U594539.pdf (5.23 MB)
New synthetic approaches towards carbocyclic analogues of natural nucleosides and nucleotides
thesisposted on 2014-12-15, 10:35 authored by Belén Ma. Domínguez Fernández
This thesis describes approaches towards the synthesis of some carbocyclic analogues of nucleosides and nucleaotides starting from the bicyclic lactam 1. The first compound considered was the analogue of cyclic adenosine diphosphate ribose 2. A crucial step in one of the retrosynthetic analyses involved conversion of a primary amine into a different functionality via a nucleophilic displacement of an amine derivative. Using a range of simple model compounds, attempts were made to achieve such a displacement via formation of a diazonium salt, a ditosyl imide or a pyridinium salt. Many side reactions such as elimination or rearrangement had taken place rather than nucleophilic substitution at the carbon bearing the amine derivative. These results led to the conclusion that this approach is not a suitable strategy to consider for further investigations into the synthesis of carbocyclic nucleotide analogues. The development of a new synthetic route towards carbocyclic thymidine 3 is described in chapter 3. Its synthesis was successfully performed in 8 steps via a linear approach which consisted of the construction of the thymine moiety on the carbocyclic cyclopentylamine 4. The amine 4, was made via a flexible pathway which also could be adapted to give a wide range of carbocyclic sugar analogues. In addition, enantiomerically pure (+)-thymidine analogue 3 was prepared from (-) 1 according to the strategy developed for the racemic series, and then converted into the phosphoramidite derivative 5. This monomer will be used to prepare hybrid DNA strands and then to undertake some biological studies on the stability compared to that of the natural DNA.
Date of award1998-01-01
Awarding institutionUniversity of Leicester