Solid-phase phosphoramidite approach

In 1981, Beaucage and Caruthers4 extended the domain of phosphorus(lll) chemistry with the development of the phosphoramidite approach to oligonucleotide synthesis (see reviews in section 1.9.5.) which, in its later variants, is unsurpassed in its speed and efficiency in both solid and solution phase. An early synthesis of thymidylic acid derivative 1.7 illustrates the phosphoramidite approach [Scheme 7.1]. The sequence begins with the conversion of the 3 -hy-droxyl of nucleoside 1.1 to the phosphoramidite 13 by reaction with chloro-... 

The phosphoramidite derivative of N-nitrothymidine (44) has been synthesised and found suitable for oligonucleotide synthesis using a standard phosphite triester solid phase approach. The N-nitrothymidine residues could be converted into a range of N -modified thymidines by reaction with primary alkyl amines. Phosphoramidite derivatives of 4-nitroindazole N and N -(2 -deoxy-p-D-ribofuranosides) (45, 46) have been synthesised, their base pairing properties investigated and found to show ambiguous base pairing. Seela has also reported the syntheses of the phosphoramidite derivatives of 8-aza-7-adenine... 

The solid-phase synthesis of oligonucleotides by the phosphoramidite approach requires the use of a solid support that is functionalized with an appropriate nucleoside. Solid supports are typically macroporous structures... 

Sakatsume O, Yamaguchi T, Ishikawa M, Hirao I, Miura K, Takaku H. Solid-phase synthesis of oligoribonucleotides by the phosphoramidite approach using 2 -0-l-(2-chloroethoxy)ethyl protection. Tetrahedron 47 8717-8728, 1991. 

Whereas enzymes synthesize DNA and RNA in a 5 to 3 direction, chemical oligonucleotide synthesis is carried out in the opposite, 3 to 5 direction using a solid phase approach. Solid phase polynucleotide synthesis requires stepwise creation of a phosphate ester intemucleotide linkage. Currently, phosphoramidite... 

The phosphite-triester approach, although originally developed through solution synthesis (22), rapidly proved its value in connection with solid-phase techniques. The phosphoramidite chemistry (23) was designed by M. H. Caruthers and coworkers especially for use with polymer supports (24). Solution syntheses accompanying this development have tested new activation methods and have clarified... 

The two most recent preparative approaches, the phosphoramidite and H-phosphonate routes, have, to my knowledge, not been used to any extent to prepare longer oligonucleotides in solution. Several papers describe the use of solution-synthesized blocks (mostly dimers prepared by the phosphotriester route) for solid-phase chain extension (56a e). The advantage of such blockwise support synthesis is the reduction of cycles and, thus, of overall time required for the preparation of longer chains. However, this may not lead to much decreased labor and expense because of prior block synthesis. Also the purifica-... 

The a-RNA synthesis was planned using the solid-phase technique in combination with the phosphoramidite methodology. Such an approach requires the preparation of the corresponding synthons, and, hence, preparation of the a-ribonucleosides. The synthesis of the necessary a-ribonucleosides in the pyrimidine series has been previously described, and their syntheses are straightforward. As shown on Figure 2, a-rU is obtained in an overall yield of 35%, and the corresponding a-rC can be easily reached from the uridine derivative. ... 

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