Enantioselective synthesis of morphine alkaloids

• Applicant: Professor Dr. Peter Metz
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 328735723

The main objective of this project is the enantioselective total synthesis of the morphine alkaloid (-)-codeine. For one, our synthesis of racemic codeine via an intramolecular nitrone cycloaddition shall be modified now in an asymmetric fashion. In this respect, the use of a chiral latent cyclohexadienone is envisaged, which is generated by introducing a temporary thiophenyl group in two complementary scenarios. Furthermore, an alternative strategy for the final steps to codeine is to be tested in order to increase the efficiency of the overall sequence. On the other hand, a first enantioselective route to the morphine alkaloid thebainone A and a conceptually novel transformation of this compound to codeine shall be developed. Again using an intramolecular nitrone cycloaddition as a key process, we were already able to construct the morphinan skeleton of the target compound in racemic form. For enantioselective synthesis, an asymmetric Heck reaction shall now be preferably used, and for conversion into codeine a concise three-step transformation of a thebainone A derivative is planned via an intermediate vinyl epoxide. Realization of this project would not only open a new access to natural morphine alkaloids but also to analogs, which can hardly or not at all be derived from the natural products.

• DFG Programme: Research Grants