PROTEAS · Programming Terpene Cyclization Through Iterative Precursor Assembly

Programming Terpene Cyclization Through Iterative Precursor Assembly

Small organic molecules represent invaluable tools for improving the quality of human life: they constitute a large fraction of the medicines currently in use, and can serve as biological probes, components of organic materials, fragrances, dyes etc. The synthesis of organic molecules however has traditionally required custom synthetic approaches that need to be carried out by trained experts, and which are often long and laborious. As already demonstrated by the rapid advances brought about by the development of automated peptide and oligonucleotide syntheses, the development of methods for the automated synthesis of custom small organic molecules from readily available building blocks would enable transformative innovation in a wide number of fields. A number of exciting advances have already been made towards this goal; the Burke group recently reported an automated platform that allows the generalized building block-based synthesis of small molecules through the use of a palladium-catalyzed coupling reaction and a special N-methyl iminodiacetic acid (MIDA) protecting group for the boronate functionality. While such an approach can be readily applied to the synthesis of many linear structures, the major challenge now lies in the assembly of complex molecular frameworks, not easily reducible to individual building blocks. Importantly, Nature solves this problem by constructing modular linear structures that are then cyclized to form complex cyclic frameworks. One such reaction is the Tail-to-Head Terpene (THT) cyclization, which features in the biosynthesis of most terpenes and accounts for a large portion of the remarkable structural diversity this class of natural products displays. Despite the synthetic potential of this reaction, it has proven difficult to carry out using artificial, non-enzymatic means; recently, however, the Tiefenbacher group reported the capability of a hexameric supramolecular assembly (a supramolecular “capsule”) to catalyze this reaction and form terpene natural products difficult to obtain via other methods. In this context, this project aims to combine these advances to provide a platform for the building block-based synthesis of complex terpene frameworks. A modular approach to linear THT cyclization precursors will allow for the investigation of the effects of specific changes in molecular structure on the outcome of the capsule-catalyzed cyclization reaction. The resulting understanding of the factors that govern the capsule-mediated THT cyclization reaction is expected to provide a method for the modular synthesis of complex molecular frameworks starting from a linear precursor, a result with profound implications for the future of automation in organic synthesis.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз