Flexible access to an array of optically-enriched conformationally-locked bicyclic morpholines and approaching bridged bicyclic piperazines

Over recent years, bridged heterocycles have emerged as desirable targets within the pharmaceutical industry. More specifically, pharmaceutical partners have become interested in exploring the bioactivity of bridged morpholines, as well as bridged piperazines. Despite the interest in these types of compounds, there is a lack of routes into these scaffolds which allow for diversification surrounding the core scaffold. Consequently, the focus of this study was to develop preparative access into these synthetically challenging, strained bicyclic 6,5-systems. The aim was for the developed routes to be practically accessible, robust, and indeed flexible, to allow a diverse array of compounds to be obtained. Initially, work focused on the synthesis of the bridged morpholine scaffold, with, in the first instance, a racemic route being targeted. The initial proposed bridged morpholine precursor, an α,β-unsaturated ester, was synthesised, however, the key final step to deliver the desired bridged morpholine proved to be unsuccessful. Following on from this, an alternative epoxide derivative was also prepared, but unfortunately did not deliver the corresponding bridged morpholine moiety. Following a series of computational studies, whereby the final (cyclisation) step for a variety of substrates was investigated, an alternative aldehyde precursor was explored. A successful synthesis to this compound was developed, and pleasingly this compound reacted to form the first bridged morpholine product within this programme. It was then shown that the route developed was sufficiently flexible to allow a further ten novel bridged morpholine compounds to be synthesised. Having developed a racemic synthesis, it was then decided to explore the possibility of performing the route asymmetrically. In this regard, the original racemic route was utilised with optically pure starting material, however, it was found that many steps in the racemic synthesis caused the original stereogenic center to epimerise. Through an extensive optimisation study, a route was established to deliver a key bridged morpholine scaffold without any appreciable loss in chirality. In addition, a key intermediate towards another further bridged morpholine scaffold was also obtained with an elevated enantiomeric ratio. The final part of this study focused on utilising the developed bridged morpholine synthesis to allow a range of bridged piperazines to be obtained. Although no bridged piperazines were synthesised, several key intermediates towards the desired piperazine series were obtained, which will allow for further research in this area to be continued.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2014

Author dc:creator

• Dunn, Rachael E. B.

DOI

10.48730/a2bm-gc75

Identifier

T13921

OAI identifier oai:identifier

oai:strathclyde:3f462548s