Cyclisation reaction of allyl alcoholscatalyzed by palladium complexes

Cilj ove doktorske disertacije bio je razvoj sintetičke metodologije za dobijanjefunkcionalizovanih bicikličnih ketona čijom daljom transformacijom bi bilo moguće sintetisatiprirodne proizvode korialstonin i korialstonidin. Sintezu pomenutih ketona moguće je ostvaritiintramolekulskom Heck-ovom reakcijom vinil-halogenida i alil-alkoholne grupe odgovarajućegpolifunkcionalizovanog ciklopentenskog derivata.Kako bi dobili uvid u faktore koji kontrolišu regioselektivnost procesa, intramolekulskuHeck-ovu reakciju najpre smo proučavali na model sistemu čijom ciklizacijom može nastatibiciklični keton (azabiciklo[4.2.1]nonan). U zavisnosti od načina ciklizacije koji u odnosu naalilnu alkoholnu funkcionalnu grupu može biti egzo i endo, postoji mogućnost dobijanjaregioizomernih proizvoda. Tokom ovih istraživanja utvrdjeno je da priroda grupa koje su vezaneza ciklopentenov prsten (etarska ili alkoholna) utiču na regioselektivnost ciklizacije, pri čemu jemoguće dobiti strukturno različite proizvode pod istim uslovima. Ciklični alilni alkoholi kojiimaju zaštićenu -OH grupu u obliku etra ciklizovani su na egzo-način. Nezaštićena alkoholnagrupa vodi nastanku endo-proizvoda ciklizacije tj. bicikličnog ketona. Proučavani su faktori kojiusmeravaju ovaj korak sa ciljem razvoja metodologije koja omogućava kontrolisanu sintezubicikličnih derivata.Razvijeni sintetički pristup primenjen je na odgovarajući cis-ciklizacioni prekursor sa alilalkoholnomgrupom u cilju sinteze bicikličnog skeleta (azabiciklo[3.2.1]oktanon) prirodnihproizvoda korialstonina i korialstonidina. Proučavanjem reakcionog puta utvrđeno je da seciklizacija odvijala na endo-način pri čemu su dobijena tri proizvoda u relativno dobrom prinosu.Ovom ciklizacijom očekivani proizvod nije dobijen. Iz tog razloga ciklični alilni alkohol jepodvrgnut oksidaciji, a potom ciklizaciji pod reduktivnim Heck-ovim uslovima. Kao jedan odproizvoda ove ciklizacije dobijen je biciklični keton koji ima azabiciklo[3.2.1]oktanski skelet.U drugom delu istraživanja razvijen je sintetički pristup policikličnim derivatima indolakoji imaju N-vinilnu grupu. Proučavane su reakcije uvođenja vinilne grupe na azotov atomindolnog prstena, kao i mogućnost anelacije dobijenih derivata reakcijom RCM...The aim of this doctoral thesis was the development of synthetic methodologies for thepreparation of functionalised bicyclo ketones whose further transformation would enable thesynthesis of natural product: corialstonidine and corialstonine. These ketones could besynthesized by an intramolecular Heck reaction of a vinyl halogenide and an allyl alcohol moietyof an appropriate polyfunctionalised cyclopentene derivative.To get insight into the elements controlling the regioselectivity the intramolecular Heckreaction was first examined on a model system whose cyclization results in thebicyclo[4.2.1]nonanon skeleton. Depending on the mode of cyclization, which in relation to theallyl alcohol functional groups can be exo and endo, regioisomeric products may be obtained.During this research it was found that the nature of substituents of the cyclopentene ring (ether oralcohol moieties) affects the regioselectivity of the cyclization, leading to different structuralproducts under the same conditions. Cyclic allylic alcohols that have a protected OH group in theform of ether are cyclized in the exo manner. The unprotected alcohol group generates endocyclization products i.e. bicyclic ketones, whose structure is the basis for the skeletons ofcorialstonidine and corialstonine. Factors that direct this step were studied with the aim ofdeveloping a methodology that would allow the controlled synthesis of bicyclic derivatives.The developed synthetic approach was applied to a corresponding cyclic allylic alcohol tosynthesise azabicyclo[3.2.1]octane, a key intermediate in the synthesis of natural productscorialstonidine and corialstonine. The study of the reaction pathway revealed that the cyclizationis carried out in the endo manner giving three products in relatively good yield. The expectedproduct was not obtained. For this reason, the cyclic allylic alcohol was oxidized, and thensubjected to cyclization under reductive Heck conditions. One of the products of this cyclizationwas a bicyclic keton, possessing the azabicyclo[3.2.1]octane skeleton.In the second part of the research, a synthetic approach to polycyclic indole derivativeswith the N-vinyl group was developed. Methods for introducing vinyl groups on the nitrogenatom of the indole ring were studied, as well as the possibility of annelating the obtainedderivatives using RCM..