Chirality of the Very First Molecule in Absolute Enantioselective Synthesis
Luciano Caglioti,a Károly Micskei,b and Gyula Pályic
aDepartment of Chemistry and Technology of Biologically Active Compounds, University “LaSapienza” Roma, Ple.A. Moro 5, I-00185 Roma, Italy.Tel.: + 39-06-4969-0062; fax: + 39-06-4991-0518;
e-mail: luciano.caglioti@uniroma1.it

b

Department of Inorganic and Analytical Chemistry, Faculty of Natural Sciences, University ofDebrecen, H-4010 Debrecen, Egyetem tér 1, P. O. Box 21, Hungary.

cDepartment of Chemistry, University of Modena and Reggio Emilia, Via Campi 183, I-41100 Modena,Italy(Received: July 3, 2007 Accepted: July 20, 2007)
Abstract
In the present paper the role of the very first chiralmolecule formed in achiral-to-chiral reactions, isdiscussed. This molecule represents obligatorily
100 % ee, with important consequences for absolute
enantioselective synthesis. Calculations show that
Soai-type autocatalytic reactions could amplify evenone molecule initial enantiomeric excess to high eeunder reasonable conditions, which enables also anexperimental control.
Introduction
Chirality, a feature of molecular geometry, ingeneral, as well as enantioselective autocatalysis, inparticular, are frontier issues of chemistry.1-6 The
origin of (molecular) chirality in living organisms(biological chirality) is also a first grade challenge
since a long time.7 It is generally accepted, thatasymmetry can be generated only by (physical ormolecular) asymmetry. Several hypotheses wereproposed, how enantiopure chiral substances could beformed without asymmetric influence. These include
stochastic fluctuations,8-13 amplified by autocatalyticmechanisms14 to high enantiomeric purity. Suchchiral autocatalytic reactions14 were experimentallydemonstrated recently.15,16 Our groups found an
empirical approach13 fairly useful in understanding
some features of these reactions.
We would like to point out here an obvious, butrarely (if ever?) mentioned aspect of chirality: therole of the very first chiral molecule formed fromachiral precursors, which is now highly actual also in
the light of recent important developments in single
molecule chemistry.17
If a chiral molecule is prepared from achiralprecursor(s), the very first molecule formed in thistransformation 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
stereochemistry.
The quantitative “enantioselectivity” of the firstchiral molecule is not exceptional, but it is a generalfeature 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- 82 -

could become “first”, with obvious effects forpreparative consequences. Some of these are asfollows:• First, in the absence of chiral additives and/orasymmetric physical fields, the synthesis of thefirst chiral molecule (from achiral precursor(s)),
in any such reaction, corresponds to the mostrigorous criteria of absolute asymmetricsynthesis;12• Second, under these conditions, however, thesense of chirality (R or S, L or D) of this firstmolecule can not be predicted;• Third, the above statement is limited to the casewhere (and until) the first molecule alone“dominates” the system with its 100 % ee;• Fourth, in the absence of chiral additive and/orasymmetric fields, the sense of chirality of asecond 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 2nd, 3rd, 4th, etc.
molecules are formed independently from thefirst one (and from each other), statistics“awakes” and the system can be described interms of probability.8-11, 18 If, on the other hand,the chirality of the first molecule predisposes thepreferential formation of one of the twoenantiomers (especially if it does so by areaction rate exceeding the rate of its ownformation) a true chiral autocatalysis candevelop. Asymmetric autocatalysis has been thegoal 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 withanother chiral (or prochiral) molecule, e.g. the firstmolecule of an amino acid (RCH(NH2)COOH) could
react with a carbohydrate (already chiral) or with aglycerol-2-monoester or -2-monoether (prochiral).
This reaction would necessarily lead to (potential)
diastereomeric products, which are no more subjectedto the law of equal probabilities. Both theautocatalytic amplification of the very first moleculeor its transformation to diastereomeric products couldModel Calculations
We tested the compatibility of the above
argumentation with chemical reality using a recently
deduced empirical formula for the description ofchiral autocatalysis13:
eeprod = eemax

eestartB + eestart(1)

whereeeprod – is the enantiomeric excess of the product in
the individual reaction cycle (%);
eemax – is the maximum enantiomeric excess achievedin the given system (%);
eestart – is the starting enantiomeric excess of theproduct 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 thereaction 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 thewhole operation as a function of the number ofautocatalytic “steps”. Figure 1 shows the results fordifferent Soai-systems, with one molecule initial ee.
The “absolute” variant of the most sensitive
Soai-reaction reaches after three cycles nearquantitative enantioselectivity.15,16 The diagrams inFigure 1 indicate, that similar ee-s can be obtained bymore reaction cycles even with the less sensitive
variants, with one molecule initial excess. For thesecond best system six and for the least sensitive
reaction cca 25-27 cycles would be necessary toachieve high enantiomeric excess. These results have
two important messages: First, the initial influence ofthe very first molecule at a realized chiralautocatalysis seems to provide plausible cycle
numbers. Second, it can be expected, that there might
be several chemical systems, which could be of chiralautocatalytic nature, only nobody has ever looked forthese, while several (more than 3-5) repetitions of thecatalytic cycle seemed to be senseless.

- 83 -10080

ee prod60402000510152025303540

step

Figure 1. Step-by-step evolution of enantiomeric excess inconsecutive autocatalytic cycles with one molecule as
starting enantiomeric excess (eestart = 1.66 10-22 %) in Soaisystems of different sensitivity (eemax,%-B respectively: 993.7 10-5 −•−; 97-3.3 10-2 −▲−; 97-9 −■−; 98-13 −♦−).

Formula (1) enables the definition of a hypotheticalSoai-type system, where only one molecule initialexcess 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. 10-24.
This is orders of magnitude lower than the B value ofthe most sensitive Soai-system, but it does not seem
impossible to reach it.

2-2 0lgee prod

have been those early event(s) which was(were)operative at the origin of biological chirality.
The formation of chiral crystals from achiralmolecules is similar to chiral (chemical) autocatalysis.
In fact, in these experiments20 the influence of thefirst chiral (crystal) nuclei can lead to a similar chiraltakeover in the whole sample, as the first chiralmolecule can do in autocatalysis. Similarly, theobserved high enantioselectivity of chain propagationin polymerization or polycondensation reactions21
can also be related to the influence of the firstmolecule in the chain.

lg B-5-10-15-20-25-30-6-10-14-18

Figure 2. Dependence of eeprod on B of the first cycle, with
one molecule as starting enantiomeric excess for Soaireactions of different sensitivity (arrow shows thehypothetic system which reaches 100% eeprod in one step).

Acknowledgements
The Authors acknowledge valuable discussions toProfs. L. Markó (Veszprém) and G. Varadi (Boston).
This research project was supported by the[Hungarian] Scientific Research Foundation (GrantOTKA, No. T046942 (K. M.) and the (Italian) MUR
FIRB-RBPR05NWWC program.

References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.

Keszthelyi, L. Quart. Rev. Biophys. 1995, 28, 473-507.
Cline, D. B. Origin of the Homochirality in Life, (Ed.:
Physical AIP Press) Woodburg, New York, 1996.
Bolli, M.; Micura, R.; Eschenmoser, A. Chem. Biol. 1997,4, 309-320.
Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
Palacios, J. C.; Barron, L. D. Chem. Rev. 1998, 98, 23912404.
Pályi, G.; Zucchi, C.; Caglioti, L. (Eds.) Advances in
BioChirality, Elsevier, Amsterdam, 1999.
Pályi, G.; Zucchi, C.; Caglioti, L. (Eds.) Progress in
Biological Chirality, Elsevier, Oxford 2004.
Pasteur, L. Ann. Chim. 1848, 24, 442-459.
Pearson, K. Nature 1898, 58, 495-496.
Pearson, K. Nature 1898, 59, 30.
Mills, W. H. Chem. Ind. 1932, 750-759.
Siegel, J. S. Chirality 1998, 10, 24-27.
Pályi, G.; Micskei, K.; Zékány, L.; Zucchi, C.; Caglioti, L.
Magyar Kémikusok Lapja 2005, 60, 17-24.
(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.

- 84 -14.
15.

16.
17.

18.
19.
20.
21.

Frank, F. C. Biochim. Biophys. Acta 1953, 11, 459-463.
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.
Kawasaki, T.; Suzuki, K.; Shimizu, M.; Ishikawa, K.;
Soai, K. Chirality 2006, 18, 479-482.
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.
(a) Lente, G. J. Phys. Chem. A 2004, 108, 9475-9478. (b)Lente, G. J. Phys. Chem. A 2005, 109, 11058-11063.
Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995,378, 767-768.
Kondepudi, D. K.; Asakura, K. Acc. Chem. Res. 2001, 34,946-954.
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.