A Concise Chemoenzymatic Total Synthesis of (+)-Scandine

This project deals with the synthesis of two closely related natural products with interesting yet difficult to prepare structural properties. The exploited methods involve aspects from the field of protein chemistry (biocatalysis) as well as reactions that are enabled by the action of traces of noble metals. The joint application of these chemical reactions under the right conditions should effect the selective formation of the correct spatial structure of the target molecule. Such synergistic approaches are also of high importance in view of the efficient and environmentally benign production of biologically active molecules and drugs. The respective research aiming at the exploration of the possibilities within this interdisciplinary field is thus considered an important and integral part of (inter)national research endeavors.

In this project, strategies for the transformation of organic compounds were "copied" from nature and recreated in the laboratory to artificially produce molecules with interesting biological activities. A group of nitrogen-containing organic molecules was studied, which are formed in nature from targeted breaking of a bond or opening of a molecular ring by highly specialized biological catalysts (enzymes). This process is of great interest to chemists as it rapidly leads to major changes in the center of a molecular structure and often its biological function. In the laboratory, a series of experiments identified suitable artificial reaction conditions to build up the molecules and simulate the natural bond breaks. Among other compounds, a sequence of 16 sequential chemical reactions was found that enabled the artificial production of the compound casuarinine H for the first time. The key to success lay in the targeted cleavage of a nitrogen-carbon bond and the opening of a molecular ring. By using the appropriate plant enzymes that induce this cleavage in nature, casuarinine H could be produced even more efficiently in only nine steps. Casuarinine H is a direct precursor of the potential Alzheimer's drug huperzine A, which, however, can only be obtained from natural sources to a limited extent. The findings and results from this project thus provide a valuable basis for future chemical and/or biotechnological manufacturing processes of potential drugs such as huperzine A to make it more available to society.