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.