Synthesis of 4'-Methoxy 2'-Deoxynucleoside Phosphoramidites for Incorporation into Oligonucleotides
Magdalena Petrová1, Ivan Rosenberg1
1Department of Bioorganic and Medicinal Chemistry, The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Abstract:
This unit contains detailed synthetic protocols for the preparation of 4'-methoxy 2'-deoxynucleoside phosphoramidite monomers for A, G, C, T, and U. First, 3'-silyl-protected 2'-deoxynucleosides (dNs) are converted in two steps to 4',5'-enol acetates as the key starting compounds. Next, 4'-methoxy dNs are prepared by a one-pot procedure comprising N-iodosuccinimide-promoted methoxylation, hydrolysis, and reduction of the formed intermediates. Finally, 3'-phosphoramidites of 4'-methoxy dNs are obtained by a routine three-step procedure. Title phosphoramidite monomers are suitable for the synthesis of oligonucleotides on solid phase according to conventional amidite chemistry. 4'-Methoxy substitution represents a simple modification of the sugar part of dNs, where β-D-erythro epimers preferentially adopt N-type (C3'-endo, RNA-like) conformation. Moreover, it imparts superior chemical stability, nuclease resistance, and excellent hybridization properties to modified 4'-methoxyoligodeoxynucleotides. The strong tendency toward RNA-selective hybridization suggests its potential utilization in antisense and/or RNAi technologies. © 2016 by John Wiley & Sons, Inc.
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