Determining the Diastereoselectivity of the Formation of Dipeptidonucleotides by NMR Spectroscopy

Abstract

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.

Spontaneous and Selective Peptide Elongation in Water Driven by Aminoacyl Phosphate Esters and Phase Changes

“…Water-soluble precursors featuring phosphate moieties have been used to construct peptide bonds. − Specifically, aminoacyl phosphate esters have been reported from Kluger et al to yield peptide bonds with protected amino acids residues. However, these systems are rarely coupled to self-assembly .…”

The protometabolic nature of prebiotic chemistry

“…152,153 Quite remarkably, using these approaches, either with mineral surface catalysts and/or activating agents to promote condensation reactions, some researchers have also reported the stereoselectivities obtained in the synthesis of oligopeptides 154,155 and oligonucleotides. [156][157][158] An interesting alternative for chirogenesis in the oligomerization of peptides was that proposed by Lahav and occurring on supramolecular bsheet templates. 159,160 Overall, all these approaches have been extensively reviewed in the literature and, thus, the present review will not go through them in detail.…”

Application of 2D EXSY and qNMR Spectroscopy for Diastereomeric Excess Determination Following Chiral Resolution of β‐Lactams

“…The plausibility of calculating diastereomeric ratios using the EXSY technique is suggested by Hussaini et al. and most recently an approach for in situ monitoring of the diastereoselectivity of peptide coupling has been reported using 31 P or 1 H NMR integration, accurately determining diastereomer ratios in crude reaction mixtures [23] . The possibility of utilising NMR for the calculation of de following LC chiral resolution for complex β‐lactam mixtures is therefore plausible [21,24] .…”