Heterobifunctional Rotaxanes for Asymmetric Catalysis

Article abstract of DOI:10.1002/anie.201913781

Heterobifunctional rotaxanes serve as efficient catalysts for the addition of malonates to Michael acceptors. We report a series of four different heterobifunctional rotaxanes, featuring an amine-based thread and a chiral 1,1′-binaphthyl-phosphoric-acid-b

Full text of DOI:10.1002/anie.201913781

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Accepted Article
Title: Heterobifunctional rotaxanes for asymmetric catalysis
Authors: Noel Pairault, Hui Zhu, Dennis Jansen, Alexander Huber,
Constantin Daniliuc, Stefan Grimme, and Jochen Niemeyer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913781
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Heterobifunctional rotaxanes for asymmetric catalysis
Noël Pairault,[a] Hui Zhu,*[b] Dennis Jansen,[a] Alexander Huber,[a] Constantin G. Daniliuc,[c]
Stefan Grimme[b] and Jochen Niemeyer*[a]
In memory of Prof. Carsten Schmuck
Abstract: Heterobifunctional rotaxanes serve as efficient catalysts for
the addition of malonates to Michael-acceptors. We report a series of
four different heterobifunctional rotaxanes, featuring an amine-based
acids in a [2]catenane.[12] The resulting bifunctional system
showed drastically enhanced stereoselectivities in comparison to
the non-interlocked monophosphoric acids in the transfer-
thread and a chiral 1,1´-binaphthyl-phosphoric acid based macrocycle. hydrogenation of quinolines.[13]
High-level DFT calculations provided mechanistic insights and
enabled rational catalyst improvements, leading to interlocked
catalysts that surpass their non-interlocked counterparts in terms of
reaction rates and stereoselectivities.
Herein, we now report the first application of a chiral acid/base-
functionalized rotaxane for asymmetric catalysis. We have
combined a Brønsted-acidic macrocycle based on a chiral
1,1´-binaphthyl-phosphate unit with a Brønsted-basic thread
featuring a central secondary amine. We envisaged that the
cooperative action of both functional groups in asymmetric
catalysis would be enhanced by the mechanical bond, thus
leading to enhanced reaction rates and stereoselectivities. Indeed,
using a combined experimental and theoretical approach, we
were able to generate rotaxanated catalysts that show markedly
increased reaction rates and stereoselectivities in comparison to
their non-interlocked counterparts.
The mechanical bond[1] has emerged as a new design element for the
generation of catalytically active species. The use of rotaxanes,[2]
catenanes[3] or molecular knots[4] offers novel possibilities in catalysis,
such as the development of switchable systems, the construction of
highly congested reaction spaces or the linking of different
functionalities via the mechanical bond.[5]
For an application in asymmetric catalysis, a number of chiral
mechanically interlocked molecules (MIMs) have been developed.[6]
In transition-metal catalysis, Leigh used rotaxanes with chiral diamine-
based macrocycles for Ni-catalyzed enantioselective Michael-
additions[7], while Goldup employed mechanically planar-chiral
rotaxane ligands for Au-mediated cyclopropanations.[8] In the realm of
organocatalysis, Leigh and Berna developed rotaxanes featuring
nucleophilic secondary amines on the axle. Making use of either
stereogenic centers in close vicinity to the amine[9] or by employing
For the synthesis of the first-generation bifunctional chiral
rotaxane (S)-1a (see scheme 1), we started by generating the
macrocyclic 1,1´-binaphthyl-phosphoric acid (S)-5a.
the macrocycle to achieve a desymmetrization of
a (pseudo)-
symmetric thread,[10] these rotaxane-catalysts were applied for
enantioselective Michael-additions or -functionalizations.
In a slightly different approach, Takata developed chiral rotaxanes
in which a catalytically active nucleophile (e.g. a thiazole or
pyridine) and a chiral BINOL-moiety are present on different
subcomponents of the MIMs.[11] Nevertheless, the close vicinity of
both components, brought about by the mechanical bond, allowed
the use of these catalysts for enantioselective acylation reactions
or in the benzoin-condensation. Our group has recently reported
the mechanical linking of two chiral 1,1´-binaphthyl-phosphoric
[a]
Dr. N. Pairault, M. Sc. D. Jansen, B. Sc. Alexander Huber,
Dr. J. Niemeyer
Institute of Organic Chemistry and Center for Nanointegration
Duisburg- Essen (CENIDE), University of Duisburg-Essen
Universitätsstrasse 7, 45141 Essen (Germany)
E-mail: jochen.niemeyer@uni-due.de
Dr. Hui Zhu, Prof. Stefan Grimme
Mulliken Center for Theoretical Chemistry
Rheinische Friedrich-Wilhelms-Universität Bonn
Beringstrasse 4, 53115 Bonn, Germany.
E-mail: hui@thch.uni-bonn.de
[b]
[c]
Scheme 1: Synthesis of rotaxane (S)-1a [i) (S)-11a (1 eq), O-allyl-
triethyleneglycol-tosylate (3 eq), Cs2CO3, 80 °C, CH3CN; 70%; ii) Grubbs-II
catalyst, CH2Cl2, 0.5 mM, 54%; iii) conc. HCl, 70 °C, THF/MeOH, 99%; iv) POCl3,
pyridine, 60 °C, then H2O, 95%; v) (S)-5a (1 eq), 21 (1.6 eq), 18 (3.3 eq),
[Cu(MeCN)4PF6], CH2Cl2, 0 °C, 33%] together with the structure of macrocycle
(S)-14a in the solid state (hydrogen atoms omitted for clarity and thermal
ellipsoids set at the 60% probability level).
Dr. C. Daniliuc
Institute of Organic Chemistry
Corrensstr. 40, 48149 Münster, Germany
Supporting information for this article is given via a link at the end of
the document.
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This was performed by alkylation of (S)-11a with O-allyl-
triethyleneglycol-tosylate, followed by ring-closing metathesis
under dilute conditions (0.5 mM) to give the 38-membered
allow ammonium-deprotonation and thus block the reactivity of
the amine, we generated the deprotonated rotaxane [(S)-1a]M+
by addition of one equivalent of metal hydroxide MOH (M =
K/Na/Li). Indeed, this gave catalytically active species, with the
highest reaction rate observed in case of LiOH (59%/83%/91%
conversion for M = K/Na/Li). Based on this, we could also
demonstrate on/off/on switching of the catalyst by subsequent
addition of LiOH/HCl/LiOH (see SI fig. S105). Significantly lower
conversion was observed for the free thread 3 (used as the free
amine R2NH, 10% conversion), and no conversion at all was
found for LiOH only or for the macrocycle/LiOH combination.
These controls clearly indicate that both metal-phosphate and
amine are required for the catalytic activity.
Next, we investigated the influence of the mechanical bond on the
catalytic behavior by using the non-interlocked mixture of
macrocycle (S)-5a and thread 3 as well as the mixture of acyclic
phosphoric acid (S)-6a (see table 1) and thread 3 as a comparison.
For all three metal-salts (KOH/NaOH/LiOH), we consistently
observed the lowest conversion for the macrocycle/thread pairs,
while slightly higher conversions were observed for the acyclic
phosphoric acid/thread pairs. However, rotaxane (S)-1a was by
far the most active catalyst in all cases, with reaction rates being
3.1 - 1.5 times higher in comparison to the acyclic phosphoric
acid/thread mixtures and even 9.2 – 2.0 times higher than those
of the macrocycle/thread mixtures.
macrocycle
(S)-13a.
Subsequent
acid-induced
MOM-
deprotection and phosphorylation gave the desired macrocyclic
phosphoric acid (S)-5a in good yield (36% over four steps). All
compounds were fully characterized by standard analytical
methods (see SI for details), in addition the macrocyclic diol 14a
could be analyzed by single-crystal X-ray analysis of a racemic
sample.
Starting from macrocycle (S)-5a, we generated rotaxane (S)-1a in
a
passive-template approach. (S)-5a was mixed with the
dialkynylated amine 21 to give the corresponding phosphate-
ammonium pseudorotaxane-complex, which was stoppered with
bulky azide 18 in the presence of Cu(I). To guarantee the isolation
+
of pure zwitterionic NH2 /POO [2]rotaxane, the compound was
washed by acidic then neutral aqueous solution after silica gel
column chromatography, yielding (S)-1a in 33% yield.
NMR-analysis (see fig. 1) reveals distinct chemical shift changes
for the rotaxane (S)-1a in comparison to the macrocycle (S)-5a,
the thread 3 and the non-interlocked mixture of (S)-5a with 3.
Finally, the interlocked nature of the rotaxane was unambiguously
shown by MS/MS-experiments, which show liberation of the
thread upon fragmentation of the macrocycle (see SI fig. S23 –
S24).
Table 1: Catalytic results for rotaxane (S)-1a and its non-interlocked
counterparts using different added bases (2 mol% catalyst, THF-d8, 25 °C).[a]
Catalyst
precursor
Added base
MOH[b]
Conversion
(%)[c]
ee
(%)[d]
Entry
1
2
-
LiOH
LiOH
<1
<1
-
-
macrocyclic acid
Figure 1: 1H NMR spectra of (a) macrocycle (S)-5a, (b) rotaxane (S)-1a, (c) 1:1
mixture of macrocycle (S)-5a and (d) thread 3 (all: 600 MHz, CDCl3, 298 K, for
numbering see scheme 1).
(S)- 5a
3
4
thread 3
-
10
<1
59
83
91
8
-
]
-
With the [2]rotaxane (S)-1a in hand, we set out to investigate its
application in asymmetric catalysis. Based on the bifunctional
phosphate-ammonium structure, we envisaged its use for the
asymmetric Michael-addition to ,-unsaturated aldehydes. Such
reactivity is known for non-interlocked phosphate-ammonium
species (e.g. the TRIP-morpholine pair).[14] The generally
accepted mechanism involves iminium-activation of the aldehyde
by the nucleophilic amine, followed by stereoselective addition of
the nucleophile to the chiral phosphate-iminium ion pair (thus
termed as asymmetric counteranion-directed catalysis, ACDC).[15]
For our investigation, we employed the addition of diethyl
malonate 8 to cinnamaldehyde 7a, which yields the chiral
Michael-adduct 9a (see table 1). Firstly, we employed the
5
KOH
NaOH
LiOH
KOH
NaOH
LiOH
KOH
NaOH
LiOH
9
16
14
0
rotaxane (S)-1a
6
7
8
macrocyclic acid
(S)-5a + thread 3
9
9
5
10
11
12
13
45
19
30
59
22
1
acyclic acid
(S)-6a + thread 3
5
14
zwitterionic rotaxane (S)-1a as
a catalyst, but almost no
conversion was observed (<1% conversion after 7 days, see SI
fig. S62-S104 for all conversion curves and chiral HPLC analyses).
Assuming that a strong phosphate-ammonium pairing would not
[a] THF-d8 used as obtained (ca. 100 ppm H2O). [b] Added as 1M solution
to THF-solution of catalyst precursor, followed by drying in vacuo, prior to
catalytic reaction. [c] Determined by 1H-NMR after 7 days. [d] Determined
by chiral HPLC for isolated products.
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With respect to stereoselectivities, both the rotaxane (S)-1a and
its non-interlocked counterparts only afforded low enantio-
selectivities (see table 1). However, three trends were observed:
In case of Na/K, the rotaxane-catalyst (S)-1a gave higher
stereoselectivities (9%/16% ee for Na/K) than the non-interlocked
catalysts (1%/5% and 0%/5% ee for Na/K). For the Li-case,
however, stereoselectivities for interlocked and non-interlocked
species were comparable (14%/14%/22% ee). Variation of the
solvent (CD2Cl2, toluene-d8 or DMSO-d6) led to unchanged or
decreased stereoselectivities (see SI table S1).
To the best of our knowledge, the phosphate-ammonium
catalyzed Michael-addition has not yet been investigated
theoretically.[16] We set out to explore the structures of rate- and
stereo-determining intermediates and to rationalize the
experimentally observed trends in reaction rates and
stereoselectivities based on high-level DFT calculations. Our well
established state-of-the-art DFT protocol (at the PW6B95-
D3/def2-QZVP + COSMO-RS // TPSS-D3/def2-TZVP + COSMO
level[17] in THF solution) was applied, and the final Gibbs free
energies (at 298 K and 1 M reference concentration) are used in
our discussion. The initial structures and reaction paths were
explored with the efficient GFN-xTB method.[17]
Liw2OH (Li(H2O)2OH) is highly exergonic by 25.0 kcal/mol to
form the lithium phosphate complex SLiw2 with two coordinated
water molecules as well as the free amine base Nmh (or NMe2H)
in THF solution. The substrate Meh (malonate) binds through two
ester groups to the lithium site of SLiw2 to replace one H2O ligand,
leading to a more C-H acidic malonate from which a proton can
be transferred to the free amine base Nmh. This proton transfer
reaction is only 1.0 kcal/mol endergonic over a low barrier of
8.4 kcal/mol thus may reversibly lead to the ammonium
phosphate SNmhH+ along with the lithium-activated malonate
MeLiw as potential Michael-donor. At this point, at least two
pathways of Michael-addition to cinnamaldehyde Pho
(cinnamaldehyde) are possible depending on if the asymmetric
phosphate anion S is involved:
In the first path, direct Michael-addition between MeLiw and Pho
occurs via the transition structure MeLiwPho_ts, which is
22.1 kcal/mol endergonic over a barrier of 23.5 kcal/mol to form
the zwitterionic adduct MeLiwPho (not shown in Figure 2), where
the enolate-type addition product is bound to the Li-water cluster.
In the presence of SNmhH+, the adduct MeLiwPho can be
stabilized by the binding of phosphate anion S to Li, followed by
facile proton transfer (via SLiwMePhon_ts) from NmhH+ to the
enolate -carbon, eventually leading to the final Michael-addition
product MePhho and regenerated SLiw2 and Nmh as actual
catalyst.
Our DFT calculations (see fig. 2) show that the stoichiometric
reaction between the non-interlocked model precatalyst
SNmhH+ (phosphate-ammonium pair) and the strong base
Figure 2. DFT computed reaction free energy paths (in kcal/mol, at 298 K, 1 M reference concentration) for the catalytic Michael-addition of model systems of
dimethylmalonate Meh and cinnamaldehyde Pho (PhCH=CHCHO) using the acyclic lithium (S)-1,1'-biphenyl-phosphate SLiw2 and dimethylamine Nmh (NMe2H)
as catalyst, formed from the exergonic reaction of the ammonium phosphate salt pre-catalyst SNmhH+ and the strong base Liw2OH (Li(H2O)2OH). The rotaxane-
catalyst is mimicked by assuming an interaction of the amine/ammonium-thread and the Li-phosphate species (shown in red). Crucial P, O, N, C and H atoms are
highlighted as violet, red, blue, grey and white balls along with grey carbon backbones while most hydrogen atoms are omitted for clarity.
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Such direct Michael-addition of free MeLiw may occur equally at
both sides of the Pho substrate, eventually leading to racemic
final adduct MePhho with an overall barrier of 24.5 kcal/mol
(difference between MeLiwPho_ts and SLiwMeh+Nmh).
rotaxanes in 28-58% yield (see scheme 2, see SI for details and
full characterization).
Alternatively, the (S)-symmetric phosphate anion S may bind to
the lithium site of MeLiw to form the unstable complex SLiwMe
before the nucleophilic addition to the Pho substrate, which may
lead to the desired stereoselectivity. In addition to the strong OLi
coordination bond, S may bind to MeLiw in two configurations
either with or without an additional OHO hydrogen-bond to the
Li-bound H2O ligand. In presence of the hydrogen-bond, the
reaction is kinetically favored by 0.7 kcal/mol and leads to
preferred formation of the (S)-product [(S)-MePhho] with an
enantioselectivity of 1.4 kcal/mol. In contrast, the (R)-product is
favored by 0.7 kcal/mol in the absence of the additional hydrogen
bond.Yet, this phosphate-directed (S)-selective channel via
SLiwMePho_tsS is still kinetically slightly less favorable (barrier
of 24.8 kcal/mol, difference between SLiwMePho_tsS and
SLiwMeh+Nmh) than the direct but racemic Michael-addition.
In order to take into account the rotaxanation in our calculations,
we mimicked the high local concentration of functional groups in
the interlocked structure by assuming an interaction between the
amine/ammonium-thread and the Li-phosphate species
(complexes SLiwMenPho_tsR and SLiwNmh, shown in red in
figure 2). Such interaction results in a reduction of the overall
barrier by about 0.8 kcal/mol for the pathway involving the
ammonium-cation Men (barrier of 23.7 kcal/mol). This shows that
for the interlocked catalyst, the reaction is kinetically competetive
over the racemic pathway, although stereoselectivity for this
pathway is small [(R)-product favored by 0.7 kcal/mol, see SI].
In summary, our DFT-computed mechanism is consistent with the
observed catalytic role of amine, metal ions and phosphate anion,
with small stereoselectivities observed mainly due to two reasons:
(1) competing binding configurations between S and the Michael-
donor MeLiw; (2) lower S affinity of MeLiw than NmhH+. Note
that the generally accepted mechanism of ACDC-type Michael-
addition via the anion-bound iminium as key intermediate (instead
of SLiwMe) was also considered in our DFT calculations but it
encounters a much higher and chemically unrealistic barrier of
about 35 kcal/mol for the SLiw2-catalyzed iminium formation in
the present case (see SI fig. S106).
Scheme 2: Structures of [2]rotaxanes (S)-1a, (S)-2a, (S)-1b and (S)-2b.
Using the optimized reaction conditions (2 mol% catalyst,
2.2 mol% LiOH, THF-d8, r.t.), we investigated the catalytic activity
and stereoselectivity of rotaxanes (S)-1a/2a/1b/2b in comparison
to the respective non-interlocked mixtures of macrocycle and
thread (see table 2).[18] Catalysts 1a and 2a, which differ in the
length of the thread, show no noticeable differences with regard
to rate or stereoselectivity (91/92% conversion after 7 days,
14/14% ee), and the same is true for their non-interlocked
counterparts (45/35% conversion, 22/23% ee).
Table 2: Catalytic results for different rotaxane-catalysts 1a/2a/1b/2b and
their non-interlocked counterparts.
Catalyst
precursor
Aldehyde
substituent X
Conversion
(%)[a]
ee
Entry
1
(%)[b]
rotaxane (S)-1a
H
H
91
45
92
35
88
76
87
78
54
40
92
56
14
22
14
23
53
9
macrocyclic acid
(S)-5a + thread 3
2
3
rotaxane (S)-2a
H
macrocyclic acid
(S)-5a + thread 4
4
H
According to the DFT-computed mechanism, the stereoselectivity
of the addition reaction could be enhanced by introducing bulky
substituents near the oxygen binding sites of S that may favor
single-mode MeLiw binding with enhanced affinity via stronger
dispersion interactions. Such a modified phosphate anion Sb,
5
rotaxane (S)-1b
H
macrocyclic acid
(S)-5b + thread 3
6
H
featuring bulky iPr-groups in the 3,5-positions, shows
a
7
rotaxane (S)-2b
H
37
7
3.5 kcal/mol higher affinity to the malonate substrate Meh as well
as an enhanced stereoselectivity (1.9 kcal/mol in favour of the
(S)-product) for the asymmetric Michael-addition.
macrocyclic acid
(S)-5b + thread 4
8
H
Based on these conclusions, we performed an evolution of the
rotaxane-structure (S)-1a and synthesized three variants. In
addition to introduction of bulky isopropyl-groups in the
3,5-positions (as suggested by DFT), we also designed a shorter
thread in order to enhance the proximity between the relevant
functional groups (phosphate and amine). The synthesis of the
novel iPr2-substituted macrocycle (S)-5b and the novel rotaxanes
(S)-2a (shorter thread only) and (S)-1b/2b (iPr2-macrocycle with
long/short thread, respectively) was performed in close analogy
to the synthesis of (S)-1a (vide supra), giving three additional
9
rotaxane (S)-1b
OMe
OMe
NO2
NO2
44
16
49
14
macrocyclic acid
(S)-5b + thread 3
10
11
12
rotaxane (S)-1b
macrocyclic acid
(S)-5b + thread 3
[a] Determined by 1H-NMR after 7 days. [b] Determined by chiral HPLC for
isolated products.
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In stark contrast to this, the iPr2-substituted rotaxanes 1b/2b give
significantly higher stereoinduction without lowering the reaction
rates (88/87% conversion, 53/37% ee), while their non-
interlocked counterparts are slightly slower and significantly less
stereoselective (76/78% conversion, 9/7% ee). The same trend
can be observed upon variation of the substrate by using
differently substituted Michael-acceptors 7b/c, featuring
p-OMe/p-NO2 substituents, which show moderate stereo-
selectivity in case of rotaxane 1b (44/49% ee), but poor stereo-
selectivity for the non-interlocked catalyst (16/14% ee).
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Pairault, J. Niemeyer, Synlett 2018, 689-698.
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[8] A.
W.
Heard,
S.
M.
Goldup,
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Despite these clear trends and the enhanced stereoselectivities
for the rotaxane-catalysts, we were wondering why the absolute
stereoselectivity remains moderate. Based on DFT-calculations,
it seems that the racemic Michael-addition between free MeLiw
and Pho still remains kinetically competitive over nearly the same
barrier as the channel involving the chiral phosphate, even in the
new catalyst design. We will address this fact in due course by
further modification of the rotaxane-structures.
[12] R. Mitra, M. Thiele, F. Octa-Smolin, M. C. Letzel, J. Niemeyer, Chem.
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In summary, we could show that the mechanical bond can indeed
serve as an efficient tool for the modification and improvement of
organocatalysts. The mechanical linking leads to a significant
increase in reaction rates for all cases investigated here, which
can be attributed to the high local concentrations of the functional
groups in the [2]rotaxane-catalyst. In terms of stereoselectivity,
we established that the length of the thread has no significant
influence, while the exact substitution pattern of the macrocycle
[14] S. Mayer, B. List, Angew. Chem. Int. Ed. 2006, 45, 4193-4195.
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i
has a major impact. Introduction of bulky Pr-groups led to a
significant increase in stereoselectivity, however only in case of
the mechanically interlocked catalysts. This finding may well pave
the route for the generation of more selective interlocked catalysts
for such organocatalytic transformations that have failed to be
realized with high stereoselectivities up to date.
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Acknowledgements
Funding by the Fonds der Chemischen Industrie (Liebig-
Fellowship to J.N.) and the German Research Foundation (DFG,
NI1273/2-1) is gratefully acknowledged. J. N. would like to thank
Prof. Carsten Schmuck for his support. We thank Prof. Benjamin
List (MPI Mülheim) for a generous donation of (S)-TRIP.
S.G. and H.Z. thank the German Science Foundation (DFG) for
financial support (Gottfried Wilhelm Leibnitz prize to S.G.).
[18] No further comparison with the combination of acyclic phosphoric acids +
threads was conducted since these did not differ in stereoselectivity in the
initial investigation using rotaxane 1a.
Keywords: mechanically interlocked molecules • rotaxanes •
organocatalysis • asymmetric catalysis • DFT
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