Archive for November 9, 2010

Selective C-H Halogenation Catalyzed by Manganese Porphyrins

By Prof. John T Groves

For many years it has been thought that chlorination reactions involving C-H bonds were intrinsically unselective, especially for complex molecules. However, highly selective chlorinations are now recognized in natural product biosynthesis that are mediated by metalloenzymes such as chloroperoxidases and the non-heme enzyme Syr3. The development of a practical catalyst for such halogenations would offer numerous possibilities for late stage drug diversification or selective fluorination. A recent publication from the Groves lab at Princeton University has made an important advance in biomimetic halogenation. Aspects of this work were supported by the National Institutes of Health, the National Science Foundation and the Department of Energy.

Graduate student Wei Liu has developed a manganese catalyst that shows great promise for the C-H chlorination of complex, drug-like molecules. In one interesting example, the terpenoid natural product sclareolide was selectively chlorinated at a single methylene position in 42% yield, despite the large number of other sites available.1

1. Wei Liu and John T. Groves, Manganese Porphyrins Catalyze Selective C-H Bond Halogenations, J. Am. Chem. Soc., 2010, 132, 12847-12849.

Discovery of a New Chemical Series Based on Metabolic Rearrangement

Surprising biotransformation leading to active metabolite

The structure elucidation and biological testing of metabolites can allow for discovery of new chemical entities.

In their CB1 therapeutic program, Dr Chien-Huang Wu et al. discovered the formation of a unique metabolite resulting from a biotransformation of their lead compound 1. Surprisingly, the imide moity of that molecule undergoes metabolic N-demethylation to form the intermediate 2. This compound rearranges by cyclization to generate the imidazole-4-one 3. More interestingly, the resulting compound showed potency and was used as a starting point to develop a new chemical series. The metabolite isolation allowed for the discovery of a new chemical series.

J. Med. Chem. 2009, 52, 4496-4510