Under oxidative conditions, certain nucleobases (for example, adenine and cytosine) can form N-oxides. Also, the C8 position of guanosine is vulnerable to hydrolytic attack under either strongly acidic or strongly alkaline conditions. The 5,6 double bond of pyrimidine nucleosides also reacts with halogens and halohydrins to give the corresponding addition products (Shabarova and Bogdanov, 1994). Selected examples of the side reactions that occur during oligonucleotide synthesis are given below.
Tri-O-acetyluridine (S.1) reacts with MSNT to produce the triazolo derivative S.2 (Figure 2.1.2; Reese and Ubasawa, 1980). During deprotection with ammonium hydroxide, S.2 gives cytidine (S.3). Interestingly, during deprotection with either the tetramethylguanidinium …show more content…
(1) They can be installed by peracylation of the nucleoside followed by chemoselective O-deacylation (Schaller et al., 1963 ; Rigoli et al., 2009). (2) “Transient” protection approach (Ti et al., 1982) has been widely used. In this procedure, the nucleoside is persilylated using a silylating agent, and the acyl function is installed on the amino group using the corresponding acid chloride or acid anhydride. (3) Some acyl functions such as benzoyl, α-phenylcinnamoyl, and naphthaloyl are directly incorporated on the nucleobase using the corresponding anhydride (Watanabe and Fox, 1966; Bhat et al., 1989). Zhu et al. (2003) reported an improved synthesis of N-benzoylated nucleosides by reducing the amounts of chlorotrimethylsilane (TMSCl) and benzoyl chloride to nearly equivalent quantities. The major advantage of this method is the easier work-up and higher yields. The original method by Ti et al. (1982) was further simplified by eliminating the addition of ammonium hydroxide. (4) The exocyclic amino group of cytidine and deoxycytidine were directly acylated using activated esters (Igolen and Morin, 1980), acid chlorides (Mishra and Misra, 1986, and references therein), or alkyloxycarbonylbenzotriazoles (Himmelsbach et al., 1984). (5) Site-selective incorporation and removal of N-acyl protecting groups have also been achieved by enzymatic methods (Prasad and Wengel, 1996). (6) Selective acylation of nucleosides has also been carried out by N-acyltetrazole (Bhat et al., 1998) and carboxylic acids activated in situ with carbonyldiimidazole (Sinha et al., 1995). (7) N-Benzoyltetrazole has been developed as a mild and selective reagent for the monobenzoylation of the exocyclic amino groups in adenine and cytosine nucleobases (Bhat et al., 1997). In a related report, 1-acetyl-4-nitrobenzotriazole readily acetylated the exocyclic amine of cytidine (Reid et al., 2006). This one step-strategy is
Tri-O-acetyluridine (S.1) reacts with MSNT to produce the triazolo derivative S.2 (Figure 2.1.2; Reese and Ubasawa, 1980). During deprotection with ammonium hydroxide, S.2 gives cytidine (S.3). Interestingly, during deprotection with either the tetramethylguanidinium …show more content…
(1) They can be installed by peracylation of the nucleoside followed by chemoselective O-deacylation (Schaller et al., 1963 ; Rigoli et al., 2009). (2) “Transient” protection approach (Ti et al., 1982) has been widely used. In this procedure, the nucleoside is persilylated using a silylating agent, and the acyl function is installed on the amino group using the corresponding acid chloride or acid anhydride. (3) Some acyl functions such as benzoyl, α-phenylcinnamoyl, and naphthaloyl are directly incorporated on the nucleobase using the corresponding anhydride (Watanabe and Fox, 1966; Bhat et al., 1989). Zhu et al. (2003) reported an improved synthesis of N-benzoylated nucleosides by reducing the amounts of chlorotrimethylsilane (TMSCl) and benzoyl chloride to nearly equivalent quantities. The major advantage of this method is the easier work-up and higher yields. The original method by Ti et al. (1982) was further simplified by eliminating the addition of ammonium hydroxide. (4) The exocyclic amino group of cytidine and deoxycytidine were directly acylated using activated esters (Igolen and Morin, 1980), acid chlorides (Mishra and Misra, 1986, and references therein), or alkyloxycarbonylbenzotriazoles (Himmelsbach et al., 1984). (5) Site-selective incorporation and removal of N-acyl protecting groups have also been achieved by enzymatic methods (Prasad and Wengel, 1996). (6) Selective acylation of nucleosides has also been carried out by N-acyltetrazole (Bhat et al., 1998) and carboxylic acids activated in situ with carbonyldiimidazole (Sinha et al., 1995). (7) N-Benzoyltetrazole has been developed as a mild and selective reagent for the monobenzoylation of the exocyclic amino groups in adenine and cytosine nucleobases (Bhat et al., 1997). In a related report, 1-acetyl-4-nitrobenzotriazole readily acetylated the exocyclic amine of cytidine (Reid et al., 2006). This one step-strategy is