Reaction of
meso-anhydrides, especially
endo-norborn-5-ene-2,3-dicarboxylic anhydride with methyl or
t-butyl (
S)-prolinate gives the corresponding enantio- and diastereomerically pure amido acids. These amido acids are versatile starting materials for the synthesis of a wide range of useful products. Thus, a Curtius rearrangement of the acid functionality (
via the corresponding acyl azide) leads to isocyanates which react with the
N or
C-terminus of amino acids and peptides to give
pseudo-peptides and peptides respectively. The resulting peptide derivatives undergo chain elongation by standard peptide synthesis to give heptapeptide analogues. Conformational analysis of the peptides by X-ray crystallography, NMR, IR, and CD spectroscopy shows that depending upon the exact nature of the norbornene derived conformational constraint, the peptide analogues adopt a parallel β-sheet, antiparallel β-sheet or β-turn conformation. This chemistry can also be used to prepare a conformationally constrained analogue of the potent ACE inhibitor, ldrapril. Similarly, the same desymmetrization methodology starting from cyclopropane-1,2-dicarboxylic anhydride can be used to prepare
pseudo-peptides incorporating a 2-amino-cyclopropane carboxylic acid residue. Alternatively, ozonolysis of the
endo-norborn-5-ene derived amido acid, followed by reduction of the intermediate dialdehyde can be controlled to give either a [3,3,0]- or [3,2,1]-bicyclic ring system, incorporating an enantiomerically pure cyclopentane with four substituents all
syn to one another. This chemistry can be further extended to give all
syn pentasubstituted cyclopentanes, by employing a 7-
anti substituted norborn-5-ene-2,3- dicarboxylic anhydride. These adducts can be manipulated to give a series of polycyclic cage compounds, which have potential applications as ionophores. Finally, the praline ester, which acts as a chiral auxiliary can be removed by lactonization using an adjacent primary alcohol to form a five-membered ring lactone.
| Date of Award | Oct 1998 |
|---|
| Original language | English |
|---|
| Awarding Institution | - University of Wales, Bangor
|
|---|
| Sponsors | EPSRC & Peboc Division - Eastman Chemical (UK) Ltd |
|---|
| Supervisor | Michael North (Supervisor) |
|---|