Natural Product Synthesis and Biosynthesis
Natural products and their total synthesis
Natural products play an important role in drug discovery. More than 60% of all newly approved drugs between 1981 and 2014 derive either directly from them or are highly inspired by their structures. The evolutionary privileged structures of natural products make them superior leads, starting from which the probability to find drug candidates is much higher than from non-natural compounds. Structure activity relationship (SAR) are an integral part of drug development and represent a particular challenge in the case of complex natural products. The efficient production of derivative libraries is a demanding task that often limits the full exploitation of the pharmacological potential of natural products.
One mayor objective is improving the available methodology towards greater efficiency, while at the same time retaining maximum flexibility in the choice of the target structure. Total synthesis has taken an impressive development during the past decades leading to the situation that, in principle, any desired target molecule is accessible by chemical means. Improved efficiency has been achieved through the development of new reactions (e.g. Olefin cross metathesis), synthetic concepts (e.g. Diversity-oriented synthesis) and technologies (e.g. Flow chemistry). With its ability to introduce non-natural groups like azides and to fine-tune even the most complex structures, chemical synthesis will remain a key technology in the future.
Eribulin is a simplified but still highly complex derivative of halichondrin from Halichondria okadai. This cytotoxic drug is used to treat metastatic breast cancer. The compound is produced by total synthesis.[2,3]
Chemoenzymatic synthesis - new synthetic tools from biosynthetic pathways
Enzymes from natural product biosynthetic pathways have superior properties and are well suited for an application in the synthesis of complex natural product scaffolds (Chemoenzymatic synthesis). Of particular importance are their high selectivity, mild reaction conditions and the fact that they can be combined to one-pot-multi-enzyme cascades. These factors help to reduce the number of overall steps, for example by making redundant elaborate protection group strategies and redox transformations. Strategically speaking, their use can lead to more efficient and direct routes to natural products.
We are studying natural product biosynthetic pathways to identify new enzymes with potential applicability in chemoenzymatic synthesis. These are made accessible using molecular biological methods and then biochemically characterised, which often goes along with a detailed investigation of the biosynthetic mechanisms occurring. The required surrogates for the putative biosynthetic intermediates are obtained by stereoselective synthesis. Ultimately, chemoenzymatic synthetic routes are built around these enzymes to take maximum advantage of their favourable properties.
 D. J. Newman, G. M. Cragg, J. Nat. Prod. 2016, 79, 629–661.