Total synthesis of (−)-herquline B and (+)-C, total synthesis of phyllantidine, and synthetic studies toward longeracemine.


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In 1996, O̅mura and co-workers reported the isolation of herqulines A and B from Penicillium herquei Fg-372. Preliminary evidence from these studies suggested tyrosine as a biosynthetic precursor to both congeners, and screens for biological activity revealed them to be inhibitors of platelet activating factor (PAF) induced aggregation (IC50 = 240 and 180 μM respectively), and relatively potent inhibition was observed toward adenosine diphosphate (ADP) induced aggregation (IC50 = 5.0 and 1.6 μM respectively). The total syntheses of (−)-herquline B and a heretofore-unrecognized congener, (+)-herquline C are described. The syntheses require 14 and 13 steps, respectively, and feature a key oxazoline reduction that sets the stage for piperazine construction. Phyllantidine (aka. Phylanthidine) was isolated in 1965 from the root bark of Phyllanthus discoides. Phyllantidine’s unique tetrahydro-1,2-oxazine ring-based structure shows leishmanicidal activity, decreasing the growth rate of promastigotes and amastigotes by 67.68% (IC50 353 µM) and 83.96% (IC50 210 µM) respectively without significant cytotoxicity toward mammalian cells (CC50 5268 µM). In addition, a separate study showed that phyllantidine inhibits NO production in lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells (IC50 12.1 µM), suggesting that it displays anti-inflammatory properties. Our efforts toward the development of a recently reported acyloxynitroso ring expansion reaction have culminated in the development of a 12-step total synthesis of phyllantidine from 1,4-cyclohexadiene, enabling further biological evaluation of phyllantidine and related analogues while providing insight into the synthetic utility of acyloxynitroso ring expansion in complex molecule synthesis. The developed synthetic route was also diverged to allosecurinine, a congener of phyllantidine, via Beckmann rearrangement. Longeracemine was isolated in 2013 from the fruits of Daphniphyllum longeracemosum and was found to possess an unprecedented 2-azabicyclo[2.2.1] core substituted with three contiguous quaternary centers. While longeracemine’s biological role remains unexplored, its unprecedented and sterically congested azabicyclic ring system inspired us to pursue its total synthesis. Our synthetic studies have culminated in the successful implementation of a 3H-pyrrole [4+2] cycloaddition that delivers a longeracemine-like azabicycle containing three contiguous quaternary stereocenters.



Total Synthesis. Alkaloid.