Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites

Abstract

The syntheses of some carbocyclic nucleosides that are conformationally locked as "northern" mimics of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a), cytosine (3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a) that underwent selective ring opening with nucleophiles. Reaction of 12a with sodium azide provided access to the uracil and cytosine analogues (3a and 3b) after construction of the pyrimidine rings, and reaction with the sodium salt of adenine provided an efficient convergent approach to 3c. The preponderance of the undesired N-7 regioisomer obtained from the coupling of 12a with 2-amino-6-chloropurine was unanticipated. Hence, the diol derivative 11 was selectively protected and coupled under Mitsunobu conditions to give, after deprotection, the desired guanine analogue 3d. With the exception of the guanine analogue, the cyclic sulfite chemistry described here represents a useful alternative as a general approach to carbocyclic nucleosides. None of the target nucleosides 3a-d demonstrated significant antiviral activity against HIV-1, HSV-1, HSV-2, and HCMV. Relative to other conformationally rigid, northern carbocyclic analogues that have shown good anti-HSV and anti-HCMV activities, it is concluded that the hydroxymethyl group is a poor substitute for the hydroxyl group in these rigid bicyclic nucleoside templates.

Sugar-Modified Nucleosides in Past 10 Years, A Review

“…Hydrolysis of the dibenzoate 282, prepared from D-glucose by a several- cB [94] cC [95] cD [95] cE [96] cF [97] cG [98] X = OH, N 3 X = OH, N 3 Fig. (14).…”

The Properties of Locked Methanocarba Nucleosides in Biochemistry, Biotechnology, and Medicinal Chemistry

“…The new vicinal diol reacted immediately with thionyl choride to give the intermediate cyclic sulfite that underwent facile oxidation to the corresponding cyclic sulfate 63. In connection with the syntheses of related 1 0 ,2 0 -dihydroxymethylbicyclo[3.1.0]hexane nucleosides, both cyclic sulfites and sulfate intermediates were used as precursors for the convergent synthesis of purine analogues [30][31][32]. For the syntheses of pyrimidine analogues, however, a linear approach is more practical, and hence compound 63 reacted with sodium azide to give the azido intermediate 64 (82%) along with a small amount of its regioisomer.…”

Rearranging The Bicyclo[3.1.0]Hexane Template Of Carbocyclic Nucleosides To Improve Binding Recognition By Kinases

“…The pseudosugar ring was prepared from known cyclopentenone 8 [4] employing two key steps: (1) a Baylis-Hillman reaction [5] to assemble the 5 -hydroxymethyl side chain, and (2) a regioselective opening of cyclic sulfite 6 to introduce the nitrogen substituent at the correct position [6] (Scheme 2). Therefore, treatment of cyclopentenone 8 with formaldehyde in the presence of imidazole in aqueous media gave the desired hydroxymethyl cyclopentenone 7 in high yield (Scheme 3).…”