DOI: 10.1002/chem.200902430
Physical Organic Study of Structure–Activity–Enantioselectivity
Relationships in Asymmetric Bifunctional Thiourea Catalysis: Hints for the
Design of New Organocatalysts
Xin Li,[a] Hui Deng,[b] Bo Zhang,[b] Jiuyuan Li,[a] Long Zhang,[b] Sanzhong Luo,*[a] and
Jin-Pei Cheng*[b]
Hydrogen-bonding catalysis, which is ubiquitous in nature,
has become a prominent organocatalytic motif that enables
a broad range of transformations.[1] Among a variety of hy-
drogen-bonding organocatalysts explored so far, chiral thio-
ureas have received special attention owing to their biden-
Mayr and co-workers reported the quantitative measure of
nucleophilicities for a series of amines to interpret their or-
ganocatalytic behaviors, elegantly illustrating the power of
physical organic parameters in guiding modern asymmetric
catalysis.[8] However, the classical physical organic parame-
ters of chiral thiourea catalysts, such as pKa values, which
are essential for evaluating their hydrogen-bonding capabili-
ty, are still missing. Although electronic tuning has been
practiced in some of the catalyst designs on a qualitative
basis,[1a] the quantitative connections between electronic ef-
fects (pKa values) and stereoselectivity, which would be
helpful guidance for designing new catalysts, have been
largely overlooked. In a single case, a linear free energy re-
lationship (LFER) was observed between catalyst acidity
and enantioselectivity in hydrogen-bonding catalyzed Diels–
Alder reactions of Rawalꢀs diene.[9] However, the direct in-
dicator of the intrinsic hydrogen-bond-donating ability, that
is, the absolute acidity scale (pKa) of the catalysts, was not
applied for the correlation. Herein, we report the first pKa
scales for chiral thiourea catalysts and their correlations
with the corresponding parameters of the bifunctional catal-
ysis. The experimentally determined pKa values not only
make direct comparisons of thioureas with either conjugated
or nonconjugated substitutes possible, but also allow predic-
tion of possible behaviors of analogous organocatalysts with
varied skeletons.
With Takemotoꢀs catalyst as a prototype, three different
classes of thiourea–tertiary amine conjugates that represents
the currently most widely applied skeletons, namely, cyclo-
hexadiamine (Takemoto and Jacobsen catalysts), cinchona,
and amino acid,[10] were chosen in this study. Accordingly,
twenty chiral thiourea–tertiary amine compounds were syn-
thesized and electronic variations were easily introduced in
the thiourea moieties with either substituted aryl groups or
alkyl groups (Table 1). The pKa values were determined in
DMSO by using the well-established overlapping indicator
method.[11] As shown in Table 1, the chiral thioureas 1, 2,
À
tate N H hydrogen-bonding ability for versatile bi- or mul-
tifunctional catalysis as in the cases such as the Jacobsen cat-
alyst,[2] Takemoto catalyst,[3] the cinchona-type catalysts,[4]
and so on.[5] Although intensive research efforts have been
devoted to studying the mechanism of bifunctional thiourea
catalysis by using either experimental or computational ap-
proaches,[1,6] the in-depth knowledge is still substantially
lacking and the use, therefore, for new catalyst designs re-
mains elusive and warrants further exploration. In this
regard, few studies have been performed on systematic ex-
amination of the structure–activity–stereoselectivity rela-
tionship, particularly from the point view of electronic ef-
fects on this type of catalysis.[7]
Physical organic parameters have long been used as pow-
erful tools towards understanding reaction mechanisms and
to serve as guidelines for the development of novel reac-
tions as well as for the design of new catalysts. Recently,
[a] Dr. X. Li, J. Li, Prof. Dr. S. Luo
Beijing National Laboratory for Molecule Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, the Chinese Academy of Sciences
Beijing, 100190 (China)
Fax : (+86)10-62554449
[b] H. Deng, B. Zhang, L. Zhang, Prof. Dr. J.-P. Cheng
Department of Chemistry
and State-key Laboratory of Elemento-organic Chemistry
Department of Chemistry, Nankai University
Tianjin, 300071 (China)
Fax : (+86)22-23499184
Supporting information for this article is available on the WWW
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 450 – 455