Decarboxylative acetoxylation using mn(ii) or mn(iii) reagent for synthesis of 4'-acetoxy-nucleoside and use thereof for synthesis of corresponding 4'-(dimethoxyphosphoryl)methoxy-nucleotide

A process for preparing a nucleoside or analogue thereof comprising a 4′-acetoxy group, wherein the nucleoside or analogue thereof comprising a 4′-acetoxy group is represented by formula I-b:

• or a salt thereof, comprising the steps:
• (a) providing a nucleoside or analogue thereof comprising a 4′-carboxyl group represented by formula I-a:
• or a salt or ester thereof, and
• (b) subjecting the nucleoside or analogue thereof of formula I-a to conditions sufficient to form the nucleoside or analogue thereof of formula I-b,
• wherein the conditions comprise a manganese(II) reagent and an oxidizing agent, or wherein the conditions comprise a manganese(III) reagent, and wherein:
• each B is independently a nucleobase or hydrogen;
• each R4 is independently hydrogen, fluoro, —OH, —OC1-6alkyl, —OCH2CH2OC1-6alkyl, or —O-protecting group (—OPG);
• each X3 is independently —O—, —S—, or —N(R)—;
• each R is independently hydrogen, a protecting group (PG), or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same atom are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur;
• each Y2 is independently hydrogen or a protecting group (PG);
• each Z is independently —O—, —S—, —N(R)—, or —C(R)2—;
• and
• each n is independently 0, 1, 2, 3, 4, or 5.

A process for preparing a nucleoside or analogue thereof comprising a 4′-acetoxy group, wherein the nucleoside or analogue thereof comprising a 4′-acetoxy group is represented by formula I-b-1:

• or a pharmaceutically acceptable salt thereof, comprising the steps:
• (a) providing a nucleoside or analogue thereof comprising a 4′-carboxyl group represented by formula I-a-1:
• or a pharmaceutically acceptable salt or ester thereof, and
• (b) subjecting the nucleoside or analogue thereof of formula I-a-1 to conditions sufficient to form the nucleoside or analogue thereof of formula I-b-1,
• wherein the conditions sufficient to form the nucleoside or analogue thereof of formula I-b-1 comprise the steps:
• (i) combining the nucleoside or analogue thereof of formula I-a-1 with dichloroethane (DCE) to form a mixture;
• (ii) adding AcOH to the mixture of step (a) with agitation;
• (ii) adding Mn(OAc)2 and (diacetoxyiodo)benzene) (DIB) to the agitated mixture of step (b);
• and
• (iv) heating the mixture of step (c) at about 80° C. for about 5 hours, wherein:
• each B is independently a nucleobase;
• each PG is a protecting group;
• each R4 is independently hydrogen, fluoro, —OH, —OC1-6alkyl, —OCH2CH2OC1-6alkyl, or —O-protecting group (—OPG);
• each Z is independently —O—, —S—, —N(R)—, or —C(R)2—;
• and
• each R is independently hydrogen, a protecting group, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same atom are taken together with their intervening atoms to form a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.