Convergent or Linear? A Challenging Question in Carbocyclic Nucleoside Chemistry

Abstract

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.

Key words

medicinal chemistry - nucleosides - carbocycles - Mitsunobu reaction - regioselectivity

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28

The ammonium salts were prepared prior to the reaction by adding stoichiometric amounts of either tetramethylam­-moni­um or tetrabutylammonium hydroxide to the BOM-protected heterocycle 4 in water. The obtained solutions were lyophilized and the crude salts were used without any further purification.