A synthetic and computational investigation of trishomocubane-amino acid derivatives.
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The class of polycyclic hydrocarbons including adamantane, pentacyclo [5.4.0.02 ,6. 03,I0.05,9]undecane (PCU) and trishomocubane have proven to be an exciting investigation for synthetic chemists. Many derivatives have been shown to possess excellent antiviral and antibacterial properties, as well as potent anti-Parkinson agents. Some improve the lipophilic nature of biologically active drugs, while others affect the three-dimensional structure of peptides once incorporated as amino acid analogues. This investigation focussed on deriving routes to improve yields of racemic 4-amino-(D3)trishomocubane- 4-carboxylic acid (tris-amino acid), the synthesis of enantiomerically pure tris-amino acid, the incorporation of tris-amino acid into a short peptide, as well as the simulation of the rearrangement of PCU to trishomocubane by using computational tools. Research into developing a more efficient hydrolysis of trishomocubane-hydantoin (trishydantoin) to yield racemic tris-amino acid, led to the development of two novel compounds: the mono-Boc [Novel Compound 1, (NC1)] and bis-Boc [Novel Compound 2, (NC2)] protected hydantoin. Base hydrolysis of NC2 quantitatively yielded the racemic tris-amino acid, which was a significant improvement on previously documented synthetic routes. The first attempt to produce enantiomerically pure tris-amino acid was through the synthesis of diastereomeric derivatives of tris-hydantoin, chromatographic separation of the diastereomers, followed by base hydrolysis of the hydantoin ring to produce enantiomerically pure tris-amino acid. This research led to the development of two novel N-protected tris-hydantoin derivatives (NC3 and NC4). Failure to chromatographically separate the diastereomers resulted in the abandonment of this particular route. The use of enzymes was, therefore, attempted to produce enantiomerically pure tris-amino acid. A novel ester derivative of tris-amino acid (NC5) was synthesised, which was followed by the application of Pig Liver Esterase (PLE). PLE is an enzyme which cleaves ester functionalities. Some success was achieved but the extremely low yields of enantiomerically pure tris-amino acid did not warrant this enzyme as a viable route for production of the desired product. Solid phase techniques were employed for the production of a tripeptide consisting of alanine-glycine-tris-amino acid (ala-gly-tris). Some difficulty was encountered in extending the amino acid sequence due to suspected Schiff base interaction between the free amino group of tris-amino acid and the carbonyl functionality of glycine in the second position. A computational study, using ab initio methods, was performed on the rearrangement of the PCU diol to 7-fluoro-11-hydroxy-trishomocubane. Two mechanisms (Proposed Mechanism 1 and Proposed Mechanism 2) were explored and both showed that the stereochemistry of the hydroxyl groups has only a marginal influence on the transition state energies of the various isomers. Both mechanisms were also indicated to occur through an intramolecular SN2 mechanism.