High-Pressure in Total Synthesis

Thiocarbonyl ylides contain a positively charged sulfur atom that is connected to a carbon atom with a free lone pair. They are unstable species and react with alkenes via a [3+2]-cycloaddition reaction to afford the sulfur containing five-membered heterocycle tetrahydrothiophene. The removal of sulfur from tetrahydrothiophene is a powerful transformation that liberates the masked carbon framework. Despite the great potential of this two-step protocol, a broad application in the synthesis of bioactive molecules is currently not possible. The available thiocarbonyl ylides show very limited variability and often only undergo the [3+2]-cycloaddition with highly reactive alkenes. In this research project, we will address these limitations by synthesizing a library of variously substituted thiocarbonyl ylides and systematically investigating their [3+2]-cycloaddition reactions under high-pressure. In seminal work, it was shown that the [3+2]-cycloaddition between a simple thiocarbonyl ylides and an unreactive alkene can be efficiently promoted under high-pressure. The extension of this concept to more complex substrates will provide access to highly substituted and polycyclic molecules that are currently inaccessible. We want to explore the biological and chemical properties of these molecules and finally utilize the building blocks to accomplish the first chemical synthesis of the natural products glauconic acid and glaucanic acids, whose biological profile has not been investigated so far. The designed syntheses aim to provide sufficient quantities to screen for antibiotic, anticancer and related biological activities, and thus contribute to the development of new lead compounds for the treatment of human diseases. In addition, the synthetic platform will be used to prepare novel derivatives of the hydrocarbon ufolane, a molecule that does not occur in nature but was previously investigated as a potential rocket fuel. Ufolane possesses several isomers and chemists could only synthesize three of them in the chemical laboratory. The implementation of the thiocarbonyl ylide [3+2]-cycloaddition strategy into the synthesis of the ufolanes will provide for the first-time four out of six isomers in enantiopure form and constitutes a significant breakthrough.

This project investigated the use of thiocarbonyl ylides, sulfur-containing zwitterionic molecules, for the synthesis of heterocyclic building blocks. We found that thiocarbonyl ylides efficiently react at high pressure (5 kbar) with a variety of double bonds via a so called [3+2]-cycloaddition reaction to afford sulfur containing five-membered heterocycles. The investigation of several post-functionalizations beyond classic desulfurization reactions revealed their potential as valuable building blocks en route to pharmaceuticals such as the antipsychotic drug Tenilapine, polyfunctionalized dienes and synthetically challenging quaternary carbon centers that are part of several bioactive molecules. A broad application of this method for the latter molecules was previously not possible due to the low reactivity of many double bonds. Based on our method we produced a library of sulfur containing five-membered heterocycles and used them for the construction of the five-membered oxygen- and nitrogen-containing heterocycles furan and pyrrole, respectively. The developed process benefits from readily available chemicals and short reaction times, requires only ambient temperatures, proceeds under mild reaction conditions, and employs an inexpensive oxidant that can be easily recycled. The mechanism behind this process was studied via experimental and computational methods and was shown to involve an unprecedented key step. The realization of our concept provided not only access to highly substituted heterocycles but also polycyclic natural products (e.g., pleurotins, glauconic acid) that were previously inaccessible in the chemical laboratory. The realization of the first chemical syntheses of these natural products paves the way for a broad bioactivity screening campaign with the aim to contribute to the development of new lead compounds for the treatment of human diseases. Our work also serves as an inspiration to convert high-pressure batch processes (up to 14 kbar) into flow systems thereby enabling broad applicability of this tool across different disciplines.