The preparation of dienes and dienophiles containing nucleic acid bases

The work presented in this thesis deals initially with the synthesis of rigid polyalicyclic dienes and dienophiles with pyrimidine moieties inbuilt in a rigid fashion (building BLOCKS). This work has allowed the production of a new class of ribbon molecules with precisely defined size, shape and position of the pyrimidine ring. In the second stage of the project, an assessment of their ability to participate in cycloaddition reactions as pyrimidine building BLOCK* components was investigated.

2,4-Dimethoxy-1,3-diazaanthracene (I) has acted as the pyrimidine transfer reagent for preparing building BLOCKs. The Diels-Alder adducts IV and V (Scheme I), prepared by reaction of I with norbomadiene, are new pyrimidine dienophilic BLOCKs. Both I and 2,4-dichloro-1,3-diazaanthracene (II) were active in photochemical [4π+4π] cycloaddition reactions with cyclopentadiene to form a second class of building BLOCKs VII and VIII (Scheme I). In addition, the photodimerisation of I and II was studied and structures IX-XII assigned on the basis of spectral and X-ray method.

The 2,4-dichloro-photoadduct VIII is of particular importance for this work since it is easily hydrolysed (2M NaOH, 60 °C, overnight) to the corresponding uracil XIII In contrast, thermal adducts IV and V were very difficult to hydrolyse (NaOH fusion) to uracils XIV and XV (Figure I).

The availability of pyrimidine BLOCKs which contain a reactive π-bond, e.g. (IV, V, VII and VIII) has enabled us to employ 3,6-di(2'-pyridyl)-s-tetrazine (XVI) and ACE (Alkene plus Cyclobutene Epoxide) coupling methods to obtain precisely functionalised ribbon molecules in a direct, convergent synthetic strategy.

The synthesis of the bis-pyrimidines by coupling norbornene reagents using 3,6-di(2'-pyridyl)-s-tetrazine is illustrated in Scheme II. In the first step, s-tetrazine XVI was reacted with pyrimidine BLOCK V under basic conditions to generate the dihydropyridazine XVII. This diaza-1,3-diene was reacted with a further equivalent of V under high pressure conditions to yield the bis-pyrimidines XVIII and XIX, which were separated by radial chromatography. The same procedure was used to link pyrimiclines to other effectors by using alternative alkenes in the second step.

The ACE coupling protocol is illustrated by the reaction of alkene VIII with the dimethoxynaphthalene-containing epoxide XX (Scheme III). The reaction can be conducted under thermal or photochemical conditions and is considered to proceed via 1,3-dipolar intermediate formed by ring-opening of the epoxide C-C bond of XX (See Chapter 4).

Each class of coupled adduct could be hydrolysed to the corresponding uracil by using either acid (XXII) or base (XXIII) hydrolysis conditions, the choice depending on the structure of the molecule in question and its substituents.

The work presented in this thesis involves a deal of new work and has been instrumental in the development of the Lego^®-based BLOCK assembly protocol for ribbon molecules construction.