A stereoselective approach toward the synthesis of 8-methyl-pyridoxatin using an intramolecular carbolithiation strategy is discussed. Model studies have proven this approach is not feasible for the synthesis of 8-methyl-pyridoxatin. / text

This thesis describes research carried out on the synthesis of tertiary alcohols or derivatives by N to C aryl/vinyl migration in lithiated carbamates. Section II.1 describes the first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer as an illustration of the methodology. It has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of alpha-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement in contrast with related ureas. Modelling work to establish the origin of this stereodivergent behaviour is reported in Section II.2. This also reports in-situ IR experiments providing evidence of the mechanistic pathway of the rearrangement of an O-benzyl-N-aryl carbamate. The scope of the N to C aryl migration in other stabilised organolithiums is shown in section II.3. The rearrangement is now addressed in more systematic manner, thus allowing the alpha-arylation of O-allyl and O-propargylcarbamates (by alpha-deprotonation) and O-vinylcarbamates (by alpha-deprotonation) to be achieved in good yields but with poor stereoselectivity. Section II.4 goes on to show that enol carbamates derived from aromatic or alpha,beta-unsaturated compounds and bearing an N-aryl substituent undergo carbolithiation by nucleophilic attack at the alpha position of the enol double bond. The resulting carbamate-stabilised allylic, propargylic or benzylic organolithium rearranges with N to C migration of the N-aryl substitutent, creating a quaternary carbon alpha to O. The products may be easily hydrolysed to generate multiply branched tertiary alcohols in good to moderate yields in a one-pot tandem reaction. Finally, Section II.5 proves that the rearrangement in lithiated carbamates can be extended to N to C vinyl transfer.

The construction of tertiary alkylamines is a synthetic challenge exacerbated by the poor electrophilicity of imines. Due to the presence of this kind of building block in a large number of bioactive molecules, the development of new strategies to synthesise the quaternary carbon centre is essential. This thesis describes the work carried out on the rearrangement of lithiated vinyl ureas in order to form α-tertiary amines. The first part presents how vinyl ureas were synthesised, using the reaction between an imine and an aryl isocyanate. The development of one-pot process allows the synthesis of a range of ureas in large scale. These vinyl ureas present unusual reactivity: the electron-rich double bond can undergo syn umpolung carbolithiation followed by retentive aryl migration in order to generate highly substituted amines after cleavage of the urea. The complete mechanism is investigated to understand fully the diastereoselective pathway of the reaction. In the next part, the rearrangement of lithiated ureas is extended to the N to C vinyl transfer. Different vinyl migrating group are investigated and α-tertiary amines have been synthesised in high yields and enantiomerically pure form using this new rearrangement. The mechanistic insights of the reaction are also studied and a retentive mechanism will be identified. Finally, N to C vinyl transfer is applied toward the synthesis of Erythrina alkaloids.