Abstract
The various cross-coupling reactions that have emerged since the 1950’s have matured into a sophisticated, target-oriented synthetic methodology. They enable the selective and efficient formation of new C-C bonds. In this vastly growing and vibrant research area, new challenges, however, keep emerging. One such challenge addresses utilizing naturally abundant resources as feedstocks, a subject of wide importance in modern organic synthesis.
Till date, use of aliphatic polyols as electrophiles in cross-coupling reactions are not known. This substance class is particularly interesting, not just because it is renewable, but also because it contains rich stereochemical information. Thus, the selective partial transformation of polyols through cross-coupling chemistry would offer an exciting platform for organic synthesis.
Another challenge in the area of cross-coupling is the development of efficient annulation reactions to generate saturated carbo- and heterocycles using poly-nucleophilic coupling agents. Whereas the annulation of C(sp2)-hybridized bifunctional reagents is well established, the translation to saturated systems remain underdeveloped. This is largely because of competing side reactions, such as β-hydride eliminations.
In the first part of the thesis, the utilization of polyol-related molecules in cross-coupling reactions has been studied. Based on literature precedence and our current research, we have developed a platform for an intermolecular competition reaction. The goal was to identify a potent directing group (DG) to direct the oxidative addition step into a primary C(sp3)–OTs bond. A reaction with limited examples in literature. Two differently substituted tosylates were reacted in one flask under selected crosscoupling conditions with the coupling agent as a limiting factor. After quenching the reaction and analyzing the product distribution, preliminary information was acquired about potential DG (Figure x1). Through these experiments, we could identify three different DG. Pyridine was found to give exceptional selectivity in a Ni-catalyzed Kumada-Corriu cross coupling. Additionally, an alkyne and a thioether could induce moderate selectivity in a Pd-catalyzed Negishi cross-coupling. This information could be used to further develop a selective cross-coupling of C–OTs bonds, based on different reaction conditions as well as directing groups.
In a subsequent approach, a cyclization reaction was designed based on a previously developed Cu-catalyzed cross-coupling of cyclic sulfate reported by our group. The goal was to establish reaction conditions to directly transform easily accessible diols into saturated carbo- or heterocycles. Literature reported bifunctional Grignard reagents were studied in the double functionalization of cyclic sulfates (Figure x2). Unfortunately, no cyclized products could be obtained. A disadvantage to a successful reaction design was the accessibility of the Grignard-reagents. It turned out to be tedious and unreliable.
In the second part of the thesis, we studied the annulation of a dinucleophilic, 1,2-bisboronic pinacol ester with a dielectrophilic bromo-chloro biphenyl moeity. We hypothesized that after a facile first cross-coupling reaction, proximity would enhance the second coupling of a secondary boronic ester (Figure x3). This notoriously challenging second Suzuki-Miyaura cross-coupling would yield dihydrophenanthrenes, a scaffold often found in bioactive molecules. In total, nineteen dihydrophenathrenes were synthesized with the selective bond formation in good isolated yields. Through, the utilization of a bromochloro dielectrophile system, a rare example of chemoselective carbocyclization was successfully developed. Moreover, we could show the high stereospecificity of our developed reaction, due to the ability to synthesize the 1,2-bisboronic ester in an asymmetrical fashion. The rapid synthesis of dihydrophenantrenes, could lead to interesting medicinal chemistry applications. Furthermore, the possibility to facilitate the challenging cross-coupling of secondary boronic esters through proximity effects provides a new approach to this important challenge.
