An indole core with an alkyl substituent in the C2-position serve as precursors for a variety of medicinally important alkaloids and their analogs. Some examples are Indomethacin (non-steroidal an anti-inflammatory drug commonly used for the treatment of rheumatoid arthritis), Tryprostatins A, B (act as a microtubule inhibitor), Neoechinulin A (shows anti-nitration, antioxidant and cytoprotective activity against peroxynitrite from SIN-1 in PC12 cells), and Terrequinone A (act as an antineoplastic agent). Due to the weak reactivity of the C–H bond at the C2-position of an indole, C2–H alkylation of indoles are still challenging for chemists. In 2019, our group synthesize Tryprostatin B (C-2 prenylated indole alkaloid) from gramine by only six steps. In that synthesis, our group introduced the prenyl group at the C-2 position of gramine (3-(dimethylaminomethyl)indole) by lithiation of N-Boc protected gramine followed by the addition of electrophilic prenyl bromide. This unusual procedure opens a new window to explore a variety of N-protected Gramines to synthesize C-2 substituted gramine salts by subsequent reactions with electrophiles which can be easily converted to several biologically and pharmaceutically important compounds. In our present research, we have examined several protecting groups and electrophiles to investigate the scope of this reaction and to probe the reaction mechanism.

Selective C-2 lithiation of protected gramine: Synthesis and mechanism

ACS Spring Meeting 2021

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