Abstract:
This thesis describes a synthetic journey that culminated in the first enantioselective total synthesis and structural revision of the natural product pestalospirane B (3). Pestalospiranes A (2) and B (3) are novel 1,9,11,18-tetraoxadispiro[6.2.6.2]octadecane spiroketal metabolites that were isolated from Pestalotiopsis virgatula inhabiting the plant Terminalia chebula. These compounds were discovered during investigations into the subculture and fermentation of Pestalotiopsis virgatula broth using a relatively new method of detection and isolation HPLCPDA- MS-SPE-NMR. The first part of this thesis describes the initial synthetic approach to pestalospiranes A (2) and B (3), which examined the use of a novel double oxidative radical cyclisation to construct the 7,6-membered spiroketal moiety of pestalospirane core 114. The first model study explored several synthetic approaches for the construction of the key substituted 1,4-dioxane intermediate 115 for application in the total synthesis of the natural products. A second model study investigated the synthesis of mono-substituted 1,4-dioxane 212 using the oxidative radical cyclisation method and demonstrated that the oxidative radical cyclisation procedure could be used to construst 7,6-membered spiroketal ring systems. Unable to access the desired intermediate 114, an alternative third model study towards the pestalospirane core 257 was devised that was based on our own proposed biosynthesis of the natural product. This strategy enabled successful construction of pestalospirane cores A (275a) and B (275b) via dimerisation of synthetic monomer 273. These investigations established a sound platform from which a total synthesis of the natural product pestalospirane B (3) could be achieved. The second part of this thesis describes considerable effort focused on identifying a suitable protecting group for the phenol group during the synthsis of the natural product. Initial attempts at late stage deprotection of isopropyl dimer 314 were unsucessful, thus a revision in protecting group strategy was enforced where access to the natural product was envisioned to allow deprotection prior to dimerisation of acetal 342. Attention, therefore focused on an acid labile protecting group that would be readily cleaved after cyclisation thereby avoiding a sensitive late-stage deprotection step to furnish the natural product. Accordingly, an EOM protecting group was chosen and ketone 334 was assembled from alkyne 339 and Weinreb amide 364b. Global deprotection of 334 under mild acidic conditions resulted in unexpected formation of ketal 342, which underwent CBS reduction and dimerisation to furnish pestalospirane B ((+)-3) as the major isomer. Interestingly, the ECD data for the proposed structure of synthetic pestalospirane B ((+)-3) and reported data of the natural product did not match. Detailed ECD and X-ray crystal structure analysis unequivovally supported the stereochemical revision of pestalospirane B (3).