Browsing by Author "Savage, Quentin R., 1997-"

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    Scalable total synthesis of (±)-hosieine A, progress towards longeracemine, and synthesis of N-Boc-3-methylpyrrole via anionic rearrangement.
    (2023-08) Savage, Quentin R., 1997-; Wood, John L. (John Louis)
    In 2014, Massiot and coworkers reported the first isolation of four alkaloids, hosieines A-D, from the roots and stems of Ormosia hosiei. These natural products possess a rarely found cytisine skeleton, and in vitro analysis showed that hosieine A had potent binding activity for the human α4β2 neuronal nicotinic receptor. In addition, hosieine A was found to be an antagonist for nicotinic acetylcholine receptors with high affinity (IC50 = 4.9 nM and Ki = 1.6 nM). The total synthesis of (±)-hosieine A is described herein. The synthesis of this natural product was accomplished in nine steps with a 9.33% overall yield, and features a gold(I) catalyzed Rautenstrauch cyclization to construct a cyclopentenone moiety that was further functionalized to the natural product. Longeracemine was isolated in 2013 by Di and coworkers from the fruits and stems of Daphniphyllum longeracemosum. Longeracemine contains a very congested azapolycyclic framework consisting of a 2-azabicyclo[2.2.1]heptane core that is not found in any other member of the Daphniphyllum alkaloid family. The complex structure also contains three contiguous, all-carbon quaternary stereocenters. To date, there has been no reported total synthesis of this natural product and its biological activity has yet to be fully explored. Synthetic progress towards assembling this natural product via a strategy featuring a key samarium(II) iodide-mediated spirocyclization reaction to construct the 2-azabicyclo[2.2.1]heptane core is described herein. During the investigation of longeracemine, an unprecedented preparation of N-Boc-3-methylpyrrole was achieved in two steps from commercially available N-Boc-hydroxylamine. This synthesis features a cheap and scalable nitroso Diels-Alder reaction and an anionic rearrangement to access the necessary synthetic components for commencement of the longeracemine synthesis.