Prebiotic Nucleoside Synthesis: The Selectivity of Simplicity

Abstract

Ever since the discovery of nucleic acids 150 years ago,^[1] major achievements have been made in understanding and decrypting the fascinating scientific questions of the genetic code.^[2] However, the most fundamental question about the origin and the evolution of the genetic code remains a mystery. How did nature manage to build up such intriguingly complex molecules able to encode structure and function from simple building blocks? What conditions were required? How could the precursors survive the unhostile environment of early Earth? Over the past decades, promising synthetic concepts were proposed providing clarity in the field of prebiotic nucleic acid research. In this Minireview, we show the current status and various approaches to answer these fascinating questions.

Keywords: deoxyribonucleoside synthesis; heterocycles; nucleoside synthesis; origins of life; prebiotic chemistry.

Figure 1

Comparison of RNA‐nucleosides 1 a–e with DNA‐nucleosides 2 a–d which lack of the 2’‐hydroxy group. In RNA mostly the bases 3 a,3 e,3 c and 3 d are implemented, whereas in DNA 3 a–d are the only occurring nucleobases.

Figure 2

Structures of d‐ribose 4 a, d‐arabinose 4 b, d‐lyxose 4 c and d‐xylose 4 d.

Scheme 1

An exemplary pathway towards ribonucleosides (R=3 a–e), from simple starting materials derived from gas‐phase reactions (blue) and sugar‐forming reactions (green).

Scheme 2

Conventional synthetic approach by Fischer ^[36] to prepare nucleosides, derived from acetobromoglucose 11 a, acetobromogalactose 11 b or acetobromorhamnose 11 c.

Scheme 3

Prebiotically plausible pathways, starting from charge discharge products of carbon dioxide, nitrogen and methane towards the purine nucleobases (left) and pyrimidine nucleobases (right),[ ⁸ , ⁴¹ , ⁴² , ⁴³ ]

Scheme 4

The supposed catalytic cycle of the formose reaction.[ ⁵² , ⁵³ ]

Scheme 5

Dry state synthesis of ribonucleosides supported by seawater salts.[ ⁹ , ⁵⁶ ] Concentration of the major ions in seawater: 0.458 m Na⁺, 0.056 m Mg²⁺, 0.010 m Ca²⁺, 0.535 m CI⁻, 0.028 m SO₄ ²⁻.

Scheme 6

Alternative prebiotic pathway towards pyrimidine ribonucleosides, giving a mixture of the non‐canonical stereoisomers α‐1 d and β‐ara‐1 d, via the newly described class of sugar aminooxazolines 14. ^[10]

Scheme 7

Synthesis of tetraaminopyrimidines starting from HCN‐derived precursors. ^[62]

Scheme 8

A different disconnection approach of sugar aminoxazolines 21 to overcome the intrinsic problem of nucleosidation.

Scheme 9

A pathway towards the pyrimidine nucleotides 31 d and 31 e via stereochemically enriched arabinose‐aminooxazoline 21 b, originating from 7, 9 and 10 a. ^[73]

Scheme 10

An improved pathway towards 1 d,e via α‐thioribocytidine α‐thio1 d utilizing 21 a as an enrichable compound. ^[77]

Scheme 11

Selective reaction and precipitation of thiazol aminals favoring 9 and 10 over C4−6‐sugars and enhances the selective formation of glycolaldehyde and glyceraldehyde aminals on the way to pyrimidine nucleotides 31. ^[78]

Scheme 12

Proposal of a concomitant synthesis of purine and pyrimidine nucleotides derived from 2‐aminooxazole 30 as a common precursor. ^[82]

Scheme 13

A unified pathway towards pyrimidine nucleotides and 8‐oxo‐purine nucleotides 31,36 from arabinose‐2‐aminooxazoline derivatives thio‐21 as common precursor. ^[79]

Scheme 14

Prebiotically plausible route towards purine nucleosides: Dry state reaction of formamidopyrimidines 29 and d‐ribose 4 a supported in alkaline borate media. ^[65]

Scheme 15

A unified pathway towards ribonucleosides starting from formamidopyrimides 29 and 3‐aminoisoxazole 38.[ ¹² , ⁶⁵ , ⁸⁵ ]

Scheme 16

Prebiotic formation of diazomethane and a carbamoylation reagent from amino acids to achieve derivatization reagents for canonical RNA nucleosides. ^[87]

Figure 3

g⁶A and t⁶A as examples for derivatives of RNA‐nucleosides. ^[92]

Scheme 17

Phosphorylation of thio‐1 e enables the formation of the corresponding thioanhydronucleoside 46 and subsequent formation of deoxythiopyrimidine ribonucleosides. ^[100]

Scheme 18

Mechanism of a highly stereo‐ and furanoselective pathway towards deoxyribonucleosides 2. ^[66]

Scheme 19

Formation of deoxyapiose nucleosides 50 as exemplary, selective pathways elucidating the precedence of deoxyribose over all further possible sugars.