Solid-phase Parallel Synthesis of 4-β-D-Ribofuranosylpyrazolo[4,3-d]pyrimidine Nucleosides

Abstract

The synthesis of pyrazolo[4,3-d]pyrimidine nucleoside library using solid-phase parallel synthesis methodology is described. Glycosylation of the trimethylsilyl (TMS) derivative of 1- and 2-(methyl)-1H and 2H-pyrazolo[4,3-d]pyrimidine-5,7-(4H, 6H)-dione (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of TMS triflate provided two novel protected nucleosides 6 and 7. The structures of 6 and 7 were assigned by 1H and 2D NMR experiments. Nucleosides 6 and 7 were then transformed to the key intermediates 12 and 15 respectively. Reaction of 12 and 15 with MMTCl resin in the presence of 2,6-lutidine afforded the necessary scaffolds B and C. Different amines (96) were introduced selectively by nucleophilic substitution on scaffolds B and C using solid-phase parallel semi-automated synthesizer. Cleavage of the products from the solid support with 30% HFIP in a parallel fashion yielded nucleoside libraries simultaneously, and they were analyzed and characterized by high-throughput LC-MS.

Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast Morphology

“…The polymer-supports were again divided into two groups, and coupling with acid derivatives E { 1 – 2 } was performed to afford hexapeptides 15 . The polymer-supports were split into independent vessels, and cleavage from the polymer-support by treatment with 30% 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)/CH 2 Cl 2 furnished 64-member cyclization precursors 4 with good to excellent purities (81–98% determined at UV 214 nm). Finally, all of the resulting cyclization precursors were subjected to macrolactonization using MNBA/4-(dimethylamino)­pyridine N -oxide (DMAPO) in parallel to afford the desired cyclodepsipeptides 5 , including four natural products in 46–77% isolated yields.…”