Monday, July 28, 2014

Tetraquinane Total Synthesis: (−)−Crinipellin A

            In addition to steroids, the cyclopentane ring system has been discussed here in the context of ‘privileged’ molecular scaffolds for drug discovery research and development programs. Aside from favorable drug-like properties and diverse bioactivity, cyclopentanoid-based natural products such as the linear triquinanes (e.g. coriolin), are very interesting synthetic targets from the standpoint of architectural molecular complexity. The crinipellins were first isolated in 1979 from a mushroom called Crinipellis stipitaria and are the only known tetraquinane natural products. Enone-containing crinipellins (e.g. crinipellin A) exhibit potent antibacterial and anticancer biological activities. Researchers from Hee-Yoon Lee’s laboratory in Daejeon, Korea have disclosed the first total synthesis of (-)-crinipellin A starting from an optically active cyclopentane (1). The new route features a cascading sequence of tandem [3+2] cycloaddition reactions that proceed in a single operation to forge the tetracyclic core in a highly stereocontrolled fashion. Lee’s approach parallels the ‘two-phase’ strategy for terpenoid total synthesis pioneered by Phil Baran at the Scripps Research Institute. Biomimetic two-phase terpene synthesis entails an intial ‘cyclase’ phase to assemble the carbocyclic skeleton followed by a series of controlled oxidative transformations (i.e. the ‘oxidase’ phase). Along similar lines, Lee’s group first constructs the requisite tetraquinane framework (2) and then adjusts the oxidation state of five carbon centers (designated above with red circles) to complete the total synthesis of crinipellin A.
            Lee designed an intricate diazo-allene system (shown below in brackets) as a precursor to a highly reactive trimethylene-methane (TMM) diyl species, poised to undergo a cascading sequence of stereocontrolled cycloaddition reactions. A p-toluenesulfonylhydrazone (5) serves as a latent diazo group, revealed upon anion formation under basic conditions. The key step in the synthesis of 5 is an iron-catalyzed SN2′-type reaction of the epoxyalkyne 3 with an acetal-containing Grignard reagent. This reaction produces the allene 4 as an inseparable (and inconsequential) 1:1 mixture of diastereomers. Three subsequent functional group interconversions afford the requisite cycloaddition substrate 5.
            Upon exposure to sodium hydride in reluxing toluene solution, 5 undergoes intramolecular [3+2] cycloaddition to fashion an intermediary heterocyclic 5,5-fused bicyclic system. Extrusion of nitrogen then gives rise to the putative TMM diyl diradical, which engages the pendant exocyclic olefin in a second cycloaddition reaction to furnish the desired tetraquinane 2 with complete stereocontrol. According to the authors, the relative stereochemical outcome is apparently governed by conformational constraints within the tether that place the bulky silyl ether in a pseudoequatorial position in the TMM diyl cycloaddition transition state. In what some might refer to as a biomimetic ‘oxidase’ phase, the advanced intermediate 2 is finally elaborated into (-)-crinipellin A by a twelve-step sequence of controlled oxidative transformations. Lee’s group also confirmed the absolute stereochemistry of the natural product through asymmetric total synthesis.

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