A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

Abstract

Imidazopyridines and pyrrolopyrimidines are an important class of compounds in medicinal chemistry. They can also be considered as deaza-modified purine nucleobases, and as such have attracted a lot of interest recently in the context of RNA atomic mutagenesis. In particular, for 1-deazaguanine (c1G base), a significant increase in demand is apparent. Synthetic access is challenging and the few reports found in the literature suffer from the requirement of hazardous intermediates and harsh reaction conditions. Here, we report a new six-step synthesis for c1G base, starting from 6-iodo-1-deazapurine. The key transformations are copper catalyzed C–O-bond formation followed by site-specific nitration. A further strength of our route is divergency, additionally enabling the synthesis of 1-deazahypoxanthine (c1I base).

Chemical Synthesis of Modified RNA

“…[45] The protection pattern of c 1 G phosphoramidite requires N 2 -trifluoroacetyl and O 6 -nitrophenylethyl groups to be able to incorporate it into long RNAs (Figure 8). [42] As the key steps, the route involves silyl-Hilbert-Johnson nucleosidation of acetyl-protected ribose and the deazaguanine precursor 6-iodo-1-deazapurine, [46] followed by copper-catalyzed coupling of the aryl iodide with benzyl alcohol. [42] For both, c 3 G and c 1 G building blocks, RNA assembly must be performed with TBDMS SPS; TOM and CEM approaches can result in stable CH 2 O RNA adducts and interstrand cross-links.…”

Chemical Synthesis of Modified RNA

“…The protection pattern of c 1 G phosphoramidite requires N 2 ‐trifluoroacetyl and O 6 ‐nitrophenylethyl groups to be able to incorporate it into long RNAs (Figure 8). [42] As the key steps, the route involves silyl‐Hilbert‐Johnson nucleosidation of acetyl‐protected ribose and the deazaguanine precursor 6‐iodo‐1‐deazapurine, [46] followed by copper‐catalyzed coupling of the aryl iodide with benzyl alcohol [42] …”