Convergent or linear? A challenging question in carbocyclic nucleoside chemistry

Article abstract of DOI:10.1055/s-2007-990847

North-methanocarbathymidine (N-MCT) is a carbocyclic nucleoside analogue with potent anti-HSV and KSHV activity. The critical step in the synthesis of N-MCT and other carbocyclic nucleoside analogues is the introduction of the nucleobase into the carbocyclic moiety. For this, convergent and linear strategies were compared side by side. In the convergent approach, the base was coupled to the carbocyclic moiety by either a Mitsunobu reaction or by displacement of a mesylate. This strategy leads to the formation of various amounts of the O2-regioisomer, depending on the applied procedure. Additionally, by-products of the Mitsunobu reaction have to be separated from the coupling products. Although lengthier, the linear strategy leads selectively to the target compound N-MCT with overall yields comparable to the convergent approaches, making this strategy more compatible for future large-scale syntheses. Georg Thieme Verlag Stuttgart.