A synthetic and computational investigation of trishomocubane-amino acid derivatives.
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Date
2003
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Abstract
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.
Description
Thesis (M.Sc.)-University of Natal, Durban, 2003.
Keywords
Theses--Chemistry., Asymmetric synthesis., Amino Acids--Synthesis., Peptides--Synthesis., Chemistry, organic.