Synthetic Studies Towards the Sulfur Isosteric Analogue of N-Methanocarbathymidine

RODRIGUEZ, JUAN BAUTISTA; ELHALEM, ELEONORA

San Petersburgo, Rusia

Simposio; International Symposium on Advances in Synthetic and Medicinal Chemistry, ASMC 07; 2007

European Federation for Medicinal Chemistry

Nucleosides have demonstrated to be an abundant source of lead drugs in the search for antiviral and antitumor agents. The isosteric replacement of the furanose ring by a cyclopentyl moiety affords a new class of metabolically more stable nucleosides analogues known as carbocyclic nucleosides. The absence of the oxygen atom at the furanose ring enhances potential structural variations at different positions not possible with conventional nucleosides. The carbanucleoside analogue N-methanocarbathymidine 1 (R = CH2) has been found to exhibit potent antiherpetic activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) (Figure 1).1 The efficacy of this carbocyclic nucleoside is even greater than that shown by acyclovir, a well-known antiherpetic agent.1 It had been considered that the isosteric replacement of the cyclopropyl moiety of 1 by an epoxy group to give 2 would be benefit for molecular recognition due to the smaller size of the epoxy group. However, it was not possible to obtain the theoretical pyrimidine derivative 2 as a consequence of intermolecular enol base attack onto the epoxy group to form a tricyclic system.2 Due to the incompatibility of an epoxy group adjacent to a pyrimidine base, it was thought that the more appropriate isosteric replacement of the cyclopropyl moiety would be a thiirane group to form 3.3 We have recently demonstrated that it is possible to synthesize simple model of pyrimidine carbanucleosides built on a 6-thiabycyclo[3.1.0]hexane system as pseudosugar unit. The synthetic approach to access to the target molecule is illustrated in the Scheme. N-methanocarbathymidine 1 (R = CH2) has been found to exhibit potent antiherpetic activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) (Figure 1).1 The efficacy of this carbocyclic nucleoside is even greater than that shown by acyclovir, a well-known antiherpetic agent.1 It had been considered that the isosteric replacement of the cyclopropyl moiety of 1 by an epoxy group to give 2 would be benefit for molecular recognition due to the smaller size of the epoxy group. However, it was not possible to obtain the theoretical pyrimidine derivative 2 as a consequence of intermolecular enol base attack onto the epoxy group to form a tricyclic system.2 Due to the incompatibility of an epoxy group adjacent to a pyrimidine base, it was thought that the more appropriate isosteric replacement of the cyclopropyl moiety would be a thiirane group to form 3.3 We have recently demonstrated that it is possible to synthesize simple model of pyrimidine carbanucleosides built on a 6-thiabycyclo[3.1.0]hexane system as pseudosugar unit. The synthetic approach to access to the target molecule is illustrated in the Scheme.