Synthesis of aldehydic ribonucleotide and amino acid precursors by photoredox chemistry

Article abstract of DOI:10.1002/anie.201300321

Light work: UV irradiation of a system formed by adding copper(I) cyanide to an aqueous solution of glycolonitrile, sodium phosphate, and hydrogen sulfide efficiently generates aldehyde precursors to the building blocks of RNA and proteins. Copyright

Full text of DOI:10.1002/anie.201300321

Angewandte
Chemie
DOI: 10.1002/anie.201300321
Prebiotic Systems Chemistry
Synthesis of Aldehydic Ribonucleotide and Amino Acid Precursors by
Photoredox Chemistry**
Dougal J. Ritson and John D. Sutherland*
In continuing studies aimed at understanding the prebiotic
origin of RNA, we recently demonstrated a Kiliani–Fischer-
type synthesis of simple sugars from hydrogen cyanide 1 using
photoredox cycling of cyanocuprates (Scheme 1).[1]
ultimate reductant in the system, and report herein our
findings with hydrogen sulfide (H2S, 10) fulfilling that role.
Although our previous Kiliani–Fischer-type synthesis
started with hydrogen cyanide 1 and proceeded through
glycolonitrile 5, compound 5 itself is probably a more
plausible starting point for the synthesis. This is because
1 produced in the atmosphere, (for example through impact
shock[3]), would have been rained into bodies of ground water
along with formaldehyde 4 (produced in the upper atmos-
phere by photoreduction of CO2[4]) with which it would have
reacted to give 5. Accordingly, in this work we initially
explored the copper-catalyzed photoreduction of 5 with 10 in
aqueous solution (containing 10% D2O to allow direct
analysis by NMR spectroscopy). As phosphate is a reagent
in a later stage of our ribonucleotide synthesis,[2] we incorpo-
rated it into the system from the outset wherein it functioned
as a pH buffer. Mixing of this solution with solid copper(I)
cyanide (10 mol% with respect to 5) resulted in the formation
of a fine black powdery precipitate, and a stirred suspension
of this powder in the solution was irradiated at 254 nm in
a quartz cuvette. Samples were withdrawn over time and
Scheme 1. Photoredox systems chemistry of hydrogen cyanide 1, with
1 also acting as the ultimate reductant.
1
analyzed by H NMR (with HOD suppression), or, if [13C2]-
labeled 5 was used, 13C NMR spectroscopy. After 2 h of
irradiation, NMR analysis (Figure 1 and Supporting Informa-
tion) showed that efficient reductive conversion of glycoloni-
trile 5 to glycolaldehyde 6 had taken place (with 6 being
detected as its hydrate 6(h) in 42% yield in solution).
However, other reduction products, namely acetonitrile 11
and acetaldehyde 12,[5] were also present (as confirmed by
sample spiking) that we had not observed in our earlier work.
Furthermore, some cyanide had been abstracted from 5 and
converted into thiocyanate 13,[6] leaving formaldehyde 4
present in the form of its hydrate 4(h) and hydrogen sulfide
addition product 14. The most obvious pathway to acetalde-
hyde 12 appeared to be deoxygenation[7] of glycolaldehyde 6
(Scheme 2), and to investigate this we irradiated a system
comprising copper(I) cyanide and a solution of 6, sodium
phosphate, and 10. Conversion into 12 occurred, but was
inefficient unless we additionally included thiocyanate 13 in
the system. This suggests that 13 in some way enables more
efficient redox cycling, and we note in this regard that
copper(I) thiocyanate is a p-type semiconductor.[8]
The photoredox cycle oxidizes 1 to cyanogen 2 and
generates associated reducing power in the form of protons
and hydrated electrons, which reduce further 1 to formalde-
hyde imine 3. Hydrolysis of 3 to formaldehyde 4 is then
followed by addition of 1 to give glycolonitrile 5. Iteration of
this process results in the sequential production of glyco-
laldehyde 6, its cyanohydrin 7, and glyceraldehyde 8. Sugars 6
and 8 are required by our recent synthesis of pyrimidine
ribonucleotides as starting materials,[2] but there is a catch.
The concurrent hydrolysis of cyanogen 2 produces cyanate 9,
which irreversibly traps the sugars 6 and 8 as cyclic adducts.
We wondered if the free sugars could be obtained by a variant
of the process in which something other than 1 served as the
[*] Dr. D. J. Ritson, Prof. Dr. J. D. Sutherland
MRC Laboratory of Molecular Biology
Francis Crick Avenue, Cambridge Biomedical Campus
Cambridge CB2 0QH (UK)
Although the formation of glycolaldehyde 6 is important
in the context of ribonucleotide abiogenesis, the formation of
acetaldehyde 12 alongside 6 and formaldehyde 4 is partic-
ularly noteworthy in the context of amino acid abiogenesis as
these aldehydes are the Strecker precursors of alanine, serine,
and glycine.[9] Thus hints of a linked origin of ribonucleotides
and amino acids began to emerge.
E-mail: johns@mrc-lmb.cam.ac.uk
[**] This work was funded by the Medical Research Council (project no.
MC_UP_A024_1009), the Engineering and Physical Sciences
Research Council, and by the Origins of Life Challenge; we thank
Harry Lonsdale for the latter. Thanks also to Willie Motherwell for
bringing certain key references to our attention.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300321.
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Figure 1. 13C NMR spectrum of the products of irradiation (2 h, pH 7) of a system made by mixing a solution of [13C2]-labeled glycolonitrile 5
(10 mm), hydrogen sulfide 10 (30 mm), and sodium phosphate (33 mm) with solid copper(I) cyanide (10 mol% with respect to 5).
In the absence of added ammonia, cyanohydrins 7 and 15
produced by rain-in of hydrogen cyanide 1 into the system
have the potential to be further reduced in a second stage of
photoredox chemistry (Scheme 2).
We had considered the formation of 7 in this way, and
envisaged its subsequent reduction as a way of producing
glyceraldehyde 8 in the same system as glycolaldehyde 6, but
at a later juncture. However, we had not previously consid-
ered the formation and reduction of acetaldehyde cyanohy-
drin 15. We thus prepared separate samples of 7 and 15 from
the parent aldehydes and hydrogen cyanide 1, and subjected
them to the photoreduction conditions (Supporting Informa-
tion). After 2 h of irradiation of a system containing
glycolaldehyde cyanohydrin 7, glyceraldehyde 8 was obtained
in 17% yield. The corresponding system based on acetalde-
hyde cyanohydrin 15 furnished lactaldehyde 16, which is the
Strecker precursor of (allo-)threonine, in 19% yield.
In the presence of added ammonia, the cyanohydrins
produced by rain-in of hydrogen cyanide 1 would be expected
to undergo slow conversion to aminonitriles. Addition of
1 and excess ammonia to the system after 4 h of first-stage
reduction resulted in the smooth conversion of the aldehydes
4, 12, and 6 into the corresponding aminonitriles 17, 18, and 19
over a period of days to weeks (Supporting Information). A
second rain-in of hydrogen cyanide 1 after the second-stage
reduction would convert some of the glyceraldehyde 8 and
lactaldehyde 16 into the cyanohydrins 20 and 21 and thence to
aminonitriles if sufficient ammonia were still in the system, or
if more was added. In support of this, when we added 1 and
ammonia to the (second-stage) photoreduction products of
acetaldehyde cyanohydrin 15, lactaldehyde 16 was smoothly
converted via cyanohydrin 21 to (allo-)threonine Strecker
intermediate aminonitrile 22 (Supporting Information).
If the first-stage reduction were to proceed to completion,
all of the glycolaldehyde 6 needed to make ribonucleotides
and serine (via 7 and 19) would instead be converted into
acetaldehyde 12. We found that 12 was the major product
Scheme 2. Photoredox systems chemistry of glycolonitrile 5, with
hydrogen sulfide 10 as the ultimate reductant.
Addition of hydrogen cyanide 1 and ammonia to such
a system would convert the aldehydes into the corresponding
cyanohydrins and aminonitrile Strecker intermediates.
Among other things, the ratio of cyanohydrin to aminonitrile
would depend on the parent aldehyde and the amount of
added ammonia. Although we are ultimately most interested
in mixed systems, we have first explored simpler variants in
which ammonia is either absent, or in excess.
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after 6 h irradiation thus 2–4 h would seem to be synthetically
most productive from a systems perspective. Not knowing the
UV light intensity on the early earth means that we cannot
convert our experimental irradiation times into real time
spans, but diurnal cycling and/or weather effects mean that
illumination periods corresponding to 2–4 of our hours are
plausible. Addition of hydrogen cyanide 1 is needed to make
cyanohydrins for the second-stage reduction as well as for
aminonitrile synthesis. If the rain-in of 1 occurred during
a dark period and was accompanied by the addition of
cyanamide, with which glycolaldehyde 6 also reacts (to make
a key ribonucleotide intermediate), then second-stage reduc-
tion of the cyanohydrins 7 and 15 giving 8 and 16 should leave
this ribonucleotide intermediate and any aminonitriles
unchanged (the nitrile carbon atoms of aminonitriles endure
less electron-withdrawal than those of cyanohydrins, and are
thus considerably less susceptible to reduction). Subsequent
addition of 1 and ammonia (or equilibration with that
reversibly contained in other aminonitriles) would then
additionally generate the aminonitrile 22.
biomolecules ultimately from C1 feedstock(s), is reminiscent
of the general scenario put forward by Wꢀchtershꢀuser.[15]
Received: January 14, 2013
Revised: March 23, 2013
Published online: April 22, 2013
Keywords: amino acids · nucleotides ·
.
photochemical reactions · reduction · solvated electrons
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[5] After 6 h irradiation, the system had simplified, and acetalde-
hyde 12 and formaldehyde 4 were the predominant products.
The apparent yield of 12 at this point was 15% (as measured by
1H NMR integration relative to an added standard of pentaer-
ythritol) based on starting glycolonitrile 5. The production of 4
also consumes 5 but the amount of 4 could not be quantitated by
integration owing to overlap with the HOD signal. We did not
quantitate products by another method because the system
generates multiple biomolecule precursors, so the yield of any
particular product has less significance than it does in conven-
tional synthetic chemistry, it being unclear what the ideal
product distribution should be: the compositional ratio of 5/6/
11/12 changes from 14:41:8:37 after 2 h to 0:15:10:75 after 4 h,
and 0:0:12:88 after 6 h.
[6] In our previous work using hydrogen cyanide 1 as substrate and
reductant, cyanate was formed by hydrolysis of cyanogen.[1] By
analogy therefore, it is possible that in this work, thiocyanate 13
is formed by (copper-catalyzed) thiolysis of cyanogen. Alter-
natively, 13 could result from the nucleophilic attack of cyanide
ion on the terminal sulfur atom of an oligosulfide formed by
oxidation of H2S 10.
[7] Known in conventional synthetic chemistry for example: M. J.
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111 – 129.
Thus the abiogenesis of the simple sugars required to
make RNA appears to be closely related to the abiogenesis of
at least four of the proteinogenic amino acids of extant
biology. This relationship suggests that the systems described
herein have a real etiological relevance, and this has
prompted us to consider geochemical scenarios that could
provide appropriate conditions and starting materials.
As well as being concentrated by trapping through
reaction with formaldehyde 4, cyanide can also be concen-
trated through complexation to ferrous ions giving ferrocya-
nide.[10] Thermal decomposition of ferrocyanide gives differ-
ent products depending on the counter cation.[11,12] Sodium
and potassium ferrocyanide give the corresponding alkali
metal cyanide salts MCN,[11] magnesium ferrocyanide gives
magnesium nitride Mg3N2,[12] and calcium ferrocyanide gives
calcium cyanamide CaCN2.[12] Rehydration of the residue
remaining after strong heating of mixed ferrocyanide salts can
thus give solutions containing cyanide, ammonia, and cyan-
amide, which are all needed for the chemistry described
herein or for later stages of ribonucleotide synthesis.[2] The
reductant hydrogen sulfide 10 and the copper(I) cyanide
based catalyst could be produced by dissolution of a copper
sulfide mineral in cyanide solution,[13] additional 10 being
produced by similar dissolution of ferrous sulfide.[14] At this
stage we do not attempt to describe a more detailed scenario
other than to point out that the RNA and amino acid
syntheses could take place in one mixed system or in several
closely related systems which then become mixed. Finally, we
note that the chemistry we describe, utilizing the reducing
power of hydrogen sulfide 10 to generate multiple (proto)-
[11] G. B. Seifer, Russ. J. Inorg. Chem. 1962, 7, 640 – 643.
[12] H. Pincass, Chem. Ztg. 1922, 46, 661; G. B. Seifer, Russ. J. Inorg.
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[13] F. Coderre, D. G. Dixon, Hydrometallurgy 1999, 52, 151 – 175.
[14] G. W. A. Foster, J. Chem. Soc. 1906, 89, 912 – 920.
[15] G. Wꢀchtershꢀuser, Microbiol. Rev. 1988, 52, 452 – 484; C.
Huber, F. Kraus, M. Hanzlik, W. Eisenreich, G. Wꢀchtershꢀuser,
Chem. Eur. J. 2012, 18, 2063 – 2080.
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