Aminas primarias, secundarias y terciarias quirales para síntesis estereoselectivade auxiliares quirales a organocatalizadores en reacciones cascada

Resumo

CHIRAL PRIMARY, SECONDARY AND TERTIARY AMINES FOR STEREOSELECTIVE SYNTHESIS: FROM CHIRAL AUXILIARIES TO ORGANOCATALYSTS IN CASCADE REACTIONS In this thesis, several synthetic strategies for obtaining enantiomerically pure compounds are described. The study is focused on the ability of certain chiral amines to promote stereoselective cascade reactions. According to the different roles that chiral amines played within the reactions, the stereoselective syntheses presented in this dissertation have been classified into four sections. Highly Stereoselective Double (R)-Phenylglycinol-induced Cyclocondensation Reactions of Symmetric Aryl Bis(oxoacids) The first double cyclocondensation reaction of (R)-phenylglycinol with aryl bis(oxoacids) has been performed to achieve aryl bis-bicyclic lactams in a highly stereoselective manner. The cyclocondensation process implied three consecutive reactions for the formation of six chemical bonds and two new stereogenic centers. The absolute configuration of the products has been unambiguously established by X-ray crystallographic analysis. Efficient cleavage of the chiral inductor by reductive opening of the oxazolidine ring and subsequent elimination of the phenylethanol moiety afforded enantiopure aryl substituted dipyrrolidines. First Asymmetric Cascade Reaction Catalysed by Chiral Primary Amino Alcohols Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael-aldol reaction. Their application in this organocascade process afforded a cyclohexanone with high levels of reactivity (up to 91% yield) and stereoselectivity (>97:3 d.r., up to 93% ee). All amino alcohol derivatives studied were able to catalyse the domino process between the benzyl benzoylacetate and the benzylideneacetone. The stereochemical outcome of the process was supported by theoretical calculations. Enantioselective Synthesis of Cyclopentene Carbaldehydes by a Direct Multicatalytic Cascade Sequence: Carbocyclization of Aldehydes with Alkynes An organocatalyst has been combined with different metals to promote a highly enantio- and diastereoselective iminium-enamine-Lewis acid catalyzed cascade sequence. Activation of an ¿,ß-unsaturated aldehyde through iminium-ion formation by using a secondary amine organocatalyst induces the Michael addition of propargylated nucleophiles. The subsequent 5-exo-dig cyclisation step involves the participation of Lewis acids to activate the alkyne toward a nucleophilic attack. After a double bond isomerization, enantiomerically pure cyclopentene carbaldehydes have been achieved. These optically active products are versatile building blocks for the synthesis fusiccocane diterpenoid analogues. Cooperative Catalysis for the First Enantioselective Formal [3+2] Cycloaddition Reaction of Isocyanoacetates to ¿,ß-Unsaturated Ketones The first enantioselective formal [3+2] cycloaddition reaction of isocyanoacetates to ¿,ß-unsaturated ketones has been developed by combining Brønsted base and Lewis acid catalysts. The polyfunctional nature of isocyanoacetates has allowed an essential double activation with cinchona alkaloid-derived organocatalysts and silver nitrate to trigger a multistep asymmetric reaction. The cooperative cascade catalysis described in this study represents a new method for the easy and rapid construction of enantioenriched 2,3-dihydropyrroles from ¿,ß-unsaturated ketones. In conclusion, the methodology developed throughout the four studies of this dissertation has contributed significantly to extending the applicability of cascade reactions for the rapid access to molecular complexity from simple key precursors. Moreover, several chiral amines have proved to be valuable tools in chemical synthesis to address new strategies for a direct entry into enantiomerically pure compounds.