Advances in amine catalysis : Brønsted acids in iminium and enamine activation

Condensation of aldehydes and ketones with primary and secondary amines results in the formation of reactive imines and iminium salts. Additionally, a loss of a proton form an iminium species leads to the formation another active intermediate: enamine. Iminium salts and enamines are more reactive than their parent compounds and thus their formation can be exploited in amine catalysis. In fact, activation of carbonyl compounds by iminium and enamine catalysis has attracted wide attention in the last decade and become a practical tool for the synthetic organic chemists. In the summary part of this thesis reactions activated via iminium ion or enamine formation are reviewed focusing on the role of the Bronsted acid co-catalyst. The described catalysts consist of a primary or secondary amine iminium or enamine catalyst and an acid co-catalyst and can often be derived from nature's chiral pool. The Bronsted acid co-catalysis plays a central role in the iminium and enamine catalysis. In the iminium catalysis the co-catalyst functions as a general acid catalyst in the iminium formation and as a general base catalyst in the some times required removal of hydrogen from the nucleophile when it has reacted to form the initial iminium intermediate. In enamine catalysis these modes are already combined in the formation of the reactive enamine species. Thereafter the co-catalyst may be used to activate and orient the approaching electrophile. In this thesis enamine catalysis was utilized in the synthesis of polypropionate building blocks by asymmetric aldol reactions. Also, combined enamine-iminium catalysis was employed in the synthesis of alpha-substituted enals, which in turn were utilized as substrates in iminium catalyzed transformations. For the iminium catalyzed transformation of alpha-substituted enals a novel aniline catalyst was developed.; Reaktiivisia imiineja ja iminiumsuoloja syntyy, kun aldehydeja ja ketoneja kondensoidaan primaaristen ja sekundaaristen amiinien kanssa. Naista imiineista voidaan lisaksi muodostaa enamiineja, kun imiinin alfa-asemasta poistetaan protoni. Seka iminiumsuolat etta enamiinit ovat reaktiivisempia kuin alkuperaiset karbonyyliyhdisteet, mika mahdollistaa niiden muodostumisen hyodyntamisen amiinien katalysoimissa reaktiossa. Iminium- ja enamiinikatalyysia tutkitaankin nykyaan laajasti seka hyodynnetaan synteettisen orgaanisen kemian tarpeisiin. Vaitoskirjan yhteenveto-osassa on tarkasteltu iminium- ja enamiinikatalysoituja reaktioita. Erityista huomiota on kiinnitetty Bronsted-happokokatalyytin rooliin. Iminium- ja enamiinikatalyytit koostuvat reaktiivisen funktionaalisuuden muodostavasta primaarisesta tai sekundaarisesta amiinista ja happokokatalyytista. Iminiumkatalyysissa kokatalyytti toimii yleisena happokatalyyttina iminium suolan muodostuksessa. Lisaksi kokatalyytti konjugaattiemas voi toimia yleisena emaskatalyyttina valivaiheiden protonisiirtoreaktioissa. Enamiinin muodostukseen tarvitaan seka kokatalyyttin yleista happo- etta emaskatalyysia. Reaktiivisen enamiinin synnyttya…