Synthesis and incorporation of a Trishomocubane Amino Acid into short Peptides
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Cage compounds have attracted pharmaceutical and biological interest amongst others as anti-Parkinson agents. The serendipitous observation of the activity of 1-aminoadamantane 1 in Parkinsonian patients against selected viruses i.e. Herpes simplex Type I & II and Influenza A2-Asian viruses/Taiwan has increased the interest in cage compounds. This study involves the synthesis of the cage amino acid 14. Due to the insolubility of pentacyclo-[6.3.0.02,6.03,10.05,9]-undecane (trishomocubane) amino acid 14 in both polar and nonpolar solvents, including DMSO (d6), the synthesis of Fmoc-tris amino acid 50 was required for analysis. The Fmoc derivative of trishomocubane amino acid was also useful for controlled* coupling of the cage amino acid 14 to short peptides. The synthesis of the Fmoc-tris amino acid fluoride derivative is described as well as that of the tri-peptide (Ala-Ala-Ala). The incorporation of the Fmoc-tris amino acid fluoride in a tetra-peptide Ala-Ala-Ala-tris and in a hepta-peptide Ala-Ala-Ala-tris-Ala-Ala-Ala will also be presented. A computational chemistry project was undertaken using density functional theory (B3LYP) at the 6-31+G(d) level of theory, so as to enhance the understanding of the mechanism of esterification. Methanol, acetyl chloride and acetic acid were used in the model for simplicity. Four membered ring transition states were obtained with both acetyl chloride and acetic acid. A six membered ring transition state is facilitated by the selective use of one methanol molecule from the solvent. Both a concerted and step-wise mechanism are presented.