Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry

Abstract

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (proto)biomolecules to pinpoint a set of closely related geochemical scenarios that are suggestive of flow and semi-batch chemistries. We now wish to report a multistep, uninterrupted synthesis of a key heterocycle (2-aminooxazole) en route to activated nucleotides starting from highly plausible, prebiotic feedstock molecules under conditions which mimic this scenario. Further consideration of the scenario has uncovered additional pertinent and novel aspects of prebiotic chemistry, which greatly enhance the efficiency and plausibility of the synthesis.

Fig. 1

Photochemical reduction of cyanohydrins. Solvated electrons and/or H^• can efficiently reduce cyanohydrins. These reactions are promoted by Cu⁺ or Fe²⁺ ions and a sulfurous stoichiometric reductant under UV irradiation

Fig. 2

Thermal metamorphosis of ferrocyanide salts. The products formed by heating ferrocyanide can be altered simply by exchanging the counter-ion of ferrocyanide and/or varying the temperature to which the salt is heated

Fig. 3

Photochemical reduction of 4 using the Fe²⁺/NaHSO₃ system. Typical conditions: glycolonitrile 4 (30 mM), Na₂SO₃ (50 mM), NaH₂PO₄ (100 mM) and K₄[Fe(CN)₆] (5 mM) in H₂O:D₂O (9:1), pH adjusted to 6.5 with degassed HCl/NaOH and the solution was irradiated. Glyceronitrile 6 was presumed to be formed due to the liberation of cyanide in the work-up procedure, whereby paramagnetic Fe_x(CN)_yL_z species were removed by the addition of NaSH to allow NMR spectra to be acquired

Fig. 4

Protection and concentration of aldehydes. ¹H NMR Spectra showing how aldehydes can be protected and concentrated under prebiotically plausible conditions via the intermediacy of their bisulfite adducts. a aldehyde = formaldehyde 2; b aldehyde = glycolaldehyde 5; c aldehyde = glyceraldehyde 10. Upper spectra—solution of aldehyde, NaH₂PO₄ and HSO₃^–; centre upper spectra—as upper spectra after heating to dryness for 40 h then redissolving in D₂O; centre lower spectra—as upper spectra without the addition of HSO₃^–; lower spectra—as centre lower spectra after heating to dryness for 40 h then redissolving in D₂O (in a, the singlet observed at 3.3 ppm, upper and centre lower spectra, is MeOH, included in commercial formaldehyde as a stabiliser)

Fig. 5

Protection of 5 at high pH and modified Strecker synthesis. ¹H NMR Spectra showing the protection of glycolaldehyde 5 by bisulfite in the presence of NH₃ and the Knoevenagel–Bucherer modified Strecker synthesis of serine aminonitrile. a Upper spectrum—5 in H₂O/D₂O with NH₃ at pH 9.2 after 10 min; lower spectrum—as upper spectrum after 7 days at room temperature. b Upper spectrum—5 and Na₂SO₃ in H₂O/D₂O with NH₃ at pH 9.2 after 10 min; centre spectrum—as upper spectrum after 7 days; lower—as centre spectrum with KCN added after 2 h, pH 9.2

Fig. 6

Reactions of 7 with NH₂CN and CaNCN. The use of cyanamide, when attempting to form 2-AO 13 from 7 (pathway A), results in the undesirable reaction of displaced bisulfite with 18, but using calcium cyanamide circumvents this problem by precipitating calcium sulfite (pathway B)

Fig. 7

Flow chemistry set-up starting with glycolonitrile 4. This arrangement was designed to simulate a possible geochemical environment on early Earth (see main text). Initial concentrations: glycolonitrile 4 (60 mM), Na₂SO₃ (200 mM), NaH₂PO₄ (50 mM) and K₄[Fe(CN)₆] (10 mM)

Fig. 8

Flow chemistry set-up starting with HMSA 9. This arrangement was designed to mimic the second variant of our geochemical scenario (see main text)

Fig. 9

The two viable routes to ribo-aminooxazoline 12 starting from 4. All steps have been demonstrated under batch conditions, but those steps depicted in magenta have been performed in flow conditions in a “continuous”, uninterrupted manner starting from glycolonitrile 4 or HMSA 9. a Route to 12 via the addition of 2-AO 13 to glyceraldehyde 10. b Route to 12 via aldol reaction of 5 and 10 after their liberation from 7 and 14, respectively