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Biomimetic synthesis of complex flavonoids from East Indian Dragon's blood & total synthesis of salimabromide
Biomimetic synthesis of complex flavonoids from East Indian Dragon's blood & total synthesis of salimabromide
East Indian Dragon’s blood – a resin from Daemonorops draco blume – has played and continues to play an enormous role in Traditional Chinese Medicine (TCM). This resin, highly priced in ancient times, is used against a variety of physical discomforts, in particular, to improve tissue generation, stimulate blood circulation and to alleviate pain. As a source of interesting and unique flavonoid natural products, renewed interest in finding biological active natural products has led to the recent isolation and characterization of the complex flavonoid trimers dragonbloodin A1 and A2. These remarkable natural products, with an unprecedented spiro hexadienone core represent the first representatives of a new class of trimeric flavonoids featuring the [3.3.1] bicyclic ketal moiety of A type proanthocyanidins. Its densely functionalized and unique structure in combination with its unknown biogenetic origin render it a highly challenging and attractive synthetic target for biomimetic synthesis approaches. Starting from phloroglucinic acid the building blocks dracorhodin perchlorate and flavan II were synthesized in a divergent route via the shared intermediate I. Trimerization under buffered conditions in a biphasic system revealed the flav-2-en containing intermediates III as intermediates towards the dragonbloodins. Exceptional sensitivity against aerial oxidation led to the investigation of the exact autoxidation products and finally revealed an unprecedented cascade reaction forging the complex skeleton of dragonbloodin A1 & A2 accompanied by endoperoxide formation towards the diastereomers IV. Reduction or hydrolysis of these peroxo semiketals gave access to a mixture of both natural products in a racemic fashion. The second part of this thesis describes the investigations on the total synthesis of salimabromide, a novel secondary metabolite from the marine myxobacterium strain enhygromyxa salina SWB007. While more than 100 natural products from terrestrial myxobacteria are known, only seven classes have been isolated from the marine counterpart. Salimabromide represents one of these classes and was only reported in 2013 from the König group. Bearing a fascinating and unprecedented carbon framework featuring two contiguous quaternary carbon centers and two aromatic bound bromide substituents, especially the difficulties in isolation and the resulting lack of material for biological studies render it an attractive and challenging target for total synthesis. Starting with inexpensive meta-anisaldehyde we were able to quickly access tetraline VI bearing both quarternary carbon centers by an unprecedented Wagner–Meerwein rearrangement/ Friedel–Crafts alkylation sequence of epoxide V. By subsequent well-orchestrated and high-yielding transformations, the ethyl side chain was introduced and all carbons of the framework assembled. A keteniminium mediated [2+2] cycloaddition affords tetracyclic cyclobutanone VIII in impressive regioselectivity and yield. A variety of late-stage oxidations including a regioselective directed Baeyer–Villiger oxidation finish the first successful total synthesis of salimabromide. By employing robust and scalable methodologies the route gives access to quantities of salimabromide in the three-digit milligram range and allows easy late-stage modifications for structure–activity relationship studies.
Total synthesis
Schmid, Matthias
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Schmid, Matthias (2019): Biomimetic synthesis of complex flavonoids from East Indian Dragon's blood & total synthesis of salimabromide. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

East Indian Dragon’s blood – a resin from Daemonorops draco blume – has played and continues to play an enormous role in Traditional Chinese Medicine (TCM). This resin, highly priced in ancient times, is used against a variety of physical discomforts, in particular, to improve tissue generation, stimulate blood circulation and to alleviate pain. As a source of interesting and unique flavonoid natural products, renewed interest in finding biological active natural products has led to the recent isolation and characterization of the complex flavonoid trimers dragonbloodin A1 and A2. These remarkable natural products, with an unprecedented spiro hexadienone core represent the first representatives of a new class of trimeric flavonoids featuring the [3.3.1] bicyclic ketal moiety of A type proanthocyanidins. Its densely functionalized and unique structure in combination with its unknown biogenetic origin render it a highly challenging and attractive synthetic target for biomimetic synthesis approaches. Starting from phloroglucinic acid the building blocks dracorhodin perchlorate and flavan II were synthesized in a divergent route via the shared intermediate I. Trimerization under buffered conditions in a biphasic system revealed the flav-2-en containing intermediates III as intermediates towards the dragonbloodins. Exceptional sensitivity against aerial oxidation led to the investigation of the exact autoxidation products and finally revealed an unprecedented cascade reaction forging the complex skeleton of dragonbloodin A1 & A2 accompanied by endoperoxide formation towards the diastereomers IV. Reduction or hydrolysis of these peroxo semiketals gave access to a mixture of both natural products in a racemic fashion. The second part of this thesis describes the investigations on the total synthesis of salimabromide, a novel secondary metabolite from the marine myxobacterium strain enhygromyxa salina SWB007. While more than 100 natural products from terrestrial myxobacteria are known, only seven classes have been isolated from the marine counterpart. Salimabromide represents one of these classes and was only reported in 2013 from the König group. Bearing a fascinating and unprecedented carbon framework featuring two contiguous quaternary carbon centers and two aromatic bound bromide substituents, especially the difficulties in isolation and the resulting lack of material for biological studies render it an attractive and challenging target for total synthesis. Starting with inexpensive meta-anisaldehyde we were able to quickly access tetraline VI bearing both quarternary carbon centers by an unprecedented Wagner–Meerwein rearrangement/ Friedel–Crafts alkylation sequence of epoxide V. By subsequent well-orchestrated and high-yielding transformations, the ethyl side chain was introduced and all carbons of the framework assembled. A keteniminium mediated [2+2] cycloaddition affords tetracyclic cyclobutanone VIII in impressive regioselectivity and yield. A variety of late-stage oxidations including a regioselective directed Baeyer–Villiger oxidation finish the first successful total synthesis of salimabromide. By employing robust and scalable methodologies the route gives access to quantities of salimabromide in the three-digit milligram range and allows easy late-stage modifications for structure–activity relationship studies.