In recent years, acetyl CoA carboxylase (ACC) inhibitors have emerged as novel targets for the treatment of type II diabetes mellitus (T2DM). ACC is a key metabolic switch which regulates lipogenesis and fatty acid oxidation. To this end, we identified a series of isomeric imidazolospiroketones 1  and 2  as  ACC inhibitors. Herein, we describe concise convergent syntheses of these imidazolospiroketone cores using 4,5-diiodoimidazole and an aldehyde as the building blocks. In both cases, the two key bond formations were between C7'-C7 and C3'-C4. For 1  , the C7'-C7 was formed via an intramolecular a 1,2- addition between an imidazolomagnesium species and an aldehyde, and the C3'-C4 resulted from an intermolecular alkylation with imidazolo nitrogen. In the case of core 2  , a 1,2- addition between an imidazolomagnesium species and an aldehyde delivered the C7'-C7 bond and a tributyltin hydride-mediated aromatic homolytic substitution cyclization afforded the C3'-C4 bond.[figure1  ]

Convergent syntheses of novel isomeric imidazolospiroketones

244th National Meeting (2012)

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