A Straightforward Stereoselective Synthesis of d- and l-5-Hydroxy-4-hydroxymethyl-2-cyclohexenylguanine

A novel and facile synthesis of 5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine 1 is described. The key steps involve a Diels−Alder reaction of ethyl (2E)-3-acetyloxy-2-propenoate 2 as dienophile with Danishefsky's diene 3 to build up the six-membered ring skeleton, a Fraser-Reid reductive rearrangement of the adduct using LiAlH4, and base-moiety introduction using a Mitsunobu reaction. Optically pure d- and l-1 were obtained via resolution of intermediate 7 with (R)-(−)-methylmandelic acid. The synthetic procedure toward racemic 1 consists of only five steps and has proven to be highly efficient toward the synthesis of cyclohexenyl nucleosides.