Manipulation of reactive intermediates for catalysis
Creators: name: Nielsen, Christian
Publisher: name: Imperial College London
Year: 2019

description: Herein disclosed are studies towards the manipulation of reactive intermediates for catalysis. Specifically, catalytic cycles are deconstructed and the reasons for a reaction’s deficiencies are interrogated with a view to remedying these failings by making logical adjustments to the reaction conditions. In the first chapter, closure of the dead-end catalytic cycle as originally reported by Jørgensen was attempted (Scheme 1). The synthesis of the of the key Diels-Alder product was improved but elimination and consequent catalytic cycle completion was unsuccessful. The stereochemical outcome in the annulation reaction was determined leading to an alternative mechanism for catalyst turnover to be proposed. In the second chapter, the mechanism of a base catalyzed conjugate addition reaction was inspected (Scheme 2). Successful decoupling and optimization for each half of the catalytic cycle yielded an 8-fold rate increase for one turnover. However, in these modified conditions product inhibition rendered the reaction stoichiometric with respect to the Jørgensen-Hayashi catalyst. In Chapter 3, decoupling of a catalytic cycle is combined with differences in the thermodynamic stability of diastereomeric enamines to enable deracemization of α,α-disubstituted aldehydes (Scheme 3). The deracemization based upon thermodynamic differences of α,α-disubstituted aldehydes are demonstrated using proline. To allow facile catalyst recovery, an immobilized Jørgensen-Hayashi catalyst was synthesized for use in flow but found to be unable to condense with the desired fragrance aldehydes. In Chapter 4, the formation of downstream intermediates which are known to cause the erosion of enantioselectivity in the aminocatalytic asymmetric α-chlorination was successfully circumvented (Scheme 4). Modification of the reaction conditions, with the aim to stabilize the charged intermediates, allows the products to be isolated with high enantioselectivity. This method fills a gap in the literature as the aminocatalytic asymmetric α-chlorination of aldehydes previously required the application of either not commercially available or expensive reagents/catalysts. In Chapter 5, the mechanism of formation of certain furanochromanes was investigated. It had been suggested that under Brønsted acid catalysis the formation of furanochromanes occurs via a concerted process (Scheme 5). It was found that an unreported isomerization from trans to cis-fused stereoisomers takes place and a combined experimental and theoretical investigation indicated that the mechanism of formation of both stereoisomers is stepwise, involving a carbocationic intermediate. Modification of the reaction conditions to stabilize this carbocationic intermediate lead to faster reaction rates and an expanded scope. Initial studies towards an enantioselective process were also explored. In Chapter 6, the activation of unbiased alkenes by Brønsted acids was examined. This type of reaction has presumably failed previously due to the difficulty of achieving protonation of this type of alkene and hence an inability to enter the catalytic cycle (Scheme 6). It was found that stabilization of the key carbocation intermediate allows entry into this catalytic manifold. Other C-C, C-H and C-S bond forming reactions proceeding via the same cationic intermediate are also described. Allsix of the aforementioned reactions had been reported to fail for reasonsthat are common to many would be catalytic cycles. Accordingly, they are representative of broader classes of reaction (i.e. inability or sluggish turnover, incompatible reaction conditions, downstream intermediates, mechanistic uncertainty and an inability to enter a cycle). Our tactic of decoupling elements of a catalytic cycle may therefore find wider application beyond the examples shown here.