Published on Web 08/31/2010
A New Class of Ligands for Aqueous, Lanthanide-Catalyzed, Enantioselective
Mukaiyama Aldol Reactions
Yujiang Mei, Prabani Dissanayake, and Matthew J. Allen*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
Received August 10, 2010; E-mail: mallen@chem.wayne.edu
resulting ligands have three sites at which the substrate can
coordinate: two “side” positions near the ethers in the macrocycle
that are equivalent by symmetry and one “top” site between the
two side sites. Our new class of ligands takes advantage of the
low degree of conformational flexibility and the water tolerance of
lanthanide complexes of macrocyclic polyaminopolycarboxylate-
based ligands. Additionally, we stereospecifically introduced methyl
groups at the methylene positions of the two remaining arms with
the goal of imparting chirality. Furthermore, by converting the
carboxylic acids into esters, we aimed to control the possible binding
sites for substrate molecules through changing the size of the R
groups of the esters. We hypothesized that this feature would be a
powerful tool for studying structure-activity relationships of our
ligands with the goal of improving the enantioselectivity.
Abstract: The development of aqueous methods for generating
enantiopure ꢀ-hydroxy carbonyl compounds is an important goal
because these subunits compose many bioactive compounds and
the ability to synthesize these groups in water has environmental
and cost benefits. In this communication, we report a new class
of ligands for aqueous, lanthanide-catalyzed, asymmetric Mu-
kaiyama aldol reactions for the synthesis of chiral ꢀ-hydroxy
ketones. Furthermore, we have used luminescence-decay mea-
surements to unveil mechanistic information regarding the cata-
lytic reaction via changes in water-coordination number. The
precatalysts presented here yielded ꢀ-hydroxy carbonyls from
aliphatic and aryl substrates with outstanding syn:anti ratios and
enantiometric excesses of up to 49:1 and 97%, respectively.
The enantioselective Mukaiyama aldol reaction is one of the most
useful protocols for synthesizing optically active ꢀ-hydroxy carbonyl
1
moieties, which are subunits of many bioactive compounds.
Lanthanide triflate-catalyzed versions of this reaction have gained
prominence in the past decade because they are water tolerant and
consequently have the benefits associated with not having to
rigorously exclude water, including being more environmentally
Figure 1. Structures of (left) a common gadolinium-containing polyami-
nopolycarboxylate-based contrast agent and (right) our ligands with two
types of water-binding sites labeled.
2
benign and less expensive. However, few examples of enantiose-
lective, lanthanide-catalyzed Mukaiyama aldol reactions in aqueous
media exist. These reactions use chiral crown ether-based ligands
The new C
7-98% yields by a simple two-step protocol starting from
commercially available (S)-2-bromopropanoic acid (95% ee) (Scheme
). No chromatographic purification was needed, and none of the
2
-symmetric ligands (R,R)-I-VI were prepared in
3
9
and result in moderate to good enantiomeric excesses (ee’s) with
aromatic aldehydes and poor ee’s with alkyl aldehydes. The lack
of a thorough mechanistic understanding of these complexes in the
presence of water has hindered the improvement of stereoselectivity
and the widespread use of these catalysts. Additionally, the
multidentate chiral ligands necessary to chelate lanthanide ions are
often difficult to synthesize and purify. Here we report the facile
1
opposite (S,S) enantiomer was observed in preparing ligands I-VI.
Ligand VII was synthesized by saponification of I. The ligands
3+
3
were complexed with Eu(OTf) in situ prior to catalysis. Eu was
chosen because it is an effective promoter of the activation of
2,6,7
aldehydes in aqueous media
decay measurements.
and because it enables luminescence-
4
,8
2
synthesis of a new class of C -symmetric lanthanide-containing
complexes that were designed using insight gained from water-
coordination-number measurements. We also report the excellent
enantioselectivity of these new precatalysts in the aqueous Mu-
kaiyama aldol reaction and the structure-activity relationships
obtained using our recently reported use of luminescence decay to
Scheme 1. Synthesis of Chiral Ligands
4
study bond formation.
Our ligand design was inspired by macrocyclic gadolinium-
5
containing contrast agents for magnetic resonance imaging. These
complexes were chosen as our starting point because they are water-
tolerant, and we hypothesized that the multidenticity of these ligands
would allow for facile incorporation of chiral centers (Figure 1).
However, we modified the ligands because the contrast agents have
only one open coordination site, whereas our previous studies
showed that a larger number of coordination sites is associated with
higher turnover frequencies. To increase the number of open
coordination sites, we replaced two of the aminocarboxylic acid
2
arms with ethers to yield a hexadentate C -symmetric system. The
a
b
The last step was stirred at 0 °C for 240 h. Determined by chiral
c
high-performance liquid chromatography (HPLC) analysis. Not determined.
Determined by H NMR spectroscopy.
d
1
Initially, we examined the structure-activity relationships of
4
chiral ligands with different R groups. The results demonstrated
that the size of the R group has a direct effect on the catalytic rate
(based on yield in a set time) and enantioselectivity of the
10.1021/ja107197p 2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 12871–12873 9 12871