Synthetic Studies Towards Purpurolide A

Abstract

Purpurolide A (37) is a sesquiterpene lactone isolated from the endophytic fungus Penicillium purpurogenum. Purpurolide A (37) exhibits anti-obesity activity, by the inhibition of pancreatic lipases, with an IC50 value of 2.83 ± 0.52 μM. Thought to be derived from the bisabolyl cation (10), purpurolide A (37) is the first natural product to arise from an oxidative cleavage of the cyclohexene ring. The novel purported biosynthesis, the resulting unprecedented 5/5/5 spirocyclic system, and the promise for an anti-obesity treatment makes purpurolide A (37) an appealing target for total synthesis. This thesis herein describes the evolution of a synthetic strategy towards the asymmetric synthesis of purpurolide A (37). The initial synthetic strategy focused on the construction of the framework from an aldol reaction between 4-methyl-2-furfural (128) and cyclopentene ester 129. Access to ester 155 was first secured from (S)-carvone by a four-step sequence, using a Favorskii rearrangement of 159 to effect the ring contraction. Unfortunately, aldol reaction of 155 with furfural (154) as a model study provided trace quantities of the conjugate addition product. In an effort to prevent the conjugate addition, the aldol reaction was attempted with cyclopentane ester 156 and aldehyde 172, however no product was observed. The aldol reaction was then attempted utilising β-ketoester 201 as an improved nucleophile for the aldol reaction, however this was also unsuccessful. A second revised overall synthetic strategy reviewed several approaches to access cyclopentene 269. The second strategy focused on use of a vinylcyclopropane-cyclopentene (VCP-CP) rearrangement of 320 or 329 to afford 270 or 330, respectively. Cyclopropanes 320 and 329 were planned to be accessed via a sulfur ylide-mediated cyclopropanation of diene 273, that unfortunately could not be effected, despite using a range of ylides. Alternatively, vinylcyclopropane (±)-375 was prepared by a six-step sequence, employing a Knoevenagel condensation which ultimately only gave minute quantities of (±)-375. The subsequent VCPCP rearrangement unfortunately did not afford cyclopentene (±)-400. Next, access to cyclopentene 269 from a bicycle such as 496 was investigated. The Danheiser annulation between allene 404 and lactones 426 or 427 proved unsuccessful. Alternatively, Michael addition of aldehyde 446 with 275 afforded malonate 483, which successfully underwent a Conia-ene reaction to give key intermediate bicycle (±)-489. The synthetic approaches investigated herein have provided important insight for future studies towards the total synthesis of purpurolide A (37). The current synthetic strategy has afforded the cyclopentane moiety with all the required functionalities for later elaboration to purpurolide A (37), which remains an ongoing synthetic pursuit of this research group.