Communications
DOI: 10.1002/anie.201001723
Asymmetric Amplification
Asymmetric Amplification in Phosphoric Acid Catalyzed Reactions**
Nan Li, Xiao-Hua Chen, Shi-Ming Zhou, Shi-Wei Luo, Jin Song, Lei Ren, and Liu-Zhu Gong*
Methodologies involving chiral resolution, chiral auxiliary
induced transformations, and asymmetric catalytic reactions,
including those catalyzed by metal, biological, and organic
catalysts, have been developed and, typically, these processes
have exploited optically pure catalysts to ensure high
enantioselectivity. In these reactions, the enantiomeric
excess (ee) of the reaction product was linearly proportional
to the ee value of the chiral catalyst or auxiliary. However,
chemists have observed numerous exceptions to this linear
relationship, some characterized by a positive nonlinear
correlation between the ee value of the reaction product
and that of the chiral catalyst or auxiliary.[1–7] This phenom-
enon, termed asymmetric amplification, has not only pro-
vided cost effective asymmetric synthetic protocols in com-
parison with those using enantiomerically pure catalysts, but
has also been considered a basis for the origin of homochir-
ality in nature.[8–9] In the last decades, metal-based asymmetric
amplified catalysis has undergone great advances.[6] Recent
applications of asymmetric amplification in organocatalysis,
particularly the use of biologically relevant molecules such as
amino acids as catalysts, have advanced the long standing
inquiry into the evolution of homochirality in the prebiotic
system.[10–13] However, the importance of asymmetric amplifi-
cation in reactions catalyzed by phosphoric acids and its
derivatives,[14–18] an important class of pentavalent phosphorus
compounds relevant to nucleic acids, has been less recog-
nized.[19]
During our studies on the phosphoric acid catalyzed
Figure 1. Asymmetric amplification in the Biginelli reaction catalyzed
by phosphoric acid 1a. The reaction was catalyzed by 1a at different
Biginelli reaction,[20] we found a strong positive nonlinear
effect (NLE) for the reaction of para-nitrobenzaldehyde (2),
thiourea (3), and ethyl acetoacetate (4) in the presence of
10 mol% of the non-enantiopure 3,3’-ditriphenylsilyl binol-
derived phosphoric acid 1a in toluene (Figure 1a).[21] In
contrast, an absolutely linear effect was observed for the same
reaction under almost identical reaction conditions except
optical purities: a positive NLE was observed in toluene (a) and a
linear effect was observed in chloroform (b). Optically pure 1a gave a
much faster reaction than the racemate in [D8]toluene (c), however
similar reaction rate was observed for optically pure and racemic 1a in
CDCl3 (d).
that chloroform was used as the reaction medium instead of
toluene (Figure 1b). Kinetic studies revealed that the opti-
cally pure phosphoric acid afforded a much faster reaction in
toluene (Figure 1c), but in chloroform, the optically pure and
the racemic catalysts exhibited comparable catalytic activities
(Figure 1d). Similarly, electron-rich benzaldehydes also par-
ticipated in the reaction to show similar positive NLE as
exemplified by 2-methylbenzaldehyde (see the Supporting
Information).
The strong dependence of the NLE upon the solvent
prompted us to investigate this observation in detail. In
proline-catalyzed reactions, the nature of the solvent played a
distinct role in the NLE, and this role was attributed to the
solubility differences between racemic and optically pure
samples.[12–13] In the phosphoric acid catalyzed Biginelli
reaction, we speculated that the significant dependence of
the asymmetric amplification upon the solvent is also
[*] Dr. X.-H. Chen, S.-M. Zhou, Dr. S.-W. Luo, J. Song, L. Ren,
Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry, University of Science and Technology
of China, Hefei, 230026 (China)
Fax: (+86)551-360-6266
E-mail: gonglz@ustc.edu.cn
N. Li, Prof. L.-Z. Gong
Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences (CAS), Chengdu, 610041 (China)
N. Li
Graduate School of Chinese Academy of Sciences, Beijing (China)
[**] We are grateful for financial support from NSFC (20732006), MOST
(973 program 2010CB833300), and the Ministry of Health
(2009ZX09501-017).
Supporting information for this article is available on the WWW
6378
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 6378 –6381