Development and study of aminocatalyzed asymmetric organic reactions
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Date
2021
Authors
de Carvalho Marques Dourado, Jorge Manuel
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Abstract
Chirality is an important feature that many Organic molecules possess and can have huge repercussions in the activity of Organic compounds. Therefore, the development of stereoselective methodologies in Organic chemistry has been an are of focus for many years. In the 2000s, organocatalysis emerged as an excellent tool for asymmetric synthesis and quickly received a great deal of attention by chemists namely, the field of aminocatalysis, where small amine-based chiral organic molecules could be used as catalysts to, not only activate carbonyl compounds but also, to provide the required facial differentiation during the chemical transformations these carbonyl molecules underwent and thus, produce enantioenriched products.
The activation of carbonyl compounds, namely aldehydes and ketones can take place either by increasing their nucleophilicity (enamine pathway or HOMO-activation pathway) or by increasing their electrophilicity (iminium ion pathway or LUMO-lowering pathway). These small chiral amine-based molecules are easily accessible from natural sources like amino acids and cinchona alkaloids. Taking advantage of the vinylogy principle, reactivity of the carbonyl substrates can be extended to more remote positions whilst maintaining total control over the stereo-outcome of the transformations. In more recent years, aminocatalysis has been proven to be an excellent way of achieving several cycloaddition reactions with excellent levels of enantiocontrol, yielding highly functionalyzed products bearing multiple contiguous stereocenters.
The focus of this Thesis will be in the computational study and subsequent application of aminocatalysis in the development of asymmetric pericyclic reactions, namely cycloadditions. Four projects will be discussed, starting with a DFT study (M06-2X/6-31+G(d,p)) on the aminocatalyzed induced dearomatization of heteroaromatic aldehydes which, following the results obtained, allowed us to develop two distinct approaches to the synthesis of dihydropyrido[1,2-a]indole scaffolds, either through an intramolecular Michael addition reaction or through an aza-Diels-Alder reaction.
The exploration of aminocatalysis as a tool for higher-order cycloadditions was also explored in this Thesis, by use of an oxo-fulvene system. However, this fulvene system proved troublesome to synthesize and the desired reactions were never studied.
Asymmetric Ireland-Claisen rearrangements were also explored in this Thesis using either H-bond catalysis or APTC. Unfortunately, lack of reactivity of the starting materials and side reactions failed to give the desired rearranged products.
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Keywords
Aminocatalysis, Pericyclic reactions, Fulvenes, Cycloadditions