First Evident Generation of Purin-2-yllithium:  Lithiation of an 8-Silyl-Protected 6-Chloropurine Riboside as a Key Step for the Synthesis of 2-Carbon-Substituted Adenosines

Abstract

Lithiation at the 2-position of purine ring has been accomplished for the first time by using 6-chloro-9-(2,3-O-isopropylidene-5-O-trityl-β-d-ribofuranosyl)-8-(triisopropylsilyl)purine (7) as a substrate and LTMP as a lithiating agent. The 8-triisopropylsilyl group in 7 did not undergo anionic migration and, thus, allowed the ready generation of the C2-lithiated species by preventing deprotonation at the 8-position. The electron-withdrawing 6-chlorine atom plays an essential role to this C2-lithiation. Reactions of the lithiated species with electrophiles gave the 2-substituted products (Me, Et, i-Pr, CH(OH)C6H11, C(OH)Me2, CHO, CO2Me, and I) mostly in good yields. Ammonolysis of the 6-chlorine atom of these products (heating at 110 °C in a sealed tube with NH3/MeOH) effected simultaneous desilylation at the 8-position to give the corresponding adenosine analogues. The whole sequence provides a new and highly general method for the synthesis of 2-substituted adenosines.

Exploring Structure−Activity Relationships of Transition State Analogues of Human Purine Nucleoside Phosphorylase

“…When the fully protected derivative 31 11 was allowed to react with n -butyllithium at −70 °C and then quenched with CD 3 OD, deuterium incorporation was observed by 1 H NMR spectroscopy only at H-8 (Scheme ). Similar treatment of a 6-chloropurine riboside derivative, but with LDA as base, has shown that both the 2- and 8-positions of the purine were readily lithiated . Consequently it might have been expected that lithiation of the 9-deazapurine derivative 31 would occur at C -2 rather than the observed C -8.…”

“…Similar treatment of a 6-chloropurine riboside derivative, but with LDA as base, has shown that both the 2-and 8-positions of the purine were readily lithiated. 28 trile derivative 42 via 43. This was then functionalized to the enamine 44 and then pyrroles 45 and 46, using standard methods, 10 from which the methylene bridged immucillins 40 and 41 were obtained.…”

Regioselective Homolytic C2–H Borylation of Unprotected Adenosine and Adenine Derivatives via Minisci Reaction

“…Given the importance of C 2 -modified adenine derivatives and NAs, substantial efforts have been devoted to introducing substitutions at the C 2 -position. Except for de novo synthesis, traditional methods for synthesizing C 2 -substituted adenine derivatives mainly encompass four types (Figure B): transition-metal-catalyzed cross-coupling reactions, nucleophilic aromatic substitutions (S N Ar), diazoniation/dediazoniation sequences (diazonium chemistry), and lithiation followed by captures of electrophiles (purine carbanion chemistry) . However, most of the aforementioned methods are sensitive to air and moisture, necessitate protection of ribosyl alcohols and C 6 -amine, and sometimes require replacing the ultimate C 6 –NH 2 group with a Cl atom to ensure the reactivities or to avoid undesired side reactions.…”

Synthesis and EPR Studies of 2-N-tert-Butylaminoxylpurine Derivatives

“…Introduction of the 2- N - tert -butylhydroxylamino group into the purine nucleus at the 2-position was carried out by lithiation of 6-chloro-8-(triisopropylsilyl)purine ( 3 ) with LTMP, and the following reaction with a nitrogen electrophile, 2-methyl-2-nitrosopropane, and the hydroxylamine 4 was obtained in 75% yield (Scheme ). Desilylation at the 8-position proceeded efficiently after acetylation of the hydroxylaminogroup of 4 and the following deprotection of hydroxyl groups gave 6-chloro-2- N - tert -butylacetoxyaminopurine 5 .…”