Synergistic Noncovalent Catalysis Facilitates Base-Free Michael Addition

Article abstract of DOI:10.1021/jacs.0c08639

Carbon-carbon bond-forming processes that involve the deprotonation of a weakly acidic C-H pro-nucleophile using a strong Br?nsted base are central to synthetic methodology. Enzymes also catalyze C-C bond formation from weakly C-H acidic substrates; howev

Full text of DOI:10.1021/jacs.0c08639

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Article
Synergistic Non-Covalent Catalysis Facilitates Base-Free Michael Addition
Jianzhu Wang, Tom A. Young, Fernanda Duarte, and Paul J. Lusby
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2020
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Journal of the American Chemical Society
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Synergistic Non-Covalent Catalysis Facilitates Base-Free
Michael Addition
Jianzhu Wang,† Tom A. Young,‡ Fernanda Duarte‡* and Paul J. Lusby†*
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†
EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh,
Scotland, EH9 3FJ, U.K.
‡ Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
ABSTRACT: Carbon-Carbon bond forming processes that involve the deprotonation of a weakly acidic C-H pro-nucleophile using
a strong Brønsted base are central to synthetic methodology. Enzymes also catalyze C-C bond formation from weakly C-H acidic
substrates, however, they accomplish this at pH 7 using only collections of non-covalent interactions. Here we show that a simple,
bio-inspired synthetic cage catalyzes Michael addition reactions using only coulombic and other weak interactions to activate
various pro-nucleophiles and electrophiles. The anion-stabilizing property of the cage promotes spontaneous pro-nucleophile
deprotonation, suggesting acidity-enhancement equivalent to several pKa units. Using a second non-covalent reagent –
commercially available 18-crown-6 – facilitates catalytic base-free addition of several challenging Michael partners. The cage’s
microenvironment also promotes high diastereoselectivity compared to a conventional base-catalyzed reaction.
using organo-naphthodiimide and C60 structures.[9] While it is
difficult to identify the precise reasons for the lack of anion-
Introduction
The organization of charge within an active site, which
selectively stabilizes intermediates and transition states using
electrostatic forces, is the basis for highly efficient enzyme
catalysis.[1] This mode of reactivity provides a blueprint for
developing synthetic catalysts that use only non-covalent
interactions.[2] Self-assembled coordination cages are prime
candidates for mimicking biological catalysts because (i) they
provide a well-defined microenvironment that is distinct from
the bulk phase and (ii) they invariably possess well defined,
permanent charge. These facets have been beautifully
demonstrated by Raymond, Bergman and Toste on numerous
stabilizing processes, what is clear is that being able to realize
this apparently simple concept could open up the field of cage
catalysis to a raft of new transformations, not least considering
the plethora of C-C bond forming reactions that involve the
deprotonation of weakly acidic C-H compounds. We now
demonstrate the full effectiveness of this approach, using a
simple cationic host system to catalyze Michael addition with
remarkable efficiency.
Results and Discussion
We have previously shown that simple Pd2L4 coordination
cages,[7d-h] like C1 and C2 (Figure 1a), can act as highly
efficient catalysts.[10a-c] The catalytic properties of these cages
do not stem from entropic effects, such as the dual
encapsulation[11a-c] or constrictive binding mechanisms[11d] that
have dominated earlier bio-inspired approaches. Instead, the
activity of C1 and C2 arises because they can enthalpically
stabilize polar intermediates and transition states (TS). This
stabilization is facilitated by using large non-coordinating
BArF counteranions, which are unable to access the cavity and
leaves a charge-dense interior that is coulombically frustrated.
Furthermore, the cationic Pd ions polarize the adjacent C-H
bonds, creating pockets of H-bond donor atoms (Figure 1a,
shown in blue) that can provide additional interactions. The
BArF counteranions also impart solubility in apolar solvents,
such as dichloromethane, leading to a poorly solvated inner
microenvironment, further increasing the recognition of polar,
reactive intermediates. Conversely, traditional small non-
coordinating anions such as BF4, PF6 and OTf bind tightly
inside the cage, especially in apolar solvents, which
significantly reduces the affinity towards other species.[10d]
occasions, who have used
a
dodeca-anionic gallium
tetrahedron to catalyze reactions that involve various cationic
intermediates, such as oxonium[3] and iminium species,[4]
carbocations[5] and positively-charged transition metal
complexes.[6]
Anionic coordination cages are relatively rare compared to the
vast number of cationic coordination assemblies that are built
from transition metal ions and neutral ligands.[7] It seems
somewhat surprising then that reports of catalysis that involve
the stabilization of reactive anionic species within cationic
cages are exceedingly rare.[8] There are several possible
explanations for this apparent anomaly. Many cationic cage-
compounds are effective hosts because they bind apolar
substrates in water using the hydrophobic effect, while the
associated anions are strongly hydrated and loosely associated
with the cage-periphery.[8d] Anionic intermediates, unlike their
cationic equivalents, can also be strongly coordinating and
thus have the potential to disrupt the cage structure. Finally,
anionic intermediates – again unlike cations – are also likely to
be less well stabilized by the flat aromatic surfaces that define
the cavity of a typical coordination cage. It should be noted,
however, that highly deficient aromatic systems can be used to
achieve catalysis by the stabilization of negatively charged
intermediates, as exemplified by the elegant work of Matile
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4BArF
4BArF
a)
product by a single substrate, an approach we had successfully
utilized to avoid product inhibition with DA catalysis.[10a]
However, the reaction of 20 mol% C1, with either
benzoquinone (Ka = 8000 M−1)[10d,e] or naphthoquinone (Ka =
3.5×105 M−1)[10d], and the relatively acidic yet weakly binding
pro-nucleophile, nitromethylacetate, Nu1H (Ka ≈ 30 M−1),
both in the absence and presence of non-coordinating base,
DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene, 10 mol%), gave
no clear evidence of Michael addition product formation
(Scheme 1a) instead only small quantities of unidentifiable
products. Other cage-complementary electrophiles, such as
dimethyl maleate (Ka = 1100 M−1) also showed no formation
of Michael adduct. While it was perhaps unsurprising that no
reaction occurred in the absence of base, the lack of reaction
between what we presumed would be a strongly bound,
activated enone and the nucleophilic Nu1− was more
N
H
N
H
2+
Pd
2+
Pd
1
2
3
4
5
6
7
8
N
H
N
H
N
H
N
H
N
N
H
H
N
H
N
H
N
N
H
N
H
N
N
H
H
2+H
Pd
2+H
Pd
N
N
N
N
C1
C2
b)
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disappointing. A closer examination of the H NMR spectra,
particularly for the reaction of dimethyl maleate (Figure S61),
gave some clues as to the lack of reactivity. Specifically, on
the addition of base to C1, Nu1H and dimethyl maleate, a
second set of cage peaks appear while the dimethyl maleate
electrophile shifts back towards the free-state. The appearance
of a second set of cage peaks indicates the formation of a
slowly exchanging species, which we infer to be the strongly
bound nucleophilic anion complex, Nu1−⸦C1. Hence, the
deprotonated nucleophile simply displaces the bound
electrophile rather than adding to the 1,4-position. The
strategy of using a cage-complementary electrophile and a
second much weaker binding nucleophile (to ensure turnover)
was then reversed, using β-dicarbonyl pro-nucleophiles that
are matched for C1 (Scheme 1b). With this strategy, we
thought that the use of a smaller electrophile, vinyl methyl
ketone, E1 (Ka < 30 M−1), would aid access to the bound
nucleophilic anion. This approach also showed no evidence of
Michael addition products. The spectroscopic data for these
reactions again indicated that the bound nucleophilic anion is
generated but that this is simply unreactive. This is particularly
clear for the reaction of Meldrum’s acid with E1. In this case,
the cage actually inhibits the reactivity that is seen with
substrates and base only (Figures S65 and S66).
Figure 1. (a) Chemical structure of non-covalent Michael
addition cage catalysts. The large, non-coordinating BArF
counteranions create a highly polar, coulombically-frustrated
cavity that can provide significant reactive intermediate and
transition state stabilization. (b) Electrostatic potential (ESP)
slices of cages C1 and C2 on the xz plane containing two
opposing ligands and the two metal centers. Positive values
(red) indicate increases in the electron density, while negative
values (blue) indicate electron density reductions. Arrows
represent the electric field defined from negative to positive
(∇ESP) where the length corresponds to the magnitude.
Despite the similarity in the chemical structures of C1 and C2,
the two cages show quite distinct catalytic properties. C2
shows excellent activity for Diels-Alder reactions with
quinone dienophiles,[10a] which are bound strongly as the two
carbonyl oxygen atoms are matched to interact simultaneously
with both H-bond donor pockets. This catalysis shows
selective TS stabilisation that is comparable to the most active
catalytic antibody.[10a] In contrast, C1 is completely inactive –
despite being able to bind quinones more strongly than C2.
Calculations show that the different catalytic behaviour stems
from the greater flexibility of C2.[10b] The surprisingly distinct
properties are also manifest in the way the cages alter the
redox properties of bound guests – but this time in reverse: C1
is able to increase the reduction potential of bound quinones
by as much as 1 V, corresponding to 90 kJ mol−1 radical-anion
stabilization energy. These redox enhancing properties have
been used to achieve electron transfer with non-bound
substrates, generating radical-cation reactivity outside the
cage.[9c] This time C2 shows no activity. Electrostatic potential
energy slices of the two cages (Figure 1b) reveal why C2 is
inferior at stabilising anionic species; the central non-
coordinating nitrogen atoms significantly neutralize the
potential, both centrally within the cavity and also at the distal
Pd sites and H-bond donor atoms. It was therefore clear that
C1 should be the favoured choice for investigating reactions
that involve encapsulated closed-shell anionic intermediates.
(a) Complemetary electrophile, weakly binding pro-nucleophile:
No catalytic Michael addition
O
O
O
base or
no base
O
MeO
MeO
+
MeO
Nu1
NO2
O
naphtho-
quinone
O
O
H
benzo-
quinone
dimethyl
maleate
(b) Complementary pro-nucleophile, weakly binding electrophile:
No catalytic Michael addition
base or
no base
O
O
O
O
O
O
+
O
O
O
E1
indane-
dione
Meldrum's
acid
dimedone
Michael addition was chosen as a representative reaction as it
was expected that a bound quinone would act as an activated
enone. External, intermolecular attack by a non-bound
anioinic nucleophile would then generate a cage-stabilized
oxy-anion intermediate. Subsequent turnover would then
involve the entropically neutral displacement of a single
Scheme 1: Single-substrate binding approaches give no
catalytic Michael addition. Dicarbonyl electrophiles and pro-
nucleophiles (shown in dashed box bind) are a match for the
H-bond donor sites of C1.
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In light of these results, we extended our screen of reactions to
difference in pKa of Nu1H and H3O+, which are +5.7 and −1.7,
respectively.[15] These values are measured in water, therefore,
a direct comparison to the non-aqueous system described here
must be treated with caution. Nonetheless, it is clear that the
cage significantly increases the acidity of the pro-
nucleophile.[16] This large shift occurs because the tetrcatioinic
cage is excellent at stabilizing the nucleophile conjugate
anion, Nu1−, through a mixture of coulombic and H-bond
interactions. This large increase in acidity parallels recent
redox studies, which showed that C1 shifts the 1 e− reduction
potential by 1 V, presumably due to similar stabilization
effects.[10c]
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a more diverse pairing of substrates, specifically the combined
use of weakly binding Nu1H and E1 (Scheme 2a). When these
reactants were mixed with C1 in dichloromethane, we were
pleasantly surprised that the formation of product P1 occurs
even in the absence of an external base (Scheme 2b, blue
squares). In contrast, the substrates only do not react under the
same conditions (Scheme 2b, red diamonds) even after a
week. Several control reactions have been carried out to
confirm that reactivity stems from the cage’s inner
microenvironment (Scheme 2c). Adding the strong binding
inhibitor pentacenedione (Ka ≈ 108 M−1) to the catalyzed
process completely halts activity. The representative
mononuclear complex, [Pd(pyridine)4](BArF)2, also shows no
reactivity. Collectively, these results show C1 is not simply
serving as a source of Lewis acidic free Pd2+ ions or Brønsted
basic pyridine groups and that catalysis is dependent on the
substrates being able to access the cage cavity. We have also
found that C2 shows no reactivity under the same conditions.
This provides further evidence that the highly homologous
cages possess quite different properties, with C1 favouring
processes that involve bound anionic species.
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Expanding the substrate scope, we found that the similar pro-
nucleophile benzoylnitromethane, Nu2H, also reacts with E1
to generate Michael product P2 quantitatively after 4.5 days
(Scheme 3). Attempts to further widen the substrate scope to
less acidic pro-nucleophiles and different Michael acceptors,
however, showed minimal reactivity. We therefore reasoned
that perhaps the limiting factor was not the stability of the
nucleophile−⸦C1 host-guest complex, but rather the
hydronium BArF species that is released from the reaction of
water with the pro-nucleophile⸦C1. While hydronium is more
likely to exist as a slightly more stable protonated water
cluster, the bulk apolar solvent and non-coordinating BArF
counteranion still make this a high energy species. In order to
stabilize the hydronium ion, we postulated that commercially
available 18-crown-6 could play this role.[17] We were thus
delighted to find that when one equivalent of 18-crown-6 was
added to the transformation of Nu1H and E1 to give P1, a
dramatic reduction in reaction time was observed, from
several days with C1 only to less than 40 min with crown
ether additive (Scheme 2b, purple crosses). The control
reaction with only 18-crown-6 and substrates gave no
reactivity over several days (Scheme 2c), showing that
synergistic non-covalent stabilization of the charge separated
state is necessary. A further control experiment with the
representative mononuclear complex [Pd(pyridine)4](BArF)2
and 18-crown-6 (Scheme 2c) also showed no reaction. With
this control reaction, significant degradation of the
mononuclear complex is observed, which again indicates that
partial destruction releasing free components (e.g. Lewis
acidic Pd2+ ions and pyridine base) is not responsible for
catalysis. Notably, C1 does not show any indication of
decomposition in the presence of 18-crown-6, highlighting
that the cage topology additionally imparts structural stability,
presumably due to cooperative chelate effects. It is also worth
noting that C2 does show some reactivity with 18-crown-6,
although much diminished compared to C1 (See Figure S8),
highlighting their differences are not dualistic.
(a)
O
O
CD2Cl2, RT
O
O
+
MeO
MeO
NO2
NO2
Nu1
E1
P1
H
(b)
100
C1 + 18-crown-6
C1
substrates only
90
80
70
60
50
40
30
20
10
0
100
80
60
40
20
0
0
20
40
time (min)
0
50
100
150
time (h)
(c) Control / additional experiments
CD2Cl2, RT
reagentsa-e
O
O
O
O
+
MeO
MeO
NO2
NO2
Nu1
E1
H
P1
aC1
+ pentacenedione (Inhibitor, Ka = 108 M-1); b[Pd(pyridine)4](BArF)2;
d18-crown-6 only; e[Pd(pyridine)4](BArF)2 + 18-crown-6
cC2
;
We have also applied the C1 / 18-crown-6 conditions to a
preparative scale reaction to demonstrate the efficiency and
simplicity of the method. In this instance, the loading of C1
and 18-crown-6 can be lowered to 2 and 10 mol%,
respectively – without any appreciable drop in yield (72 mg
isolated yield, 91%, 2 days). The catalytic use of 18-crown-6
is also consistent with it binding a quantity of released H3O+
that is equal or less than the mol% of C1 (assuming the
affinity of crown-ether for hydronium is sufficiently high).
Scheme 2: Base-free Michael addition catalysis. General
reaction conditions: C1 (0.5 mM, 20 mol%), Nu1H (12.5
mM), E1 (2.5 mM), 18-crown-6 (2.5 mM), CD2Cl2, RT.
The reactivity of C1 is remarkable considering its chemical
structure (Figure 1a): it does not possess the Brønsted base
functionality present in small molecule H-bond catalysts[12]
nor any Lewis acid site, which makes it distinct from base-free
transition metal systems.[13] The control experiment with
[Pd(pyridine)4](BArF)2 further indicates that this functionality
does not arise under experimental conditions due to the
dissociation of components. In the absence of an obvious
Brønsted base, it is likely that residual water elicits the
deprotonation of Nu1H.[14] It is interesting to note the
Armed with this combined non-covalent method, we turned to
a wider scope (Scheme 3) of both different electrophiles (E2-
4) and pro-nucleophiles (Nu3-5H). Methyl acrylate, E2, is
seen as a challenging electrophile, much less reactive and
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difficult to activate than E1 yet product P3 is generated in
Page 4 of 9
quantitative yield.[18a] Also a bifunctional Brønsted base-
hydrogen bond catalyst (quinine-squaramide) also mediates
the formation of P1 (2 mol% cat, toluene, RT, 4 h).[18b]
Significantly, however, these small molecule non-covalent
approaches use ca. two orders of magnitude higher
concentrations compared to the C1 / 18-crown-6 system.[12,18]
To make a more accurate evaluation, we have explored some
representative hydrogen-bond catalysts under identical
conditions to facilitate a direct comparison (Table 1). In
contrast to the C1 and C1 / 18-crown-6 systems (Entries 1 and
2), representative non-covalent catalysts NC1 and NC2, give
no catalysis on their own, or with 18-crown-6 (Entries 3-6).
Adding the organic base DBU, which has a basicity (estimated
pKa of DBUH+ is 12) sufficient to deprotonate Nu1H (pKa =
5.7), to the H-bond catalysts does generate low yields of
product (Entries 7 and 8). However, these yields are actually
worse than when DBU is used on its own (Entry 9). To make
another comparison, we have also added DBU to the C1
catalyzed reaction (Entry 10). Unlike the small molecule H-
bond catalysts, adding DBU to C1 significantly improves
reactivity compared to the individual catalysts (Entry 10 vs
Entry 1 and Entry 9), giving close to quantitative yield in just
1 hour. This indicates two further points. First, it clearly shows
that the 18-crown-6 is a highly efficient additive, giving a
similar effect to a strong organic base (Entries 2 vs 10; see
Figure S8 for kinetic profiles). In addition, the enhancement
attained by adding C1 to a reaction in which Nu1H would be
deprotonated anyway (Entries 9 vs 10) would suggest that the
cage plays a bigger role than just enhancing the acidity of the
pro-nucleophile.
1
2
3
4
5
6
7
8
excellent yield under catalytic conditions. Also, products P3 to
P5 demonstrate that the cage can activate electrophiles with a
range of different functional groups. This functional group
tolerance also applies to different pro-nucleophiles, with nitrile
containing Nu4H and Nu5H giving products P7 and P8, also
in excellent yields. It is also worth noting that pro-
nucleophiles Nu3-5H are significantly less acidic than either
Nu1H or Nu2H, based on their reported pKa values (≈ 10-11),
further highlighting the remarkable acidification “power” of
this combined non-covalent catalytic method.
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+
C1
EWG
EWG
EWG
EWG
18-crown-6
EWG
EWG
N
Substrates:
O
O
OMe
NO2
E1
E2
E3
E4
O
O
O
N
O2N
MeO
Ph
Ph
NO2
NO2
H
N
N
Nu1
Nu2
Nu3
Nu4
Nu5
H
H
H
H
Products:
O
O
O
O
MeO
Ph
NO2
P1
98% (0.7 h)
C1
NO2
P2
Table 1. Comparison of the C1 / 18-crown-6 with other
non-covalent catalyst systems.
97% (0.2 h)
C1
100% (111 h;
only)
O
95% (163 h;
only)
91%a (44 h)
CD2Cl2, RT
O
O
O
O
O
O
O
+
N
MeO
MeO
catalyst
system
Ph
OMe
Ph
MeO
NO2
NO2
NO2
NO2
P4
73% (151 h)
NO2 NO2
Nu1
E1
H
P1
P3
P5
94% (9 h)
100% (88 h)
O
O
S
N
O
O
O
O
Ar
Ar
N
N
N
O2N
Ar
Ar
N
H
N
H
N
H
H
Ph
NC1
NC2
DBU
N
P7
N
P8
Ar = 3,5-(CF3)2C6H3
P6
62% (80 h)
95% (12 h)
100% (45 h)
Entry Catalyst system
% Yield
(1 h)
% Yield
(52 h)
Scheme 3. Substrate scope for synergistic base-free Michael
Addition catalysis. Conditions: 0.5 mM C1, 2.5 mM 18-crown-6,
2.5 mM electrophile, 12.5 mM pro-nucleophile, CD2Cl2, RT.
Yield determined by H NMR spectroscopy. Isolated yield using
E1 (0.42 mmol), NuH1 (0.63 mmol), C1 (8.4 µmol, 2 mol%) and
18-crown-6 (42 µmol, 10 mol%), CH2Cl2 (70 mL), RT, 44 h.
1
2
3
4
5
6
7
8
9
10
C1
2
54
C1 / 18-crown-6
NC1
≥ 98
≥ 98
1
a
No reaction
No reaction
No reaction
No reaction
NC2
NC1 / 18-crown-6
NC2 / 18-crown-6
NC1 / DBU
NC2 / DBU
DBU
It has been revealing to compare this bio-inspired cage
catalysis to small molecule non-covalent approaches. Quite
surprisingly, we could find no reports of catalytic methods for
generating products P2-8. However, the catalytic formation of
P1 under similar conditions has been described. The sub-
stoichiometric use of organic-soluble bases (e.g. DABCO,
NMP, NMI, DBU) under similar conditions (e.g. 10 mol% cat,
chloroform, 60 °C, 18 h) have been used to give P1 in
1
0
38
15
44
2
C1 / DBU
≥ 98
≥ 98
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Conditions: Nu1H (12.5 mmol), E1 (2.5 mmol), Cat (20
syn and anti-isomers interconvert under catalytic conditions to
ascertain whether stereoselectivity is an actual thermodynamic
effect. This was done by repeating the same catalysis but
adding a small quantity of the syn and anti-product mixture
shortly after the reaction starts. The syn isomer concentrations
in this experiment remain unchanged (see Figure S57)
showing that the diastereospecificity is kinetically rather than
thermodynamically controlled. However, the preferential
binding of isomers 5a-b still show that the cage cavity is
capable stereospecific differentiation, it is just that
diastereoselectivity is not caused by product recognition.
1
2
3
4
5
6
7
8
mol%), DBU (10 mol%), 18-crown-6 (2.5 mmol), CD2Cl2 (500
µL). Yields determined by 1H NMR spectroscopy.
The cage promoted Michael addition reaction shows a
surprisingly diverse substrate scope compared to other
examples of confined microenvironment catalysis. With
completely enclosed capsule-type assemblies, catalysis is
highly dependent on the volume of the encapsulated
substrates, intermediates and transition states.[19] In contrast,
C1 possesses a partially open structure with portals into which
remote substituents can project. This also facilitates the
kinetics of product-substrate turnover. While complementarity
still plays a key role in the guest encapsulation with C1, it is
not determined predominately by overall substrate size
(although there are still limitations). Instead, the strength of
binding is controlled by complementary polar interactions;
guests with suitably positioned functional groups that can
simultaneously interact with the cage’s two H-bond donor
pockets show the highest affinity (e.g. quinones). It is
therefore interesting that several of the substrates would be
considered poorly complementary for the cage because they
possess relatively weak H-bond acceptor groups (e.g. esters,
nitro, nitrile) that are incorrectly aligned for optimal binding
(e.g. Nu3H, Nu4H, Nu5H). This contrasts many examples of
cage catalysis, which are based on strong substrate binding.[8a-
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(a)
H
O2N
O2N
Ha
NO2
MeO2C
MeO
O
P5c,d
Nu1
H
DBU
+
C1
/ 18-crown-6
H
O2N
Ha
NO2
MeO2C
P5a,b
NO2
E4
c,10a]
Here we show exactly the opposite, with high-affinity
reactants showing no reactivity (Scheme 1) whereas poorly
interacting substrates deliver highly efficient catalysis
(Scheme 3). This infers that complementarity is manifest in
the recognition of key intermediates and/or TS, which is often
considered the hallmark of enzyme catalysis.
Despite the more open cavity that facilitates a diverse
substrate scope, C1 can still exhibit the types of interesting
selectivity that have often characterized catalysis within
enclosed systems. In this case, our attention was drawn to the
1
catalytic formation of P5 because the H NMR spectrum was
relatively simple considering the formation of three
contiguous stereocenters, which corresponds to four pairs of
diastereoisomers (Figure 2a,b). Indeed, this reaction exhibits
complete selectivity for just the two anti-isomers, P5a-b. For
comparison, the same reaction was carried out but using DBU
1
in place of C1 / 18-crown-6. The H NMR spectrum of this
reaction showed the expected formation of all four syn and
anti-product diasteriomers, P5a-d, in an approximately
equimolar ratio (Figure 2a,b).
To investigate this selectivity, a 1H NMR titration between C1
and P5a-d was carried out (Figure 2c). Due to the difficulty in
separating the diastereomers, this experiment was conducted
qualitatively with the mixture of all four isomers obtained
from the DBU-only mediated process. Adding increasing
amounts of C1 to P5a-d reveals shifts in both the
characteristic internal H-bond donor signal of the cage and the
product Ha cyclohexyl resonances, confirming the formation
of host-guest complexes (Figure 2c). Significantly, the signals
of the anti-isomers P5a-b show the largest shift and one of the
syn-isomer resonances moves noticeably less (Figure 2c,
signal at ca. 4.97), which indicates that the cage can
differentiate the syn and anti-diastereomeric products.
Calculations at the SMD(DCM)-M06-2X/def2-TZVP//PBE0-
D3BJ/def2-SVP level of theory with the individual isomers
agree with the qualitative titration data (See Supporting
Information, section 6). We have also investigated whether the
Figure 2. Stereoselective cage catalysis. (a) The DBU catalyzed
formation of P5 give all four diastereomers, P5a-d whereas C1
produces only the pair of anti-diastereoisomers P5a,b. (b) The
1
Partial H NMR spectra (CD2Cl2, 500 MHz) of reaction mixtures
for C1 / 18-crown-6 (top) and DBU (bottom) catalyzed reactions.
The syn- and anti-diastereomers are colored green and red. (c)
Partial 1H NMR spectra (CD2Cl2, 600 MHz) for the titration of C1
into diastereomers P5a-d. The C1 signals corresponds to the
inward facing o-pyridyl proton. The intensity of the C1 signal has
been normalized to match the resonances of P5a-d.
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To probe what appears to be a kinetic effect, we have carried
Page 6 of 9
1
out further calculations, focusing efforts on modelling the
initial anionic intermediate, P5-I1− (Figure 3; see Supporting
Information, section 6). This intermediate can exist as
epimeric diastereomers, wherein the two newly formed
stereogenic centers possess either the same (i.e., RR/SS) or
opposite (i.e., RS/RS) configurations. Furthermore, each
diastereomer can exist in two distinct conformations, with the
nitroester-methine group in either the pseudo-axial or
equatorial positions. In the absence of the cage, the two
conformations of both diastereomers are similar in energy,
separated by 3.5 kcal mol−1. In contrast, the range of relative
energies of the four encapsulated species (pseudo-axial and
equatorial conformations for both diastereomers) is a much
larger 12.8 kcal mol−1. There is also a pronounced bias (5 kcal
mol−1) towards one of the diastereomers with a pseudo-axial
conformation. This conformation positions the acidic α-proton
of the nitroester-methine group such that it can undergo a
stereospecific intramolecular proton transfer, likely mediated
by water.[20] This mechanism would deliver the proton to the
same face (Figure 3, bottom) generating the anti-cyclohexyl
stereochemistry in intermediate P5-I2− (Figure 3, top), which
goes on to give the anti-stereochemistry observed in the
product. This intramolecular proton transfer also erases the
acyclic stereogenic center that arises in the C-C bond forming
step. The generation of both anti-product isomers indicates
that the final intermolecular proton transfer is not
stereospecific.
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Figure 3. Stereoselective catalytic pathway. Top: An initial
intramolecular proton-transfer would generate the observed anti-
diastereoselectivity. Bottom:
Most stable encapsulated
diastereomeric conformer of P5-I1− calculated at the
SMD(DCM)-M06-2X/def2-TZVP//PBE0-D3BJ/def2-SVP level
of theory.
Conclusions
We have successfully demonstrated that a simple cationic
coordination cage can be utilized to catalyze a chemical
transformation by stabilizing anionic intermediates. Despite
the simplicity of this concept, the lack of similar examples
marks this out as a significant step forward in cage catalyzed
methods. Moreover, synergizing the anion-stabilizing
properties of the cage with the cation-stabilizing properties of
a crown ether has facilitated a non-covalent method that is
highly active and versatile. Catalysis also occurs without the
functionality that is considered a pre-requisite for this type of
reactivity (e.g. Brønsted base, Lewis Acid) making the method
extremely mild. This form of charge-separated catalysis, built
on compartmentalization of incompatible intermediates, could
play a significant role in the development of new non-covalent
approaches.
O2N
H
O2N
H
NO2
MeO
O
NO2
MeO2C
P5a,b
E4
Nu1
There remains several open questions regarding how the cage
operates so efficiently. First, the remarkable reactivity can
only be partly attributed to acidity enhancement as several
strong-binding pro-nucleophiles show no catalysis. Instead
catalysis only occurs when a weak-binding pro-nucleophile is
combined with a small, weakly interacting electrophile, which
would suggest that dual-activation is key. Cage catalysis that
does not involve strongly bound substrates is still not a
common strategy, yet this and other pioneering studies show
that complementarity towards key intermedies (and ideally
TS) should be the primary consideration.[3-6,21] The other side
of catalytic efficiency – turnover – can also still be considered
a challenge for many cage-catalyzed methods. This is
particularly true for the catalysis of transformations that
involve the fusion of smaller fragments, as is the case here.
However, we observe efficient turnover even though it likely
involves single product displacement by two very weakly
binding substrates. Further studies are currently underway
designed to shed light on these fundamental questions, which
could ultimately lead to the development of new non-covalent
catalysts that possess enzyme-like efficiencies.
Stereospecific
intramolecular
proton transfer
NO2
NO2
H
H
CO2Me
O2N
O2N
CO2Me
P5-I1
P5-I2
Experimental Methods
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Journal of the American Chemical Society
General. All reagents and solvents were purchased from
Supporting Information
1
2
3
4
5
6
7
8
Alfa Aesar, VWR, Sigma Aldrich or Fluorochem. Column
chromatography was carried out using Geduran Si60 (40-63
μm) as the stationary phase and TLC was performed on
precoated Kieselgel 60 plates (0.20 mm thick, 60F254. Merck,
Germany) and observed under UV light at 254 nm. All
substrates and reagents were purified prior to use: E1, E2, E3,
E4 and Nu3H were purified by distillation; Nu1H and Nu4H
were purified by silica plug (eluent: CH2Cl2); Nu2H and
Nu5H were recrystallized from iPrOH; 18-crown-6 was
purified by sublimation. Cage C1 was prepared using the
previously reported method.9d All reactions were carried out
under air and at room temperature, unless otherwise stated.
The Supporting Information is available free of charge on the
ACS Publications website. This includes details of all catalytic
experiments, kinetic data, titration data and characterization of
all products.
AUTHOR INFORMATION
Corresponding Author
Paul.Lusby@ed.ac.uk
9
fernanda.duartegonzalez@chem.ox.ac.uk
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All 1H and 13C NMR spectra were recorded on either a a 400
MHz BrukerAV III equipped with BBFO+ probe (Ava400), a
500 MHz Bruker AV III equipped with a DCH cryo-probe
(Ava500), a 500 MHz Bruker AV IIIHD equipped with a
Prodigy cryo-probe (Pro500) or a 600 MHz Bruker AV IIIHD
equipped with a TCI cryo-probe (Ava600) at a constant
temperature of 300 K. Chemical shifts are reported in parts per
million. Coupling constants (J) are reported in hertz (Hz).
Apparent multiplicities are reported using the following
standard abbreviations: m = multiplet, q = quartet, t = triplet, d
= doublet, s = singlet. All analysis was performed with
MestReNova, Version 14.0.0. All assignments were confirmed
using a combination of COSY, NOESY, HMBC and HSQC
NMR spectra.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We acknowledge the University of Edinburgh for a Principal’s
Career Development and Edinburgh Global Research
Scholarships for JW, and the EPSRC Theory and Modelling in
Chemical Sciences Doctoral training Centre (EP/L015722/1)
for a studentship to TAY, generously supported by AWE.
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(72.4 mg, 91%). H NMR (500 MHz, CDCl3) δ 5.22 (dd, J =
8.4, 6.1 Hz, 1H), 3.79 (s, 3H), 2.65 – 2.50 (m, 2H), 2.48 – 2.34
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EWG
EWG
Non-covalent activation of
pro-nucleophiles under
base-free conditions
+
+
EWG
O
High activity and effecient
turnover
+
+
O
O
O
O
O
Wide substrate scope -
despite enclosed reactivity
EWG
EWG
EWG
High stereoselectivity
+
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