Studies of Cyclization Reactions for the Formation of Carbazole Alkaloids

Abstract

Karbazol-alkaloider er en gruppe naturstoffer kjent for sine spennende biologiske aktiviteter. Karbazol-alkaloidet Clausenalansine A ble isolert fra frukten til Clausena lansium og har vist nevrobeskyttende aktivitet mot Parkinsons sykdom. Clausenalansine A og dens analoger er derfor verdifulle ressurser i søken etter nye behandlinger for nevrodegenerative sykdommer. I denne oppgaven ble mellomprodukter mot Clausenalansine A syntetisert. Utgangsmaterialet var 3-aminofenol og 4-bromanisol. 3-Aminofenol ble beskyttet med tbutyldifenylsilyl. Produktet av denne reaksjonen var 3-((t-butyldifenylsilyl)oksy)anilin med et utbytte på 77%. Produktet reagerte med 4-bromanisol i en Buchwald-Hartwig aminering. Produktet av denne reaksjonen var 3-((t-butyldifenylsilyl)oksy)-N-(4-metoksyfenyl)anilin med et utbytte på 30%. En oksidativ krysskoblingsreaksjon ble forsøkt for å danne karbazol-enheten. Dette resulterte i produktet 2-((t-butyldifenylsilyl)oksy)-6-metoksy-9H-karbazol. Karbazolet ble avbeskyttet, og 6-metoksy-9H-karbazol-2-ol ble syntetisert med et utbytte på 5% over to trinn. Det var interessant i dette prosjektet å utforske en orto-formylering på et karbazol-derivat. Grunnet lavt utbytte ble reaksjonen utført på N(4-metoksifenyl)-3-aminofenol, som ble syntetisert fra 3-((t-butyldifenylsilyl)oksy)-N-(4-metoksyfenyl)anilin med et utbytte på 81%. Orto-formylering ga ikke ønsket produkt. En ny syntesevei til Clausenalansine A ble utforsket med 3-brom-4-nitroanisol og 4- hydroksyfenylborsyre som utgangsmaterialer. En Suzuki-kobling ble utført på 4-brom-3- nitroanisol og 4-hydroksyfenylborsyre, og 2-nitro-4-metoksy-4'-hydroksybifenyl ble isolert med kvantitativt utbytte. Det ble forsøkt å danne karbazol-enheten med en reduktiv sykliseringsreaksjon. Dette var ikke vellykket, og det ønskede produktet ble ikke observert.

Carbazole alkaloids are a group of natural products known for their exciting biological activities. The carbazole alkaloid Clausenalansine A was isolated from the fruits of Clausena lansium and was found to have neuroprotective activity against Parkinson’s disease. Clausenalansine A and its analogues are valuable resources in the search for new treatments for neurodegenerative diseases. In this thesis, intermediates towards Clausenalansine A were prepared. The starting material was 3-aminophenol and 4-bromoanisole. 3-aminophenol was protected with TBDPS. The product of this reaction was 3-((t-butyldiphenylsilyl)oxy)aniline in a yield of 77%. The product reacted with 4-bromoanisole in a Buchwald-Hartwig amination. The product of this reaction was 3-((t-butyldiphenylsilyl)oxy)-N-(4-methoxyphenyl)aniline in a yield of 30%. An oxidative cross-coupling reaction was performed to form the carbazole moiety. This led to the product 2-((t-butyldiphenylsilyl)oxy)-6-methoxy-9H-carbazole. The carbazole product was deprotected, and 6-methoxy-9H-carbazole-2-ol was synthesised with a yield of 5% over two steps. It was interesting in this project to explore the ortho-formylation reaction on a carbazole product. Due to low yields, it was instead performed on N(4-methoxyphenyl)-3-aminophenol, which was synthesized from 3-((t-butyldiphenylsilyl)oxy)-N-(4-methoxyphenyl)aniline with a yield of 81%. The ortho-formylation did not yield the desired product. A new synthesis path to Clausenalansine A was explored with 3-bromo-4-nitroanisole and 4- hydroxyphenylboronic acid as starting materials. A Suzuki coupling was performed on 4- bromo-3-nitroanisole and 4-hydroxyphenylboronic, and 2-nitro-4-methoxy-4’- hydroxybiphenyl was isolated with a quantitative yield. A reductive cyclization reaction was performed to form the carbazole moiety. This was not successful, and the desired product was not observed.