Synthesis of novel cage amino acid analogues.

Abstract

Amino acids are important building blocks for the synthesis of a large number of biologically active compounds and drugs. Amino acids with the pentacyclo-undecane (1) and trishomocubane (2) frameworks fall into the class of conformationally constrained non-natural amino acids. Conformationally constrained amino acids are found in many naturally occurring, biologically active compounds. It was found that incorporating cage structures into drugs induces a range of positive effects: promotes transport across the cell membrane, drugs can be designed to target the central nervous system, increased receptor site specificity, and retards metabolic degradation. In the light of this, it was decided to investigate the incorporation of cage amino acids into peptides. A synthetic route has been established for the efficient synthesis of amino acids 1 and 2, and for their incorporation into peptides. Several chiral macrocyclic crown ethers and related analogues have been shown to be capable of forming complexes enantioselectively with chiral organic ammonium salts. The design and synthesis of host chiral macrocycles which are able to distinguish between the enantiomers of guest organic ammonium salts is of interest in the areas that include synthesis of enzymes, electrodes for specific ions or molecules, drugs targeted for specific sites, and enantiomer separation. A synthetic procedure has been established for the synthesis of cage annulated chiral crown ethers derived from amino acids. The advantage of using cage compounds in crown ethers is due to increased rigidity, increased solubility in non-polar solvents and increased chirality. Various techniques for the determination of enantiomeric recognition have been studied and include NMR spectroscopy, fluorescence emission spectroscopy and computational methods. The cage crown ether 3 represents a typical example of these new cage annulated, chiral crown ethers.