Studies towards the synthesis of (S)-tyrosine based calix[4]arenes and innovative synthetic protocols towards para-tert-butylcalix[n]arenes

• Main Author: Sharma, Sunil Vishnuprasadji
• Published: University of East Anglia 2008
• Subjects: 572.696
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446503

The design of synthetic receptors capable of binding to a chosen protein surface is a significant challenge due to the need to match the unsymmetrical distribution of charged, electrostatic and hydrophobic domains and cover a sufficiently large area for high affinity. The potential of peptidocalix[4]arenes as synthetic receptors for the recognition of specific protein surfaces has been reported. Calix[4]arenes are macrocyclic compounds that comprise of phenolic units bridged by methylene functions. The growing interest in calixarene chemistry is a result of their considerable versatility through upper- and lower-rim derivatisation, and their ability to complex both neutral and ionic guests. This thesis describes the synthesis of a unique series of calix[4]arenes functionalised at the upper-rim with a-amino acid moieties. The functionalisation of (S)-tyrosine via a basecatalysed hydroxymethylation and subsequent efficient protocols towards ortho-methylene bridged phenol dimers and trimers are discussed. The primary synthetic strategy towards the target calix[4]arenes proceeds via convergent methodology. The synthesis of innovative calix[4]arene scaffolds incorporating chiral, non-racemic (S)-tyrosine residues via [3+1] and [2+2] fragment condensation methods are also described. The fragment condensation employing tin(lV) chloride affords the corresponding calix[4]arenes in yields as high as 90%. The optical purity of the synthesised (S)-tyrosine based calix[4]arenes and the intermediates have been established by chiral HPLC. The thesis also describes the first microwave-assisted acid-catalysed synthesis of para-tertbutylcalix[ n]arenes. The astonishing effect that certain metal sulfate, triflate or tetrafluoroborate salts have on the chemoselectivity and efficiency of the cyclic oligomerisation process is discussed. A metal-mediated second-sphere co-ordination process is proposed to explain the metal salt effect. A ferrocenium tetrafluoroborate catalysed' synthesis of para-tert-butylcalix[njarenes is discussed. The ferrocenium salts presumably act via a single-electron transfer mechanism affording calix[4]-[9]arenes in > 88% yields. This is the first report of a microwave-assisted synthesis of calixarenes involving such unique mechanisms. Development of a straightforward Lewis acid mediated synthesis of the previously very difficult to procure para-tert-butylcalix[9]arene in conjunction with para-tertbutylcalix[8]arene is discussed. The calix[8]- and [9]arenes are synthesised via a one-pot reaction in excellent yields. This innovative reaction proceeds readily at ambient temperature; uses inexpensive starting materials and is amenable to multigram scale.