Prebiotic stereoselective synthesis of purine and noncanonical pyrimidine nucleotide from nucleobases and phosphorylated carbohydrates

Article abstract of DOI:10.1073/pnas.1710778114

According to a current RNA first model for the origin of life, RNA emerged in some form on early Earth to become the first biopolymer to support Darwinism here. Threose nucleic acid (TNA) and other polyelectrolytes are also considered as the possible first Darwinian biopolymer(s). This model is being developed by research pursuing a Discontinuous Synthesis Model (DSM) for the formation of RNA and/or TNA from precursor molecules that might have been available on early Earth from prebiotic reactions, with the goal of making the model less discontinuous. In general, this is done by examining the reactivity of isolated products from proposed steps that generate those products, with increasing complexity of the reaction mixtures in the proposed mineralogical environments. Here, we report that adenine, diaminopurine, and hypoxanthine nucleoside phosphates and a noncanonical pyrimidine nucleoside (zebularine) phosphate can be formed from the direct coupling reaction of cyclic carbohydrate phosphates with the free nucleobases. The reaction is stereoselective, giving only the β-anomer of the nucleotides within detectable limits. For purines, the coupling is also regioselective, giving the N-9 nucleotide for adenine as a major product. In the DSM, phosphorylated carbohydrates are presumed to have been available via reactions explored previously [Krishnamurthy R, Guntha S, Eschenmoser A (2000) Angew Chem Int Ed 39:2281-2285], while nucleobases are presumed to have been available from hydrogen cyanide and other nitrogenous species formed in Earth's primitive atmosphere.

Full text of DOI:10.1073/pnas.1710778114

Prebiotic stereoselective synthesis of purine and
noncanonical pyrimidine nucleotide from nucleobases
and phosphorylated carbohydrates
Hyo-Joong Kima,1 and Steven A. Bennera,b
aFirebird Biomolecular Sciences LLC, Alachua, FL 32615; and bFoundation for Applied Molecular Evolution, Alachua, FL 32615
Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved September 18, 2017 (received for review June 14, 2017)
According to a current “RNA first” model for the origin of life, RNA
emerged in some form on early Earth to become the first biopoly-
mer to support Darwinism here. Threose nucleic acid (TNA) and
other polyelectrolytes are also considered as the possible first Dar-
winian biopolymer(s). This model is being developed by research
pursuing a “Discontinuous Synthesis Model” (DSM) for the forma-
tion of RNA and/or TNA from precursor molecules that might have
been available on early Earth from prebiotic reactions, with the goal
of making the model less discontinuous. In general, this is done by
examining the reactivity of isolated products from proposed steps
that generate those products, with increasing complexity of the re-
action mixtures in the proposed mineralogical environments. Here,
we report that adenine, diaminopurine, and hypoxanthine nucleo-
side phosphates and a noncanonical pyrimidine nucleoside (zebular-
ine) phosphate can be formed from the direct coupling reaction of
cyclic carbohydrate phosphates with the free nucleobases. The re-
action is stereoselective, giving only the β-anomer of the nucleo-
tides within detectable limits. For purines, the coupling is also
regioselective, giving the N-9 nucleotide for adenine as a major
product. In the DSM, phosphorylated carbohydrates are presumed
to have been available via reactions explored previously [Krishna-
murthy R, Guntha S, Eschenmoser A (2000) Angew Chem Int Ed
39:2281–2285], while nucleobases are presumed to have been avail-
able from hydrogen cyanide and other nitrogenous species formed
in Earth’s primitive atmosphere.
sizes (furanose and pyranose) of the ribose, and reactions that
lack stereo- and/or regioselectivity.
Accordingly, a second approach considers condensation of
fragments of the nucleobase and/or the carbohydrate to form a
composite, with the nucleoside “finished” after the glycosyl bond is
formed. For example, Carell and coworkers (8) reported the re-
action of ribose (and ribose-borate) with formylated amino-
pyrimidine nucleobase fragments that, after coupling, further react
to produce purine nucleosides. This reaction is regioselective with
respect to the nucleobase, giving N-9 purine nucleosides in high
yield. With respect to the carbohydrate, both furanoses and pyra-
noses were formed.
Pyrimidine nucleosides have always been more difficult to
obtain under prebiotic conditions. However, Sanchez and Orgel
(9) reported many years ago the formation of cytidine derivative
by the reaction of a ribose derivative with cyanamide to give an
aminooxazoline; the synthesis of the heterocycle was finished by
reaction with cyanoacetylene and phosphate-assisted ring open-
ing to make cytidine nucleotide (10). More recently, Powner
et al. (11) produced pyrimidine nucleoside phosphates by a
process where both the carbohydrate and the nucleobase were
introduced as fragments, and finished after the two precursor
fragments were coupled.
We return here to a search for pathways to nucleos(t)ides that
used completed heterocycles as starting materials (Fig. 1). This
would avoid the requirement for prebiotic availability of the re-
active cyanamide and cyanoacetylene. Nucleobases as metastable
units may have been prebiotically available by either polymeriza-
tion of hydrogen cyanide (HCN) (12, 13) or by thermal conden-
sation of formamide in the presence of borate minerals (14).
prebiotic synthesis nucleotide phosphorylated carbohydrate
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ife on Earth is thought to have begun with the emergence of
an informational molecule that could be replicated, with er-
L
rors, where those errors are themselves replicable. These are
believed to be necessary and perhaps sufficient features to sup-
port Darwinian evolution, which in turn is believed to be the only
mechanism by which organic matter can spontaneously self-
assemble to give properties that we value in life (1, 2). Based on
an analysis of its role in modern biology and its presumed in-
creased role in ancient biology, RNA is one of the most prom-
inently sought first informational molecules, although threose
nucleic acid (TNA) (3) and peptide nucleic acid (4) have both
been proposed as alternative candidates. However, considering
their watery environment, the first genetic polymers likely had
repeating charges in their backbones (5). TNA and RNA both
have these, and are polyelectrolytes.
Significance
Much recent research into the origins of life focuses on the
hypothesis that RNA emerged on early Earth by an abiotic
process, and gave Earth its first access to Darwinian evolution.
This article provides a key step in this process. Here, we show
that the phosphorylated ribonucleoside building blocks for
RNA can be made stereoselectively under a prebiotic plausible
condition with canonical and noncanonical purines, and with
one noncanonical pyrimidine. It also shows that threose nu-
cleoside phosphates can be synthesized in a similar way. This
result is significant in terms of numbers of steps, high stereo-
and regiochemistry, scope, involvement of minerals, and like-
lihood of the prebiotic availability of its starting materials.
Therefore, most current efforts in prebiotic chemistry have
concentrated on seeking pathways to make RNA (or TNA) from
materials that were formed without life on early Earth (6). Nu-
cleosides are subunits of these biopolymers, and multiple pre-
biotic routes to these have been proposed.
For example, the direct condensation of ribose itself with
purine nucleobases (adenine and hypoxanthine) is known to
provide the corresponding ribonucleosides (7). However, such
procedures, as previously reported, suffer from low yields for
β-furanonucleosides and the formation of mixtures as a result of
multiple nucleophilic centers on the heterocycle, multiple ring
Author contributions: H.-J.K. designed research; H.-J.K. performed research; H.-J.K. and
S.A.B. analyzed data; and H.-J.K. and S.A.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
1To whom correspondence should be addressed. Email: hkim@firebirdbio.com.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1710778114/-/DCSupplemental.
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Fig. 1. Prebiotic pathway to ribo- and threofuranosyl nucleotides. The reaction of phosphorylated ribose (5) and threose (7) with nucleobases yielded ribo-
and threofuranosyl nucleoside 2′-phosphates. Phosphorylated carbohydrates 5 and 7 can be available from ribose 4 and threose (6) and amidotriphosphate
(3) in prebiotic plausible conditions.
We were further inspired by work of Krishnamurthy et al. (15)
that used an amidotriphosphate (16) derived from cyclic trime-
taphosphate (17) as a prebiotic reagent to add phosphate to
prebiotic carbohydrates to give cyclic sugar phosphates. Previous
work on the “Discontinuous Synthesis Model” (DSM) (18) for
the prebiotic formation of RNA suggested that such carbohy-
drates might have been present prebiotically through the borate-
moderated condensation of glycolaldehyde, glyceraldehyde (19,
20). Threose might have been present, perhaps even in enan-
tiomerically enriched form, by the peptide-catalyzed condensa-
tion of glycolaldehyde alone (21, 22). Glycolaldehyde, in turn,
may have been prebiotically available by electrical discharge of
humid CO2 atmospheres (23), or by the reaction of formalde-
hyde with HCN by photoreduction (24). It is also found around
solar-type young stars (25).
was obtained using NMR spectroscopy with isolated material (SI
Appendix, sections 3.13–3.15).
However, entirely dispositive with respect to the particular
regioisomer formed with respect to the heterocycle was UV
spectroscopy, as the N-9 purine nucleoside (adenosine) shows
UV absorption maximum at 256 nm at pH 3.3 and 259 nm at
pH 7. This is different from a nucleoside analog connected
through exocyclic NH2 of adenine, which has UV absorption
maxima at 264 nm at pH 3.3 and 267 nm at pH 7 (SI Appendix,
section 2.10). UV absorption spectroscopy (Fig. 2) clearly es-
tablishes this product as the N-9 purine nucleoside. The synthesis
conditions also yielded two other purine nucleoside phosphates,
hypoxanthine phosphate (9) and 2,6-diaminopurine phosphates
(10) (SI Appendix, sections 2.2 and 2.3).
Interestingly, whereas the reaction between ribose-1,2-cyclic
phosphate (5) gave purine nucleotides fairly well, it did not
provide the analogous pyrimidine nucleotides with the standard
pyrimidine bases, uracil or cytosine. However, the reaction did
work quite well with pyrimidin-2-one (14) as a nucleobase. Al-
though pyrimidin-2-one nucleoside is not standard in modern
RNA, it may have existed in the first RNA-like polymers, to be
subsequently replaced by uracil or cytosine (26).
Results
As the first step, we tested the reaction of ribose-1,2-cyclic
phosphate (5), a product reported as a possible prebiotic in-
termediate by Krishnamurthy et al. (15), with adenine (8). This
reaction, done by mixing the components and heating at 85 °C,
gave adenosine-2′-phosphate (11) in 15% yield as a major product
(Fig. 2). The identity of 11 was confirmed by the comparison with
authentic commercial adenosine-2′-phosphate, which showed
We then asked about the position of the phosphate groups,
which ends up this process at the 2′- position. This is not the
side of linkage in standard RNA, where the phosphate is pre-
identical behavior in HPLC mobility. Further proof of the structure sented at either the 3′- or the 5′-position. However, we found
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Fig. 2. Synthesis of purine and pyrimidine ribonucleoside-2′-phosphates by the reaction of ribose-1,2-cyclic phosphate (5) and nucleobases in the presence of
metal ions (calcium or magnesium). The reaction was analyzed by reversed-phase HPLC. (A) HPLC of the reaction of 5 and adenine (8). (B) HPLC of adenosine
2′-monophosphate. (C) HPLC of coinjection of A and B. (D) Extracted UV spectrum of the peak at 12.2 min of B. For the detailed characterization of the reaction of 5
with 8, 9, 10, 11, see SI Appendix.
that ribonucleoside-2′-phosphates can be converted to the cor-
responding 5′-phosphates by incubation in the presence of bo-
rate, which preferentially coordinates free 2′- and 3′-hydroxyl
groups. Accordingly, heating adenosine-2′-phosphate with urea,
borate, and phosphate provided adenosine-5′-phosphate and
adenosine (Fig. 3A). The resulting adenosine-5′-phosphate
would then feed into the next step of the DSM to be used, once
activated, for oligomeric RNA synthesis (27).
Further experiments showed that borate was important to this
process. Without borate, incubation of adenosine-2′-phosphate
with urea resulted in the cleavage of 2′-phosphate group to give
free phosphate, adenosine, and the nucleoside, as well as a
complex mixture of phosphorylation products that included
monophosphates (2′-, 3′-, 5′-, and 2′,3′-cyclic, etc.) and di-
phosphate (Fig. 3B). This suggests that borate plays an important
role not to waste prebiotic material by controlling the reactivity
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A
B
Adenosine
18%
5’-AMP
15%
2’,3’-cAMP
3’-AMP
13%
Adenine
4%
10%
2’-AMP
8%
max=256nm
29%
max=256nm
65%
9%
Fig. 3. Reversed-phase HPLC profile of the incubation of adenosine-2′-phosphate (11). (A) Incubation of adenosine-2′-phosphate in the presence of urea,
borate, and sodium phosphate. (B) Incubation of adenosine-2′-phosphate in the presence of urea, sodium phosphate, and no borate.
of hydroxyl groups by coordinating to cis-diol of ribonucleotide
and forces phosphorylation on the 5′-OH (28).
in the case of adenine, and 2,6-diaminopurine and N-3 nucleotides
are major products for 2-pyrimidinone. Thus, they suggest that the
direct coupling of preformed carbohydrates and preformed het-
erocycles need not be considered a prebiotic dead-end.
TNA is an alternative potential prebiotic informational polymer
that might have appeared on Earth before the RNA world (3).
Accordingly, we examined the direct condensation of threose and
adenine under the same dry conditions. The reaction provided two
products having together as much as a 70% yield (SI Appendix,
section 2.9). Those products showed the same mass spectra as
synthetic threofuranosyl adenine (40 in SI Appendix). However,
their HPLC mobilities did not match those of 40. This suggested
that those products have nucleosidic bonds on exocyclic NH2 group
of adenine (SI Appendix, section 1.9). This suggestion was con-
firmed by UV spectroscopy.
The stereoselectivity of the reaction can be rationalized by the
cyclic structure of the cyclic carbohydrate phosphates 5 and 7.
Since these reactions are not catalyzed by any enzyme-like
macromolecules, the reactive intermediate is not thought to be
involvement of an oxocarbenium ion, but rather to proceed by
concerted mechanism (30). Under this rationalization, reaction
from the α-face is blocked by the cyclic phosphate, which acti-
vates the 1-position of the carbohydrates. This reactivity and
stereoselectivity resemble the modern organic synthetic method
that uses Vorbrüggen reaction conditions, which also has a cyclic
intermediate as a reactive species (31).
The coupling reaction proceeds under dry state at elevated
temperature (≥70 °C). Further, the reaction requires divalent
metal ions, magnesium or calcium. In some cases, the presence
of ammonium formate increases the reaction yield (Methods and
SI Appendix, section 5).
Finally, although borate need not be present for the coupling
reaction, it does control subsequent reactivity of the 2′-phos-
phorylated nucleoside derivatives. In the presence of borate,
these 2′-phosphorylated nucleoside derivatives undergo rear-
rangement in urea in the presence of inorganic phosphate to give
the 5′-phosphorylated nucleoside derivatives. Absent borate,
complex mixtures are seen. Borate is also useful in making the
precursor carbohydrates without substantial decomposition.
Whether the coupling of carbohydrate-1,2-cyclic phosphate and
nucleobases is a feasible prebiotic reaction pathway to nucleoside
phosphates therefore rests on the availability of various precursor
components. These include cyclic trimetaphosphate, ammonia,
and ribose (or threose), which generate the cyclic phosphate pre-
cursors. These in turn rely on the availability of glyceraldehyde and
glycolaldehyde, or glycolaldehyde with formaldehyde in the pres-
However, reaction of threose-1,2-cyclic phosphate (7) and
purine and noncanonical pyrimidine nucleobases gave threose
nucleoside-2′-phosphates (Fig. 4 and SI Appendix, section 5.3).
These structures were proven by comparison with authentic
synthetic compounds (SI Appendix, sections 1 and 2). Here, the
glycosidic bond is formed to a ring nitrogen, not to an exocyclic
amino group, as judged by UV spectroscopy.
Threose-1,2-cyclic phosphate proved to be under these condi-
tions a slightly more receptive carbohydrate than ribose. Thus,
whereas ribose-1,2-cyclic phosphate (5) does not react with uracil
(20) to any detectable extent, threose-1,2-cyclic phosphate (7)
reacted with uracil (20) to produce the corresponding nucleotide in
0.4% yield as its 2′-phosphorylated derivative. Here, of course, the
phosphate is at a site involved in internucleotides in TNA. Thus,
TNA remains an interesting alternative to RNA, if only as the
sequential process that eventually generates RNA on a prebiotic
Earth (29).
Discussion
These results show that the reaction of ribose-1,2-cyclic phosphate
(5) and threose-1,2-cyclic phosphate (7) with a range of purine
nucleobases gives ribonucleosides or threonucleosides first as their
2′-phosphates. The condensation reaction is stereoselective, giving
β-nucleotides only, and regioselective; N-9 nucleotides predominate ence of borate. For the nucleobases, this presumes a hydrogen
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A
B
max=248nm
max=259nm
18%
max=260nm
max=249nm
max=256nm
19%
C
D
max=303nm
max=299nm
max=259nm
max=262nm
20%
0.4%
Fig. 4. Synthesis of purine and pyrimidine threofuranosyl nucleoside 2′-phosphates by the reaction of threose 1,2-cyclic phosphate (7) and nucleobases in the
presence of metal ions (calcium or magnesium). The reaction was analyzed by reversed-phase HPLC. (A) HPLC of the reaction of 7 and adenine (8). (B) HPLC of
the reaction of 7 and hypoxanthine (9). (C) HPLC of the reaction of 7 and pyrimidin-2-one (14). (D) HPLC of the reaction of 7 and uracil (20).
and analyzed by reversed-phase HPLC with 20 μL of injection. The yield (based
on the amount of starting nucleobase) of the reactions is summarized in SI
Appendix, section 5.1.
cyanide-type reaction to generate them, either directly or indirectly
by way of formamide.
Methods
Preparative Synthesis of Adenosine-2′-Phosphate (11). An aqueous mixture
Reaction of Ribose-1,2-Cyclic Phosphate (5) and Nucleobases. Ribose-1,2-cyclic
containing adenine (7.5 mM, 0.8 mL), ribose-1,2-cyclic phosphate (15 mM,
phosphate (5) was prepared following the published method (15, 32). The reaction
0.8 mL), and CaCl2 (150 mM, 0.16 mL) was dried and heated at 85 °C for 18 h.
It was dissolved in water (6 mL) and purified on ion-exchange prep HPLC to
give white solid after lyophilization (∼0.3 mg, 12% based on adenine).
Preparative HPLC purification was done using an ion-exchange column
of 5 and nucleobases was conducted in an Eppendorf tube containing nucleobase
[adenine (8), hypoxanthine (9), 2,6-diaminopurine (10), or 2-hydroxypyrimidine hy-
drochloride (14), each 5 μL of 3.75 mM], ribose 1,2-cyclic phosphate (5) (5 μL of
15 mM), either MgCl2 (5 μL of 3.75 mM) or CaCl2 (5 μL of 3.75 mM), with/
without ammonium formate (5 μL of 3.75 mM). The tube was placed in an
oven at 85 °C for 18 h with the lid open. It was resuspended in water (0.3 mL)
(22 mm i.d., 250 mm length, 5 μm; DNAPac PA-100; Thermo Fisher Scientific)
on a Waters Delta 600 module. The column was eluted with a gradient of (A)
water and (B) 1 M ammonium bicarbonate. The elution program created a
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linear gradient started from 100% A to 70% A at 15 min with flow rate of
10 mL/min. Peak detection was conducted using the 260-nm absorbance.
Reaction of Threose-1,2-Cyclic Phosphate (7) and Uracil. The reaction was
conducted in an Eppendorf tube containing uracil (5 μL of 3.75 mM), threose-
1,2-cyclic phosphate (7) (5 μL of 15 mM), MgCl2 (5 μL of 3.75 mM), and so-
dium hydroxide (5 μL of 100 mM). The tube was placed in an oven at 70 °C
for 18 h with the lid open. It was resuspended in 1 M TEAA buffer (0.3 mL)
and analyzed by reversed-phase HPLC with 20 μL of injection.
HPLC Analysis of the Reaction Products of Ribose-1,2-Cyclic Phosphate (5) and
Nucleobases. HPLC analysis was done with a C-18 reversed-phase narrow-
bore column (3 mm i.d., 150 mm length, 5 μm; SunFire; Waters) on a Wa-
ters 2695 separation module equipped with 996 photodiode array detector.
The column was eluted with a gradient of (A) aqueous 20 mM KH2PO4 with
5 mM tetrabutylammonium bromide (pH 3.3, adjusted by phosphoric acid)
and (B) 100% acetonitrile. The elution program created a linear gradient
that started from 99% A to 2.5 min, 97% at 5.5 min, 89.5% at 17.5 min, and
65.0% at 23.5 min with total flow rate of 0.8 mL/min. Peak detection and
integration were conducted with the signal at 260 nm for adenine, hypo-
xanthine, 2,6-diaminopurine and 300 nm for pyrimidin-2-one. Full UV spec-
tra (230 ∼ 400 nm) were also obtained.
HPLC Analysis of the Reaction Products of Threose-1,2-Cyclic Phosphate (7) and
Nucleobases. HPLC analysis was done with a C-18 reversed-phase narrow-
bore column (3 mm i.d., 150 mm length, 5 μm; SunFire; Waters) on a Wa-
ters 2695 separation module equipped with 996 photodiode array detector.
The column was eluted with a gradient of (A) aqueous 25 mM triethy-
lammonium acetate and (B) 100% acetonitrile. The elution program created
a linear gradient started from 100% (by volume) A to 85% A at 10 min
with flow rate of 0.5 mL/min. Peak detection and integration were con-
ducted with the signal at 260 nm for adenine, hypoxanthine, uracil and
300 nm for 2-hydroxypyrimidine. Full UV spectra (230 ∼ 400 nm) were
also obtained.
The yield of the coupling reaction was determined by the peak integration
of the products compared with the integration of nucleosides having the
same nucleobases (SI Appendix, section 5.2).
The yield of the coupling reaction was determined by the peak integration
of the products compared with the integration of nucleosides having the
same nucleobases (SI Appendix, section 5.4).
Reaction of Threose-1,2-Cyclic Phosphate (7) and Nucleobases. Threose-1,2-cyclic
phosphate (7) was prepared following the published method (15). The reaction
was conducted in an Eppendorf tube containing nucleobase [adenine (8), hy-
poxanthine (9), 2-hydroxypyrimidine hydrochloride (14), each 5 μL of 3.75 mM],
threose-1,2-cyclic phosphate (7) (5 μL of 15 mM), either MgCl2 (5 μL of 3.75 mM)
or CaCl2 (5 μL of 3.75 mM) with/without ammonium formate (5 μL of 3.75 mM).
The tube was placed in an oven at 70 °C for 18 h with the lid open. It was
resuspended in water (0.3 mL) and analyzed by reversed-phase HPLC with 20 μL
of injection. The yield of the reactions is summarized in SI Appendix, section 5.3.
ACKNOWLEDGMENTS. We thank Professor Andrew Ellington and one un-
named referee for calling our attention to specific literature. This publication
was made possible through the support of John Templeton Foundation Grant
54466. The opinions expressed in this publication are those of the authors and
do not necessarily reflect the views of the John Templeton Foundation.
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