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.

Tuesday, November 26, 2013

Limonoids: Tandem Polycyclizations of Unsaturated Epoxynitriles

      Limonoids are oxidatively modified tetranortriterpenoid phytochemicals found in the Rutaceae and Meliaceae plant families. The most well-known and economically important genus in the Rutaceae family is Citrus. The abbreviated survey of representative limonoid structures depicted below underscores the molecular diversity contained within this bioactive class of natural products. Limonin and limonin glucoside are enriched in citrus fruits such as orange and lemon. Ongoing research programs are investigating the promising therapeutic benefits of these architecturally captivating natural products in human diseases. Oxidatively modified limonoids are terpenoids that have undergone oxidative ring fragmentation and/or rearrangement of the intact steroid-like prototypic ring skeleton. Within this limonoid subclass, examples such as xyloccensin O represent the pinnacle of molecular complexity for synthetic and medicinal chemists. Finally, azadiradione and other limonoids isolated from the Neem tree (e.g. the famous insecticide azadirachtin) are known for their potent insect antifeedant activity. Relatively few total synthesis strategies offer practical synthetic access to large quantities of complex limonoids and derivatives thereof. This post highlights a concise and stereocontrolled synthetic entry into the BCDE skeletal substructure of steroidal limonoids related to azadiradione.
          The laboratory of Fernandez-Mateos in Salamanca, Spain has recently described a remarkable titanocene(III)-promoted cascade radical cyclization  protocol that culminates in a unique 4-exo cyclization onto a nitrile to fashion a complex polycyclic carbocyclic ring skeleton, potentially suitable for subsequent elaboration into natural terpenoidal systems. For example, as shown below, homolytic cleavage of the oxirane 1, induced by in situ-generated titanocene chloride, facilitates a subsequent 6-endo radical cyclization onto the pendant olefin that proceeds in a diastereoselective fashion via a chairlike transition state. A subsequent cascade of iterative tandem cyclizations is then terminated by radical cyclization onto the nitrile to furnish the ornate tetracyclic fused cyclobutanone (2) with excellent efficiency and stereocontrol, given the complexity of the overall transformation.
          This technology has been applied to the synthesis of the azadiradione BCDE fragment, as depicted below. To begin, the racemic unsaturated epoxynitrile 3 was obtained from alpha-ionone, an aroma compound derived from the degradation of carotenoids, by a short synthetic sequence. Next, the key titanocene(III)-promoted cascade radical cyclization of 3 stereoselectively produces the tricyclic intermediate 4 in outstanding yield. Ring expansion of the cyclobutanone motif embedded within 4 is then achieved by implementation of the Buchner-Curtius-Schlotterbeck reaction, wherein nucleophilic attack on the carbonyl group is proceeded by extrusion of nitrogen gas and, finally, a 1,2-migratory rearrangement. The ring-expanded product 5 is easily decarboxylated and converted to its corresponding hydrazone derivative 6, which enables subsequent palladium-catalyzed installation of the C17 furanyl system via the intermediacy of the vinyl iodide 7. Heterolytic cleavage of the epoxide derived from 8 was then promoted by exposure to silica gel and concomitant migration of hydrogen from C16 to C17 afforded a mixture of C17 stereoisomers that was epimerized to the 17-alpha diastereomer 10 upon treatment with triethylamine. Finally, dehydrogenation to the azadiradione BCDE fragment 11 was accomplished by utilization of the well-established Grieco selenoxide elimination.