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Synthetic studies toward A-74528 and synthesis of cyclic azobenzenes
Synthetic studies toward A-74528 and synthesis of cyclic azobenzenes
Part I: Synthetic studies toward A-74528 With thirty carbons A-74528 is one of the two largest type II polyketides known to date. It has a promising bioactivity linked to modulating RNAse L activity and mRNA degradation as part of the innate immune system and features a set of six contiguous stereocenters, which is atypical for this type of polyketide. Two approaches toward the synthesis of A-74528 were investigated. A failed initial approach allowed identification of the most challenging reactions in the envisioned synthesis and supplied suitable model systems for studying the planned late-stage transformations. Following a revised approach, a highly advanced intermediate that already contains the full carbon skeleton of the hexacyclic core fragment of A-74528 was synthesized in a racemic fashion. Initial attempts to further evolve the most advanced synthetic intermediate toward the natural product failed and further investigations will be necessary. The key reactions of the revised approach is a highly diastereo- and regioselective molybdenum-catalyzed allylation, which enabled an efficient and convergent coupling of the two key building blocks, a ketoester and an allyl carbonate, and a gold-catalyzed alkyne activation forming the last ring system of the core fragment of A-74528. Part II: Synthesis of cyclic azobenzenes Diazocines, cyclic azobenzenes with an eight-membered ring, have distinct photophysical properties and are very promising to be useful photoswitches. However, there have been almost no applications of this type of azobenzene, due to the generally lowyielding synthesis and limited access to functionalized derivatives. To enable the use of diazocines, a new synthetic approach based on the oxidative cyclization of dianiline precursors was developed. Furthermore, methods for the synthesis of the cyclization precursors as well as the late-stage derivatization of diazocines were developed. This allowed the preparation of more than forty, diversely functionalized diazocines. The yields of the oxidative cyclization proved to be predominantly good to moderate and in general significantly better than for all previously reported methods. The photophysical properties of the obtained diazocines were compared and several trends were identified.
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Maier, Martin
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Maier, Martin (2020): Synthetic studies toward A-74528 and synthesis of cyclic azobenzenes. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Part I: Synthetic studies toward A-74528 With thirty carbons A-74528 is one of the two largest type II polyketides known to date. It has a promising bioactivity linked to modulating RNAse L activity and mRNA degradation as part of the innate immune system and features a set of six contiguous stereocenters, which is atypical for this type of polyketide. Two approaches toward the synthesis of A-74528 were investigated. A failed initial approach allowed identification of the most challenging reactions in the envisioned synthesis and supplied suitable model systems for studying the planned late-stage transformations. Following a revised approach, a highly advanced intermediate that already contains the full carbon skeleton of the hexacyclic core fragment of A-74528 was synthesized in a racemic fashion. Initial attempts to further evolve the most advanced synthetic intermediate toward the natural product failed and further investigations will be necessary. The key reactions of the revised approach is a highly diastereo- and regioselective molybdenum-catalyzed allylation, which enabled an efficient and convergent coupling of the two key building blocks, a ketoester and an allyl carbonate, and a gold-catalyzed alkyne activation forming the last ring system of the core fragment of A-74528. Part II: Synthesis of cyclic azobenzenes Diazocines, cyclic azobenzenes with an eight-membered ring, have distinct photophysical properties and are very promising to be useful photoswitches. However, there have been almost no applications of this type of azobenzene, due to the generally lowyielding synthesis and limited access to functionalized derivatives. To enable the use of diazocines, a new synthetic approach based on the oxidative cyclization of dianiline precursors was developed. Furthermore, methods for the synthesis of the cyclization precursors as well as the late-stage derivatization of diazocines were developed. This allowed the preparation of more than forty, diversely functionalized diazocines. The yields of the oxidative cyclization proved to be predominantly good to moderate and in general significantly better than for all previously reported methods. The photophysical properties of the obtained diazocines were compared and several trends were identified.