Archive for September 9, 2010

Selective C-H Hydroxylation, Halogenation, & Catalyzed by Iron and Manganese Porphyrins

By Prof. John T Groves

For many years the ‘Holy Grail’ in oxidative catalysis has been the selective functionalization of unactivated C-H bonds in complex molecules. In the case of hydroxylation, such processes could provide access to metabolites and analogs of drug molecules much the way cytochrome P450 enzymes do. As for halogenation, highly selective chlorinations are now recognized in natural product biosynthesis that are mediated by metalloenzymes such as chloroperoxidases and the non-heme enzyme Syr3. Two recent publications from the Groves group at Princeton University have made advances in biomimetic catalysis on both fronts. Aspects of this work were supported by the National Institutes of Health, the National Science Foundation and the Department of Energy.

Work by graduate student Seth Bell has led to an extraordinarily efficient and fast catalysis of C-H hydroxylation.(1) The catalyst is a water-soluble iron porphyrin that is simple to prepare and to use (A). Xanthene hydroxylationoccurred with a very large rate constant, greater than 106 M-1s-1. The highly sensitive hydroxylation product, 9-xanthydrol, could be obtained in 90% yield at 48% conversion (B). Kinetic and mechanistic analysis revealed that strong C-H bonds, up to 100 kcal/mol, could be hydroxylated with this catalyst. Notably, over oxidation, which is a normal course of events with other oxidants, was very limited in this case.

In another recent development in the Groves lab, 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 (C), the terpenoid natural product sclareolide was selectively chlorinated at a single methylene position in 42% yield, despite the large number of other sites available.(2)

1. Seth R. Bell and John T. Groves, A Highly Reactive P450 Model Compound I, J. Am. Chem. Soc., 2009, 131, 9640-9641.
2. Wei Liu and John T. Groves, Manganese Porphyrins Catalyze Selective C-H Bond Halogenations J. Am. Chem. Soc., 2010, 132, ASAP.

Blocking a amide bond hydrolysis

Blocking a amide bond hydrolysis

Understanding the fate of your lead compound can help you to design your drug candidate. In the following example Fujimoto et al. (J. Med. Chem., 2010, 53 (9), 3517-3531) after elucidation of an active minor metabolite, designed a compound that blocked the main metabolism pathway, a hydrolysis.

In the course of their FXa inhibitor drug discovery program, the authors were able to optimize the properties of their previous best compound 1 by blocking the site of amide bond hydrolysis. Indeed, compound 2 was identified as the main metabolite of compound 1 in human microsome but not in monkey. This difference made pharmacokinetic properties difficult to be predicted in human based on monkey studies. To minimize this issue the authors focused on finding new FXa inhibitors with improved stability toward hydrolysis. Metabolism studies of compound 1 showed the formation of an active minor metabolite resulting from hydroxylation, the compound 3. Additionnally, this compound showed significant decrease in hydrolysis to compound 2 in human microsome. This could resolve the issue of pharmacokinetic prediction using monkey data. Drug design work around compound 3 allowed the authors to find a clinical candidate 4 with better pharmacokinetic properties. Basaed on this example, we believe that novel approaches to synthesize metabolites are now absolutely required to better optimize lead compounds. The HepatoChem Technology platform affords such an opportunity by allowing rapid access to metabolites directly from the compound of interest in a biomimetic fashion.