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Biomimetic synthesis of (−)-PF-1018 and development of photoswitchable GABAA receptor potentiators
Biomimetic synthesis of (−)-PF-1018 and development of photoswitchable GABAA receptor potentiators
Part I: The first total synthesis of (−)-PF-1018 was achieved using a biomimetic approach. The key step of the synthesis comprises an unprecedented Stille/8π electrocyclization/Diels−Alder cascade which is an exception to the ubiquitous 8π/6π electrocyclization sequence which gives rise to all the other members of the cyclooctatriene-derived natural product family, such as endiandric acids and the elysiapyrones. Part II: We describe the principles of design and the synthesis of a photoswitchable benzodiazepine. The azo-extension approach on the benzodiazepine scaffold relied on the early introduction of the azobenzene moiety at the ortho-position of the pendant phenyl ring. This resulted in the isolation of new azobenzophenone intermediates as well as the envisioned azobenzodiazepine. We also describe the design and synthesis of the first reported photoswitchable Z-drugs. The design was built on a lead compound found in a virtual screening campaign based on the benzodiazepine binding model. Again, the strategy relied on the early introduction of the azobenzene moiety, giving rise to new types of heterocyclic azobenzenes.
Diels-Alder Cycloaddition, Electrocyclization, Total Synthesis, Biomimetic Synthesis, Tetramic Acids, Cyclooctatriene Derivatives, Photopharmacology, GABAA Receptor, Azobenzene, Z-Drug, Benzodiazepine
Quintela Varela, Hugo
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Quintela Varela, Hugo (2019): Biomimetic synthesis of (−)-PF-1018 and development of photoswitchable GABAA receptor potentiators. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Part I: The first total synthesis of (−)-PF-1018 was achieved using a biomimetic approach. The key step of the synthesis comprises an unprecedented Stille/8π electrocyclization/Diels−Alder cascade which is an exception to the ubiquitous 8π/6π electrocyclization sequence which gives rise to all the other members of the cyclooctatriene-derived natural product family, such as endiandric acids and the elysiapyrones. Part II: We describe the principles of design and the synthesis of a photoswitchable benzodiazepine. The azo-extension approach on the benzodiazepine scaffold relied on the early introduction of the azobenzene moiety at the ortho-position of the pendant phenyl ring. This resulted in the isolation of new azobenzophenone intermediates as well as the envisioned azobenzodiazepine. We also describe the design and synthesis of the first reported photoswitchable Z-drugs. The design was built on a lead compound found in a virtual screening campaign based on the benzodiazepine binding model. Again, the strategy relied on the early introduction of the azobenzene moiety, giving rise to new types of heterocyclic azobenzenes.