Synthesis and use of 2′-substituted-N6-modified nucleosides

#The field of the invention is synthesis of nucleosides, their analogs, and uses thereof.

#There are numerous methods known in the art to prepare nucleoside analogs, wherein such compounds may include modifications on the heterocyclic base as well as on the sugar moiety. In some approaches, modifications are introduced into the already synthesized nucleoside to yield the desired nucleoside analog, while in other approaches the sugar portion is modified and then coupled to the heterocyclic base (which may or may not be modified) to generate the desired nucleoside analog.

#However, and particularly where the desired nucleoside analogs include reactive groups (e.g., OH groups in the sugar, NH2 group in the heterocyclic base), various difficulties are frequently encountered. For example, where the modification of the heterocyclic base and/or the sugar portion in a nucleoside requires relatively strong acidification or other relatively harsh conditions, the glycosidic bond in the nucleoside may be destroyed in the process. In another example, modification reagents may react not only with the desired functional group(s) in the heterocyclic base, sugar, and/or nucleoside, but may also modify reactive groups where those are unprotected. Moreover, even where relatively high selectivity may be achieved using protecting groups and modification reagents using particular reaction conditions, such conditions may lead to subsequent problems in isolation, isomeric purification, and/or instability of the desired product.

#FIG. 1 is a schematic of one exemplary synthetic route according to the inventive subject matter in which (a) a 2′-modified sugar is prepared using selective deprotection and oxidation of a hydroxy group, (b) the so obtained protected keto-sugar is regioselectively converted to the corresponding beta-substituted sugar, (c) the sugar is coupled to a modified heterocyclic base to form the corresponding modified nucleoside, and (d) the modified nucleoside is reacted with a dual nucleophilic reagent under conditions to provide selective reaction for generation of the desired reaction product.

#FIG. 2 is a schematic of another exemplary synthetic route according to the inventive subject matter in which a protected nucleoside is modified in the 6-position at the heterocyclic base while deprotecting the protected nucleoside with the modification reagent.

#The inventors discovered a synthetic procedure in which 2′-substituted N6-modified nucleosides and their analogs can be prepared in high yields and purity under conditions that favor highly selective reaction of a precursor with only one or tow reactive centers in a dual nucleophilic reagent. Furthermore, contemplated procedures will advantageously reduce undesired oxidation of various desired reaction products.

#With respect to the sugar portion of contemplated molecules, it should be appreciated that the procedures according to the inventive subject matter will be synthesized in a large and practical scale using selective deprotection and oxidation via a Dess-Martin reagent. Such reaction conditions are thought to allow fast and efficient oxidation without generation of undesired side products that would otherwise require one or more purification/isolation steps.

#Furthermore, and with respect to the selective modification of the N6-position in a heterocyclic base (and most preferably of adenine), it should be recognized that contemplated processes will provide conditions under which a dual nucleophilic reagent will react with high selectivity to provide the desired product. Thus, as one exemplary desired product, it should be appreciated that 2′-beta-methyl-N6-amino-N6-methylribofuranosyladenosine may be selectively prepared in several steps from a sugar component and a heterocyclic base.