A solution-phase synthesis of active esters of 3Ј-fluorophorelabeled deoxynucleoside 5Ј-monophosphates was developed for thymine and cytosine as nucleobases by using two different BODIPY dyes. Starting from the respective 2Ј-amino-2Ј,3Ј-dideoxynucleoside-5Ј-monophosphate, the fluorescent

Proteins are composed of l‐amino acids, but nucleic acids and most oligosaccharides contain d‐sugars as building blocks. It is interesting to ask whether this is a coincidence or a consequence of the functional interplay of these biomolecules. One reaction that provides an opportunity to study this interplay is the formation of phosphoramidate‐linked peptido RNA from amino acids and ribonucleotides in aqueous condensation buffer. Here we report how the diastereoselectivity of the first peptide coupling of the peptido RNA pathway can be determined in situ by NMR spectroscopy. When a racemic mixture of an amino acid ester was allowed to react with an 5′‐aminoacidyl nucleotide, diastereomeric ratios of up to 72 : 28 of the resulting dipeptido nucleotides were found by integration of 31P‐ or 1H‐NMR peaks. The highest diastereomeric excess was found for the homochiral coupling product d‐Ser‐d‐Trp, phosphoramidate‐linked to adenosine 5′‐monophosphate with its d‐ribose ring. When control reactions with an N‐acetyl amino acid and valine methyl ester were run in organic solvent, the diastereoselectivity was found to be lower, with diastereomeric ratios≤62 : 38. The results from the exploratory study thus indicate that the ribonucleotide residue not only facilitates the coupling of lipophilic amino acids in aqueous medium but also the formation of a homochiral dipeptide. The methodology described here may be used to search for other stereoselective reactions that shed light on the origin of homochirality.

Oligonucleotides are indispensable tools in diagnostics, therapeutic applications and molecular biology. The low base pairing strength of thymine with adenine complicates their use. Ethynylpyridone C-nucleosides are analogs of thymidine that pair more strongly and with improved base selectivity, and sequences containing these analogs show improved target affinity and selectivity, but their routine use is hampered by diminished yields of solid-phase syntheses with the known building blocks. A partial loss of base protecting groups during the acidic deblocking step of chain extension cycles was identified as the cause of lower yields. Here we report the synthesis of an improved phosphoramidite building block featuring a pivaloyloxymethyl (POM) base protecting group. This building block gives oligonucleotides containing the strongly pairing ethynylmethylpyridone C-nucleoside in high yield and purity via solid-phase synthesis.

The origin of homochirality is one of the unresolved issues of prebiotic chemistry. Why are the amino acids found in proteins of the l configuration? Perhaps peptido nucleotides could have played a role as transitional species, as suggested visually by the Archaeopteryx in the image. It was recently shown that these phosphoramidate‐linked species form spontaneously from simple precursors. Now, the diastereoselectivity of the the dipeptide‐forming step has been determined by in‐situ NMR spectroscopy, revealing that homochiral products are preferred. This is reported in the Full Paper by C. Richert et al. (DOI: 10.1002/chem.202101630).