CONSTRUCTING CHIRAL CENTRES VIA O→C ARYL AND ACYL MIGRATIONS: EXPLORING REACTION POTENTIAL

Abstract

Detailed within this thesis are the production of diasteromerically enriched α-aryl carbonyl compounds prepared by a new and mild method based on the Truce-Smiles rearrangement; the synthesis of 1,3-dicarbonyl compounds utilising a Baker-Venkataraman rearrangement; and the synthesis of salicylic acid derivatives and amides by a novel Baker-Venkataraman-retro-Claisen cascade. In addition, the in vitro screening of the cyclooxygenase inhibitory activity of some of the diarylethers of the acetamide based substrates prepared, has been undertaken.
The introduction summarises the significance and use of both the Truce-Smiles and Baker-Venkataraman rearrangement reactions in the synthesis of α aryl and α acyl carbonyl compounds, respectively. Additionally, a detailed review on some currently available chiral auxiliaries along with their applications is also mentioned. The discussion begins with the application of phase transfer catalysts, based on cinchona alkaloids, for the induction of chirality in ketone-based precursors. Further discussion continues with the synthesis of amide-based substrates from lactones and amines, and the use of C2-symmetric chiral auxiliaries to induce chirality during aryl migration. Using such an approach, a new and mild method for the production of diasteromerically enriched α aryl carbonyl compounds has been achieved. It was found that propanamide-based substrates did not rearrange whilst acetamide-based substrates did, favouring a five-membered transition state during aryl migration. In these initial efforts, only modest diastereoselectivies (dr= max. 1.7:1) were observed.
The amide-based substrates did not undergo the Baker-Venkataraman rearrangement, but instead suffered from facile hydrolysis. Thereafter, the section focuses on the investigation of a serendipitously discovered, novel Baker-Venkataraman-retro-Claisen cascade and its subsequent applications in the synthesis of important amides, in which, unusually, the ketone appears to act as an alkyl donor and the carbamoyl moiety as an alkyl acceptor.
A separate chapter is given to the cyclooxygenase activity of some of the diarylethers prepared, wherein the diarylethers of certain acetamides were screened for their activities against cyclooxygenase enzymes, COX I and COX II. The preliminary results showed that the best compound was a pyrrolidyl-acetamide based precursor which showed good to modest inhibitory activity against both COX I and COX II (25-37% and 44-70%, respectively) in the in vitro screening assay.
The thesis concludes with the experimental section encompassing the experimental details, spectroscopic and analytical analysis of all the compounds prepared and described.