Rhynchophylline and isorhynchophylline are oxindole alkaloids isolated from Uncaria rhynchophylla by Kondo. A recent study has shown that rhynchophylline also exerts neuroprotective effects and potential applications in the treatment of Alzheimer’s disease (AD). To further study the bioactivity of rhynchophylline, we initiated this program aim to develop a reliable and flexible chemical synthesis of enantioenriched rhynchophylline and isorhynchophylline as well as their analogs. In the first part, we summarized the prior art in the synthesis of rhynchophylline and designed a synthetic route for the asymmetric total synthesis of rhynchophylline and isorhynchophylline, which featured by the introduction of chirality using Bosch’s chiral lactam, and Carreira’s [3+2] ring-expansion...[ Read more ]

Rhynchophylline and isorhynchophylline are oxindole alkaloids isolated from Uncaria rhynchophylla by Kondo. A recent study has shown that rhynchophylline also exerts neuroprotective effects and potential applications in the treatment of Alzheimer’s disease (AD). To further study the bioactivity of rhynchophylline, we initiated this program aim to develop a reliable and flexible chemical synthesis of enantioenriched rhynchophylline and isorhynchophylline as well as their analogs. In the first part, we summarized the prior art in the synthesis of rhynchophylline and designed a synthetic route for the asymmetric total synthesis of rhynchophylline and isorhynchophylline, which featured by the introduction of chirality using Bosch’s chiral lactam, and Carreira’s [3+2] ring-expansion reaction for the construction of the tetracyclic spirooxoindole skeleton. Functional group transformation leading to the Oishi’s intermediate, which was further elaborated to rhynchophylline and isorhynchophylline in 17 and 16 steps, respectively. This strategy was then extended for the synthesis of rhynchophylline analogs, three-component reaction, and spirocyclopentane skeleton synthesis.

To address the problematic transformation in the synthesis of rhynchophylline, in the second and third part, we further explored the methodology in the synthesis of spirooxoindole natural product and simplified the synthetic route, which was featured by an intermolecular reductive Heck reaction or Michael addition-Fukuyama Reduction-Methylation sequence to introduce the methoxyacrylate moiety and direct cyclization of bromoethyloxoindole with cyclic imines. The optimized route was then applied in the collective total synthesis of rhynchophylline, isorhynchophylline, corynoxeine and isocorynoxeine. In the fourth part, we employed Aza-Achmatowicz rearrangement in the construction of enantiomerically pure α,β-unsaturated-δ-lactam featured by enzymatic resolution to introduce the chirality and a Negishi coupling to install the two-carbon unit. The resulting highly functionalized lactam was then applied in the collective asymmetric total synthesis of isocorynoxeine, corynoxeine, isorhynchophylline, rhynchophylline.