The development and application of organocatalytic asymmetric epoxidation

Epoxides are widely encountered within organic and biological chemistry, being present in many secondary metabolites and pharmaceuticals. In addition, the unique functionality of the epoxide has been exploited to facilitate the synthesis of many organic molecules. A particularly attractive way to stereoselectively epoxidise a substrate is to employ an organocatalytic system. Our group has been actively pursuing research in this area for over a decade and we have developed several catalytic systems capable of excellent stereocontrol in the epoxidation of alkene substrates. In considering possible refinements to catalyst structure, we targeted two development paths: i) variation of the dihedral angle Φ within the atropos azepinium systems - shown by Lacour to strongly influence the levels of stereoinduction,1 and ii) introduction of a substituent α- to the iminium nitrogen, which we envisaged would also influence the stereochemical outcome of any process occurring at the catalytically active centre. The application of the combined optimisations to existing catalyst frameworks allowed us to create a second generation of catalyst that was capable of furnishing epoxides in ees of up to 97% for tri-substituted unfunctionalised alkenes. We observed a tangible improvement upon the previous generation, and, in explanation, we offer an in-depth discussion on the influence of α-substitution on the ratio of sp2N-sp3C rotamers, and the importance of that ratio on the improved enantiocontrol. As part of an extended research program within our group, we also report the emergence of atropisomerism of the traditionally tropos sp2C-sp2C axis contained within biphenyl systems, presumably caused by efficient stereochemical relays mediated by the α-substituent. Lastly, we were able to successfully apply our methodology in the enantioselective total synthesis of (+)-scuteflorin A.2,3 The key epoxidation step proceeded in 99% ee and 99% yield, as part of a 7-step sequence that was completed with a 14.3% overall yield. 1. R. Novikov, G. Bernardinelli, J. Lacour, Adv. Synth. Catal., 2009, 351, 596. 2. J. Li, Y. Ding, X. –C. Li, D. Ferreira, S. Khan, T. Smillie, I. A. Khan, J. Nat. Prod., 2009, 72, 983 3. C. J. Bartlett, D. Day, Y. Chan, S. M. Allin, M. J. McKenzie, A. M. Z. Slawin, P. C. B. Page, J. Org. Chem., 2012, 77, 772.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2011

Author dc:creator

• Bartlett, Chris

Language dc:language

en