A Supramolecular Chiral Auxiliary Approach: "remote Control" of Stereochemistry at a Hierarchically Assembled Dimeric Helicate

Article abstract of DOI:10.1002/chem.201600158

Dimeric hierarchically-assembled titanium(IV) helicates are in solvent-dependent equilibrium with the corresponding monomers. Statistically formed mixtures of such complexes bearing chiral stereocontrolling ligands and achiral diene-substituted ligands sh

Full text of DOI:10.1002/chem.201600158

DOI: 10.1002/chem.201600158
Communication
&
Supramolecular Chemistry
A Supramolecular Chiral Auxiliary Approach: “Remote Control” of
Stereochemistry at a Hierarchically Assembled Dimeric Helicate
[a]
[a]
[a]
[b]
David Van Craen, Markus Albrecht,* Gerhard Raabe, Fangfang Pan, and
Kari Rissanen
[b]
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
Abstract: Dimeric hierarchically-assembled titanium(IV)
helicates are in solvent-dependent equilibrium with the
corresponding monomers. Statistically formed mixtures of
such complexes bearing chiral stereocontrolling ligands
and achiral diene-substituted ligands show high diastereo-
selectivity and reasonable enantioselectivity in the Diels–
Alder reaction with maleimides if the reaction proceeds
with the dimer but not with the monomer. Thus, solvent
dependent switching between the monomer and dimer
enables on/off switching of the enantioselectivity.
Chemo-, regio-, and stereoselectivity are of utmost importance
in CÀC bond-forming reactions to obtain well-defined organic
products. This is not only fundamental in organic synthesis but
also has some significant influence in industrial applications as
well as in biochemical processes. The stereochemistry of a CÀC
bond-forming reaction is usually controlled either by a chiral
[
1]
[2]
auxiliary or by a chiral catalyst.
In the present study, we describe a supramolecular chiral-
auxiliary approach in which the source of the chiral informa-
tion and the reactive unit are separated. Incorporation of both
moieties into one aggregate allows us to perform a stereoselec-
tive reaction, which affords a chiral product after disassembly.
The expensive chiral stereocontrolling building block (auxiliary)
is recovered. Furthermore, solvent control of the degree of the
hierarchical supramolecular aggregation allows on/off switch-
ing of the enantioselectivity of the reaction.
Figure 1. a) The concept of “remote control” of stereochemistry in a supra-
molecular chiral auxiliary approach as discussed in this study; b) two exam-
ples for “remote control” of stereoselectivity in metal catalysis.
Few examples for the “remote control” of stereoselectivity
[
3]
have been described. Figure 1 shows the selected supra-
nonchiral phosphanes either by a coordination or electrostatic
attraction. The obtained chelating ligands form catalytically
active metal complexes. A comparable “remote control” by
a long distance induction is also found in nanoparticle-cata-
[4]
[5]
molecular chiral catalysts A and B, in which stereochemistry
is introduced by a building block forming an aggregate with
[
6]
lyzed reactions. For example, a chiral palladium-nanoparticle-
[
a] D. Van Craen, Prof. Dr. M. Albrecht, Prof. Dr. G. Raabe
Institut für Organische Chemie
[6]
catalyzed allylation results in over 80% ee.
The term “helicate” was introduced by Lehn in 1987 for in-
trinsically chiral oligonuclear complexes formed by self-assem-
RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Markus.Albrecht@oc.rwth-aachen.de
[
7]
bly of metal ions and two or more linear ligand strands. Hier-
archical approaches to the self-assembly of dinuclear helicates
[
b] F. Pan, Prof. Dr. K. Rissanen
Department of Chemistry
[8]
involving imine condensation were developed by Hannon
University of Jyväskylä
[
9]
[10]
and Nitschke. Raymond et al. described helicate-type com-
plexes with phosphane-substituted triscatecholates bridged by
P.O. Box 35, 40014 University Jyväskylä (Finland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600158.
[
11]
three metal ions as spacers. A decade ago, we found hier-
Chem. Eur. J. 2016, 22, 3255 – 3258
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Communication
Table 1. Synthesis of mixtures of complexes from achiral reactive ligand
1-H
2
2 2
and the chiral ligands S-2-H and R-2-H .
Entry
Complex
1-H
Equiv]
2
2-H
[Equiv]
2
Configuration
at metal
[a]
[
1
2
3
4
5
Li
Li
Li
Li
Li
4
4
4
4
4
[(1)
[(1)
[(1)
[(1)
[(1)
6
5
3
1
3
Ti
(S-2)
(S-2)
(S-2)
(R-2)
2
]
6
5
3
1
3
0
1
3
5
3
rac.
DD
DD
DD
LL
[
b]
b]
b]
1
Ti
Ti
Ti ]
5 2
2
]
]
Scheme 1. Formation of dimeric hierarchically self-assembled lithium-
bridged titanium(IV) helicates, which are in solvent dependent equilibrium
with the corresponding monomers.
[
3
2
[
[
b]
3
2
Ti ]
[19]
[
a] Confirmed by CD. [b] A statistical mixture of complexes based on
archically assembled lithium-bridged titanium(IV) helicates with
aldehyde-, keto-, or ester-functionalized catechol ligands
the given ratio of ligands is present.
[
12]
(
Scheme 1).
The use of appropriate chiral ligands affords the dimeric
[13,14]
complexes in enantiomerically pure form.
The configura-
complexes as observed by ESI mass spectrometry. Four consti-
tutional isomers of the monomer and thirteen constitutional
isomers of the dimer (as well as corresponding stereoisomers)
are possible. Twelve of the latter bear at least one of the chiral
ligands 2 to control the stereochemistry of a post-assembly
functionalization reaction at the coordinated ligand 1. All
Diels–Alder reactions at the helicate were performed with
three equivalents of a dienophile, based on diene units. After
hydrolytic work-up, the Diels–Alder product was isolated and
the chiral ligand was recovered (77%).
tion at the homochiral metal complex units of the dimer is
locked due to the interlocking of the ester side chains. Inver-
sion of the stereochemistry at the two metal complex moieties
only occurs by kinetically slow dissociation into the monomers.
The monomers are labile at the metal complex units and un-
dergo nondissociative Bailar or Ray-Dutt twist rearrange-
[
15]
+
ments. In solvents that coordinate Li well (e.g. DMF),
mainly a monomer is observed, whereas less polar solvents
(
e.g. THF) strongly favor the dimeric helicate.
Herein, we describe the formation of triple lithium-bridged
The Diels–Alder reaction with N-methylmaleimide (3a) was
[
17]
helicates from statistical mixtures of an achiral ligand that are
first tested with racemic Li [(1) Ti ] (characterized by X-ray).
4 6 2
[
16]
able to undergo a post-assembly functionalization
by
The reaction proceeded quantitatively (observed by ESI-FTMS)
in THF at 708C in a closed tube with an isolated yield of 96%
after an acidic cleavage resulting in 4a (Table 2) with high dia-
stereoselectivity (only one isomer observed). According to our
a Diels–Alder reaction, and a chiral ligand for “remote control”
of the stereoselectivity at the reactive ligand (Figure 2).
Table 2. Diels–Alder reactions at self-assembled helicates.
Figure 2. Schematic representation of the concept of “remote control” for
stereoselective CÀC bond forming reactions with helicates based on mix-
tures of chiral ligands and nonchiral ligands bearing a reactive unit.
Entry
x
2
R
Equiv. Solvent
t
T [8C] Y [%] ee [%]
1
2
3
4
5
6
7
8
9
6
5
3
3
3
3
1
3
3
-
Me 18
THF
THF
THF
THF
THF
THF
THF
THF
DMF
2 d
7 d
70
20
96
76
<1
55
71
72
45
74
30
rac.
7
S-2 Me 15
S-2 Me
S-2 Me
S-2 Me
S-2 Me
S-2 Me
R-2 Me
S-2 Me
9
9
9
9
3
9
9
42 d À32
–
21 d
7 d
0
20
21
25
20
26
À23
5
The achiral diene ligand 1-H , as well as the chiral ligands
2
[
13]
S-2-H2 and R-2-H were reacted with TiO(acac) and Li CO
3
20 h 70
20 h 70
20 h 70
20 h 70
2
2
2
to obtain the helicates listed in Table 1. All complexes, except
Li [(1) Ti ], were obtained as Li [(1) (2) Ti ] (x=1–6) mixtures,
4
6
2
4
x
6Àx
2
with a close to statistical distribution of the ligands within the
Chem. Eur. J. 2016, 22, 3255 – 3258
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Communication
assumption, Diels–Alder reactions with the helicates obtained
from ligand mixtures proceed with some enantioselectivity.
The dependence of the stereoselectivity on the composition of
mixed complexes, temperature, and solvent are listed in
Table 2. The enantiopurity of the product depends on the aver-
age number of chiral ligands in the complex. A dinuclear heli-
cate with ligand 1 to ligand S-2 ratio of 5:1 leads to 76% of
the Diels–Alder product with only 7% ee at room temperature
after 7 days. Increasing the number of chiral ligands to a ratio
of 3:3 results in a similar yield of 71%. However, the ee increas-
es to 25%. Further increase of the amount of S-2 does not
lead to a significant increase of the ee. The Diels–Alder reaction
does not show dramatic changes of selectivity between 0 and
that some enantioselectivity can
be achieved by “remote control”
with the chiral moiety of the auxili-
ary located relatively far away from
the reacting unit (closest distance
between the chiral center of ligand
2 to the prochiral carbon atom of
1 in the complex: 9 bonds; dis-
Figure 3. The major isomer of
4
c. Stereochemistry was as-
signed based on experimental
tance between the chiral titanium and computed CD signals and
center and the prochiral carbon with comparison of the litera-
[18,19]
ture NMR data
.
atom of 1: 7 bonds). The studied
system allows solvent dependent
switching between the dimeric
7
08C. Nevertheless, reaction times are shorter at elevated tem-
and the monomeric complex. In case of the monomer, stereo-
selectivity is nearly switched off. The monomer is configura-
tionally more flexible than the dimer and no well-defined ori-
entation of the stereocontrolling unit towards the diene is en-
forced.
peratures. Use of the corresponding ligand R-2 leads to the
Diels–Alder product preferring the other enantiomer (entry 8).
In THF as solvent the titanium complexes are present as dimer-
ic helicates. Changing the solvent to DMF, results in the mono-
mer as predominant species. In the Diels–Alder reaction of 3a
and Li [(1) (S-2) Ti ], this leads to product 4a with a non-signif-
In summary, this study introduces new supramolecular con-
cepts for the auxiliary control of CÀC bond forming reactions
even though the obtained enantioselectivities are only moder-
ate. The enantioselectivity is influenced by a chiral unit, which
is independent from the reactive moiety and can be easily re-
covered in close to 80% after reaction. A toolbox of chiral
units can be developed in order to easily test different building
blocks for different reactions. Furthermore, due to the solvent
dependence of the monomer/dimer equilibrium, the stereose-
lectivity of the reaction can be turned on or off by simple sol-
vent switching. Future work has to focus on the improvement
of the enantioselectivity and catalytic systems have to be
found.
4
3
3
2
icant enantioselectivity of only 5% ee.
In order to show the scope of the Diels–Alder reaction, more
dienophiles were tested as substrates in the reaction with
Li [(1) (S-2) Ti ] at 0 and 708C (Table 3). Enantioselectivities at
4
3
3
2
Table 3. Substrate scope of the “remote-controlled” Diels-Alder reaction.
Acknowledgements
T=708C
T=08C
Entry
3
R
Y [%]
ee [%]
Y [%]
ee [%]
We thank the international graduate school SeleCa of the DFG
for support. The determination of enantioselectivities by Prof.
Magnus Rueping and Cornelia Vermeeren is gratefully acknowl-
edged.
1
2
3
4
5
3a
3b
3c
3d
3e
Me
Et
tBu
Cy
Bz
72
78
77
75
77
20
19
15
25
21
55
75
69
84
75
21
20
15
27
32
Keywords: Diels–Alder reaction · helicates · lithium · self-
assembly · titanium
0
8C and elevated temperatures (708C) in all cases, except for
N-benzylmaleimide 3e, show no significant temperature de-
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Received: January 13, 2016
Published online on February 2, 2016
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