Syntese av karbazoler : et intermediat mot Clausenalansine A

Abstract

Karbazoler er heterosykliske alkaloider som har vist å inneha spennende, biologiske egenskaper. Blant disse er clausenalansine A isolert fra planten Clausena lansium. Forbindelsen og analoger av denne har vist seg å ha nevroaktive egenskaper, og kan muligens brukes som medisin mot nevrodegenerende sykdommer som Parkinson sykdom. I denne oppgaven er det utprøvd metoder for syntese mot clausenalansine A og analoger av denne. Arbeidet har gitt beskyttelse av 4-bromfenol med TBDPS til (4-bromfenoksy)-tert-butyl-difenylsilan (1). Buchwald-Hartwig aminering av 1 og 3-metoksyanilin (2) ga N-(4-((tert-butyldifenylsilyl)oksy)fenyl)-3-metoksianilin (3) i gode utbytter, før oksidativ krysskobling til 6-((tert-butyldifenylsilyl)oksy)-2-metoksy-9H-karbazol (4) ble utprøvd. Dette ga vellykket reaksjon, men i lavere utbytte enn tidligere rapportert. Videre ble det utført vellykket kløving av metyleter til 6-((tert-butyldifenylsilyl)oksy)-9H-karbazol-2-ol (5), men det ikke var mulig å få ren forbindelse. Orto-formylering av karbazol 5 ble utprøvd med mikrobølgeoppvarming, men dette var mislykket. Beskyttelse av amin 3 ble utprøvd, og ga vellykket reaksjon til N-(4-((tert-butyldifenylsilyl)oksy)fenyl)-N-(3-metoksyfenyl)-4-nitrobenzensulfonamid (16). Oksidativ krysskobling ble prøvd ut for amin 16 i med mikrobølgeoppvarming, men dette var ikke vellykket. 3-aminofenol ble beskyttet med TBDPS i en syntese som ga 3-((tert-butyldifenylsilyl)oksy)anilin (10). Videre ble det utført Buchwald-Hartwig aminering som ga 3-((tert-butyldifenylsilyl)oksy)-N-(4-metoksyfenyl)anilin (11) i et moderat utbytte, men det var ikke mulig å få produktet rent. Oksidativ krysskobling til 2-((tert-butyldifenylsilyl)oksy)-6-metoksy-9H-karbazol (12) ble utført med mikrobølgeoppvarming i 1 time ved 140°C. Denne reaksjonen var vellykket, men ga lavt utbytte og produktet var urent. Til slutt ble det utført avbeskyttelse av fenol til 6-metoksy-9H-karbazol-2-ol (13) i en vellykket reaksjon.

Carbazoles are heterocyclic alkaloids that have shown interesting biological activities. Among these is clausenalansine A isolated from the plant Clausena lansium. This compound and its analogues have shown neuroactive traits and can possibly be used as medicine for neurodegenerative diseases such as Parkinson’s disease. In this thesis, synthetic methods toward clausenalansine A and its analogues have been investigated. Work has shown protection of 4-bromophenol with TBDPS to (4-bromophenoxy)-tert-butyldiphenylsilan (1). Buchwald-Hartwig amination of 1 and 3-metoxyaniline (2) was successful and produced N-(4-((tert-butyldiphenylsilyl)oxy)phenyl)-3-metoxyaniline (3) in good yield. Oxidative cross-coupling of compound 3 to 6-((tert-butyldiphenylsilyl)oxy)-2-metoxy-9Hcarbazole (4) was attempted. This resulted in a successful reaction, but the yield was lower than previous reported. Successful cleavage of the methyl group gave compound 6-((tertbutyldiphenylsilyl)oxy)-9H-carbazole-2-ol (5), but it was not possible to purify the product. Ortho-formylation of carbazole 5 was attempted by microwave heating, but this was not successful. Protection of amine 3 was attempted in a successful reaction to N-(4-((tertbutyldiphenylsilyl)oxy)phenyl)-N-(3-metoxyphenyl)-4-nitrobenzenesulfonamide (16). Oxidative cross-coupling of 16 was attempted by microwave heating, but this was unsuccessful. 3-aminophenol was in a synthesis protected with TBDPS producing 3-((tertbutyldiphenylsilyl)oxy)aniline (10). Then, Buchwald-Hartwig amination to 3-((tertbutyldiphenylsilyl)oxy)-N-(4-metoksyphenyl)aniline (11) was successfully executed in a moderate yield, but it was not possible to purify the product. Oxidative cross-coupling by microwave heating for 1 hour by 140°C was completed, resulting in 2-((tertbutyldiphenylsilyl)oxy)-6-metoxy-9H-carbazole (12). This reaction was successful, but yield was low, and purification not possible. For the last reaction, carbazole 12 was deprotected to 6-metoxy-9H-carbazole-2-ol (13) in a successful reaction.