Synthesising nature's molecules
Natural substances are important sources of biologically important molecules for treating disease. Over 9,000 natural products, many of which exhibit biological activity, contain pyrrolidines first isolated from flowers and/or one of their derivatives, pyrrolidinones. These are nitrogen-containing heterocycles, or cyclical molecular structures whose ‘circle’ is made up of more than one type of atom, in this case one nitrogen (N) and four carbons (C). In order to exploit the therapeutic potential of pyrrolidines and pyrrolidinones, organic chemists require efficient and cost-effective synthesis procedures capable of being scaled up for commercial production. European researchers sought to develop novel transition metal-mediated and transition metal-catalysed synthesis of these compounds via funding of the ‘New methodology for the synthesis of bioactive pyrrolidines and pyrrolidinones’ (Biopyrr) project. The transition metals of choice were palladium (Pd), zinc (Zn) and manganese (Mn).The project scientists focused on five-endo and five-exo cyclisations (ways of forming five-member rings) of alkynyl amino malonates. Both Pd- and Zn-catalysed cyclisation methods produced a selectively high yield of the pure isomer of interest without contamination from the mirror-image, non-superimposable version of the same molecule. Both methods were also capable of six-exo cyclisation and synthesis of other heterocycles. Development of the former techniques led to the discovery of five-endo cyclisation of propargylic amino malonates that yielded high quantities of useful pyrroline or pyrrolinone building blocks. Given the lack of information regarding these reactions, researchers further characterised them for the formation of N-containing cycles to be used in the synthesis of carbocycles (homocycles of carbon). The novel synthesis techniques using inexpensive and non-toxic transition metals proved to be flexible, efficient, cost-effective and environmentally friendly. At the close of the project, scientists were beginning Zn-catalysed and Mn-mediated synthesis of a pyrrolidinone-based core for oxazolomycin-A synthesis. The oxazolomycin family is a class of novel bioactive compounds with antiviral, antibiotic or antibacterial and cytotoxic (anti-tumour) activity. The Biopyrr consortium has successfully developed highly efficient and cost-effective catalytic and non-catalytic synthesis methods for production of highly functionalised heterocycles including the N-containing pyrrolidines and pyrrolidinones ubiquitous in biologically active natural products.