Plausible origins of homochirality in the amino acid catalyzed neogenesis of carbohydrates

Article abstract of DOI:10.1039/b500589b

The intrinsic ability of amino acids to catalyze the asymmetric formation of carbohydrates, which enzymes have mediated for millions of years, with significant amplification of enantiomeric excess suggests a plausible ancient catalytic process for the evo

Full text of DOI:10.1039/b500589b

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Plausible origins of homochirality in the amino acid catalyzed
neogenesis of carbohydrates{
Armando Co´rdova,* Magnus Engqvist, Ismail Ibrahem, Jesu´s Casas and Henrik Sunde´n
Received (in Cambridge, UK) 13th January 2005, Accepted 17th February 2005
First published as an Advance Article on the web 1st March 2005
DOI: 10.1039/b500589b
amplified. The hydroxyproline and proline-catalyzed one-step
The intrinsic ability of amino acids to catalyze the asymmetric
formation of carbohydrates, which enzymes have mediated for
millions of years, with significant amplification of enantiomeric
excess suggests a plausible ancient catalytic process for the
evolution of homochirality.
synthesis of erythrose 1 and allose 2 was selected as the model
system (eqn. 1).12,15
The origins of the homochirality of natural amino acids and sugars
have intrigued researchers for decades.1 The theoretical basis for
the evolution of high asymmetry from a diminutive imbalance
of enantiomers was suggested more than half a century ago.2
The autocatalytic amplification of enantiomeric excess of a chiral
molecule was experimentally demonstrated by Soai and
co-workers in the treatment of pyrimidine-5-carboxaldehyde with
diisopropylzinc.3 The reaction serves as a mechanistic model for
the chemical evolution of homochirality, however, the zinc
addition chemistry involved in this transformation is unlikely to
have occurred in a prebiotic environment. Extraterrestrial amino
acids have been found on carbonaceous meteorites with enantio-
meric excesses of up to 9%.4 This investigation has led to the
speculation of amino acid catalysis as a potential route for the
evolution of biological homochirality.5–7 Amino acids with low
optical purity may have initiated the asymmetric neogenesis of
hexose carbohydrates, which natural enzymes have catalyzed for
millions of years.8 The asymmetric amplification of sugars is
directly connected to the evolution of homochiral RNA synthesis
as well as to the chiral-selective amino acylation,9,10 which is the
first step in the asymmetric protein synthesis. In this context, it
would be of paramount interest to determine whether chiral
amplification occurs in the plausible amino acid-catalyzed asym-
metric formation of hexose carbohydrates.
ð1Þ
Hence, a-benzyloxy acetaldehyde (1 mmol) was treated with a
catalytic amount of proline (10 mol%) in DMF (1 mL). After
2 days the reaction was quenched and the corresponding 2,4,6-tri-
O-benzyl allose 2 was isolated by silica-gel column chromato-
graphy. Next, allose 2 was converted to the corresponding
peracetylated sugar and the enantiomeric excess (ee) was
determined. The reaction performed with enantiomerically pure
L-proline (. 99% ee) furnished the L-sugar 2 as a predominant
diastereomer with . 99% ee. Next, the one-step amino acid-
catalyzed asymmetric synthesis of allose 2 was examined using
enantio-enriched L-proline as the catalyst (Fig. 1).
Initially, proline with an ee of 80% was used as the catalyst
and allose 2 was furnished with . 99% ee. The ee of the furnished
sugar 2 did not significantly decrease until the optical purity of the
catalyst was below 30% ee. For example, the reaction mediated by
We recently found that amino acids catalyze the incorporation
of molecular oxygen into carbonyl compounds and furnish
glycolaldehydes.7 The derived glycolaldehydes are also substrates
for the amino acid-catalyzed formation of tetroses under prebiotic
conditions.5,11 In addition, we found that amino acids catalyze the
asymmetric neogenesis of natural hexose sugars.12
With these results in hand we were intrigued by the possibility
that non enantiomerically pure amino acids may have set the seed
for the evolution of homochirality of carbohydrates.12–15 Herein,
we report that amino acids catalyze the unprecedented formation
of hexose carbohydrates with remarkably high amplification of
enantiomeric excess. The intrinsic ability of amino acids to catalyze
the asymmetric neogenesis of carbohydrates provides a mechanism
by which a small initial imbalance in chirality is significantly
Fig. 1 Relation between the enantiomeric excess (ee) of L-proline and
that of the newly formed sugar 2 in the one-step catalytic asymmetric
synthesis of 2.
{ Electronic supplementary information (ESI) available: experimental
procedures. See http://www.rsc.org/suppdata/cc/b5/b500589b/
*acordova1a@netscape.net; acordova@organ.su.se
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proline with 20% ee furnished sugar 2 with 55% ee. Hence, the
amino acid-catalyzed formation of the hexose exhibited a
significant non-linear effect.6a,16–18 In fact, this is the largest
permanent non-linear effect observed for a proline-catalyzed
reaction. The reaction catalyzed by proline with 10% ee, which is
similar to the optical purity (9% ee) of the extraterrestrial amino
acids found on the Murchison meteroite,4 furnished the hexose
sugar with a significant augmented enantiomeric excess (33% ee).
Thus, amino acids with a low optical purity may have initiated and
set the seed of homochirality of sugars. We also performed the
reaction utilizing D-proline (. 99 ee) as the catalyst and isolated
the opposite enantiomer of the sugar ent-2 with . 99% ee. In
addition, the enantiomeric excess of the allose 2 was below
the detection level when racemic D,L-proline was employed as the
catalyst. These results demonstrate that the configuration of the
amino acid determines the configuration of the sugar 2.
The amino acid-catalyzed formation of hexoses is a sequential
one-pot direct catalytic asymmetric aldol reaction (Fig. 2), where
the initially formed erythrose derivative undergoes a second
enamine-catalyzed aldol reaction to yield the sugar with excellent
diastereo- and enantioselectivity. The stereoselectivity of the
erythrose is set in the first aldol addition step and dictated by
the catalytic enamine intermediate, which is formed between
the amino acid and the glycoladehyde donor.12–15,18 Next, the
erythrose adds to the re-face of the catalytic enamine intermediate
via transition state I and allose is formed. The rate of the second
anti-selective aldol reaction is significantly slower than the initial
aldol addition, which is established by the higher amount
of erythrose intermediate as compared to allose. Hence, the
hexose formation is the rate-determining step. Furthermore, the
tetrose intermediate is less stable than the final hexose
adduct.19 We therefore believe that the interaction between
non-enantiomerically pure proline and the tetrose intermediate is
important for the amplification of asymmetry in the sequential
aldol additions.
Scheme 1 (a) A two-step synthesis of a polyketide hexose. The first step
is performed with racemic proline and the next step with enantiomerically
pure D-proline. (b) The potential mechanism of the D-proline catalyzed
anti-selective aldol reaction step.
yield with , 5% ee. Hence, D-proline catalyzed a plausible
dynamic kinetic resolution and reacted faster with one of the
two enantiomers (Scheme 1b). The high selectivity of this
transformation indicates that significant enhancement of enantio-
meric excess of natural hexoses was present in the second amino
acid-catalyzed aldol addition step.
In a prebiotic scenario, the amino acids plausibly catalyzed the
formation of both homochiral tetroses and hexoses according to
the routes presented herein.5 The initial transfer of asymmetry to
the tetrose sugars may have been significantly amplified to the
more stable hexose sugars. This mechanism would also have led to
the development of different sugar diastereomers. Both tetroses
and hexoses have been suggested as building blocks of ancient
RNA.20 The amino acid-catalyzed amplification of asymmetry to
sugars might potentially have been further amplified to and by
ancient RNA.9,10
To establish whether proline is able to discriminate between the
two enantiomers of anti-b-hydroxy-aldehydes in sequential cross-
aldol reactions,12 we investigated the proline-catalyzed anti-
selective propionaldehyde addition to racemic anti-b-hydroxy
aldehydes (Scheme 1a). For example, propionaldehyde was reacted
with racemic aldol adduct 3 in the presence of a catalytic amount
of D-proline. The reaction proceeded with excellent selectivity and
polyketide hexose 4 was isolated in 22% yield with . 19 : 1 dr and
95% ee together with remaining acceptor aldehyde 3 in 72%
In summary, it seems conceivable that the amino acid-catalyzed
formation of hexoses presented herein may be an example of the
theoretical basis for the evolution of homochirality of sugars
from a low optical purity of the catalysts. The intrinsic ability of
amino acids to catalyze the asymmetric formation of carbohy-
drates, which enzymes have mediated for millions of years,
suggests a plausible ancient catalytic process that perhaps still
occurs both on Earth and elsewhere in the universe. Further
kinetic and molecular modelling studies are ongoing.
We gratefully acknowledge the Swedish National Research
Council and the Wenner-Gren Foundation for financial support.
We also thank Prof. Hans Adolfsson and Prof. Jan.-E. Ba¨ckvall
for valuable discussions.
Armando Co´rdova,* Magnus Engqvist, Ismail Ibrahem, Jesu´s Casas and
Henrik Sunde´n
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Sweden. E-mail: acordova1a@netscape.net;
acordova@organ.su.se; Fax: + 46 8 15 49 08; Tel: +46 8 162479
Fig. 2 The amino acid-catalyzed asymmetric one-step synthesis of allose
2 and the plausible T.S. I of the second aldol addition step.
2048 | Chem. Commun., 2005, 2047–2049
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P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43,
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Notes and references
14 For the proline-catalyzed asymmetric aldol reactions see: (a) B. List,
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U. Eder, R. Sauer and R. Wiechert, Angew. Chem., Int. Ed., 1971, 10,
496. For proline-catalyzed asymmetric cross-aldol reactions see:
A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc., 2002,
124, 6798; A. B. Northrup, I. K. Mangion, F. Hettche and
D. W. C. MacMillan, Angew. Chem., Int. Ed., 2004, 43, 2152.
15 It was previously believed that proline does not catalyze the formation
of natural hexoses, see: A. B. Northrup and D. W. C. MacMillan,
Science, 2004, 305, 1752; E. J. Sorensen and G. M. Sammis, Science,
2004, 305, 1725. At present we do not know why the hexoses were not
observed.
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Chem. Commun., 2005, 2047–2049 | 2049