Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water.

Peptide biosynthesis is performed by ribosomes and several other classes of enzymes, but a simple chemical synthesis may have created the first peptides at the origins of life. α-Aminonitriles-prebiotic α-amino acid precursors-are generally produced by Strecker reactions. However, cysteine's aminothiol is incompatible with nitriles. Consequently, cysteine nitrile is not stable, and cysteine has been proposed to be a product of evolution, not prebiotic chemistry. We now report a high-yielding, prebiotic synthesis of cysteine peptides. Our biomimetic pathway converts serine to cysteine by nitrile-activated dehydroalanine synthesis. We also demonstrate that N-acylcysteines catalyze peptide ligation, directly coupling kinetically stable-but energy-rich-α-amidonitriles to proteinogenic amines. This rare example of selective and efficient organocatalysis in water implicates cysteine as both catalyst and precursor in prebiotic peptide synthesis.

pH controlled assembly of a self-complementary halogen-bonded dimer.

Phenols and their corresponding phenoxide anions can form halogen bonds with neutral iodotriazoles. The strength of these interactions depends critically on the protonation state of the oxygen atom - the interaction of the phenoxide anion is more than an order of magnitude stronger than the corresponding phenol. The assembly of a molecule bearing both an iodotriazole and a phenoxide anion into a self-complementary dimer, stabilised by two halogen bonds between the phenoxide anions and the neutral iodotriazoles has been demonstrated. The corresponding phenol shows no halogen bond mediated assembly either in the solid or in the solution state. This assembly process can be actuated simply by a change in protonation state - treatment of the phenol with one equivalent of base results in deprotonation and assembly of the dimer. The structure of the homodimer formed by the phenoxide-bearing iodotriazole has been determined in the solid state and 19F NMR spectroscopy demonstrates that the assembled dimer persists in solution and that it has significant stability. 19F NMR spectroscopy has also been used to demonstrate that the assembly process is completely reversible.

Cooperative Binding in a Phosphine Oxide-Based Halogen Bonded Dimer Drives Supramolecular Oligomerization.

Triphenylphosphine oxide forms halogen-bonded (XB) complexes with pentafluoroiodobenzene and a 1,4-diaryl-5-iodotriazole. The stability of these complexes is assessed computationally and by 31P NMR spectroscopy in toluene-d8 solution, where both complexes are weakly associated. This knowledge is applied to the design and synthesis of two self-complementary phosphine oxide-iodotriazole hybrids that incorporate a phosphine oxide XB acceptor and a 1,4-diphenyl-5-iodotriazole XB donor within the same molecule. The self-complementary design of these modules facilitates their assembly in both toluene-d8 and, surprisingly, DCM-d2 into dimers, with significant stabilities, through the formation of halogen-bonded diads. The stability of these assemblies is a result of significant levels of cooperative binding that is present in both solvents. The connection of two of these hybrid units together, using a flexible spacer, facilitates the aggregation of these modules in DCM-d2 solution, through halogen bonding, forming oligomeric assemblies.

Neutral iodotriazoles as scaffolds for stable halogen-bonded assemblies in solution.

The halogen bond (XB) donor properties of neutral 1,4-diaryl-5-iodo-1,2,3-triazoles are explored using a combination of computational and experimental results and are shown to be competitive in halogen bonding efficiency with the classic pentafluoroiodobenzene XB donor. The SNAr reactivity of these donors permits the facile assembly of an iodotriazole functionalised with a 3-oxypyridine XB acceptor, thus generating a molecular scaffold capable of undergoing dimerisation through the formation of two halogen bonds. The formation of this halogen-bonded dimer is demonstrated by 1H and DOSY NMR experiments and a plausible structure generated using DFT calculations.