Mechanistic investigations of organocatalytic and gold-catalyzed reactions and synthetic approach towards a chiral bifunctional catalyst

Abstract

The first part of this thesis focuses on the mechanistic studies of an intermolecular cyclization reaction between an α,β-unsaturated aldehyde and an electron deficient primary alkyne to a cyclopentene carbaldehyde. Based on the concept of dual activation, a combination of a chiral secondary amine and a gold(I) catalyst are applied to induce the reaction. Precisely, the <em>L</em>-proline-derived base catalyst first enables a 1,4-addition of both substrates (Michael addition). Afterwards, a 5-<em>exo-dig</em>-cyclization occurs. Since the mechanism of the first reaction is already well explored, this thesis mainly focuses on the cyclization process. To obtain information of the mechanistic events, reaction monitoring was performed <em>via</em> a combination of ESI-MS and GC-MS. By means of ESI-MS, it was possible to detect transient species directly from the reaction solution. On one hand, the ESI-MS experiments enabled simultaneous detection of many components. On the other hand, this technique could not deliver precise information about the species’ concentration in solution. As a consequence, the kinetic behavior of the components was monitored with GC-MS measurements in parallel. <br /> At the starting point, two general mechanisms were conceivable. The first suggestions included the formation of an iminium ion that activates the aldehyde moiety in parallel to the Lewis acid activation of the primary alkyne. In the second approach, the secondary amine merely reacts as a base. Thus, only the gold(I) complex binds to the Michael product. Nevertheless, the need of assistance from the <em>L</em>-proline derivative was uncontroversial. The reaction monitoring <em>via</em> ESI-MS provided spectra containing species that were in accordance with both catalytic cycles suggested. The characterization of those species was supported by CID experiments. Additionally, an interesting deprotoaurated molecule was detected. However, the hypothesis that the gold catalyst would bind to the alkyne before the cyclization occurs could be ruled out by isotopic labeling of the primary alkyne’s proton and later by successful application of a phenyl-substituted alkyne. Thereby, it was possible to demonstrate that the scope of substrates can be extended to substituted alkynes. Interestingly, mono- and diaurated species were detected simultaneously for every substrate combination. The gold-containing molecules were observable with and without an amine attached to them. In accordance with other mechanistic studies, all species containing two gold atoms were identified as <em>gem</em>-diaurated species that emerge as product of the ESI process and do not participate in the reaction itself. Finally, base exchange experiments with pyridine and triethylamine demonstrated that binding of the <em>L</em>-proline derivative is crucial for the cyclization reaction. Thus, the iminium ion cycle was confirmed and completed. Additionally, GC-MS monitoring showed that the reaction is limited by the rate determining step (RDS) of the Michael addition which is the addition to the first iminium ion. The cyclization’s RDS could be revealed to be the release of the amine catalyst. Both RDS could be determined due to variation of the reaction solution’s pH value. <br /> Inspired by the efficiency of the dual activation reaction, attempts were made to synthesize a gold catalyst that also enables iminium and enamine formation. Precisely, it was planned to combine an N-heterocyclic carbene ligand with an <em>L</em>-proline moiety. To connect both fragments, an ether bridge with a simple alkyl chain was used that promised maximum flexibility of the ligand. With this approach, a favorable alignment of both catalytic moieties was anticipated. The first synthetic steps could be conducted successfully. Thereafter, the connection of the alkyl linker to the proline moiety proved to be challenging. At least two side products were identified by means of ESI-MS. Nevertheless, two following reaction steps were performed successfully. Even though, only small amounts of the ligand precursor could be obtained, this demonstrated that the general route is viable. However, the connection of the two fragments most probably occurs more efficiently if the leaving group is placed on the proline-fragment instead of the alkyl chain. <br /> In the third part of this thesis a kinetic study of a domino cyclization with oxidative coupling induced by aurochloric acid is presented. Prior mechanistic investigations of this working group via ESI-MS already provided insights into the mechanistic events. While simultaneous ESI-MS measurements showed no differences to the first study, reaction monitoring with quantitative UHPLC-coupled UV/Vis spectroscopy in parallel debunked the hypothesis that reaction times of several hours are required. Moreover, the reaction proved to occur too fast to be monitored by the original setup. Finally, a significant deceleration of the whole reaction was provoked by dilution of the initial reaction solution. This confirmed that the domino cyclization with oxidative coupling is terminated within minutes.