Foden, Callum Starkie; (2019) Thiol catalysed prebiotic peptide ligations in water. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The universally conserved assignment of amino acids to the genetic code is cognate with the role of peptides predating all life on Earth. Catalytically competent and small oligopeptides would provide a rational step from amino acids to extant enzymes. Consequently, methods to form peptide bonds prebiotically are of great interest but they remain a significant challenge. The formation of peptide bonds through the ligation of amino acids is hampered by a disparity in the acid dissociation constants of the reacting ends, and – despite being thermodynamically favourable – a high energy barrier. Carboxylate activation chemistries have sought to overcome this by utilising highly reactive activating agents, but product yields are generally low. This work focuses on nitriles, and has aimed to challenge this view by employing their direct activation. Section 2.2: Inspired by the role boron has played in the synthesis of amides and its presence on Earth, a strategy for the direct, unprotected activation and ligation of aminonitriles was pursued. This was demonstrated to be unfavourable regardless of boron’s presence, verifying that this ambitious type of ligation is not sufficient for the meaningful production of oligopeptides. Section 2.3: Cysteine was found to have an exquisite reactivity with aminoacetonitrile and the formation and hydrolysis of a thiazoline product identified as a potential route to a native chemical ligation type strategy in which indications of thioester where observed by 13C NMR. Deleterious side reactions meant that this ligation strategy was unlikely to be feasible on the early Earth. Section 2.4: Recognising the importance of prebiotically plausible protecting groups, the direct activation of α-amidonitrile with N-acetylcysteine was found to enable an aqueous, mild, and organocatalytic reaction for the synthesis of peptides. The full set of Ac-GlyN-AA-OH amidines from amino acid ligations and Ac-Gly-AA-NH2 peptides from amino amide ligations were characterised to validate the robust scope of the reaction. Harnessing the thiazoline and chemistry developed in the previous section, the addition of cysteine to an otherwise inert solution of coupling partners facilitated a ligation. A host of other thiols, prebiotically plausible and otherwise, were also found to enable the transformation. These findings represent a significant advance in aqueous amide bond forming strategies.

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