Manipulation of reactive intermediates for catalysis
File(s)
Author(s)
Nielsen, Christian
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2019-09
Date Awarded
2019-12
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Spivey, Alan
Bures Amat, Jordi
Hellgardt, Klaus
Sponsor
Pharmacat
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)