Enantioselective supramolecular catalysis induced by remote chiral diols

Article abstract of DOI:10.1021/ja207912d

A new method of creating libraries of chiral diphosphines is presented. Supramolecular coordination compounds based on Ti, Rh, achiral ditopic ligands, and chiral diols were synthesized by in situ mixing and used as catalysts in the asymmetric hydrogenation of (Z)-methyl 2-acetamido-3-phenylacrylate, giving ee's of up to 92%. The ditopic ligands contain a Schiff base that coordinates to the assembly metal Ti and a phosphine as a ligand for Rh. Chirality is introduced by coordination of the chiral diols to Ti. The controlling chiral center and the substrate are separated by as much as 13 A.

Full text of DOI:10.1021/ja207912d

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Enantioselective Supramolecular Catalysis Induced by Remote
Chiral Diols
Piet W. N. M. van Leeuwen,* David Rivillo, Matthieu Raynal, and Zoraida Freixa†
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
S Supporting Information
b
structural diversity, as judged from the enantioselectivities re-
ABSTRACT: A new method of creating libraries of chiral
diphosphines is presented. Supramolecular coordination
compounds based on Ti, Rh, achiral ditopic ligands, and
chiral diols were synthesized by in situ mixing and used as
catalysts in the asymmetric hydrogenation of (Z)-methyl
2-acetamido-3-phenylacrylate, giving ee’s of up to 92%. The
ditopic ligands contain a Schiff base that coordinates to the
assembly metal Ti and a phosphine as a ligand for Rh.
Chirality is introduced by coordination of the chiral diols to
Ti. The controlling chiral center and the substrate are
separated by as much as 13 Å.
ported. In all of these systems, the chiral inducer is located
directly on the catalytic metal and connected via covalent bonds
to the supramolecular devices, which have to be synthesized one
by one. The use of a second metal in such systems that enhances
the ee's has been reported.10c Chiral additives have been used to
obtain or improve ee’s drastically, but in those cases, the chiral
additives also coordinate directly to the catalytic metal and the
reacting atoms are in close proximity of the chiral center.10dꢀf
Introduction of the chiral element in a supramolecular fashion
would reduce the synthetic effort drastically. There are few ex-
amples of synthetic, noncovalent supramolecular systems that
induce enantioselectivity in catalysis,11 but in these cage systems,
the metals do not participate in the catalysis. For metal-catalyzed
reactions, to date only systems based on enzymes,12 DNA,13 and
chiral counterions14 have used a chiral source that is not covalently
linked to the catalyst. Here we present a new approach in which
the chiral inducer is a simple chiral diol that coordinates to an
assembly metal, together with two achiral ditopic ligands that
form the bidentate phosphine ligand holding the catalytic metal
(Figure 1).
upramolecular catalysis, the happy marriage between supra-
S
molecular chemistry and homogeneous catalysis, has taken a
lofty flight in the past decade.1ꢀ3 Here we focus on the supra-
molecular construction of catalysts.4 Supramolecular assembly of
ligand systems has the advantage through the synthesis of a limited
number of small building blocks, large libraries of metalꢀligand
complexes and thus catalysts can be obtained.1 Such catalyst
libraries are needed for catalyst optimization, the development of
accidentally encountered leads, and the discovery of new reac-
tions. Rapid screening studies using such ligand libraries for
known reactions have led to unprecedented enantiomeric ex-
cesses for substrates that hitherto failed to give selective con-
versions.5 Screening of ligand libraries is especially important for
the discovery of enantioselective catalysts, as in this area the
predictive power is limited. Sophisticated methods for reducing
the number of experiments in screening studies have been in-
troduced.6 Structural diversity, a modular synthesis, and the
possibility of fine-tuning are key requirements. Reetz and co-
workers developed and applied the idea of using monodentate
ligands to form bisligand complexes as enantio-, diastereo-, and
regioselective catalysts.7 In such mixtures of two ligands, com-
plexes of the formula ML2 containing homocombinations and
heterocombinations may form, and sometimes the formation of
latter was preferred. Supramolecular tools for inducing the for-
mation of heterocombinations only were introduced by Breit,
Takacs, and Reek and van Leeuwen.1 In both approaches, the
chiral elements are embedded in the monodentate fragment, all
of which must be synthesized one by one, the chiral source most
often being BINOL, TADDOL, or amino acids. In view of the
extreme versatility of BINOL-derived phosphorus ligands in
rhodium-catalyzed hydrogenation,8 it is not surprising that
supramolecular systems based on this ligand have also led to
highly enantioselective hydrogenation reactions. Many TADDOL-9
and BINOL-derived10 supramolecular ligand libraries show high
The new systems introduced here contain a remote chiral
center, and the chiral information is transferred to the catalyti-
cally active center via a large number of atoms. A covalent example
of remote chiral induction in catalytic hydrogenation was re-
ported by RajanBabu and co-workers, in which a remote chiral
dendron induced enantioselectivity in a tropos diphosphine over
14 atomꢀatom bonds.15
The Schiff bases 1ꢀ816 and a wide variety of easily accessible
chiral diols were reacted with Ti(iPrO)4 to give a library of chiral
diphosphines. It turned out that rather bulky diols were needed
with this set of ditopic ligands [see the Supporting Information
(SI)], and therefore, here we present only the more bulky chiral
diols 9ꢀ18 (Chart 1). For the in situ-prepared assemblies,
isopropanol was left in the reaction mixture, as it did not interfere
with the catalysis.
Six isomers (AꢀF) can form, including Δ and Λ diastereoi-
somers (Figure 2). 1H and 31P NMR spectroscopy showed that
the order of addition of diols or ditopic ligands was not important. In
some instances only one compound was observed, but mostly
mixtures of isomers were obtained that showed C1 and C2 sym-
metry in the 1H and 31P NMR spectra (not all diols were studied;
see the SI). Diols 10 and 11 showed a strong preference for only
one species of C2 symmetry, as judged from the imine 1H and 31
P
chemical shifts. Fujita17a and Johnson17b also observed the formation
Received: August 26, 2011
Published: October 21, 2011
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2011 American Chemical Society
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of different isomers for the complexes (NꢀO)2MCl2 (NꢀO =
Schiff base; M = Ti, Zr), but A/B was often the preferred one.
Comparison of the 1H NMR spectra of the ligands based on 10
and 11 with those of Fujita suggests that A/B is the most likely
structure. In the five-coordinate cationic species (NꢀO)2MCl+,
the exchange of Δ and Λ isomers is extremely fast,18 but in the
present hexacoordinate complexes this is not to be expected,
certainly not in the complexes containing bulky diols. After Rh
coordination by addition of Rh(nbd)2BF4 (nbd = norbornadiene)
to the diphosphine, the systems are presumably rather rigid.
Isomers E and F (Figure 2) are not capable of forming chelate
complexes, and most likely, if they were present, they converted
to structures AꢀD over time. The chelate ring formed by
phosphine coordination (12- or 14-membered rings) can intro-
duce another element of asymmetry, depending on the orienta-
tion of the meta-substituted aryl groups.19 Diols 10 and 11 gave
one isomer and only traces of other isomers. For other diols
studied, mixtures of diastereoisomers were formed, although
fewer isomers were observed than might have been expected.
Most of the complexes showed C1 symmetry.
intensities corresponding to a nonsymmetric coordinated nor-
bornadiene and two different methyl groups of the coordinated
chiral diol were observed at significantly different chemical shifts
The heterobimetallic complex [(nbd)Rh{(4,40)Ti(11)}]BF4
was isolated as a pure compound in 92% yield from the reaction
mixture by precipitation with hexane. Two imine and methoxy
protons with different chemical shifts (δCdNH = 8.44 and
8.03 ppm; δOMe = 4.05 and 4.01 Hz) and equal intensities
suggested it to be a single diastereoisomer with C1 symmetry
(Figure 3). Furthermore, a total of eight signals with equal
Figure 2. Conformational isomers expected for a complex of type
(PꢀN,O)2Ti(O,O*).
Figure 1. Schematic representation of the supramolecular strategy for
Figure 3. 1H and 31P{1H} NMR spectra of [(nbd)Rh{(4,40)Ti(11)}]-
forming chiral bidentate ligands via self-assembly.
BF4 in CDCl3.
Chart 1. Ditopic Ligands 1ꢀ8 and Chiral Modifiers 9ꢀ18 Used Here
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Table 1. Screening of Diols and Ditopic Ligands with Substrate 19a
a Conditions: solvent, 0.6 mL of CH2Cl2;[Rh(nbd)2BF4] =3.1mM;[Ti(OiPr)4] =3.8mM;[19] = 338 mM; Ti/diol/ditopic ligand/Rh = 1:1.1:1.6:0.8; PH =3
bar; room temperature; reaction time, 3 h; conversion, 100%. Minus signs denote formation of the S product. b Substrate/Rh = 1000. c Using (R)-VAPOL (214).
(δCH = 0.39 and 0.22 ppm). MALDI-MS analysis provided
evidence for the proposed composition.
ratio was raised to 1000 for ligand combination 4/10, also full
conversion was reached in 12 h, and interestingly, the ee usually
went up. The H2 pressure (3ꢀ10 bar) had only a small effect on
the ee values, but since they were slightly higher at 3 bar, those
results are used here. The best diols are the TADDOL and
BINOL ones, while phosphine-Schiff base 4 stands out as the
best ditopic ligand so far. The ortho substituent on ligand 6 (see
1ꢀ5) turned out to have a surprisingly strong influence on the
outcome. Fujita and co-workers also found a major influence of
the ortho substituent on the FI polymerization catalysts.20
VAPOLs 14 (R) and 140 (S) have opposite absolute configura-
tions, and indeed, the resulting products also showed S and R
configurations. The same was true for 10 (4R,5R) and 11
(4S,5S), which gave R and S products, respectively. Increasing
the steric bulk on the TADDOL somewhat further with 1-naphthyl
groups (12) caused a deterioration in the results. In general, more
electron-rich ditopic ligands showed higher ee's, the results being
very similar for 1, 3, and 4. The electronic properties probably
contribute to the formation of a more stable single isomer, as was
found for 4/10. A slightly more bulky i-Pr substituent on the ether
oxygen diminishes the enantioselectivity. The smaller and electron-
poor ligands 5, 6, and 8 gave low ee's but performed best with the
bulky TADDOL diols. (3,5-Me2C6H3)4-TADDOL (17), which
was too bulky for ditopic ligands 1ꢀ4, gave the best result with the
naphthalene-based ditopic ligand 8. Dinitro-substituted ligand 7
gave 50% ee in combination with 11 but yielded a product with
3
Notably, the chirality introduced at the top of the molecule by
the diol is transduced all the way down to the bridgehead protons
of norbornadiene, which appear as an AB doublet in the spec-
trum. These bridgehead hydrogen atoms are separated by 13
bonds from the chiral inducer atom, or more than 14 Å according
to MM2 models!
The supramolecular ligand library was explored in the rho-
dium-catalyzed asymmetric hydrogenation of prochiral alkenes.
The supramolecular catalysts were prepared by in situ mixing in a
mini-multireactor inside a glovebox. Initially a stoichiometric ratio of
Ti/ditopic ligand/diol/Rh = 1:2:1:1 (see the SI) was pursued, but it
was found that in many cases a ratio of 1:1.6:1.1:0.8 yielded better
results for the ee, probably because deviations of the stoichiom-
etry occurred on such a small scale of preparation and slight
excesses in the order shown were beneficial. After closing, the
autoclave was transported to the high pressure line. In prelimin-
ary control experiments, we studied Rh/11 in the absence of
titanium and in combinations with either triphenylphosphine or
4; in the absence of one of the supramolecular components, no
enantioselectivity was found (see the SI). Table 1 shows the
results of the screening of the supramolecular catalysts based on
1ꢀ8 and selected diols 9ꢀ18 in the hydrogenation of 19.
All of the reactions showed full conversion after 3 h, although
the reaction times were not optimized. When the substrate/Rh
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opposite configuration; the complex formed in this case may be
different from the other ones. Since bulky, wide-bite-angle diols
seemed the best choice, SPANdiol (13) was tested, and here also
ditopic ligands 1, 3, and 4 afforded a lead. Hydrogenation of the
aliphatic substrates itaconic acid dimethyl ester and methyl 2-acet-
amidoacrylate using the same catalytic conditions as for 19 showed
the same trends (see the SI); all of the selectivities were lower, but
they were not optimized for these substrates.
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’ ASSOCIATED CONTENT
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Supporting Information. Syntheses of the ligands and
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diols, their analytical data, and additional catalysis results and
spectra of bimetallic complexes. This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
pvanleeuwen@iciq.es
Present Addresses
†Ikerbasque Research Professor, Universidad del País Vasco
UPV-EHU, Departamento de Quimica Aplicada, Facultad de
Ciencias Quimicas, Apdo. 1072, 20080 San Sebastian, Spain.
’ ACKNOWLEDGMENT
Dr. N. D. Clꢀement and Dra. H. Goitia Semeco are acknowledged
for their assistance. This work was supported by grants from the
Spanish Government MICINN: a “Ramon y Cajal” Contract
(Z.F.), CTQ2005-03416, CTQ2008-00683, Consolider Ingenio
2010 (CSD2006_0003).
’ REFERENCES
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(2) Supramolecular Catalysis;vanLeeuwen,P.W.N.M.,Ed.;Wiley-VCH,
Weinheim, Germany, 2008.
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