groups known to those skilled in the art, and may also contain optional ether groups. The alkyl groups may also contain additional amino groups which may be primary, secondary or tertiary amino groups. Examples of primary amines as used herein include, but are not limited to n-butylamine, tert.› butylamine, n-hexylamine, 2-methoxyethylamine, ethylene diamine, 2-(N,N-diethylamino )ethylamine, cyclohexy› lamine and the like. Examples of secondary amines as used herein include, but are not limited to diethylamine, di-n› propylamine, 1,2-dimethylethylene diamine and the like. The alky 1 groups R and R’ in secondary amines may or may not be identical. 

The term "solid support" as used herein refers to a polymer, that is insoluble in the media employed in the reaction steps performed to synthesize oligonucleotides, and is derivatized to comprise hydroxyl groups. The polymer can be an inor› ganic polymer, including, but not limited to silica, alumina and controlled pore glass (CPG), or an organic polymer, including, but not limited to polystyrene, polyacrylamide, polymethacrylate, polyvinylalcohol, or other synthetic poly› mers, carbohydrates such as cellulose and starch or other polymeric carbohydrates, or other organic polymers and any copolymers, composite materials or combination of the above inorganic or organic materials. The hydroxy groups of a solid support may be unprotected or protected, e.g. with a DMT› protective group, or with another hydroxyl group protective group. During oligonucleotide synthesis a solid support is treated with various reagents in several synthesis cycles to achieve the stepwise elongation of a growing oligonucleotide chain with individual nucleotide units. The nucleoside unit at the end of the chain which is directly linked to the solid support is termed "the first nucleoside" as used herein. The first nucleoside is bound to the solid support via a linker moiety, i.e. a diradical with covalent bonds to both the poly› mer of the solid support and the nucleoside. The linker stays intact during the synthesis cycles performed to assemble the oligonucleotide chain and is cleaved after the chain assembly to liberate the oligonucleotide from the support. 

The term "acidic reagent" as used herein refers to an acidic solution. Acidic solutions in this context may be aqueous solutions with a pH ofless than 7, e.g. the solution of a protic acid in water or a buffer solution with a pH ofless than 7, or non-aqueous solutions, e.g. the solution of an acid in an organic solvent. Examples of acidic reagents include, but are not limited to diluted mineral acids, e.g. 0.01 M hydrochloric acid in water or 0.01 M sulfuric acid in water, mixtures of carboxylic acids with water, e.g. 80% acetic acid in water or 40% formic acid in water, aqueous citrate buffers, e.g. citrate buffer pH 3, aqueous acetate buffer, e.g. acetate buffer pH 4, solutions of dichloroacetic acid in organic solvents, e.g. 3% dichloroacetic acid in dichloromethane or toluene, solutions of acetic acid in dichloromethane, e.g. 10% acetic acid in dichloromethane, and the like. 

The term "acid labile linker" as used herein refers to a linker moiety which is susceptible to cleavage with an acidic reagent. 

The term "2’-protective group" as used herein refers to a protective group applied to the 2’-hydroxy group of ribo› nucleosides. In particular, the term 2’-protective group refers to the protective group R$_{2 }$for nucleoside phosphoramidites in formulae (2) and (3). The cleavage of2’-protective groups is orthogonal to the cleavage of front end protective groups in an oligonucleotide synthesis, i.e. they stay intact during the syn- thesis cycles on the solid support and are collectively removed after the chain assembly. Preferably, the 2’-protec- 

tive groups are removed simultaneously with the cleavage of the linker to the support and with the removal of nucleobase protective groups. 

The extension of an oligonucleotide chain during a phos- phoramidite mediated synthesis on a solid support is typically pursued in the 3’ to 5’ direction with phosphoramidites (2). During synthesis with (2) the front end protective group is removed from the 5’-position and the subsequent coupling occurs between a support-bound 5’-hydroxy group and a 3’-phosphoramidite group of (2). The extension of the oligo› nucleotide chain may alternatively be pursued in the 5’ to 3’ direction with phosphoramidites (3). During synthesis with (3) the front end protective group is removed from the 3’-po› sition and the subsequent coupling occurs between a support- bound 3’-hydroxy group and a 5’-phosphoramidite group of (3). The latter approach is exemplified in the synthesis of oligodeoxynucleotides with 3’-DMT protected deoxynucleo› side 5’-phosphoramidites, as described by e.g. Robles et al. (1995) Nucleic Acids Res. 23:4151-61 (1995). The synthesis cycles for the chain elongation in 3’ to 5’ direction and the chain elongation in 5’ to 3’ direction are nevertheless very similar, if not identical for a given type of employed phos› phoramidites. Any feature of the present invention described in this disclosure for the chain elongation in 3’ to 5’ direction is therefore directly applicable to chain elongation in 5’ to 3’ direction and chain elongation in 5’ to 3’ direction is conse› quently well within the breath and scope of the invention. 

Phosphoramidites which are applied in the coupling step of an oligonucleotide synthesis cycle are typically monomer phosphoramidites, i.e. they contain one nucleoside unit as displayed in formulae (2) and (3). It has nevertheless been demonstrated that suitably constructed dimer phosphoramid› ites, i.e. phosphoramidites derived from dinucleotides as described by Kumar et al. (1984) J. Org. Chem. 49:4905-12, or trimeric phosphoramidites, i.e. phosphoramidites derived from trinucleotides as described by Ono et al., Nucleic Acids Res. 23, 4677-82 (1995), can be applied successfully in a phosphoramidite mediated synthesis of oligonucleotides on a solid support. The synthesis cycles for monomeric, dimeric, trimeric and possibly higher oligomeric phosphoramidites are nevertheless very similar to each other, if not identical, provided the type of employed phosphoramidite as defined through the nature of the groups Ri, R$_{2}$ , R$_{3}$ , R$_{3}$ ’ and R$_{4 }$ in (2) and (3) is identical. Any feature of the present invention described in this disclosure for the use of monomeric phos› phoramidites is therefore directly applicable to the use of dimeric, trimeric or higher oligomeric phosphoramidites in the synthesis of oligonucleotides on solid supports. The appli› cation of dimeric, trimeric or higher oligomeric phosphora- midites in the synthesis of oligonucleotides on solid supports is consequently well within the breath and scope of the inven› tion. 

The present invention discloses novel nucleoside phos› phoramidites which are useful for the synthesis of oligonucle- otides. The novel phosphoramidites of the invention are rep› resented by formulae (2) and (3) wherein R$_{1 }$ denotes an acyl group as defined above. The novel phosphoramidites are fur› ther characterized therein that the acyl group R$_{1 }$ is cleavable in a synthesis cycle of the phosphoramidite mediated synthe- sis of oligonucleotides on solid supports with an organic base such as a primary amine, a secondary amine, or a mixture thereof. 

In a preferred embodiment of the invention the nucleobase protective groups, if present, are cleavable after the assembly of the respective oligonucleotides with an acidic reagent. In another embodiment of the invention one or more of the nucleobase protective groups is cleavable under neither 

