Development of α’-hydroxy enones as Michael acceptors for organocatalytic enantioselective conjugate addition of aldehydes and α-branched nitroalkanes

The development of catalyst-controlled enantioselective conjugate addition methods has experienced spectacular progress nowadays, in part due to implementation of organocatalytic activation strategies, both covalent and non-covalent. Despite huge advances in the field, state of the art methods still present limitations and as such cannot address every single synthetic challenge. For example, while nitroalkenes have been widely used as Michael acceptors in a wide variety of organocatalytic enantioselective conjugate additions, other acceptors such as α,- unsaturated carbonyl compounds have been less commonly used, probably due to their lower reactivity. Among them, simple acrylates in general lack reactivity in the addition of nucleophiles, making it necessary to prepare and use more reactive acrylates or to employ more elaborate catalysts that lead to a greater activation of this acceptor. On the other hand, the Michael addition involving nitro-containing compounds as donors has been widely explored due to the versatility of the nitro group, which can be afterwards transformed into numerous functionalities. However, the asymmetric Michael addition of α-branched nitroalkanes is still a challenging reaction because this substitution generates steric hindrance that obstructs both deprotonation and the approach to the acceptor. Furthermore, a new quaternary stereocenter is formed in the reaction, which makes the stereocontrol more challenging. Moreover, in the few examples of additions of asymmetric α-branched nitroalkanes to enones reported, the nitroalkanes bear an electron-ithdrawing group at the alpha position. Presumably, the higher acidity of this kind of nitro compounds and their aptitude for catalyst two-point binding are critical for success. We hypothesized that purposely designing α’-hydroxy enones acting as acrylate surrogates may serve to solve some of the above limitations owing to their reactivity and coordinating ability, as it has been previously disclosed by our laboratory. Thus, several α’-hydroxy enones bearing different substituents at Cα’ were prepared and tested in the Michael reactions of aldehydes and α-branched nitroalkanes. In this Doctoral Thesis we have demonstrated that in contrast to simple enones, which usually require additional activation by an external H-bond donor additive or cocatalyst, α’-hydroxy enones react with enolizable aldehydes in the presence of commercially available diphenylprolinol ether catalysts (C1 or C3) as the only promoters affording adducts bearing a tertiary stereocenter, in good yields (up to 82%) and high enantioselectivity (up to 97:3 er) (Scheme 1). Ulterior transformation of adducts into carboxylic acids, ketones and aldehyde building blocks, was also carried out. Additionally, in this study we show the Michael-type enantioselective organocatalytic addition of several asymmetric α-methyl nitroalkanes to different α’-hydroxy enones using N,Ndiacylaminals (developed by our groups and successfully used in various carbon-carbon bond formation reactions) as Brønsted base/hydrogen bond catalysts (Scheme 2). α’-Hydroxy enone bearing geminal 3,5-bis(trifluoromethyl)phenyl groups showed the greatest reactivity with several α-methyl nitroalkanes at 0 °C in presence of C17 (20 mol%), achieving the products in good yield (up to 82%) and high enantiomeric ratio (up to 96:4). The elaboration of adducts into carboxylic acid, ketone, aldehyde and nitrile functionalities was also successfully assessed.