Nucleotides, Part LXVI,β-Heteroarylethyl Groups - New Phosphate-Protecting Groups for Phosphotriester Chemistry

Abstract

The b-heteroaryl-substituted ethanols 6 ± 10 were synthesized and, together with pyridine-2-ethanols and pyridine-4-ethanols, were tested as a new type of phosphate-protecting groups in the synthesis of oligonucleotides by the phosphotriester approach. The synthesis of 5'-O-(monomethoxytrityl)thymidine 3'-(bheteroarylethyl 2,5-dichlorophenyl phosphates) 13 ± 17 and 21 provided useful monomeric building blocks in which the various blocking groups could be removed selectively by acid (MeOTr), oximate (2,5-dichlorophenyl phosphate), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (heteroarylethyl phosphate) treatment. The new, fully blocked dimers 38 ± 41, with b-heteroarylethyl protecting groups in the phosphate moiety, were synthesized. The b-heteroarylethyl groups show a broad range of stability towards base treatment in aprotic solvents depending upon the activation of the HÀC(b) atoms by the heterocyclic moiety.1. Introduction. ± The use of b-eliminating phosphate-protecting groups can be regarded as an important improvement in phosphotriester chemistry [2] since cleavage of the phosphotri-to the phosphodiester stage will proceed without nucleophilic attack at the P-atom, avoiding a potential breakdown of the internucleotidic linkage. Among those protecting groups are the b-cyanoethyl (ce) group [3], the methyl-substituted bcyanoethyl groups [4], and the b-(alkylsulfonyl)-and b-(arylsulfonyl)ethyl groups [5]. Since these blocking groups are relatively sensitive to base treatment and eliminate already with ammonia and amines, a more stable type was found in the 2-(4-nitrophenyl)ethyl (npe) group [2a], which is inert towards amines but will be cleaved by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a much stronger base in a clean beliminating process. The npe group has proven its advantages in a series of oligonucleotide syntheses [6], which could be extended to a unified blocking-group strategy by introduction of the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group for base protection [7] and the 2-(2,4-dinitrophenyl)ethoxycarbonyl (dnpeoc) [8], the 2-(4-nitrophenyl)ethylsulfonyl (npes) [9], and the 2-(dansylethoxycarbonyl) (dnseoc) [10] groups for sugar-OH blocking. To broaden the spectrum of b-eliminating protecting groups for oligonucleotide chemistry, the use of N-containing heteroaryl residues has been tested as activators in b-elimination reactions [11]. Since an sp 2 -hybridized ring Natom reveals a similar activation power as a NO 2 group, the pyridinyl, pyrimidinyl, and pyrazinyl moieties were chosen as new entities in these investigations.

Heterocyclizations of β-alkoxy, β-diaminoalkyl, and related β-functionalized enones (enals) with NCN-binucleophiles

“…A wide range of β-enaminals bearing an α-substituent have been reported, including compounds with alkyl 10 [40,44,45], cycloalkyl 11 [46], nitrile 12 [47][48][49][50][51], imide 13 [52], ester groups 14 [38], chorine [53], and other moieties (Scheme 5). Formyldiene 15 was used as a versatile reagent for the synthesis of a series of 5-vinylpyrimidines [54].…”

“…Formyldiene 15 was used as a versatile reagent for the synthesis of a series of 5-vinylpyrimidines [54]. 5-(Het)aryl-substituted pyrimidines could be prepared by using aryl-substituted enones 16 [53,[55][56][57] or those decorated with thiohetaryl groups [58].…”