Cyclisation Strategies for the Synthesis of Novel Boron-Containing Heterocyclic Scaffolds

Heterocycles are prevalent within biologically active molecules, with >70% of FDA approved drugs featuring at least one nitrogen heterocycle. Analysis of the literature has revealed that over the past 40 years, chemists have shifted from using cyclisation reactions to incorporating cyclic motifs using pre-formed building blocks. Boronic acid derivatives represent a versatile class building blocks due to their routine preparation, scope of transformations, stability, and ease of handling. However, there is a significant disparity in the number of heterocyclic boronates reported in the literature compared with carbocyclic. This discrepancy is further exacerbated by comparisons in the availability of sp2-rich boronates compared with saturated heterocyclic building blocks.

We have developed two synthetic routes to borylated lactams using a reliable conjugate borylation/cyclisation strategy. Initial investigation of our first methodology revealed N-alkyl amino enoates cyclise upon borylation, with the resulting borylated lactams showing an intolerance to chromatographic purification. Reducing the nitrogen nucleophilicity through the preparation of N aryl amino enoates halts the cyclisation during the conjugate borylation reaction, allowing for isolation of the linear boronic ester products. Acid-mediated cyclisation then furnishes the desired lactams without the need for further purification. We have demonstrated that this process can be made enantioselective through using a Cu-catalyst ligated with a chiral phosphine ligand. Furthermore, we have shown that these scaffolds are suitable for a range of transformation including reduction to the corresponding cyclic amine and Suzuki-Miyaura coupling with aryl bromides. Building on this success, we have developed a second methodology utilising N-Boc amino enoates that allows for expanded complexity of the scaffolds such as increased ring size, substitution on the ring and alkyl or no substitution on the nitrogen. In addition to this we have optimised an enantioselective conjugate borylation procedure which furnishes boryl amino esters with excellent distereo- and enantioselectivities.

Additionally, pyridines are an important unsaturated motif within biologically active molecules, which can influence the potency and pharmacokinetic properties of the molecule. Borylated pyridines are typically obtained through Miyaura or C-H borylation. There exist relatively few examples of anulative methods to directly prepare borylated pyridines, which is surprising considering the synthetic value of these building blocks. We have expanded on the diboration/6π-electrocyclisation previously reported by Harrity and co-workers to incorporate hydrazones, as a suitable alternative to aldoxime ethers, overcoming issues observed with isomeric mixtures. Using this procedure, we have prepared three examples of the thienopyridine scaffold. We have also shown that a desilylation procedure offers improved combined yield, compared with the previously reported one step procedure, for the preparation of monosubstituted scaffolds.