Abstract
Longeracemine, a member of the Daphniphyllum family of alkaloids contains a novel carbon framework featuring a highly functionalized 2-azabicyclo[2.2.1]heptane core as part of an overall 5/6/5/5/6/5 skeleton. A synthetic intermediate containing the core of longeracemine has been efficiently prepared by employing a stereoselective SmI2-mediated cascade reaction to advance a 7-azabicyclo[2.2.1]heptadiene to a 2-azabicyclo[2.2.1]heptene that is functionally poised for conversion to the natural product.
Highlights
We report that a novel SmI2-mediated cascade reaction, involving a spirocyclization and rearrangement, affords a 2-azabicyclo[2.2.1]heptene framework that is suitably functionalized for advancement to 1 (Scheme 1c)
Advancing the derived neopentyl sulfones might be possible in a synthesis, substrates wherein sulfur is replaced by carbon were envisioned as much more viable
We considered the differences in the known bond dissociation energies (BDE) of C–H bonds adjacent to ester, sulfone, and alkyl moieties (Scheme 2c)
Summary
Since the isolation of daphnimacrine in 1909 by Yagi,1a over 320 members of the Daphniphyllum family have been isolated from evergreen shrubs and trees from southeast Asia.1 Daphniphyllum alkaloids have been shown to exhibit a wide variety of biological activities including cytotoxicity against a number of cancer cell lines, antioxidant properties, inhibition of platelet aggregation, insecticidal, and anti-HIV activity.1c,2g In addition to their promising pharmacological pro les, these alkaloids are structurally diverse and possess a plethora of polycyclic fused structures, and as such, have gained a wide-interest in the synthetic community as highly sought-a er and attractive targets for total synthesis.2 The Daphniphyllum alkaloids isolated to date, have been found to contain 35 unique carbon frameworks,2g and longeracemine, which was isolated in 2013 by Di and co-workers from the fruits of Daphniphyllum longeracemosum,3 possesses a novel structure consisting of a 2-azabicyclo[2.2.1]heptane core. Synthetic studies toward longeracemine: a SmI2mediated spirocyclization and rearrangement cascade to construct the 2-azabicyclo[2.2.1] heptane framework†
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