Publication:

Study of the asymmetric Boekelheide rearrangement reaction for 2-alkyl pirydines

It is widely known that the biological activity of a molecule can be strongly determined by its chirality. In organic and pharmaceutical chemistry, very commonly, the synthesised compounds must be stereochemically pure due to its interest as bioactive molecules. There are several strategies for obtaining non-racemic products. In this work, the focus is on two methods: chiral auxiliary and chiral metallic catalysis. The Boekelheide rearrangement reaction is a [3,3]-sigmatropic rearrangement of pyridyl N-oxides to corresponding 2-(1-hydroxy)alkyl pyridines. Both asymmetric synthesis strategies, chiral auxiliary and chiral metallic catalysis, were applied to this reaction with the aim of inducing stereocontrol. The interest of this project relies on developing new methods for obtaining stereochemically pure compounds that could broaden knowledge in this field of organic chemistry. The limited literature about the Boekelheide rearrangement also motivatesthis work. In this Master Thesis, it has been demonstrated that the chiral auxiliary strategy was extremely efficient in the diastereoselective Boekelheide rearrangement reaction. The HPLC measurements indicate that it has been achieved excellent stereocontrol with an enantiomeric ratio of 99/1, leading to 98% enantiomeric excess for the pyridylglycol synthesised by this method. Synthetic procedures were designed to have access to all the substrates needed in this work. After each synthetic step, the products were purified by flash column chromatography, with its subsequent structural analysis by Nuclear Magnetic Resonance of 1H and 13C. Although all the synthetic pathways have given very good results, they can be widely improved in order to obtain enantiopure 2-(1-hydroxy)alkyl pyridine derivatives and is worthy of more research. Unfortunately, the chiral metallic catalysis strategy did not direct the stereocontrol of the Boekelheide rearrangement, rendering a racemate.