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New Aspects of Soai's Asymmetric Autocatalysis.

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DOI: 10.1002/anie.200501742
Asymmetric Amplification
New Aspects of Soais Asymmetric Autocatalysis
Joachim Podlech* and Timo Gehring
asymmetric amplification · asymmetric photolysis ·
autocatalysis · nonlinear effects · zinc
origin of the homochirality of
biomolecules (e.g., amino acids and
carbohydrates) is still puzzling. While
mechanisms have been found for the
formation of enantiomerically enriched
biomolecules without the help of enzymes or other chiral biocatalysts, it is
still not clear how these generally small
enantiomeric excesses could have been
amplified under prebiotic conditions.[1]
In this context, an example of asymmetric autocatalysis reported by Soai and
co-workers in 1990[2] has found ongoing
interest. Though was featured in a Highlight back in 1996,[3] significant and
stunning improvements since then justify an updated treatise.
In Soai,s example heteroaromatic
carbaldehydes react with organozinc
compounds, and the product serves as
an asymmetric catalyst for its own formation (Scheme 1). Soai and co-workers
tested a plethora of substrates, and the
best results were obtained with 2-(tertbutylethynyl)pyrimidine-5-carbaldehyde (1).[4] Addition of diisopropylzinc
in toluene or cumene at 0 8C led to the
nonracemic secondary alcohol 2 even
when no source of chirality had been
added (15–91 % ee). In a series of runs
the sense of rotation in the product was
randomly distributed.[5]
Similar results were obtained by
Singleton et al., but in some experiments they observed a nonrandom distribution of enantiomers even without
any chiral inductor added.[6] This has
been explained by trace amounts of
[*] Prof. Dr. J. Podlech, T. Gehring
Institut f2r Organische Chemie
Universit5t Karlsruhe (TH)
Fritz-Haber-Weg 6
76131 Karlsruhe (Germany)
Fax: (+ 49) 721-608-7652
Scheme 1. Asymmetric autocatalysis in the
formation of secondary alcohols. R = CCtBu;
X = H, ZniPr.
optically active impurities present but
not detectable in the solvents.
Even higher enantioselectivities
were obtained when a small amount of
product with a small enantiomeric excess was added. Addition of the S
alcohol 2 (0.8 % with 0.00005 % ee)
led to product 2 with 57 % ee (S configuration).[7]
Soai et al. observed that not only the
product itself but also other chiral
sources can be used to induce high
selectivities (Figure 1). These chiral
sources initiated the formation of product with a small enantiomeric excess,
which promoted the faster and more
selective formation of further product.
Almost every imaginable chiral source
has been tested over the last decade:[5]
compounds with chiral centers, including chiral alcohols, amines, epoxides,
carboxylic esters, and amino acids can
be used as chiral initiators. Even an
almost negligible asymmetry, as in (S)a-deuterobenzyl
0.05 mol %, > 95 % ee), is sufficient to
produce the R product with 95 % ee.[8]
planes of chirality (e.g., substituted
[2.2]paracyclophanes), with axes of chirality (e.g., [5]- and [6]helicenes and
(K[Co(edta)·2 H2O],
edta = ethylenediaminetetraacetate), and crystals with
enantiomorphous faces (e.g., sodium
chlorate and quartz ) were also applicable. The latter used as d quartz led to
an S product with 80–90 % ee; l quartz
Figure 1. A selection of chiral initiators used in the Soai reaction.[5]
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 5776 – 5777
resulted in 84–89 % ee R product.[9] The
enantiopurity of product 2 was even
higher when the product of a first run
was used as catalyst in a second run.
Usually after three consecutive runs, the
product was obtained with > 99.5 % ee.
A recent publication by Soai et al.
describes an especially interesting twostep protocol.[10] A minimal enantiomeric excess (estimated to be about
0.005 % ee) of the standard product
was obtained by asymmetric photolysis
of racemic alcohol 2 with r circularly
polarized UV light. The resulting actually nonracemic alcohol 2 (the authors
use the term “cryptochiral” for a nondetectable deviation from the racemate)
was used as a catalyst (1 %) in the
standard reaction to yield the R product
2 with 65 % ee. This result is especially
interesting since the enantiomeric excesses of amino acids in meteorites were
attributed to a similar photolysis. These
amino acids might have been a source
for nonracemic organic material in the
prebiotic era.[11]
Although the principle of asymmetric autocatalysis is very simple, functional examples are scarce, if not restricted to Soai,s system.[5] Autocatalysis
occurs when a chiral product acts as a
catalyst for its own formation (Figure 2).
Nevertheless, the mechanism of the Soai
reaction is still not completely understood. The kinetic models presented in
literature[12–14, 17] considering the formation of catalytically active dimers or
higher oligomers[14] are in line with the
experimental data, but experimental
proof of these proposed intermediates
is lacking.
It is obvious that the reaction has to
be significantly faster in the presence of
the catalyst. But the mechanism for
asymmetric autocatalysis should include
both the catalysis of the formation of
one enantiomer and an inhibition of the
generation of the other enantiomer. This
inhibition might be possible through
removal of the catalyst,s minor enantiomer by formation of inactive heterodimers (R)·(S) (or higher oligomers).
Similar nonlinear effects have been
Angew. Chem. Int. Ed. 2005, 44, 5776 – 5777
Figure 2. General scheme for asymmetric autocatalysis.
discussed for dialkylzinc additions in
the presence of nonracemic amino alcohols first described by the groups of
Noyori[15] and Kagan.[16]
The Soai reaction was obviously not
a prebiotic process since the reaction
conditions (utilization of highly hygroscopic organometallic compounds) are
not very likely in the primordial broth.
Nevertheless, one might think of other
reactions with greater biological relevance proceeding by means of similar
mechanisms. The chemical community
is looking forward to further examples
of this fascinating type of reaction.
Published online: August 3, 2005
[1] J. Podlech, Cell. Mol. Life Sci. 2001, 58,
44 – 60; B. L. Feringa, R. A. van Delden,
Angew. Chem. 1999, 111, 3624 – 3645;
Angew. Chem. Int. Ed. 1999, 38, 3418 –
[2] K. Soai, S. Niwa, H. Hori, J. Chem. Soc.
Chem. Commun. 1990, 982 – 983.
[3] C. Bolm, F. Bienewald, A. Seger, Angew.
Chem. 1996, 108, 1767 – 1769; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1657 –
[4] T. Shibata, S. Yonekubo, K. Soai, Angew. Chem. 1999, 111, 746 – 748; Angew.
Chem. Int. Ed. 1999, 38, 659 – 661.
[5] K. Soai, T. Shibata, I. Sato, Bull. Chem.
Soc. Jpn. 2004, 77, 1063 – 1073.
[6] D. A. Singleton, L. K. Vo, J. Am. Chem.
Soc. 2002, 124, 10 010 – 10 011; D. A.
Singleton, L. K. Vo, Org. Lett. 2003, 5,
4337 – 4339.
[7] I. Sato, H. Urabe, S. Ishiguro, T. Shibata,
K. Soai, Angew. Chem. 2003, 115, 329 –
331; Angew. Chem. Int. Ed. 2003, 42,
315 – 317.
[8] I. Sato, D. Omiya, T. Saito, K. Soai, J.
Am. Chem. Soc. 2000, 122, 11 739 –
11 740.
[9] K. Soai, S. Osanai, K. Kadowaki, S.
Yonekubo, T. Shibata, I. Sato, J. Am.
Chem. Soc. 1999, 121, 11 235 – 11 236.
[10] T. Kawasaki, M. Sato, S. Ishiguro, T.
Saito, Y. Morishita, I. Sato, H. Nishino,
Y. Inoue, K. Soai, J. Am. Chem. Soc.
2005, 127, 3274 – 3275.
[11] J. Podlech, Angew. Chem. 1999, 111,
501 – 502; Angew. Chem. Int. Ed. 1999,
38, 477 – 478.
[12] I. Sato, D. Omiya, H. Igarashi, K. Kato,
Y. Ogi, K. Tsukiyama, K. Soai, Tetrahedron: Asymmetry 2003, 14, 975 – 979.
[13] T. Buhse, Tetrahedron: Asymmetry 2003,
14, 1055 – 1061.
[14] D. G. Blackmond, Proc. Natl. Acad. Sci.
USA 2004, 101, 5732 – 5736.
[15] M. Kitamura, S. Okada, S. Suga, R.
Noyori, J. Am. Chem. Soc. 1989, 111,
4028 – 4036.
[16] C. Girard, H. B. Kagan, Angew. Chem.
1998, 110, 3088 – 3127; Angew. Chem.
Int. Ed. 1998, 37, 2922 – 2959.
[17] I. D. Gridnev, J. M. Serafimov, J. M.
Brown, Angew. Chem. 2004, 116, 4992 –
4995; Angew. Chem. Int. Ed. 2004, 43,
4884 – 4887.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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