spirocyclization of halogenated bisindolylethanes 237/250 or 267. Ultimately, these attempts were unsuccessful, and neither the [5,6]- (249) or [5,5]- (266) spirobisindole frameworks were accessible using this methodology. In a second approach we examined the use of a Fischer indolization strategy that would construct the spirobisindole frameworks 249 and 260 from aldehydes 291 and 295, respectively. Unfortunately this strategy failed, and resulted in the unexpected side-products 292, 299, and 300. Finally, a revised approach to construct the [5,5]-spirobisindole frameworks present in spiroindimicins B-D was examined, which featured an intramolecular Heck reaction of 422 followed by Fischer indolization of 425 to furnish the [5,5]-spirobisindole 426. Upon the success of this strategy, the ketone 419 was converted to vinyl sulfone 442, which served as the precursor for a Schöllkopf-Magnus-Barton-Zard (SMBZ) reaction to install the pyrrole 445 and hence secure the entire natural product framework. Deprotection steps gave (±)- spiroindimicin C (137) which upon methylation gave (±)-spiroindimicin B (136). Efforts made towards spiroindimicin D using this methodology are also described.