Saturday, December 14, 2013

Limonoids: Total Synthesis of the Mexicanolides


            Construction of the polycyclic skeletal architecture of the mexicanolide class of limonoid (tetranortriterpenoid) natural products by chemical means is fraught with difficulty, even by today’s synthetic standards. In 1971, Connolly and co-workers converted an alternate tetranortriterpenoid (7-oxo-7-deacetoxykhivorin) into mexicanolide in the course of a 7-step partial synthesis. Over the next 40 years, little or no additional tactical refinements or conceptual advancements to facilitate access to the mexicanolide system were reported in the synthetic literature. Then, in 2012, Williams’ laboratory at the University of Queensland reported the first total synthesis of (-)-mexicanolide, as well as the related bicyclononanolide, (-)-khayasin. Similar to Connolly’s pioneering work, Williams’ synthetic strategy exploits putative biogenetic relationships existing between several known limonoid natural products, including azedaralide (3), cipadonoid B (9) and proceranolide (12).
            Williams’ biomimetic synthetic approach to the mexicanolides dictated condensation of the advanced optically active building blocks, azedaralide (3) and the methyl cyclohexenol ether 7. To begin, the asymmetric synthesis of 3 was enabled by implementation of a chiral borane (DIP-Cl)-controlled aldol condensation, which established the vicinal stereocenters resident in the beta-hydroxy enone 2. Intermediate 2 was then elaborated into the natural product 3 by a three-step sequence that was previously executed by the same group during their synthesis of racemic azedaralide.
            Another chiral borane-mediated enantioselective aldol reaction produced the hydroxy ketone 5, which underwent base-promoted cyclization to give 6 with minimal stereoerosion. The cyclic enone 6 was then converted into the requisite methyl enol ether 7 using methyl triflate.
            Next, a ketal-Claisen rearrangement involving the advanced optically active building blocks 3 and 7 was utilized to secure the all-carbon quaternary center resident in (-)-cipadonoid B (9). A computational investigation of the mechanistic reaction pathway leading to 9 (3 + 7 à 9) guided the optimization of the stereoselectivity and efficiency of this highly complex, one-pot, cascading transformation. The alpha-oxirane (10), derived in one step from cipadonoid B, then underwent reductive single-electron fragmentation to generate a reactive enolate species (11). The enolate 11 then engaged the proximal exocyclic olefin in an intramolecular 1,6-conjugate addition that accomplished a 6-endo-trig cyclization to fashion the mexicanolide ring skeleton of proceranolide (12). Again, the daunting complexity of the overall transformation (i.e. 10 à 12) must be acknowledged in the assessment of the seemingly moderate efficiency (30% isolated yield) of the process. The advanced intermediate 12 was successfully converted into the tetranortriterpenoid natural products (-)-mexicanolide and (-)-khayasin by straightforward redox adjustment and esterification, respectively. It should be noted that the campaign by the Williams laboratory that is described above constitutes one of only three total synthesis studies that culminated in the completion of an intact limonoid natural product. In addition to Williams’ limonoid research efforts, Steven Ley’s 79-step, 22 year total synthesis of azadirachtin and E. J. Corey’s total synthesis of azadiradione round out the remainder of the (to the best of my knowledge) comprehensive list. This astonishing fact stands as a testament to the formidable scientific challenges associated with the chemical synthesis of bioactive limonoids.

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