Synthesis of the Multidrug Reversal Agent Ko143 and Its Parent Natural Product Fumitremorgin C

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Abstract
Ko143 is a tetracyclic, synthetic analog of the fungal metabolite fumitremorgin C. Ko143 is a potent and specific inhibitor of the membrane‐bound efflux transporter ABCG2, and it reverses ABCG2‐mediated drug resistance in cancer cells. Here, we describe an improved synthesis of Ko143 that relies on the highly selective, substrate‐controlled reduction of an imine that is formed in a Bischler–Napieralski reaction with the amide derived from 6‐methoxy‐l‐tryptophan methyl ester and isovaleric acid as a key step. We have also developed a new route to 6‐methoxy‐l‐tryptophan methyl ester from Cbz‐l‐aspartic acid methyl ester, m‐anisidine and differently substituted benzaldehydes. With p‐nitrobenzaldehyde as one of the starting materials, this route gave access to 6‐methoxy‐l‐tryptophan methyl ester in five steps and 20 % overall yield; however, it is less efficient than a previously reported synthesis of 6‐methoxy‐l‐tryptophan methyl ester from 6‐methoxy indole.
Funding Information
  • Eidgenössische Technische Hochschule Zürich

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