Stereoselective Synthesis of Boron-Containing sp3-Rich Building Blocks

Resumo

In this doctoral thesis we have focused on the development of novel approaches to obtain borylated cyclopropanes and spirocyclobutanes. These scaffolds are privileged structures in medicinal chemistry as the strained ring provides rigidity and at the same time three-dimensionality. These two properties, make them ideal fragments to explore new areas of chemical space. Moreover, the versatility of the C−B bond allows for the synthesis of a wide range of molecules from a common intermediate. In the first chapter, we reported a new route to synthetize chiral α-hydroxy cyclopropylboronates from vinyl epoxides using a copper(I) salt and a commercially available phosphine ligand. We demonstrated that our method is stereospecific and cyclopropanes with four contiguous stereocenters can be obtained by proper selection of the structural features of the starting material. In the second chapter, we described the regioselective hydroboration of spirocyclobutenes. The combination of a commercially available phosphine ligand with an inexpensive copper(I) salt provided access to different spirocyclobutylboronates as single regioisomers. Moreover, the versatility of the products was demonstrated through different functionalizations of the C−B bond. Additionally, we developed a synthetic route to prepare a bioisostere of the approved drug Donepezil. In the third chapter, we developed two approaches for the preparation of chiral spirocycles trough the diboration of spirocyclobutenes. First, we developed a transition-metal-free diboration to prepare spirocycles in a diastereoselective fashion. Then, we stablished an asymmetric version to obtain optically active spirocycles using a platinum catalyst and a phosphonite chiral ligand. Moreover, selective functionalization of the boryl moieties in the products (Suzuki-Miyaura cross-coupling, oxidation and amination) allows unique control on the directionality and nature of the substituents on the spirocycle framework and provides access to a wide variety of cyclobutyl-spirocycles from a common intermediate.