C2 alkylated indoles are a part of many bioactive natural products such as tryprostatin A and B, which exhibit anticancer activity through cell cycle disruptions, asterriquinones which act as anticancer agents by inhibiting the binding of Grb2 adaptor protein with tyrosine-phosphorylated EGF receptor, and WIN 55,212–2 is a potent analgesic that strongly binds with cannabinoid receptors. There have been many reported transformations that introduce C2 substitution into indoles, but there is limited C2 alkylation of indoles. We have discovered a simple alkylation at the C2 position of N-protected gramines under relatively mild reaction conditions that was investigated herein. The designed transformation involves the reaction of N-protected gramines with n-BuLi and a variety of alkyl halides to produce C2, N’-dialkylated gramine salts in moderate to high yield. We demonstrated that both gramine’s methylene N and directing groups such as N-Boc of indole cooperate to facilitate C2 lithiation and provide the highest conversion to the product. This reaction was a key step in our 6-step total synthesis of a natural product, tryprostatin B, and we are currently investigating this reaction for the synthesis of novel tryprostatin analogs and other natural products.

Evaluation of an approach for the synthesis of C2 alkylated gramines

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