Synthesis of Artificial Receptor Motifs for Anion Binding and Organocatalysis

The initial part of this works involves the evaluation of a related series of bisamides for rational correlation between anion complexation and organocatalysis: remarkable enhancement of hydrogen bonding to anions was observed along with significant increases in catalytic activity in the Morita-Baylis-Hillman reaction. In addition, X-ray crystallography showed a large degree of pre-organisation was observed in one receptor by incorporation of bis(trifluoromethyl)aniline groups along with a thioamide functionality. A novel bifunctional amide/N-acylsulfonamide within the series gave the best catalytic profile for the initial receptors/organocatalysts. Following on from the initial work, a series of bifunctional hybrid (thio)urea/amide molecules were designed and also tested for their anion binding properties and catalytic activites. A urea/amide hybrid produced the highest binding constants while a thiourea/amide analogue gave optimal catalytic properties in the aforementioned reaction with yield of up to 79% obtained. Catalyst-substrate binding studies were undertaken for the most successful catalysts and a catalytic mechanism related to receptor/catalyst acidity was proposed. Another major part of this work involved the design and screening of a range of simple Naryl and N-heteroaryl pyrrolidine amide organocatalysts incorporating N-pyridyl and Nquinolinyl groups in the synthetically useful aldol reaction of isatin with acetone. The ‘reverse amide’ N-pyridyl pyrrolidinylmethyl amide catalysts proved highly catalytically active but gave disappointing enantioselectivities. However, an N-3-pyridyl prolinamide catalyst gave the aldol adduct in high yields and high enantioselectivity with up to 72% ee of the (S)-isomer. Conditions were optimised for this catalyst and in particular an additive screen identified a link between the pKa of the acid additive and the yield and enantioselectivity. An N-acylsulfonamide prolinamide was also identified as a catalyst for this reaction giving the (R)-enantiomer in 68% ee.