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 O
2-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.
medicinal chemistry - nucleosides - carbocycles - Mitsunobu reaction - regioselectivity
