School of Chemistry - Theses
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ItemThe synthesis of bicyclic lactams using the concept of self-terminating radical cyclisations( 2012)This thesis explores the scope of self-terminating radical cyclisations for the synthesis of bicyclic lactams, which could be of potential pharmaceutical interest. Self-terminating radical cyclisations enable transformation of suitable alkynes to bicyclic compounds under tin-free conditions using O-centred radicals as oxidants. Firstly, β-Lactam substituted alkynes 96 were synthesised, which could undergo the NO3• induced cascade to generate bicyclic β-lactams 97. Energy and geometry calculations were performed to generate potential energy surfaces of the NO3• induced radical cascade with 96 and predicted that the reaction cascade is both thermodynamically and kinetically favourable. The success of the self-terminating radical cyclisations with the NO3• and lactam substituted alkynes relies upon the favourability of the HAT step (e.g. 98 to 99), which is the rate-determining step. Thus the presence of the ring clamp reduces the degrees of freedom of the chains to allow the vinyl radical site and hydrogen atom donor to be in favourable configurations for HAT. Thus, focus was put back on the NO3• induced cascade with other lactam substituted alkynes. In order to reduce the ring strain imposed by the β-lactam ring clamp, it was replaced with a larger ring, i.e. a γ/δ-lactam ring. Energy calculations predicted potential energy surfaces for the NO3• induced radical cascade with the lactam substituted alkynes 190 and these indeed suggested that the radical cascade became more favourable as the lactam ring increased in size. Experimental studies gave strong indications that radical reactions of NO3• with the γ/δ-lactam substituted alkynes 190a/b afforded bicyclic lactams 191a/b and 202a/b via the self-terminating radical cyclisation. Interestingly, the formation of 1,2-diketones 203a/b were also present in the reaction mixture, suggesting that the self-terminating radical cyclisation was not the most favourable pathway. The molecular formulae of the products formed in the radical reaction were confirmed with HRMS. CID analysis gave structural evidence for the bicyclic framework of the bicyclic lactam products, e.g. bicyclic δ-lactams 191b and 202b possess a [4.3] and [4.4] bicyclic framework respectively. The addition of a single O-atom to the γ/δ-lactam substituted alkynes 190a/b, observed from HRMS analysis, can be explained by the self-terminating radical cyclisation. Overall, there was great difficulty in the synthesis of the lactam substituted alkynes, and reaction of them with NO3• via the self-terminating radical cyclisation granted limited success. It can be concluded that generating bicyclic lactams via self-terminating radical cyclisations is not a suitable method of choice.