An Improved Synthesis of 2-Amino-1,3-oxazoles under Basic Catalysis

Cockerill, Anthony F.; Deacon, Ashley M.; Harrison, Roger G.; Osborne, Daire; Prime, Diana M.; Ross, William T.; Todd, Alec; Verge, J. P.

doi:10.1055/s-1976-24127

Cited by 55 publications

(42 citation statements)

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“…We have recently found that 2-aminooxazole 6, a condensation product of glycolaldehyde and cyanamide, 7 reacts with glyceraldehyde to give pentose aminooxazolines in a remarkable process that is essentially quantitative and is highly stereoselective for the ribo-and arabino-products. 8 We thus wondered if it might be possible to produce 2 from 6 and 5 (Scheme 3).…”

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confidence: 99%

Two-Step Potentially Prebiotic Synthesis of α-d-Cytidine-5‘-phosphate from d-Glyceraldehyde-3-phosphate

2006

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A prebiotically plausible synthesis of ribonucleotides is required to support the "RNA world" hypothesis. 1 The conversion of D-ribose-5-phosphate 1 to the aminooxazoline 2, and thence to R-Dcytidine-5′-phosphate 3, by sequential treatment with cyanamide and cyanoacetylene was demonstrated over 30 years ago (Scheme 1), 2 but no prebiotic synthesis of 1 has been reported.Not only is ribose notoriously difficult to synthesize as anything other than a component of a complex mixture, 3 but it is unstable, 4 and prebiotic phosphorylation furnishes the 1-, 2-, and 3-phosphates and not the 5-phosphate. 5 D-Pentose-5-phosphates, including 1, are theoretically accessible by aldol reaction of glycolaldehyde 4 and D-glyceraldehyde-3-phosphate 5, but such an approach is likely to be thwarted experimentally by the instability of 5 under the alkaline conditions required to enolize 4 (Scheme 2).The enolate of 5 is easily formed by intramolecular general base catalysis by the phosphate dianion in mild alkali and eliminates phosphate rapidly. 6 Expectations that this E1cb irreversible elimination behavior of 5 would prevent an aldol synthesis of 1 were realized at the outset of this study. It was found that incubation of a D 2 O solution of 4 and 5 for a day at pD ) 9.4 resulted in significant elimination of phosphate from 5 even before 4 had undergone significant enolization (as evidenced by the lack of exchange of the CH 2 (and CH) protons of 4 for deuterons). Incubation of a solution of 4 and 5 at neutral pD did not result in elimination of phosphate from 5, but neither was aldolization evident.We have recently found that 2-aminooxazole 6, a condensation product of glycolaldehyde and cyanamide, 7 reacts with glyceraldehyde to give pentose aminooxazolines in a remarkable process that is essentially quantitative and is highly stereoselective for the ribo-and arabino-products. 8 We thus wondered if it might be possible to produce 2 from 6 and 5 (Scheme 3). However, in addition to the possibility that elimination from 5 might still occur faster than the addition of 6, there was also the chance that the stereoselectivity found in the earlier reaction of 6 with glyceraldehyde might be altered by the presence of the phosphate group in 5. 9 To investigate this potential reaction, we incubated a solution of 5 and 6 (both 69 mM) in H 2 O at pH ) 7 and room temperature. After 2 days, an aliquot was removed and lyophilized, and the residue was dissolved in D 2 O for 1 H NMR analysis. A series of doublets (J ) 5-6 Hz) in the range of δ ) 5.4-6.0 ppm suggested that pentose aminooxazoline-5′-phosphates had been formed in good yield ( Figure S1, Supporting Information). 10 One stereoisomer was dominant to the extent that it exceeded the sum of the other stereoisomers. By sample spiking with an authentic standard of 2 prepared from 1, we were able to determine that this predominant stereoisomer was 2. To characterize the other products, the mixture was treated with alkaline phosphatase, divided into aliquots, and then separately spiked wit...

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Two-Step Potentially Prebiotic Synthesis of α-d-Cytidine-5‘-phosphate from d-Glyceraldehyde-3-phosphate

2006

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“…One way of incorporating the remarkable conversion of 17 and 18 to 12 into a complete RNA synthesis is shown. Synthesis of 17 from glycolaldehyde and cyanamide [29], and conversion of 12 to 13 [14] extend the experimentally demonstrated chemistry (green lines). Needed are a conversion of dihydroxyacetone [30] to 18, a means of phosphorylating and anomerising 13, and activated nucleotide polymerisation (blue lines).…”

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confidence: 54%

“…We thus have a very powerful reaction that not only leads to a nucleoside precursor in high yield, but also purifies it by a crystallisation process that effectively amplifies any ee values in the input glyceraldehyde. Since 17 is a condensation product of glycolaldehyde and cyanamide [29], this route to 12, and thence 13, can be seen to involve mixed oxygenous and nitrogenous chemistry (Fig. 12).…”

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confidence: 99%

RNA: Prebiotic Product, or Biotic Invention?

Anastasi

Buchet

Crowe

et al. 2007

Chemistry & Biodiversity

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Spectacular advances in structural and molecular biology have added support to the 'RNA world' hypothesis, and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early earth. Difficulties in achieving a prebiotically plausible synthesis of RNA, however, have led many to ponder the question posed in the title of this paper. Herein, we review recent experimental work on the assembly of potential RNA precursors, focusing on methods for stereoselective C-C bond construction by aldolisation and related processes. This chemistry is presented in the context of a broader picture of the potential constitutional self-assembly of RNA. Finally, the relative accessibility of RNA and alternative nucleic acids is considered.

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“…These reagents have found application in the synthesis of the simple heterocycles as well as their benzofused derivatives by reaction with a-hydroxy [466] or a-amino ketones (an extension of the Marckwald synthesis in which cyanamide replaces cyanate, thiocyanate and isothiocyanate as a counterpart of a-aminoaldehydes or ketones) (Scheme 10.164) [467,468].…”

Section: 56mentioning

confidence: 99%