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Abstract

Following the recently published synthesis of nominal Njaoamine I,[4] it was decided to synthetize a new member of this family: Njaoamine C. This natural product differs from Njaoamine I by hydroxylation at the C8-position of the quinoline core. Moreover, the northern macrocycle is a 15-membered cycle instead of a 17-membered cycle and the cycle contains an alkene not an alkyne. These differences offer both opportunities and challenges. Following the work of Dr. Meng et. al.[4] it was possible to synthesize the tricyclic core of the natural product up to the step before the connection of both fragments. For the synthesis of the quinoline-fragment, two strategies were envisaged. It was first planned to synthesize the unfunctionalized quinoline fragment using the same route previously developed for Njaoamine I[4] and to introduce the required hydroxy group via a late-stage C-H activation. We reproduced this already reported work and several unfunctionalized quinoline intermediates were synthesized to perform several tests of C-H activation. However, the tests seemed to show that the reaction conditions for the C8-borylation of the quinoline might not be compatible with our substrate.
In parallel, we also investigated an alternative strategy, starting with an already hydroxylated starting material, the commercially available 7-benzyloxyindole, to avoid the late-stage C-H activation. Although this new synthesis is lengthier, it led to the required fragment in 17 steps with an overall yield of 14%.
The synthesis is still on-going, and we are confident to synthesize the target Njaomine C in the near future and so deliver at the same time. The next example for the great robustness and opportunities of the alkyne-metathesis as method to synthesize macrocyclic natural products.