Cyano-Ethoxy Carbonyl Case Study

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The cyano-ethoxy carbonyl protection Manoharan et al. (1999) developed 2(cyanoethoxycarbonyloxy)succinimide S.27a a stable, crystalline, and convenient reagent for the protection of pendant akylamines in oligonucleotides (Figure X.X.X). The 2-cyanoethyl (ce) group is the most common phosphate protecting group in oligonucleotides; however, ce and corresponding 2-(cyanoethoxycarbonyl) group were not utilized for the nucleobase protection until 2000. Merk et al. (2000) developed 2-(cyanoethoxy)carbonyl (ceoc) protection for the protection of the excocylic amino group of adenine, guaninine, and cytosine. The (2-cyanoethoxy)carbonylation reactions were carried out with either 2-cyanoethyl carbonochloridate (S.27b ) or 1-((2-cyanoethoxy)carbonyl)-3-methyl-1H …show more content…
The oligonucleotides containing benzyl carbamates were deprotected by hydrogenation. (1-((Benzyloxy)carbonyl)-3-methylimidazolium tetrafluoroborate (Rapoport’s reagent S.) is the most widely utilized reagent for the protection of the exo-N6-group of purines with CBz. In the case of 2-deoxyguanosine, O6 oxygen was also protected as benzyl ether in addition to N-(benzyloxycarbonyl)carbamate.

Figure X.X.X Benzyloxycarbonyl N-alkylimidazolium salts

In a recent report, more facile preparation of carbamate protected nucleoside was demonstrated by using various commercially available chloroformates. The 6-exocyclic-amino group of purine nucleosides was efficiently protected with various chloroformates S.31 utilizing N-methylimidazole (NMI), affording N6-carbamoyl adenosines S.32 in good to excellent yields (Figure X.X.X; Cho et al., 2012). The N6-CBz-adenosine nucleosides were used for the preparation of the corresponding phosphoramidate pronucleotides in excellent yield by reacting with phenyl phosphoryl chloride (Cho et al., 2011 and 2012).

Figure X.X.X Carbamate protection of adenosine
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In general, protected thymine is not used during oligonucleotide synthesis. However, during deprotection of oligonucleotides under basic conditions, acrylonitrile is formed during the deprotection of the cyanoethyl phosphate protecting group. Consequently, N3-cyanoethylation has been observed via Michael addition at the N3 position of thymine nucleobase with the liberated acrylonitrile. The formation of N3-cyanoethyl thymidine was efficiently suppressed by using nitromethane as a scavenger of acrylonitrile during oligo deptotection (Umemoto et al., 2005). A set of fully protected deoxynucleoside phosphoramidites S.40a-d completely eliminated the N-cyanoethylation (Figure X.X.X; Tsunoda et al., 2010). Fully protected adenine and cytosine nucleoside were prepared by simply treating the substrate with phthaloyl chloride and hunigs base in THF. Synthesis of fully protected thymine cytosine, and guanine nucleoside (S41a-c), affording S.42a, S.40d, and S.42b is shown in Figure

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