Nucleosides, Dimroth rearrangement

Dimroth rearrangement has taken place in the C-nucleoside series, whereby the reaction of ethyl 2,5-anhydro-6-0-benzoyl-D-allonodithioate (322) with 2-hydrazinopyrimidine did not afford the 3-substituted... 

The marine ascidian metabolite purine aplidiamine-9- 3-D-ribofuranoside was prepared by T. Itaya et al. by alkylation of 8-oxoadenosine with 4-benzyloxy-3,5-dibromobenzyl bromide followed by a Dimroth rearrangement and acid hydrolysis. The rearrangement was induced by treating the nucleoside in boiling IN NaOH for 1h. The desired rearranged nucleoside was formed in 58% overall yield. 

The condensed 1,2,4-triazole ring of 577 was formed as a result of condensing the jS-D-ribofuranosylcarbodithioate 512 with 2-hydrazino-4-hydroxy-6-methylpyrimidine. Unlike the l,2,4-triazolo[l,5-c]pyrimidine analog 568, the l,2,4-triazolo[4,3-fl]pyrimidin-3-yl C-nucleoside 577 did not undergo Dimroth rearrangement (89MI5) (Scheme 154). 

Based-induced Dimroth rearrangement of the 3-(/3-D-galactopyranosyl)-l,2,4-triazolo[4,3-a]pyrimidine 569 (Section XI,V) also gave the corresponding l,2,4-triazolo[l,5-a]pyrimidin-2-yl pyranose C-nucleoside 570 (94MI5) (Scheme 151). 

Notably, the Dimroth rearrangement has been shown to occur in nature with the purine and pyrimidine bases of nucleosides and nucleotides upon exposure to certain chemical entities. For example, 3,4-epoxybutene, styrene oxide and other aromatic hydrocarbon based epoxides, butadiene and butadiene monoxide, chloroethylene oxirane, chlorambucil, and acrolein, " among others, have been shown to facilitate Dimroth rearrangement, and in some cases subsequent cross-linking of DNA. While interesting from a mechanistic and biological perspective, these reactions will not be reviewed here. 

C-Nucleosides have also been prepared via Dimroth rearrangement. These compounds are desirable targets for the treatment of bacterial and viral infections due to their metabolic stability toward phosphorylase enzymes. Condensation of C-nucleoside 15 and 2-hydrazinopyrimidine 16 in refluxing ethanol led to the production of a nonisolatable purine analog intermediate, which underwent spontaneous Dimroth rearrangement to yield 17. This compound was isolated after treatment with methanolic ammonia to give the desired product in 45% yield. 

Loakes and co-workers observed the spontaneous Dimroth rearrangement of nucleosides 32, 34 and 36 in the presence of a catalytic amount of sodium methoxide in methanol during hydrolysis of the acetate protecting groups. The authors noted that a similar rearrangement did not occur in the presence of aqueous sodium hydroxide. The authors speculated that Dimroth rearrangement occurs in the former case, but not in the latter due to the formation of a methyl ester intermediate that can recyclize. In the latter case, an intermediate carboxylate ion, which does not recyclize, is formed. 

Kinetic studies have shown that the substituent at position 1 and pH also play an important role in the Dimroth rearrangement of adenine and adenosine derivatives. For adenine derivatives substituted at position 1, the individual rates for methyl, ethyl and propyl derivatives were comparable, while the benzyl derivative rearranged faster (not shown). Above pH 10, methyl-substituted adenine derivatives rearranged fastest, while the benzyl-substituted derivatives rearranged the slowest. Subsequently, the authors found that adenosine 130 rearranged faster at pH values below 10, whereas adenoside 128 rearranged faster at pH values above 10, and in both cases the reaction rates were enhanced by the presence of ribose. The authors attributed these observations to the electronic effects of the substituents, which play a greater role at pH values less than 10 where the nucleoside remains protonated. At pH values above pH 10, the adenine/adenosine derivatives are neutral and sterics plays a more important role. 

Itaya and co-workers used a Dimroth rearrangement to synthesize aplidiamine, a unique, naturally occurring 8-oxoadenine derivative, and its nucleoside analog. Interest in aplidamine stems from its architectural homology to members of the phosmidosine family of antifungal antibiotic... 

An interesting synthesis of these C-nucleosides utilized the easily accessible 5-(j3-D-ribofuranosyl)tetrazoles 235 as masked C-glycosyl-diazometh-ane. Reacting 235 with 2-chloro-3-nitropyridine gave a mixture of 1,2,4-triazolo[4,3-fl]pyridin-3-yl (236) and l,2,4-triazolo[l,5-a]pyridin-2-yl (237) C-nucleosides. The latter (237) resulted from thermally induced Dimroth-like rearrangement of the former (236) (86MI9) (Scheme 70). Compounds 236 and 237 possess considerable cytotoxic effect (86MI9). 

---