Octahydroquinolines constitute the core of several natural products and active pharmaceutical ingredients. As part of our research program, we previously developed a synthetic method to access octahydroquinolines by amide activation followed by two successive intramolecular trappings with tethered carbon nucleophiles. The principal limitation to this method resides in the weak reactivity observed in the second cyclization. To broaden the scope of such a method, we used an N-Boc group as an unusual electrophilic carbon of higher reactivity. Hence, octahydroquinolines are constructed in high convergence from a dinucleophilic partner (2-methoxyallylsilane shown) and a simple linear substrate containing a carbamate and an enol ether prepared in around 5 steps from commercially available amino acids. Two cycles and three C-C bonds are created in the key step involving five consecutive one-pot transformations, namely carbamate (Boc) activation, enol ether intramolecular trapping, Prins reaction with the external dinucleophile, dealkylation (t-Bu) of the resulting iminium ion, amide activation and Vilsmeier-Haack cyclisation. We also report the innovative use of methyl enol ether moiety both as a nucleophile and an electrophile. This strategy allows substitution on the piperidine ring (R2, R3) and at the ring junction (R1), as well as the preparation of different ring sizes (n = 0-2). The resulting conjugated iminium ion is dealkylated and hydrogenation furnishes a series of functionalized aza-bicyclic compounds. A proposed reaction mechanism and an extended reaction scope will be presented.

From amino acids to octahydroquinolines: A new, facile and efficient one-pot five-transformation cascade

254th National Meeting (2017)

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