ArticlePDF Available

Chirality of the very first molecule in absolute enantioselective synthesis



In the present paper the role of the very first chiral molecule formed in achiral-to-chiral reactions, is discussed. This molecule represents obligatorily 100 % ee, with important consequences for absolute enantioselective synthesis. Calculations show that Soai-type autocatalytic reactions could amplify even one molecule initial enantiomeric excess to high ee under reasonable conditions, which enables also an experimental control.
- 82 -
Chirality of the Very First Molecule in Absolute Enantioselective Synthesis
Luciano Caglioti,
Károly Micskei,
and Gyula Pályi
Department of Chemistry and Technology of Biologically Active Compounds, University “La
Sapienza” Roma, Ple.A. Moro 5, I-00185 Roma, Italy.Tel.: + 39-06-4969-0062; fax: + 39-06-4991-0518;
Department of Inorganic and Analytical Chemistry, Faculty of Natural Sciences, University of
Debrecen, H-4010 Debrecen, Egyetem tér 1, P. O. Box 21, Hungary.
Department of Chemistry, University of Modena and Reggio Emilia, Via Campi 183, I-41100 Modena,
(Received: July 3, 2007 Accepted: July 20, 2007)
In the present paper the role of the very first chiral
molecule formed in achiral-to-chiral reactions, is
discussed. This molecule represents obligatorily
100 % ee, with important consequences for absolute
enantioselective synthesis. Calculations show that
Soai-type autocatalytic reactions could amplify even
one molecule initial enantiomeric excess to high ee
under reasonable conditions, which enables also an
experimental control.
Chirality, a feature of molecular geometry, in
general, as well as enantioselective autocatalysis, in
particular, are frontier issues of chemistry.
origin of (molecular) chirality in living organisms
(biological chirality) is also a first grade challenge
since a long time.
It is generally accepted, that
asymmetry can be generated only by (physical or
molecular) asymmetry. Several hypotheses were
proposed, how enantiopure chiral substances could be
formed without asymmetric influence. These include
stochastic fluctuations,
amplified by autocatalytic
to high enantiomeric purity. Such
chiral autocatalytic reactions
were experimentally
demonstrated recently.
Our groups found an
empirical approach
fairly useful in understanding
some features of these reactions.
We would like to point out here an obvious, but
rarely (if ever?) mentioned aspect of chirality: the
role of the very first chiral molecule formed from
achiral precursors, which is now highly actual also in
the light of recent important developments in single
molecule chemistry.
If a chiral molecule is prepared from achiral
precursor(s), the very first molecule formed in this
transformation will necessarily represent 100%
enantiomeric excess, until this species is alone. This
fact can be regarded as an axiom (“primary
statement, which needs no proof) of preparative
The quantitative “enantioselectivity” of the first
chiral molecule is not exceptional, but it is a general
feature of all achiral-to-chiral transitions. Even more,
if the first chiral molecule disappears from the system
by a (fast) secondary reaction, then all molecules
could become “first”, with obvious effects for
preparative consequences. Some of these are as
First, in the absence of chiral additives and/or
asymmetric physical fields, the synthesis of the
first chiral molecule (from achiral precursor(s)),
in any such reaction, corresponds to the most
rigorous criteria of absolute asymmetric
Second, under these conditions, however, the
sense of chirality (R or S, L or D) of this first
molecule can not be predicted;
Third, the above statement is limited to the case
where (and until) the first molecule alone
“dominates” the system with its 100 % ee;
Fourth, in the absence of chiral additive and/or
asymmetric fields, the sense of chirality of a
second molecule (in the same system) can not be
predicted too, if its formation is independent of
the first molecule. Consequently, at this point
the system bifurcates. If the 2
, 3
, 4
, etc.
molecules are formed independently from the
first one (and from each other), statistics
“awakes” and the system can be described in
terms of probability.
8-11, 18
If, on the other hand,
the chirality of the first molecule predisposes the
preferential formation of one of the two
enantiomers (especially if it does so by a
reaction rate exceeding the rate of its own
formation) a true chiral autocatalysis can
develop. Asymmetric autocatalysis has been the
goal of several research efforts, however, only
one well-documented example has been reported
yet: the alkylation of N-heterocyclic aldehydes
by zink dialkyls.
15, 16, 19
The fate of the very first chiral molecule could
take an additional, important turn: it could react with
another chiral (or prochiral) molecule, e.g. the first
molecule of an amino acid (RCH(NH
)COOH) could
react with a carbohydrate (already chiral) or with a
glycerol-2-monoester or -2-monoether (prochiral).
This reaction would necessarily lead to (potential)
diastereomeric products, which are no more subjected
to the law of equal probabilities. Both the
autocatalytic amplification of the very first molecule
or its transformation to diastereomeric products could
- 83 -
have been those early event(s) which was(were)
operative at the origin of biological chirality.
The formation of chiral crystals from achiral
molecules is similar to chiral (chemical) autocatalysis.
In fact, in these experiments
the influence of the
first chiral (crystal) nuclei can lead to a similar chiral
takeover in the whole sample, as the first chiral
molecule can do in autocatalysis. Similarly, the
observed high enantioselectivity of chain propagation
in polymerization or polycondensation reactions
can also be related to the influence of the first
molecule in the chain.
Model Calculations
We tested the compatibility of the above
argumentation with chemical reality using a recently
deduced empirical formula for the description of
chiral autocatalysis
= ee
is the enantiomeric excess of the product in
the individual reaction cycle (%);
is the maximum enantiomeric excess achieved
in the given system (%);
is the starting enantiomeric excess of the
product at the beginning of an individual cycle,
which is defined for the first reaction cycle as added
quantity of the product prior to the start of the
reaction with respect to the substrate (mole-%);
ee (as usual) = (R-S)/(R+S) 100 or (S-R)/(R+S) 100,
where R and S are the molar quantities of the R and S
enantiomers formed in the reaction (%);
B – constant.
In consecutive autocatalytic cycles, this formula
allows to calculate the evolution of ee during the
whole operation as a function of the number of
autocatalytic “steps”. Figure 1 shows the results for
different Soai-systems, with one molecule initial ee.
The “absolute variant of the most sensitive
Soai-reaction reaches after three cycles near-
quantitative enantioselectivity.
The diagrams in
Figure 1 indicate, that similar ee-s can be obtained by
more reaction cycles even with the less sensitive
variants, with one molecule initial excess. For the
second best system six and for the least sensitive
reaction cca 25-27 cycles would be necessary to
achieve high enantiomeric excess. These results have
two important messages: First, the initial influence of
the very first molecule at a realized chiral
autocatalysis seems to provide plausible cycle
numbers. Second, it can be expected, that there might
be several chemical systems, which could be of chiral
autocatalytic nature, only nobody has ever looked for
these, while several (more than 3-5) repetitions of the
catalytic cycle seemed to be senseless.
Figure 1. Step-by-step evolution of enantiomeric excess in
consecutive autocatalytic cycles with one molecule as
starting enantiomeric excess (ee
= 1.66 10
%) in Soai-
systems of different sensitivity (ee
,%-B respectively: 99-
3.7 10
; 97-3.3 10
; 97-9 ; 98-13 ).
Formula (1) enables the definition of a hypothetical
Soai-type system, where only one molecule initial
excess leads to near-quantitative enantioselectivity in
one step. The results are shown in Figure 2: such
Soai-system should have a B constant of cca. 10
This is orders of magnitude lower than the B value of
the most sensitive Soai-system, but it does not seem
impossible to reach it.
Figure 2. Dependence of ee
on B of the first cycle, with
one molecule as starting enantiomeric excess for Soai-
reactions of different sensitivity (arrow shows the
hypothetic system which reaches 100% ee
in one step).
The Authors acknowledge valuable discussions to
Profs. L. Markó (Veszprém) and G. Varadi (Boston).
This research project was supported by the
[Hungarian] Scientific Research Foundation (Grant
OTKA, No. T046942 (K. M.) and the (Italian) MUR
FIRB-RBPR05NWWC program.
0 5 10 15 20 25 30 35 40
lg B
- 84 -
1. Keszthelyi, L. Quart. Rev. Biophys. 1995, 28, 473-507.
2. Cline, D. B. Origin of the Homochirality in Life, (Ed.:
Physical AIP Press) Woodburg, New York, 1996.
3. Bolli, M.; Micura, R.; Eschenmoser, A. Chem. Biol. 1997,
4, 309-320.
4. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
Palacios, J. C.; Barron, L. D. Chem. Rev. 1998, 98, 2391-
5. Pályi, G.; Zucchi, C.; Caglioti, L. (Eds.) Advances in
BioChirality, Elsevier, Amsterdam, 1999.
6. Pályi, G.; Zucchi, C.; Caglioti, L. (Eds.) Progress in
Biological Chirality, Elsevier, Oxford 2004.
7. Pasteur, L. Ann. Chim. 1848, 24, 442-459.
8. Pearson, K. Nature 1898, 58, 495-496.
9. Pearson, K. Nature 1898, 59, 30.
10. Mills, W. H. Chem. Ind. 1932, 750-759.
11. Siegel, J. S. Chirality 1998, 10, 24-27.
12. Pályi, G.; Micskei, K.; Zékány, L.; Zucchi, C.; Caglioti, L.
Magyar Kémikusok Lapja 2005, 60, 17-24.
13. (a) Micskei, K.; Póta, G.; Caglioti, L.; Pályi, G. J. Phys.
Chem. A. 2006, 110, 5982-5984. (b) Micskei, K.; Maioli,
M.; Zucchi, C.; Caglioti, L.; Palyi, G. Tetrahedron
Asymmetry 2006, 17, 2960-2962. (c) Maioli, M.; Micskei,
K.; Caglioti, L.; Zucchi, C.; Pályi, G.; J. Math. Chem.
accepted, 2007.
14. Frank, F. C. Biochim. Biophys. Acta 1953, 11, 459-463.
15. Soai, K.; Sato, I.; Shibata, T.; Komiya, S.; Hayashi, M.;
Matsueda, Y.; Imamura, H.; Hayase, T.; Morioka, H.;
Tabira, H.; Yamamoto, J.; Kowata, Y. Tetrahedron:
Asymmetry 2003, 14, 185-188.
16. Kawasaki, T.; Suzuki, K.; Shimizu, M.; Ishikawa, K.;
Soai, K. Chirality 2006, 18, 479-482.
17. Selected recent references: (a) Kolomeisky, A. B.; Fisher,
M. E. Ann. Rev. Phys. Chem. 2007, 58, 675-695. (b) Wirth,
M. J.; Legg, M. A. ibid. 2007, 58, 489-510. (c) Paul, J.;
Hearn, J.; Howard, B. J. Mol. Phys. 2007, 105, 825-839.
(d) Jung, C.; Hellriegel, C.; Michaelis, J.; Braeuchle, C.
Advanced Mater. 2007, 19, 956-960. (e) Seidel, R.;
Dekker, C. Curr. Opin. Struct. Biol. 2007, 17, 80-86. (f)
Anon. Biopolymers 2007, 85, 106-114. (g) Science
(Washington, DC) 2007, 316, No. 5828: Special Section,
pp. 1143-1158.
18. (a) Lente, G. J. Phys. Chem. A 2004, 108, 9475-9478. (b)
Lente, G. J. Phys. Chem. A 2005, 109, 11058-11063.
19. Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995,
378, 767-768.
20. Kondepudi, D. K.; Asakura, K. Acc. Chem. Res. 2001, 34,
21. Green, M. M.; Park, J.-W.; Sato, T.; Teramoto, A.; Lifson,
S.; Selinger, R. L. B.; Selinger, J. V. Angew. Chem. Int.
Ed. 1999, 38, 3139-3154.
... The Soai reaction shows extreme sensitivity towards the chiral induction exerted by even very low quantities both of the autocatalyst [16][17][18][19][20][21][22][23][24] and of added (enantiomerically pure or enriched) "foreign" chiral molecules [25][26][27][28][29][30][31]. It has also been proved experimentally that such inductor molecules may include enantiomers of simple chiral organic compounds with chirality due only to stable isotopic substitution [32][33][34][35][36][37][38][39]. ...
... We calculated the expectable enantiomeric excesses (e.e. 50% , %) with the Pars-Mills equation [40,48] (with 50% confidence, see also Supporting Materials 2) for sample sizes that could appear in usual micropreparative work (ranging from millimol to femtomol) (Table 1). [16][17][18][19][20] and theoretical considerations [21][22][23][24], the isotope chirality in the tert.-butyl group in compounds 1 and/or 3 could influence the outcome of the most sensitive variant of the Soai reaction, however, taking into regard that it is separated from the pyrimidyl unit by the rigid C 2 moiety, and thus from the decisive molecular events around the new stereocenter, this option appears as scarcely probable, but cannot be excluded. ...
... It has been demonstrated by simple combinatorial/stochastic calculations that, in aldehyde, in the organometallic reagent, as well as in the autocatalyst of the Soai reaction, excess chiral structures can be present. The quantity of these structures in the usual range of micropreparative laboratory practice, from millimol to femtomol sample sizes, could reach such levels, which are higher than the sensitivity threshold of the asymmetric autocatalysis towards chiral induction, demonstrated experimentally [16][17][18][19][20] and evaluated theoretically [21][22][23][24]. In the relevant literature, however, no experimental or theoretical effort has been published earlier that deals with this problem. ...
Full-text available
Isotopic chirality influences sensitively the enantiomeric outcome of the Soai asymmetric autocatalysis. Therefore magnitude and eventual effects of isotopic chirality caused by natural abundance isotopic substitution (H, C, O, Zn) in the reagents of the Soai reaction were analyzed by combinatorics and probability calculations. Expectable enantiomeric excesses were calculated by the Pars-Mills equation. It has been found that the chiral isotopic species formed by substitution in the otherwise achiral reagents provide enantiomeric excess (e.e.) levels that are higher than the sensitivity threshold of the Soai autocatalysis towards chiral induction. Consequently, possible chiral induction exerted by these e.e. values should be taken into account in considerations regarding the molecular events and the mechanism of the chiral induction in the Soai reaction.
... The possibility of obtaining high (almost quantitative) enantiomeric excesses initiated by even very small starting difference in the concentration of the enantiomeric product, or very low concentration of chiral auxiliary, have been demonstrated succesfully in the last few years [12][13][14][15][16][17][18][19][20][21][22][47][48][49][50][51]. The first chiral molecule formed at the very begining of an achiral-to-chiral reaction could have a particular role, if a sufficiently sensitive amplifying mechanism is available (as in the casae of the Soai-reaction) [52][53][54][55]. This "very first" molecule could be one of the chiral conformers discussed in the present paper. ...
Full-text available
Autosolvation is an important factor in stabilizing the architecture of medium complicated molecules. It is a kind of “supramolecular force” acting in intramolecular manner, consisting of orbital-orbital interactions between polar groups, separated by more than one covalent bonds within the same molecule. This effect facilitates also the development of chiral conformations. Two typical alkylcobalt carbonyl type molecules are discussed here as examples of autosolvating intramolecular interactions, leading to dramatic selection of chiral conformers and indicating also to the limits of the effect. The conformers stabilized by autosolvation and their interconversion are excellent examples of a “molecular clockwork”. Operation mode of these molecular clockworks gives some insight into the intramolecular transfer of chiral information. Keywords: alkylcobalt carbonyls; conformation; autosolvation in alkylcobalt carbonyls; chiral conformations; molecular mechanics; interconversion of conformers; anchimeric effect
Full-text available
Solutions of very low concentrations can not be treated by the usual concept of concentration. Stochastic calculations are performed for the analysis of such solutions, containing one or a few molecule(s). It is concluded, that these systems escape the usual concentration parameters. Two "case histories" are also shown for demonstration of practical consequences of the theoretical analysis.
The role of single chiral molecules in attempts at understanding the origins of terrestrial life as well as of biological chirality is discussed. The “single chiral molecule” hypothesis may represent some progress in these problems.
Full-text available
Absolute asymmetric synthesis (AAS) is the preparation of pure (or excess of one) enantiomer of a chiral compound from achiral precursor(s) by a chemical reaction, without enantiopure chiral additive and/or without applied asymmetric physical field. Only one well-characterized example of AAS is known today: the Soai-autocatalysis. In an attempt at clarification of the mechanism of this particular reaction we have undertaken empirical and stochastic analysis of several parallel AAS experiments. Our results show that the initial steps of the reaction might be controlled by simple normal distribution (“coin tossing”) formalism. Advanced stages of the reaction, however, appear to be of a more complicated nature. Symmetric beta distribution formalism could not be brought into correspondence with the experimental observations. A bimodal beta distribution algorithm provided suitable agreement with the experimental data. The parameters of this bimodal beta function were determined by a Pólya-urn experiment (simulated by computer). Interestingly, parameters of the resulting bimodal beta function give a golden section ratio. These results show, that in this highly interesting autocatalysis two or even perhaps three catalytic cycles are cooperating. An attempt at constructing a “designed” Soai-type reaction system has also been made.
Natural-abundance isotopic substitution in isotopically prochiral groups of otherwise achiral molecules can provide stochastically formed enantiomeric excesses which exceed the sensitivity threshold of sensitive asymmetric autocatalytic (Soai-type) reactions. This kind of induction of chirality should be taken into consideration in in vitro model experiments and offer a new kind of entry into primary prebiotic or early biotic enantioselection in the earliest stages of molecular evolution.
Origin(s) of biological chirality appear(s) to be intimately connected to origin(s) of life. Prebiotic evolution toward these important turning points can be traced back to single chiral molecules. These can be small (monomeric) units as amino acids or monosaccharides or oligomers as oligo-RNA type molecules. Earlier speculations about these two kinds of entries to biological chirality are critically reviewed.
Full-text available
Individual molecular motors, or motor proteins, are enzymatic molecules that convert chemical energy, typically obtained from the hydrolysis of ATP (adenosine triphosphate), into mechanical work and motion. Processive motor proteins, such as kinesin, dynein, and certain myosins, step unidirectionally along linear tracks, specifically microtubules and actin filaments, and play a crucial role in cellular transport processes, organization, and function. In this review some theoretical aspects of motor-protein dynamics are presented in the light of current experimental methods that enable the measurement of the biochemical and biomechanical properties on a single-molecule basis. After a brief discussion of continuum ratchet concepts, we focus on discrete kinetic and stochastic models that yield predictions for the mean velocity, V(F, [ATP], ...), and other observables as a function of an imposed load force F, the ATP concentration, and other variables. The combination of appropriate theory with single-molecule observations should help uncover the mechanisms underlying motor-protein function.
Conference Paper
These proceedings represent papers presented at the symposium on the subject of homochirality in life held in Santa Monica, California. The topics discussed included models of chiral symmetry breaking, interstellar medium, origin of genetic materials and future perspectives and experiments. There were 23 papers presented and all have been abstracted for the Energy Science and Technology database.(AIP)
Background: Why did Nature choose furanosyl-RNA and not pyranosyl-RNA as her molecular genetic system? An experimental approach to this problem is the systematic comparison of the two isomeric oligonucleotide systems with respect to the chemical properties that are fundamental to the biological role of RNA, such as base pairing and nonenzymic replication. Pyranosyl-RNA has been found to be not only a stronger, but also a more selective pairing system than natural RNA; both form hairpin structures with comparable ease. Base sequences of pyranosyl-RNA can be copied by template-controlled replicative ligation of short activated oligomers (e.g. tetramer-2',3'-cyclophosphates) under mild and potentially natural conditions. The copying proceeds with high regioselectivity as well as chiroselectivity: homochiral template sequences mediate the formation of the correct (4'-->2')-phosphodiester junction between homochiral tetramer units provided they have the same sense of chirality as the template. How could homochiral template sequences assemble themselves in the first place? Results: Higher oligomers of pyranosyl-RNA can self-assemble in dilute solutions under mild conditions by ligative oligomerization of tetramer-2',3'-cyclophosphates containing hemi self-complementary base sequences. The only side reaction that effectively competes with ligation is hydrolytic deactivation of 2',3'-cyclophosphate end groups. The ligation reaction is highly chiroselective; it is slower by at least two orders of magnitude when one of the (D)-ribopyranosyl units of a homochiral (D)-tetramer-2',3'-cyclophosphate is replaced by a corresponding (L)-unit, except when the (L)-unit is at the 4' end of the tetramer and carries a purine, when the oligomerization rate can be approximately 10% of that shown for a homochiral isomer. The oligomerization of homochiral tetramers is not, or only weakly, inhibited by the presence of the non-oligomerizing diastereomers. Conclusions: Available data on the chiroselective self-directed oligomerization of tetramer-2',3'-cyclophosphates allow us to extrapolate that sets of tetramers with different but mutually fitting base sequences can be expected to co-oligomerize stochastically and generate sequence libraries consisting of predominantly homochiral (D)- and (L)-oligomers, starting from the racemic mixture of tetramers containing all possible diastereomers. Such a capability of an oligonucleotide system deserves special attention in the context of the problem of the origin of biomolecular homochirality: breaking molecular mirror symmetry by de-racemization is an intrinsic property of such a system whenever the constitutional complexity of the products of co-oligomerization exceeds a critical level.
During the past decade, chirally autocatalytic systems that exhibit unusual and interesting phenomena, such as spontaneous chiral symmetry breaking and stochastic behavior, have been identified. In this Account we outline the context in which chiral autocatalysis is of interest, summarize recent advances, and discuss our current understanding of the underlying kinetics and mechanisms. In addition, we note some fundamental aspects of amplification of enantiomeric excess and sensitivity of symmetry breaking transitions to asymmetric factors.
The kinetic equations of growth of symmetrically mutually antagonistic self-reproducing systems are considered and shown to lead to instability. It follows that spontaneous asymmetric synthesis is a natural property of life: a laboratory demonstration is not necessarily impossible.RésuméLes équations cinétiques de la croissance de systèmes auto-reproductibles mutuellement antagonistes symétriquement, permettent de conclure à l'instabilité. Il en résulte que la synthèse asymétrique spontanée est une propriété naturelle de la vie: une démonstration expérimentale n'est pas nécessairement impossible.ZusammenfassungEs werden die kinetischen Wachstumsgleichungen von symmetrisch wechselseiting antagonistischen, sich selbstvermehrenden Systemen betrachtet und gezeigt, dass sie zu Instabilität führen. Es folgt, dass die spontane asymmetrische Synthese eine natürliche Eigenschaft des Lebens ist: eine Laboratoriumsdemonstration ist nicht notwendigerweise unmöglich.
An enantiomerically enriched pyrimidyl alkanol with either S or R configurations was obtained stochastically from the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of achiral silica gel in conjunction with asymmetric autocatalysis with amplification of chirality.
  • J C Palacios
  • L D Barron
Palacios, J. C.; Barron, L. D. Chem. Rev. 1998, 98, 2391- 2404.
  • K Soai
  • T Shibata
  • H Morioka
  • K Choji
Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767-768.
  • D K Kondepudi
  • K Asakura
Kondepudi, D. K.; Asakura, K. Acc. Chem. Res. 2001, 34, 946-954.