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
