Stereospecific Cross-Coupling of Secondary sp3-Electrophiles

Pd-catalyzed cross-coupling reactions are the most straightforward and general method for carbon-carbon bond formation. The only exception to the claim of universality is the coupling of secondary sp3-hybridized electrophiles. In this proposal an innovative method concerning this problem is outlined. By varying the substructure of established BUCHWALD biarylphosphine ligands, the resulting electron-rich catalysts might be suitable for the oxidative addition of sterically hindered secondary sp3-electrophiles. For proof of concept two natural products will be synthesized with the newly developed methodology integrated.

Pd-catalyzed cross-coupling reactions are the most straightforward and general method for carbon-carbon bond formation. The only exception to the claim of universality is the coupling of secondary sp3-hybridized coupling partners. Until now, they can only be coupled under certain circumstances. The goal of this project was the development of a universal method for the coupling of secondary Csp3-electrophiles as well as nucleophiles. For the coupling of secondary Csp3-elektrophiles, BUCHWALD biarylphosphine ligands were varied in a way that the resulting electron-rich catalysts might be suitable for the oxidative addition of sterically hindered secondary sp3-electrophiles while still leaving enough room for them to access the Pd-center. Unfortunately none of the synthesized ligands showed activity in Pd-catalyzed cross coupling reactions. For the coupling of secondary Csp3-nucleophiles we could develop a series of ligand design principles that will broadly enable the continued search for practical and effective methods for stereospecific Csp3 cross-coupling reactions. We could show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp3 boronic acids. By using our new P(oBnPh)3 ligand, we were able to synthesize the natural product, xylarinic acid B, and all three of its Csp3 stereoisomers through this simple approach. This example shows that the building block based synthesis of Csp3-rich natural products or drug candidates and their isomers is possible. To synthesize more complex molecules via this synthetic strategy, bifunctional building blocks are necessary, which are then coupled together iteratively. Therefore, one of the reactive functional groups in the building block has to be masked. For Csp2 cross coupling reactions, such a protecting group is known and widely used. However, harsher coupling conditions necessary for Csp3 cross coupling reactions cleave this protecting group leading to unselective side reactions and the formation of undesired by-products. We could improve the stability of the protecting group and develop a second generation iterative synthesis platform which now also includes Csp3 cross coupling reactions. By automating this synthesis platform, faster and easier access of complex organic molecules is guaranteed and will hopefully facilitate the discovery of new applications.