Periodic Reporting for period 2 - CRAFTMOL (From Simplicity to Complexity: Crafting Molecular Architectures via Cascade Polyene Cyclizations)
Reporting period: 2023-08-01 to 2025-01-31
Polyene cyclizations are among the most powerful and intriguing chemical transformations for rapid assembly of molecular architectures. However, the very limited substitution pattern of known substrates and nature's inability to accommodate heteroatoms or substituents other than simple alkyl groups limit molecular diversity, complexity and functionality. We aim to address these limitations by investigating a series of novel heteroatom-substituted and tri/tetrasubstituted polyenes. The participation of these structural units in the cyclization will open up previously inaccessible reaction pathways and enable efficient, selective and practicable routes to anticancer, anti-inflammatory and antiviral molecules.The overall goal of this project is to realize innovative polyene cyclization pathways with unprecedented diversity, thus providing a strong boost to synthetic organic chemistry. The realization of the presented tasks will provide synthetic access to structurally complex and diverse molecular architectures that have previously eluded synthesis or required lengthy reaction sequences. We will first investigate substrates containing trisubstituted double bonds and allenes and explore their behavior in cyclizations involving a transannular/cross-termination step. The realization of this concept will provide a highly modular synthetic platform for the rapid construction of more than 15 bioactive natural products. In parallel, we will explore tetrasubstituted double bonds and allenes to realize the first synthesis of a structurally diverse family of natural products with unique biological activities.
In our initial studies, we achieved the first synthesis of a complex pimarane natural product. The key cyclization precursor was synthesized via a highly modular approach in only six steps. The developed strategy is based on a powerful polyene cyclization that establishes five stereocenters, forms four carbon-carbon bonds, and generates four six-membered rings. The final step involves a unique transannular endo termination. This transformation was unprecedented in the chemical literature. We later established a synthetic platform for the construction of complex ent-pimarane natural products that were previously inaccessible via chemical synthesis. The developed synthesis benefits from robust transformations and allows for selective late-stage diversification. Highlights include an HFIP-mediated bicyclization to establish the trans-decalin stereochemistry and an arene hydrogenation/oxidation/alkylation sequence to install the crucial C13 quaternary stereocenter. The key intermediate was prepared in 10 steps and served as a late branching point to selectively modify the A- or C-ring of the tricyclic core. In total, eight natural products were accessible in 11-16 steps from commercially available starting materials. This work represents the first divergent total synthesis of ent-pimarane natural products. The developed synthesis allowed us to prepare sufficient amounts for biological screening, which is performed in collaboration with the Koeberle group (MPI Innsbruck). To access (neo)triperifordin, we investigated a powerful cationic polyene cyclization to reach the tricyclic carbon skeleton. In this context, we will extend our studies to internal allenes and investigate their behavior in novel cyclization reactions. For the terpene alkaloid greenwaylactam A we found that the C3 position of the indole (C3 position of the "enamine" motifd) undergoes a HFIP-assisted cationic cyclization. Blocking the C3 position of the indole allowed a switch in regioselectivity and provided access to polyavolensinol via an unprecedented N-termination. This regiodivergent synthetic platform allows for the first time selective diversification via C- or N-termination.
We have also achieved the first chemical synthesis of waixenicin A, a highly potent TRPM7 ion channel inhibitor (16 nM). A sequential elongation strategy allowed selective sidechain installation and provided access to waixenicin A and enabled a biomimetic access to xeniafaraunol A. In addition, we introduced a valuable alternative to the classic Stork-Jung vinyl silane. The paved the way to access closely related natural products as well as derivatives with deep structural modifications.
In the course of our studies, we have also found reaction conditions that allow, for the first time, methyl-initiated cyclization of a wide range of substrates. In nature, the selective transfer of a methyl group to an alkene followed by cyclization involves S-adenosylmethionine (SAM)-dependent bifunctional methyltransferase cyclase (BMC) enzymes. For more than four decades, chemists have been unable to mimic BMC enzymes in the laboratory. The developed bioinspired reaction proceeds under mild conditions, is completed in less than five fours at ambient temperature, and tolerates a variety of (hetero)arenes as terminating units. The cyclization provides a variety of previously inaccessible molecular architectures in good to excellent yields. We believe that our findings are of immense interest because 1) the method is not limited by the enzymatic substrate specificity of the two known methyltransferases, and 2) the substrate scope allows escape from the canonical isoprene pattern (C5 building blocks), thus significantly expanding the chemical space.
We have also achieved the first chemical synthesis of waixenicin A, a highly potent TRPM7 ion channel inhibitor (16 nM). A sequential elongation strategy allowed selective sidechain installation and provided access to waixenicin A and enabled a biomimetic access to xeniafaraunol A. In addition, we introduced a valuable alternative to the classic Stork-Jung vinyl silane. The paved the way to access closely related natural products as well as derivatives with deep structural modifications.
In the course of our studies, we have also found reaction conditions that allow, for the first time, methyl-initiated cyclization of a wide range of substrates. In nature, the selective transfer of a methyl group to an alkene followed by cyclization involves S-adenosylmethionine (SAM)-dependent bifunctional methyltransferase cyclase (BMC) enzymes. For more than four decades, chemists have been unable to mimic BMC enzymes in the laboratory. The developed bioinspired reaction proceeds under mild conditions, is completed in less than five fours at ambient temperature, and tolerates a variety of (hetero)arenes as terminating units. The cyclization provides a variety of previously inaccessible molecular architectures in good to excellent yields. We believe that our findings are of immense interest because 1) the method is not limited by the enzymatic substrate specificity of the two known methyltransferases, and 2) the substrate scope allows escape from the canonical isoprene pattern (C5 building blocks), thus significantly expanding the chemical space.
We have discovered novel reaction pathways and developed a powerful method to mimic nature's methylcyclization reactions. This has allowed efficient synthetic access to structurally diverse molecular architectures that were previously inaccessible, and enabled deep structural modifications of natural molecules that are currently inaccessible via fermentation or semi-synthesis. We expect to find interesting biological activities for the generated compound library and plan to intensify our screening collaborations.
We have gained a better understanding of polyene cyclizations and their mode of cyclization and want to transfer this knowledge to novel substrates such as internal allenes. The work also served as inspiration to develop powerful methods and synthetic strategies beyond the polyene cyclizations studied so far. In addition, we aim to generate a library of bioactive pimarane natural products to be used in an anti-inflammatory screening campaign at the MPI Innsbruck. Natural and non-natural xenicin natural products will be screened for their TRPM inhibitory activity. The realization of a bio-inspired methyl cyclization fills a long-standing methodological gap and opens new directions for both early and late stage applications.
We have gained a better understanding of polyene cyclizations and their mode of cyclization and want to transfer this knowledge to novel substrates such as internal allenes. The work also served as inspiration to develop powerful methods and synthetic strategies beyond the polyene cyclizations studied so far. In addition, we aim to generate a library of bioactive pimarane natural products to be used in an anti-inflammatory screening campaign at the MPI Innsbruck. Natural and non-natural xenicin natural products will be screened for their TRPM inhibitory activity. The realization of a bio-inspired methyl cyclization fills a long-standing methodological gap and opens new directions for both early and late stage applications.