A New Silyl Ether-Type Linker Useful for the Automated Synthesis of Oligonucleotides Having Base-Labile Protective Groups

Abstract

A new silyl-type linker for the automated solid-phase synthesis of oligodeoxynucleotides was developed. A hydrosilane-type reagent for introduction of the silyl linker was synthesized in an overall yield of 50% from 1,4-dibromobenzene. By using this linker, an oligonucleotide having base-labile protecting groups could be isolated from the controlled pore glass under neutral conditions.

Efficient Release of Base‐Sensitive Oligonucleotides from Solid Supports using Fluoride Ions

“…To obtain thymidine‐loaded HCP resin 5 , first we synthesized 2′‐ O ‐silyl nucleoside 6 according to the procedure reported by Kobori (Figure 2). 17 Initially, reagent 6 was introduced into aminopropyl‐CPG, but the loading efficiency did not reach more than 6 μmol g –1 . In a second attempt, the loading reaction was performed by using amino resin 7 (25 μmol g –1 ), which contains a 4‐aminobutyric spacer arm introduced by reaction of aminomethyl‐HCP resin (35.9 μmol g –1 ) with 4‐aminobutyric acid.…”

“…Compound 6 (193 μmol, 210 mg, 5 equiv.) prepared following the procedure described by Kobori17 was dissolved in dry DMF (5 mL) in the presence of HOBT (193 μmol, 26 mg, 5 equiv.) and DIEA (385 μmol, 66 μL, 10 equiv.).…”

Solid-phase synthesis of base-sensitive oligonucleotides

“…Sensitivity to β-elimination may be utilized in sulfonylethyl-based (8, Schwyzer et al, 1984) 10 Mild fluoride ion promoted cleavage and under neutral pH may be obtained with silyl linker arms (Routledge, et al, 1995) (Figure 4). [16][17][18][19] A typical cleavage procedure is treatment with a mixture of acetic acid buffered tetrabutylammonium fluoride (e.g. Photolysis offers perhaps the mildest possible method for release.…”

Synthesis and Properties of Oligonucleotides Incorporating Modified Nucleobases Capable of Watson–Crick‐Type Base‐Pair Formation

“…In this synthesis, a Bu 4 NFlabile linker was developed to release the base-protected oligomers [94,95]. At the 5 0 -end, an amino group was attached to the oligonucleotide chain via a spacer.…”