Total Synthesis of Gonytolide C

Abstract

Chromanones, particularly those containing the 2-γ-butyrolactone unit, are an emerging class of heterocycles that constitute the core of numerous pharmaceutically relevant natural products bearing both monomeric and dimeric frameworks. This thesis describes a full account of the evolution of a convergent total synthesis of gonytolide C (30a), as a representative member of the 2-γ-butyrolactone-substituted chromanone natural products, with the view that the methodology established will be applicable to the synthesise of other members of the natural chromanone family including the more complex dimers. Two synthetic strategies were explored in this work to access the 2-γ-butyrolactone-substituted chromanone core 266 of gonytolide C (30a). The initial approach hinged on carbon-carbon bond formation through intermolecular conjugate addition of a furan-based nucleophile (e.g. 132 or 241) to a chromone substrate 147. Both conventional catalysis using chiral copper(II)-complexes and the more recently developed rhodium-catalysed asymmetric 1,4-addition of boron nucleophiles (e.g. 241) were investigated. Considerable efforts were devoted to effect the desired conjugate addition, however, all attempted reactions proved inefficient and this intermolecular conjugate addition strategy was considered particularly challenging with the combination of chromone Michael acceptors and furan nucleophiles as substrates. An alternative strategy to synthesise the 2-γ-butyrolactone core 266 that involved carbon-heteroatom bond formation through intramolecular oxa-Michael addition of a hydroxyenone substrate was also attempted. Several hydroxyenone substrates (e.g. 287 and 288) were constructed and used to examine the subsequent oxa-Michael cyclisation in order to develop a viable synthetic route towards gonytolide C (30a). A convergent and flexible synthesis of the natural product together with its C-2 epimer was eventually achieved in 12 steps (longest linear sequence) from readily available commercial materials. The assembly of the core of gonytolide C (30a) relied on an Horner-Wadsworth-Emmons (HWE) olefination followed by the efficient intramolecular oxa-Michael addition. Robust and highly efficient preparations of both the phosphonate 301 and ketone coupling partner 331 for the HWE reaction were established. The spectroscopic data (NMR, HRMS, IR) and specific rotation of synthetic gonytolide C (30a) were in full agreement with those reported for the natural product. This synthetic study enabled further investigation of an asymmetric oxa-Michael cyclisation to synthesise enantioenriched 2-γ-butyrolactone chromanones and thus established a sound platform for future endeavours to achieve a stereoselective synthesis of the more complicated, chiral dimeric natural products.