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Synthesis of nitrogen heterocycles. total synthesis of Lycopodium alkaloids and development of photoswitchable glutamate derivatives
Synthesis of nitrogen heterocycles. total synthesis of Lycopodium alkaloids and development of photoswitchable glutamate derivatives
Part I: The first part of this thesis describes efforts towards the Lycopodium alkaloids lycopladine H and lycojaponicumin D and the chemistry developed in the course of these studies. We first pursued a divergent transannular Mannich reaction from a medium-size ring precursor. Extensive screening to suppress dimerization eventually led to a ring-closing metathesis protocol that allowed us to investigate the final steps of the synthesis. An advanced tetraol could be obtained, but we were unable to access the triketone to investigate the final cyclization step. In a second approach, when trying to isomerize a terminal alkyne to the internal alkyne, we observed clean cyclization to the hydrindanone bearing an all-carbon quaternary stereocenter instead. Further investigations revealed that potassium tert-butoxide in DMSO efficiently mediates the ring closure to form a range of 5-5 and 6-5 systems. We realized that hydrindanones form the core of many Lycopodium alkaloids, such as the aromatic fawcettimine-type natural product lycoposerramine R. Leveraging our cyclization, we were able to access (−)-Lycoposerramine R in 7 steps overall including allylic oxidation to the enone to set up a Kröhnke-type pyridone synthesis. In an extension of the method, we adapted the Ciufolini pyridine synthesis to access the two pyridine-containing natural products lycopladine A and carinatine A with the fastest enantioselective syntheses to date, the latter through a newly developed telescoped biscyclization. Part II: The second part of this thesis focuses on our efforts to control glutamate receptors with light in the context of photopharmacology. We developed ATG, a photoswitchable subtype-selective agonist of NMDA receptors. ATG (azobenzene-triazole-glutamate) can be switched into its active cis-form using 740 nm light. Extensive testing in Xenopus oocytes, murine brain slices and retinae demonstrated its potential for NMDA receptor activation in vivo. To complement ATG and its functionally equivalent "cis-locked" stilbene analog STG (stilbene-triazole-glutamate), we next developed PNRA (photoswitchable NMDA receptor antagonist). This photoswitchable hydroxyquinolone-azobenzene represents the first photoswitchable antagonist of NMDA receptors. It shows unusual NMDA receptor subunit selectivity and thus represents a platform for further development. Part III: In the third part of this work, we designed and synthesized a small set of photoswitchable analogues of PPARgamma agonists based on the thiazolidinedione drug rosiglitazone. Preliminary in vitro studies demonstrated the ability to reversibly control PPARgamma with light.
Lycopodium-Alkaloide, Totalsynthese, Carbozyklisierung, Glutamat, Photopharmakologie
Hartrampf, Felix
2017
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Hartrampf, Felix (2017): Synthesis of nitrogen heterocycles: total synthesis of Lycopodium alkaloids and development of photoswitchable glutamate derivatives. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Part I: The first part of this thesis describes efforts towards the Lycopodium alkaloids lycopladine H and lycojaponicumin D and the chemistry developed in the course of these studies. We first pursued a divergent transannular Mannich reaction from a medium-size ring precursor. Extensive screening to suppress dimerization eventually led to a ring-closing metathesis protocol that allowed us to investigate the final steps of the synthesis. An advanced tetraol could be obtained, but we were unable to access the triketone to investigate the final cyclization step. In a second approach, when trying to isomerize a terminal alkyne to the internal alkyne, we observed clean cyclization to the hydrindanone bearing an all-carbon quaternary stereocenter instead. Further investigations revealed that potassium tert-butoxide in DMSO efficiently mediates the ring closure to form a range of 5-5 and 6-5 systems. We realized that hydrindanones form the core of many Lycopodium alkaloids, such as the aromatic fawcettimine-type natural product lycoposerramine R. Leveraging our cyclization, we were able to access (−)-Lycoposerramine R in 7 steps overall including allylic oxidation to the enone to set up a Kröhnke-type pyridone synthesis. In an extension of the method, we adapted the Ciufolini pyridine synthesis to access the two pyridine-containing natural products lycopladine A and carinatine A with the fastest enantioselective syntheses to date, the latter through a newly developed telescoped biscyclization. Part II: The second part of this thesis focuses on our efforts to control glutamate receptors with light in the context of photopharmacology. We developed ATG, a photoswitchable subtype-selective agonist of NMDA receptors. ATG (azobenzene-triazole-glutamate) can be switched into its active cis-form using 740 nm light. Extensive testing in Xenopus oocytes, murine brain slices and retinae demonstrated its potential for NMDA receptor activation in vivo. To complement ATG and its functionally equivalent "cis-locked" stilbene analog STG (stilbene-triazole-glutamate), we next developed PNRA (photoswitchable NMDA receptor antagonist). This photoswitchable hydroxyquinolone-azobenzene represents the first photoswitchable antagonist of NMDA receptors. It shows unusual NMDA receptor subunit selectivity and thus represents a platform for further development. Part III: In the third part of this work, we designed and synthesized a small set of photoswitchable analogues of PPARgamma agonists based on the thiazolidinedione drug rosiglitazone. Preliminary in vitro studies demonstrated the ability to reversibly control PPARgamma with light.