Skoulikas, Michail (2020) Novel Morpholine-Based MTORC Inhibitors as Anti-Tumour Agents. Masters thesis, University of Huddersfield.

The mammalian target of rapamycin (mTOR) kinase has been widely studied over the
past years due to its involvement on cell growth and proliferation on cancer cell lines. A
common structural motif of some potent ATP-competitive inhibitors of mTOR is the bridgedmorpholine
ring attached to various heteroaromatics, such as the thienopyrimidine ring.
However, there are no reported compounds that have the bridged-morpholine ring connected
to the heteroaromatic moiety via a carbon-carbon bond.

This report describes a method to prepare the bridged-morpholine moiety, starting from
simple commercially available materials. The key C-C bond next to the nitrogen was made
via an iminium ion intermediate and the use of simple Grignard reagents, such as
methylmagnesium bromide and ethylmagnesium bromide, in the presence of a boron
trifluoride etherate. Although the exact configuration of the formed C-C bond was not
assigned, evidence suggests that it was obtained as a single diastereomer in the case of the
ethyl substituted compound and as a mixture of diastereomers in the case of the methyl
substituted compound. In addition, attempt to introduce an aryl substituent was made via
Grignard chemistry, but the reaction was not as regioselective as in the case of alkyl groups.

In addition, C-N linked morpholine and bridged-morpholine containing
thienopyrimidine derivatives, which are known to be potent and selective mTOR inhibitors,
were made in order to be used as a reference point for mTOR inhibition.

FINAL THESIS - Skoulikas.pdf - Accepted Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

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