Sadler, Matthew James (2011)
Ph.D. thesis, University of Birmingham.
This thesis describes the diastereoselective synthesis of 2,4,5-trisubstituted piperidines using carbonyl-ene and Prins cyclisations and their application in natural product synthesis. Following on from previous work in the group, we investigated how a preinstalled substituent in the 2-position can help to control the sense of induction at the two newly forming stereocentres.
We utilised the Prins reaction in the formal synthesis of pseudodistomin F, a marine alkaloid that posses a 2,4,5-tribsubstituted piperidine core. An initial first generation synthesis focused on the construction of a cyclisation precursor containing a crotyl-ene component, however, cyclisation with anhydrous hydrogen chloride at -78 °C resulted in side product formation, presumably resulting from the relative instability of the secondary carbocation. Changing the ene component to a prenyl group resulted in successful cyclisation to yield the trans, cis-2,4,5-trisubstituted piperidine, with diastereomeric ratios of up to 200:1. An improved second generation synthesis completed the formal synthesis of pseudodistomin F on a multi-gram scale. Progress towards the total synthesis of pseudodistomin F by a third generation synthesis was undertaken.
An investigation into how varying the electronics of the Prins reaction would alter the diastereoselectivity was conducted with a range of para-substituted cinnamyl substrates. The results indicated that selectivity in favour of the trans diastereomer was favoured as the electron withdrawing power of the substituent increased.
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