Flexible access to an array of enantiomerically-enriched oxabisipidines and their use as chiral ligands in asymmetric synthesis

A broad series of optically-enriched oxabispidine scaffolds incorporating a range aryl, heteroaryl, and alkyl side arms has been successfully prepared, utilising an optically-pure common oxazine intermediate and commercially available aldehydes. In efforts towards establishing efficient access to such molecules, a fully optimised route, which is amenable to the preparation of the optically-pure oxazine on a multigram scale, has been developed. In addition to the development of a general trifluoromethanesulfonic acid-activated intramolecular Mannich-type cyclisation protocol, which is accommodating to a wide range of aldehyde substrates, alternative conditions have also been developed for more challenging substrates. More forcing conditions utilising p-toluenesulfonic acid at elevated temperatures have been utilised for highly electron-rich aldehyde substrates, whereas the employment of a benzotriazole additive was required for enolisable alkyl aldehyde substrates. In addition to the broad range of bicyclic oxabispidines prepared under the conditions described, a more synthetically challenging and structurally complex tricyclic derivative has also been successfully prepared. Further to the investigations into the scope of the developed approach to the construction of such scaffolds, efforts to confirm the proposed Mannich-type cyclisation mechanism, both experimentally and computationally, are disclosed. Additionally, a number of NMR studies have been performed to confirm the stereochemistry of the family of oxabispidine derivatives. With a library of enantiomerically-enriched oxabispidines in hand, manipulation of the nitrogen functionalities was undertaken to allow the preparation of further oxabispidine derivatives, which could have potential applications as ligands in asymmetric synthesis, as well as derivatives of interest to pharmaceutical industry partners. Following this work, a programme of research centred on the utilisation of oxabispidine scaffolds within the arena of magnesium-mediated asymmetric deprotonation processes was undertaken. Initial investigations focused on the use of the phenyl-substituted bis-secondary oxabispidine, with studies into the formation of both the corresponding magnesium bisamide and lithium amide species. Such endeavours indicated that the chiral amine species must be introduced as the bis-HCl salt. Investigations into the use of such amide base species in the deprotonation of 4-tert-butylcyclohexanone to generate the corresponding enantioenriched enol phosphate product were undertaken. Whilst under lithium-mediated conditions, promising levels of enantioselectivity could be achieved (73:27 er at -78°C), only poor to moderate yields of the desired product were attained. Similarly poor reactivity was observed with the corresponding magnesium-amide base counterpart, with no improvement in the selectivity of the deprotonation process. Altering the substituent of the oxabispidine scaffold to incorporate a more electron-donating group, and therefore a potentially more reactive magnesium amide, did not lead to the desired increase in yield. Furthermore, with a view to increasing the reactivity of the oxabispidine magnesium amide system, the employment of Nmethylated oxabispidine derivatives, bearing both phenyl and methyl side arms, was studied to allow the generation of chelating alkyl magnesium amides. As with previous oxabispidine-derived magnesium amides, these base systems were screened in the deprotonation of 4-tert-butylcyclohexanone, but again only poor yields of the enol phosphate product were recovered (≤ 25% yield at room temperature) with no significant enantioselectivity being observed, despite significant experimental efforts.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2015

Author dc:creator

• Goldie, Laura

Advisors dc:contributor.advisor

• Kerr, William
• Steven, Alan
• Gill, Duncan

DOI

10.48730/drvv-y835

Identifier

uk.bl.ethos.647865
T13983

OAI identifier oai:identifier

oai:strathclyde:jw827b762