Arylation of Pharmaceutically Relevant Strained Rings Using Electronically Tuned Redox-Active Esters

Strained rings are increasingly important for the design of pharmaceutical candidates due to their improved pharmacokinetic and safety profiles, as well as their ability to orient substituents into favorable geometries for the potential improvement of the binding affinity to the biological target. Despite their importance, methodologies to cross-couple strained rings have been underdeveloped. The most abundant source of strained carbocycles and heterocycles is the corresponding carboxylic acid, making methods that employ this substrate pool attractive. Coupling of these carboxylic acids with halides, a second source of abundant building blocks, would allow for rapid access to a diverse set of functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide esters, derived from the carboxylic acid in one step or in situ, with various aryl and heteroaryl halides under reductive conditions. The key to this success was the electronic modification of the NHP ester to make them less reactive, as well as the discovery of a new ligand, t-BuBpyCamCN, that avoids problematic side reactions. This method enables the incorporation of 3-membered rings, 4-membered rings, and bicyclic fragments onto (hetero)arenes derived from (hetero)aryl iodides and (hetero)aryl bromides, allowing for straightforward and direct access to arylated strained rings

Total synthesis and isolation of citrinalin and cyclopiamine congeners.

Many natural products that contain basic nitrogen atoms--for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously

Total synthesis and isolation of citrinalin and cyclopiamine congeners

It is said that carbon, the most abundant element in organic matter, supplies life’s quantity, whereas nitrogen supplies its quality. It is therefore unsurprising that many natural products that contain basic nitrogens (alkaloids) are coveted for their benefit to human health. However, nitrogen is known to mire many chemical syntheses because of its basicity and susceptibility to oxidation. This challenge may be heightened by the presence of more than one nitrogen atom in a targeted complex alkaloid, but can be met by the selective introduction and removal of functional groups that mitigate basicity, as highlighted herein with the first chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C through (13)C feeding studies, supports the existence of a common bicyclo[2.2.2]diazaoctane containing biogenetic precursor to these compounds as has been proposed previously