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ChemComm
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DOI: 10.1039/C8CC01929K
Journal Name
COMMUNICATION
nm) for 16 h in aqueous solution at pH 6.5 or 8.0. The products of prebiotic chemistry have proposed non-aqueous reaction steps,
irradiation were then subjected to ammoniacal deacetylation, and often to overcome perceived problematic effects of reaction
we were pleased to observe 22% (pH 6.5) and 17% (pH 8.0) modulation by water and the so-called “water problem”.19
anomerization to yield the natural cytidine and uridine Therefore we were intrigued to investigate the effect of the non-
ribonucleotides (β-ribo-4/β-ribo-9, Fig. 2, blue). Acetylation aqueous acetylation on photoanomerization. Interestingly,
inhibited the formation of oxazolidinone ribo-6 by blocking the C2'- irradiation of α-ribo-8 lead to remarkably low photoanomerization
hydroxyl group, but remarkably, acetylation also completely yield with only trace yield observed after 16
h (Fig. 4,
suppressed C2'-epimerization. It is of note suppressing C2'- Supplementary information S10). However, we observed
epimerization preserves the ribo-stereochemistry of α-ribo-7 (Fig. unprecedentedly high nucleobase photohydrolysis to uridine
3), and prevents formation of arabino-isomers during nucleotide α-ribo-14 (51%), alongside significant nucleobase loss
photoanomerization.
(19%) and oxazolidinone ribo-6 (6%) after 16 h.
We next turned our attention to the role of the 5'-phosphate in the We recognize the contingency of changing nucleotide concentration
irradiation of α-ribo-7. Selective tri-O-acetylation of α-cytidine (α- during acetylation and irradiation. High concentrations are not
ribo-10) was readily observed upon reaction N-acetylimidazole (10 realistic in the context of the earth Earth’s oceans, however are
eq.) in water at pH 8 to furnish 2',3',5'-(triacetyl)-α-cytidine (α-ribo- reasonable to consider in fresh water environments, where the
11) in 90% yield (65% isolated yield, Fig. 5). However, interestingly, process of dilution with water is not difficult to imagine in a
subsequent irradiation – at initial pH 6.5 – now lead to significant prebiotic context. Moreover the UV screening effect of the water
levels of ester hydrolysis and concomitant formation of column further suggests fresh water, rather than a deep ocean,
oxazolidinone by-product ribo-12 (33%; Supplementary information environment for prebiotic nucleotide photochemistry. Therefore,
Fig. S9). This hydrolysis had not been observed upon irradiation of finally we carried out the one-pot acetylation-photoamonerization-
α-ribo-7 at pH 6.5, and was significantly suppressed at pH 8.0, which deacetylation (Supplementary Figure S8), which was observed to
is in line with the buffering capacity of the 5'-phosphate moiety. We yield comparable anomerization results. Again no arabino-
recognized that Dewar pyrimidine intermediates are observed nucleotides were observed to form during irradiation. The influx of
during
the
photochemical
irradiation
of
pyrimidine high-pH eluent, to liberate or introduce simple nucleophiles (such
nucleotides,2,11,18 and therefore suspected that hydrolysis was as ammonia),13 are also not thought to be unreasonable and
incurred upon pH fluctuation during irradiation. Photochemical provide a simple, effective and potentially prebiotic method to
irradiation was suspected to yield transient concentrations of liberate the vincinal diol of β-ribo-4. Given the observed propensity
hydroxide capable of hydrolyzing the ester moieties, for example, of nucleobase acetylation to inhibit anomerization, it is of note that
upon Dewar pyrimidine 13 C5-protonation (Fig. 5). This suggested aqueous (prebiotically plausible) acetylation yielded only α-ribo-7
that efficient acetyl protection of the 2'-hydroxyl moeity of cytidine and not α-ribo-8. Moreover, as life is a chemical system that has
required a sufficient buffering capacity during irradiation to prevent evolved to exploit reactions, products and processes that occur in
photochemical induced pH fluctuations. To test this hypothesis we water, it is should not be seen as a surprise that aqueous reactions
next introduced phosphate buffer into the irradiation of α-ribo-11, (more so than reactions in organic solvents) reflect the structure
and we were pleased to observe that near complete ester stability and pattern of biological chemistry. It is necessary that prebiotic
was now observed during a comparable irradiation (Supplementary chemistry embraces water as a solvent, and changes the mindset
information Fig. S9).
that invokes water as a “problem”. Prebiotic chemistry must come
to terms with the principle that water is a part of the solution, and
not the problem.
RO
RO
RO
NH2
NH2
O
O
O
Cyt
N
N
hν
N
N
We gratefully acknowledge financial support from the Engineering
and Physical Science Research Council (EP/K004980/1) and the
Simons Foundation (318881).
H2O
O
O
RO
OR
RO
OAc
RO
OAc
OH
13
17
α-ribo-10 R = H
α-ribo-11 R = Ac
i)
RO
NH2
RO
Conflicts of interest
O
O
N
O
N
NH
+
There are no conflicts to declare.
O
O
O
O
RO
OH
RO
12 R = H
18
19
20 R = Ac
Notes and references
Figure 5. Photochemical induced ester hydrolysis and oxazolidinone
formation upon irradiation of cytidine nucleotides.15 i) N-acetyl
imidazole, H2O, pH 8, 90%. Cyt=cytosine.
1
G. F. Joyce Nature 2002, 418, 214-221; L. E. Orgel Biochem.
Mol. Biol. 2004, 39, 99-123; A. Eschenmoser Angew. Chem.
Int. Ed. 2011, 50, 12412-12472; J. W. Szostak J. Syst. Chem.
2012, 3, 2; K. Ruiz-Mirazo, C. Briones and A. de la Escosura
Chem. Rev. 2014, 114, 285-366.
M. W. Powner, B. Gerland and J. D. Sutherland, Nature,
2009, 459, 239–242.
S. Stairs, A. Nikmal, D.-K. Bučar, S.-L. Zheng, J. W. Szostak and
Finally, having observed the suppression of C2'-epimerization upon
diol acetylation, we investigated the effect of nucleobase
acetylation. Nucleobase acetylation had not been observed upon
prebiotic (aqueous) acetylation of α-ribo-4, but was facile under
non-aqueous acetylation protocols. Numerous investigations into
2
3
M. W. Powner, Nat. Commun., 2017, 8, 15270.
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