McGonagle, Fiona I.
The development of one-pot tandem reactions for the synthesis of polycyclic y-lactams.
PhD thesis, University of Glasgow.
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A novel tandem process has been developed for the stereoselective synthesis of bicyclic γ-lactams. Treatment of an allylic alcohol with trichloroacetonitrile, in the presence of DBU, affords the corresponding allylic trichloroacetimidate. This is then subjected to a tandem Overman rearrangement/RCM/Kharasch cyclisation, forming the desired bicyclic lactam in high yield and high enantiomeric excess. Overall, the one-pot tandem process involves three mechanistically distinct processes catalysed by palladium(II) (step 1) and Grubbs 1st generation catalyst (steps 2 and 3). The use of a thermal Overman rearrangement in tandem with the Grubbs catalysed RCM/Kharasch cyclisation was also investigated. Furthermore, a microwave-assisted tandem process was developed which resulted in the accelerated synthesis of the desired bicyclic γ-lactams. A two-step tandem process was then developed for the synthesis of bicyclic allylic amides, a closely related core unit to that found in a number of important commercially available drugs. Finally, progress has been made towards the total synthesis of (±)-deethylibophyllidine, which will utilise a tandem RCM/Kharasch cyclisation to construct the C and D rings of the natural product.
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