(Enantio-) Selective Alkylation Reactions Enabled by Cobalt Porphyrin Catalysis
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Beschreibung
Due to their versatility, porphyrins are among the most important classes of macrocyclic compounds in chemistry. Based on their intriguing and diverse properties, they have been used as transition metal catalysts for decades, e.g. in oxygenation and amination reactions. Recently, the potential of cobalt porphyrins as alkylation catalysts has been disclosed. When treated with diazo compounds, they form metal carbenes with a unique radical structure that allows for so called metalloradical catalysis (MRC).
In this context, an intramolecular cobalt-catalyzed alkylation was approached with 2-isoindolinones as substrates of choice. The requisite diazo compound was tethered to the nitrogen atom with a variable carbon chain length, thereby enabling the synthesis of saturated heterocycles (n = 5-7). Selective insertion into a C(sp3)−H bond was found to be a viable method for synthesizing 24 different products, demonstrating a high functional group tolerance for the transformation. In addition, the method was applied to a concise total synthesis of the natural product lennoxamine.
In order to facilitate an enantioselective intramolecular approach, 3,4-dihydroisoquina-zolin-2-ones were identified as possible substrates. In a similar manner as for the 2-isoindolinones, a varying alkyl tether was attached to the 3-position of the substrate. The conversion to the corresponding saturated heterocycles proceeded smoothly with an achiral cobalt porphyrin catalyst (27 examples, n = 5-7). Gratifyingly, the same reaction was observed with a nonsymmetric cobalt porphyrin that possessed a chiral lactam motif, which allowed for two-point hydrogen bonding with the substrate, resulting in an enantiomeric excess of up to 99%. Inspired by this excellent catalytic performance, mechanistic analyses of the transformation were performed, including deuteration experiments, DFT calculations, and NMR titrations.
Autor*in
Christoph Buchelt
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Organische Chemie Dissertation Technische Universität München