Simultaneous Nucleotide Activation and Synthesis of Amino Acid Amides by a Potentially Prebiotic Multi‐Component Reaction

Mullen, Lee; Sutherland, John D.

doi:10.1002/anie.200702870

Cited by 33 publications

(20 citation statements)

References 13 publications

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“…Though the following analysis has not been developed in the original report, this observation strongly suggests that 5(4H)-oxazolone are the actual aminoacylating species and then that overactivation by cyclization also accounts for the observed reactivity of a-amino acid residues in peptides without specific neighbouring groups (Scheme 5). Substitutes for EDC, which was not likely to be present on the early Earth [namely, cyanamide (Lohrmann 1972;Brack 2007), cyanoacetylene (Orgel 2002), or isocyanides (Mullen and Sutherland 2007)] or photochemical processes (Hagan 2010) may have led to C-terminus activation. Therefore 5(4H)-oxazolones may be reasonably conceived as potential prebiotic intermediates.…”

Section: Intramolecular Reaction Of Activated Carboxyl Groupsmentioning

confidence: 99%

Activation of carboxyl group with cyanate: peptide bond formation from dicarboxylic acids

et al. 2011

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The reaction of cyanate with C-terminal carboxyl groups of peptides in aqueous solution was considered as a potential pathway for the abiotic formation of peptide bonds under the condition of the primitive Earth. The catalytic effect of dicarboxylic acids on cyanate hydrolysis was definitely attributed to intramolecular nucleophilic catalysis by the observation of the 1H-NMR signal of succinic anhydride when reacting succinic acid with KOCN in aqueous solution (pH 2.2-5.5). The formation of amide bonds was noticed when adding amino acids or amino acid derivatives into the solution. The reaction of N-acyl aspartic acid derivatives was observed to proceed similarly and the scope of the cyanate-promoted reaction was analyzed from the standpoint of prebiotic peptide formation. The role of cyanate in activating peptide C-terminus constitutes a proof of principle that intramolecular reactions of adducts of peptides C-terminal carboxyl groups with activating agents represent a pathway for peptide activation in aqueous solution, the relevance of which is discussed in connexion with the issue of the emergence of homochirality.

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Section: Intramolecular Reaction Of Activated Carboxyl Groupsmentioning

confidence: 99%

Activation of carboxyl group with cyanate: peptide bond formation from dicarboxylic acids

et al. 2011

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“…1) and to a neutral product. The addition of an H 2 S molecule leads to a lower activation energy barrier, ∆ C ≈ 22 kcal/mol, than the addition of an H 2 O, ∆ C ≈ [2][3][4][5][6][7][8][9] kcal/mol. This is most likely because the pKa of H 2 S about half that of water (pKa (H 2 S) ≈ 7) and thus it is much more likely for H 2 S to dissociate and donate a proton.…”

Section: B Adding Explicit Water and Hydrogen Sulfide Moleculesmentioning

confidence: 99%

Reaction Dynamics of Cyanohydrins with Hydrosulfide in Water

Valleau

Martı́nez

2019

J. Phys. Chem. A

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We studied the reaction dynamics of a proposed prebiotic reaction theoretically. The chemical process involves acetone cyanohydrin or formalcyanohydrin reacting with hydrosulfide in an aqueous environment. Rate constants and populations of reactant and product bimolecular geometric orientations for the reactions were obtained by using density functional theory for the energies, transition state theory for the rates and matrix exponentiation as well as the hybrid tau-leaping algorithm for the population dynamics. The role of including the solvent explicitly versus implicitly was also investigated. We found that adding water or hydrogen sulfide molecules explicitly lowers the activation energy barrier and leads to a more efficient reaction pathway. In particular, hydrogen sulfide was a better proton donor. Further, when adding the solvent explicitly a synchronous reaction mechanism was observed while a concerted reaction mechanism was seen when using an implicit solvent model.Finally, we studied the role of including more than one reactant and product bimolecular orientation geometry in the dynamics.Including all pathways, reactant to reactant, product to product, reactant to product and product to reactant reduced the reaction half-time by two orders of magnitude and was therefore determined to be fundamental for an accurate description of the dynamics. Overall, we found that most reactions which involve formalcyanohydrin occur more rapidly or at the same speed as reactions which involve acetone cyanohydrin at room temperature.

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“…These expectations were realised using nucleotides as the phosphate dianions, and we found that treatment of a 2¢-or 3¢-nucleotide with an excess of an isonitrile, and an aldehyde (+ ammonia) gave the corresponding nucleoside-2¢,3¢-cyclic phosphate in extremely high yield. 2 In the absence of ammonia, a-hydroxy acid amides were formed as co-products, and, in its presence, a-amino acid amides were also formed. The amounts of the co-products 6 that were formed were greater than the amounts of the cyclic nucleotide product suggesting that the nitrilium ions 1 also underwent direct hydration to 6.…”

mentioning

confidence: 98%

“…2 In the Passerini and Ugi reactions, isonitriles add reversibly to aldehydes and iminium ions, respectively, to give nitrilium ions 1 3 (Scheme 1).…”

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confidence: 99%

Potentially Prebiotic Passerini-Type Reactions of Phosphates

Sutherland¹,

Mullen²,

Buchet³

2008

Synlett

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Monoalkyl phosphates can take the place of carboxylic acids in the Passerini reaction, but excesses of aldehyde and isonitriles are required, and transfer of the phosphate to the newly formed hydroxyl group does not take place. By rendering the phosphate addition intramolecular, the efficiency of the reaction is substantially increased. Phosphate transfer can take place when cyanovinyl phosphate is used rather than a monoalkyl phosphate.As part of a long-standing interest in multicomponent reactions involving isonitriles, 1 we recently started to investigate the possibility that such reactions played a role in prebiotic chemistry. 2 In the Passerini and Ugi reactions, isonitriles add reversibly to aldehydes and iminium ions, respectively, to give nitrilium ions 1 3 (Scheme 1).Attack of these nitrilium ions by carboxylate anions gives intermediates 2 that undergo intramolecular acyl transfer giving the products 3. We speculated that alkyl phosphate dianions 4 might be able to substitute for carboxylate anions in this chemistry, and considered it possible that the resultant imidoyl phosphates 5 would undergo reactions other than the intramolecular phosphoryl transfer that might be expected on the basis of the Passerini and Ugi reactions. Specifically, we reasoned that nucleophilic attack on phosphorus by water, or an internal hydroxyl group from the alkyl phosphate, if one were available, and suitably disposed, would displace an a-hydroxy-or a-amino acid amide 6, and either regenerate the original phosphate dianion, or give a cyclic phosphate diester 7. These expectations were realised using nucleotides as the phosphate dianions, and we found that treatment of a 2¢-or 3¢-nucleotide with an excess of an isonitrile, and an aldehyde (+ ammonia) gave the corresponding nucleoside-2¢,3¢-cyclic phosphate in extremely high yield. 2 In the absence of ammonia, a-hydroxy acid amides were formed as co-products, and, in its presence, a-amino acid amides were also formed. The amounts of the co-products 6 that were formed were greater than the amounts of the cyclic nucleotide product suggesting that the nitrilium ions 1 also underwent direct hydration to 6. When 5¢-nucleotides were subjected to the same reaction conditions, the co-products 6 were formed more rapidly than they were in no nucleotide controls, but no altered nucleotide products were formed. We explained these observations by invoking hydrolysis of the intermediate 5 in the case of the 5¢-nucleotide due to the low effective concentration of the 3¢-hydroxyl group. In the case of the 2¢/3¢-nucleotides, the 3¢/ 2¢-hydroxyl group in the intermediates 5 has a much higher effective concentration, and out-competes water in the attack of the activated phosphate. From a prebiotic chemistry standpoint, the chemistry of the 2¢/3¢-nucleotides in the presence of ammonia is the more interesting as simultaneous formation of stably activated nucleotides, and aamino acid derivatives takes place. From the standpoint of conventional organic synthesis, however, the chemistry of the 5¢-n...

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Simultaneous Nucleotide Activation and Synthesis of Amino Acid Amides by a Potentially Prebiotic Multi‐Component Reaction

Cited by 33 publications

References 13 publications

Activation of carboxyl group with cyanate: peptide bond formation from dicarboxylic acids

Activation of carboxyl group with cyanate: peptide bond formation from dicarboxylic acids

Reaction Dynamics of Cyanohydrins with Hydrosulfide in Water

Potentially Prebiotic Passerini-Type Reactions of Phosphates

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