Anion-π Catalysis of Enolate Chemistry: Rigidified Leonard Turns as a General Motif to Run Reactions on Aromatic Surfaces

Article abstract of DOI:10.1002/anie.201600831

To integrate anion-π, cation-π, and ion pair-π interactions in catalysis, the fundamental challenge is to run reactions reliably on aromatic surfaces. Addressing a specific question concerning enolate addition to nitroolefins, this study elaborates on Leonard turns to tackle this problem in a general manner. Increasingly refined turns are constructed to position malonate half thioesters as close as possible on π-acidic surfaces. The resulting preorganization of reactive intermediates is shown to support the disfavored addition to enolate acceptors to an absolutely unexpected extent. This decisive impact on anion-π catalysis increases with the rigidity of the turns. The new, rigidified Leonard turns are most effective with weak anion-π interactions, whereas stronger interactions do not require such ideal substrate positioning to operate well. The stunning simplicity of the motif and its surprisingly strong relevance for function should render the introduced approach generally useful. Served on a platter: Simple, compact, and precisely sculpted Leonard turns are introduced to firmly and reliably place reactions on aromatic surfaces, minimizing entropic costs to maximize enthalpic gains. The significant change in selectivity (η^d/f) from less desirable decarboxylation with loose turns (right) to more relevant enolate addition pathways on π-acidic surfaces with rigidified Leonard turns (left) demonstrates the power of this concept.

Full text of DOI:10.1002/anie.201600831

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International Edition: DOI: 10.1002/anie.201600831
German Edition: DOI: 10.1002/ange.201600831
Preorganization Very Important Paper
Anion–p Catalysis of Enolate Chemistry: Rigidified Leonard Turns as
a General Motif to Run Reactions on Aromatic Surfaces
Yoann Cotelle+, Sebastian Benz+, Alyssa-Jennifer Avestro, Thomas R. Ward, Naomi Sakai, and
Stefan Matile*
Abstract: To integrate anion–p, cation–p, and ion pair–p
interactions in catalysis, the fundamental challenge is to run
reactions reliably on aromatic surfaces. Addressing a specific
question concerning enolate addition to nitroolefins, this study
elaborates on Leonard turns to tackle this problem in a general
manner. Increasingly refined turns are constructed to position
malonate half thioesters as close as possible on p-acidic
surfaces. The resulting preorganization of reactive intermedi-
ates is shown to support the disfavored addition to enolate
acceptors to an absolutely unexpected extent. This decisive
impact on anion–p catalysis increases with the rigidity of the
turns. The new, rigidified Leonard turns are most effective with
weak anion–p interactions, whereas stronger interactions do
not require such ideal substrate positioning to operate well. The
stunning simplicity of the motif and its surprisingly strong
relevance for function should render the introduced approach
generally useful.
plish the involved enolate chemistry under biological con-
ditions. However, under unoptimized conditions without
enzymes in solution, the addition of MAHTs, such as 1a,
via malonate half thioester (MHT) conjugate bases, to
enolate acceptors, such as nitroolefin 2, fails to cleanly
generate the relevant addition product 3a (Figure 1).[2]
Instead, decarboxylation is the favored reaction, leading to
the less useful thioester 4a as the major product. Several
elegant solutions have been developed to tame the capricious
MHTanions, including bioinspired approaches to asymmetric
enolate addition to various acceptors.[3]
“Rien ne sert de courir; il faut partir à point. Le Li›vre et la
Tortue en sont un tØmoignage.” Thus begins Jean de La Fon-
taine (1621–1695 AD) to recount the ancient Greek fable
from Aesop (620–560 BC). The result is known. In the context
of chemical transformations, Aesopꢀs fable perfectly describes
the challenge to selectively catalyze a disfavored reaction. A
most intriguing example for “tortoise-and-hare catalysis”
occurs at the beginning of the biosynthesis of most natural
products and is repeated most impressively in the polyketide
pathway.[1] Malonyl-CoA, a malonic acid half thioester
(MAHT), has evolved as the substrate of choice to accom-
Figure 1. a) Addition of MAHT 1a (R1 =SPMP, PMP=para-methoxy-
phenyl) or b-keto acid 1b (R1 =Ph) to nitroolefin 2 (R2 =Ph), forming
the disfavored (d) addition products 3a/3b or the favored (f)
decarboxylation products 4a/4b. b) The original meta-aryl turns place
the enolate tautomer far from the p surface. c) “Top-down” addition of
remote enolates (RI3) to nitroolefins on the p surface. d) Fixed
(magenta) Leonard turns should place MHTs close to the p surface to
influence the equilibrium between the MHT tautomers. e) “Bottom-up”
addition of enolates on the p surface (RI1) to nitroolefins far from the
p surface.
[*] Dr. Y. Cotelle,[+] S. Benz,[+] Dr. A.-J. Avestro, Dr. N. Sakai, Prof. S. Matile
Department of Organic Chemistry
National Centre of Competence in Research (NCCR) Molecular
Systems Engineering
University of Geneva, Geneva (Switzerland)
E-mail: stefan.matile@unige.ch
Homepage: www.unige.ch/sciences/chiorg/matile/
Dr. A.-J. Avestro
Department of Chemistry, Northwestern University
Evanston IL (USA)
Dr. A.-J. Avestro
Current address: Department of Chemistry
University of Durham, Durham (UK)
Complementary to the more common cation–p interac-
tions on p-basic aromatic surfaces,[4] anion–p interactions
occur on p-acidic surfaces. Their existence has been proposed
by theoreticians a bit more than a decade ago and verified
experimentally for the solid, solution, and gas phase.[5,6] The
functional relevance of anion–p interactions has been dem-
onstrated for self-assembly,[7] transport,[8,9] and, most recently,
also for catalysis.[2,10,11] In this context, the selective accel-
eration of the disfavored addition of MAHT 1a to nitro-
Prof. T. R. Ward
Department of Chemistry
NCCR Molecular Systems Engineering
University of Basel, Basel (Switzerland)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201600831.
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olefins 2 has been realized[2] in the presence of naphthalene-
diimides (NDIs).[10,12] Their p-acidic surface has been intro-
duced as ideal for differentiating between planar MHT
tautomers with delocalized charges (as in reactive intermedi-
ate RI1, Figure 1d) and deplanarized tautomers with charges
localized on the carboxylate (as in RI2). This discrimination
was expected to influence the energy of the transition states
leading to enolate addition and decarboxylation in different
ways and thus to control the selectivity of the reaction.
However, in our original design, the catalytic amine was
positioned quite far from the p surface. Ion pairing to the
conjugate ammonium cation should also remove the MHT
anion from this surface (RI3, Figure 1b), enabling the nitro-
olefin acceptor 2 on the p surface to be approached by the
MHT from above or in a “top-down” fashion (transition state
TS1, Figure 1c). This architecture should thus provide
excellent stabilization of nitronate intermediates by anion–p
interactions while having minimal influence on the equilib-
rium between the MHT tautomers, which results in poor
selectivity. The objective of the present study was to develop
general design strategies to enhance selectivity by 1) moving
the MHT substrates as close as possible to the p surface
(Figure 1d), that is, to have the enolate approach the nitro-
olefin from below or in a “bottom-up” fashion, and by
2) allowing the nitronate to reach the p surface only upon its
formation during enolate addition (TS2, Figure 1e). The
significance of the results described herein suggests that the
newly introduced, rigidified Leonard turns[13] represent a gen-
eral design principle for enabling reactions to occur on
aromatic surfaces and thus for harnessing the full potential of
anion–p,[2,5–8,10,11] cation–p,[4] and ion pair–p interactions[9] for
catalysis.
The new catalysts and controls 5–19 were designed and
synthesized based on lessons learned from the original
catalysts 20–24 (Figure 2; for details on their synthesis and
evaluation under standard conditions, see the Supporting
Information). Anion–p catalyst 9 was conceived as the
starting point for our systematic study. Kept as simple as
possible, it contains a single NDI surface with two ethylsulfide
substituents as handles to tune the p acidity (R1),[14] an
l-leucyl-n-hexylamide tail to ensure solubility (R2), and
a Leonard turn in its purest form.
Introduced almost fifty years ago[13] as trimethylene
chains, Leonard turns can be considered more generally as
three tetrahedral atoms that are in a half-chair conformation
and attached to an aromatic surface at one end. The first atom
following at the other end will find itself at a very short
distance from the aromatic system, literally forced to be on
top of the ipso atom of the aromatic ring. Leonard turns have
been used extensively in functional systems, often not
explicitly.[6,9,11,15] In catalyst 9, the Leonard turn consists of
two methylene groups and the sp3-hybridized nitrogen atom
of the amine base.[6] The proton transferred to this nitrogen
atom should then end up at a short distance above the imide
nitrogen atom of the NDI, which in turn should place the
MHT carbonyl group at the positive end of the imide carbonyl
Figure 2. a) Catalyst selectivity, hd/f =hd/hf, that is, the yield hd of the intrinsically disfavored product (3a) divided by the yield hf of the favored
product (4a) in the presence of catalysts 5–24 in [D8]THF at 208C. b) Catalyst selectivity at 78C for 3a and 4a. c) Catalyst selectivity at 78C for 3b
and 4b. All sulfoxides were isolated as mixtures of stereoisomers. See Table 1 for exact values and conditions. * Most important trends with
comparable structures. ** Not measured.
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moieties, in line with the bonds leading to the naphthalene
(Figures 1d,e).
the presence of Leonard turns (Figure 2a and Table 1,
entries 5–8).
Control compound 13, with a loose tetramethylene turn,
In view of these considerations, we were delighted to find
that under routine conditions at 208C,[2] our first Leonard
catalyst 9 catalyzed the addition of MAHT 1a to nitroolefin 2
selectively: The intrinsically disfavored (d) addition product
3a was obtained in hd = 65% yield, with the naturally more
favored (f) decarboxylation product 4a generated in hf = 34%
(Table 1, entry 5). The resulting selectivity, hd/f = 1.9, was
outstanding considering that the original catalyst 23, which
features a loose turn, failed to cause the desired selectivity
inversion (hd/f = 0.8; Figure 2a and Table 1, entry 19). The
new Leonard catalyst 9, as simple as it gets, was already as
good as the most developed original tweezer catalyst 22, with
two NDIs next to the amine and two sulfones in the NDI core
maximizing effective molarity and p acidity, respectively
(Figure 2a and Table 1, entry 18). Increasing selectivity
upon oxidation of the sulfides in the core of 9 to sulfoxides
in 10 and sulfones in 11 (hd/f = 2.5 and 2.8) and the absence of
selectivity inversion with control catalyst 12 without a p sur-
face (hd/f = 0.7) confirmed operational anion–p interactions in
failed to perform as well as Leonard catalyst 9 (Figure 2a).
However, increasing selectivity inversion with increasing
p acidity in 13–15 revealed the existence of “tortoise-and-
hare” anion–p catalysis also with looser turns (Table 1,
entries 9–11). Control compound 16, with a bulky Hünigꢀs
base analogue in the Leonard turn, performed only slightly
better than control 17 without a p surface (hd/f = 0.9 vs. hd/f
=
0.7; Table 1, entry 12 and 13), presumably because the steric
crowding hinders operational anion–p interactions. Increas-
ing the effective molarity of the p surfaces in tweezer-like
Leonard catalysts 18 and 19 did not improve the outstanding
activity of the most simple, most compact monomeric
Leonard catalysts 9–11 (Figure 2a and Table 1, entries 14
and 15 vs. 5–7).
In catalyst 5, the flexible Leonard turn of catalyst 9 is
rigidified (see TS2 in Figure 1e). In doing so, the selectivity
inversion increased to hd/f = 3.1 (Table 1, entry 1). Increasing
the p acidity in catalysts 6 and 7 further improved the activity
to hd/f = 3.8 and hd/f = 4.4 (Table 1, entries 2 and 3).
The hd/f = 0.9 value for control 8 without a p surface
Table 1: Characteristics of the anion–p catalysts and control compounds.[a]
confirmed that these quite spectacular results orig-
Cat.[b] p Acidity[c] Substrate[d] hd
[%][e]
hf
[%][f]
hd/f[g]
DDGTS
°
inate from maximizing the anion–p interactions with
the rigidified Leonard turn in catalysts 5–7. Com-
parisons over the full series of comparable architec-
tures, from original and loose turns in 23 (hd/f = 0.8)
and 13 (hd/f = 1.1) to flexible Leonard turns in 9
(hd/f = 1.9), beautifully illustrate the unique power of
fixed Leonard turns in 5 (hd/f = 3.1) to run reactions
on p surfaces and maximize contributions from
anion–p interactions for catalysis (Figure 2a). The
same trend holds true at maximal p acidity, moving
from hd/f = 2.3 for loose turns in 15 to hd/f = 2.8 with
flexible Leonard turns in 9 and hd/f = 4.4 with fixed
Leonard turns in 7.
[kJmolÀ1 [h]
]
1
2
3
4
5
6
7
8
9
5
6
7
8
+
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
84 (74) 12 (24)
87 (77) 11 (20)
7.0 (3.1) À3.6 (À3.0)
7.9 (3.8) À3.9 (À3.5)
9.6 (4.4) À4.3 (À3.9)
+ +
+ + +
À
86 (80)
9 (18)
57 (47) 39 (52)
78 (65) 19 (34)
80 (68) 15 (27)
84 (74) 13 (26)
59 (43) 40 (56)
70 (50) 28 (47)
81 (64) 19 (32)
83 (68) 16 (30)
73 (43) 25 (48)
1.5 (0.9)
–
9
+
4.1 (1.9) À2.3 (À2.3)
5.3 (2.5) À2.9 (À2.9)
6.5 (2.8) À3.4 (À3.4)
10
11
12
13
+ +
+ + +
À
1.5 (0.7)
–
+
2.5 (1.1) À1.2 (À1.1)
4.3 (2.0) À2.4 (À2.6)
5.2 (2.3) À2.9 (À2.9)
2.9 (0.9) À1.5 (À0.6)
10 14
11 15
12 16
13 17
14 18
15 19
16 20
17 21
18 22
19 23
20 24
21
22
23
24 10
25 11
26 12
+ +
+ + +
+
À
(40)
87 (51) 12 (23)
89 (54)
(54)
(0.7)
–
Reactions run at 78C instead of 208C gave the
same overall trends (Figure 2b). For example, the
steady increase from original and loose turns in 23
(hd/f = 2.3) and 13 (hd/f = 2.5) to flexible Leonard
turns in 9 (hd/f = 4.1) and fixed Leonard turns in 5
(hd/f = 7.0) remained intact (Figure 2a). The overall
higher selectivity is consistent with the notion of
strengthened anion–p interactions at lower temper-
atures. In this instance, the impact of flexible as well
as fixed Leonard turns was less pronounced, whereas
the effective molarity of the p surfaces became more
important. For example, loose tweezers 22 at max-
imal p acidity reached the selectivity of fixed
Leonard turns 5 at minimal p acidity (Figure 2b);
at 208C, 22 was clearly less active than 5 (Figure 2a).
Moreover, the overall best performance was found
for tweezers 19 with flexible Leonard turns and
intermediate p acidity (hd/f = 11.1), although the
fixed Leonard turns in monomeric 7 were almost
as good (hd/f = 9.3, Figure 2b); at 208C, 19 was much
less selective than 7 and also 5 (Figure 2a). This
overall reduced importance at lower temperature
+
7.3 (2.0) À3.7 (À2.6)
+ +
+
+ +
+ + +
+
8 (27) 11.1 (2.2) À4.6 (À3.4)
71 (50) 23 (48)
80 (59) 14 (36)
80 (59) 11 (31)
69 (46) 30 (54)
60 (37) 30 (53)
3.1 (1.0) À1.2 (À0.9)
5.7 (1.6) À2.9 (À2.0)
7.3 (1.9) À3.5 (À2.6)
2.3 (0.8) À0.7 (À0.8)
À
2.0 (0.7)
1.9
3.0
1.4
1.9
–
5
7
9
+
65
74
59
64
68
42
34
25
41
33
32
57
À2.3
À3.4
À1.6
À2.3
À2.6
–
+ + +
+
+ +
+ + +
À
2.1
0.7
[a] Reactions were conducted in [D8]THF with 20 mol% of the catalyst and
monitored by 1H NMR spectroscopy. [b] Catalysts, see Figure 2 for their structures.
[c] Qualitative indication of the p acidity, À=no p surface. [d] Substrates; 1a:
200 mm with 2m 2; 1b: 200 mm with 1.5m 2. [e] Yield of the intrinsically disfavored
products 3a/3b in THF at 78C (in parentheses: hd at 208C). [f] Yield of the
intrinsically favored products 4a/4b at 78C (208C). [g] Selectivity hd/f =hd/hf at 78C
(208C). [h] Selective catalysis: The difference in the Gibbs free energies
DGTS° (catalyst) of the two transition states leading to the intrinsically favored (f)
and disfavored (d) products, calibrated against the nearest control DGTS° (8, 12, 17,
24); DGTS° =ÀRTln(hd/f),[16] DDGTS° =DGTS° (catalyst)ÀDGTS° (control). Data for
20–24 are from Ref. [2].
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suggests that the contributions from flexible and in particular
those from fixed Leonard turns are mainly entropic, that is,
a most practical and most significant expression of the
classical concept of preorganization.
substrates readily decarboxylate in solution.[17] However, with
a suitable catalyst, they too are capable of adding to nitro-
olefins.[18] Under standard reaction conditions at ambient
temperature, it was found that b-keto acids decarboxylate
more rapidly than MHTs. Consequently, all reactions were
conducted at 78C (see the Supporting Information). A rise in
product selectivity with increasing p acidity of the catalysts,
along with the confirmation of selectivity inversion with
control 12 at low temperature (hd/f = 0.7), are already strong
indicators for operational anion–p interactions analogous to
the results observed with MHT substrates. Indeed, the use of
flexible Leonard turns increased the selectivity from hd/f = 1.4
for sulfide 9 to hd/f = 1.9 for sulfoxide 10 and hd/f = 2.1 for
sulfone 11 (Figure 2c and Table 1, entries 23–25). As antici-
pated, fixed Leonard turns at minimal p acidity in 5 were as
good as flexible turns at maximal p acidity in 11 (Table 1,
entries 22 and 26). Indeed, fixed Leonard turns at maximal
p acidity in 7 afforded a selectivity of hd/f = 3.0—the highest
selectivity—demonstrating that rigidifying a Leonard turn is
equally applicable as a strategy for promoting the successful
formation of intrinsically disfavored addition products with
b-keto acids.
It has been established previously[2] that a combination of
selective deceleration of the intrinsic decarboxylation in favor
of accelerating the disfavored addition gives rise to the
observed inversion of selectivity. These most intriguing trends
were expected to emerge from the ability of anion–p
interactions to distinguish the planar MHT enolate as in RI1
from the non-planar malonate tautomer as in RI2 (Fig-
ure 1d). Assuming a Curtin–Hammett situation where the
two classes of tautomers are in rapid equilibrium, the
°
difference in Gibbs free energy DGTS of the two transition
states leading to addition (d) or decarboxylation (f) is
determined by the ratio d/f of the products (Table 1).[16] The
°
resulting DGTS values of the catalysts were then calibrated
against the background contributions of amine bases without
nearby p-acidic surfaces. The dependence of the obtained
°
DDGTS values (Table 1) on the p acidity was roughly linear
^
for fixed Leonard turns in 5–7 ( ), flexible Leonard turns in
&
*
9–11 ( ), and loose turns in catalysts 13–15 ( ; Figure 3). The
Compared to other noncovalent interactions, such as
hydrogen, halogen, or chalcogen bonds, in catalysis,[19] inter-
actions with aromatic surfaces are much less directional, thus
creating the challenge to ideally place a substrate on such
a p surface. This study offers a general and practical solution.
Currently, we are most interested in applying the lessons
learned to other reactions[20] and to more complex sys-
tems.[21,22]
Acknowledgements
We thank the NMR and the Sciences Mass Spectrometry
(SMS) platforms for services and the University of Geneva,
the European Research Council (ERC Advanced Investiga-
tor), the Swiss National Centre of Competence in Research
(NCCR) Molecular Systems Engineering, the Swiss NCCR
Chemical Biology, and the Swiss NSF for financial support.
A.-J.A. thanks the US NSF for a GROW Fellowship and the
Swiss SERI/FCS for a Government Excellence Scholarship.
°
Figure 3. Differential transition-state stabilization DDGTS for 5–7
&
^
*
( , vs. 8), 9–11 ( , vs. 12), and 13–15 ( , vs. 12) as a function of the
LUMO energies for NDIs with sulfides (À3.92 eV), sulfoxides
(À4.31 eV), and sulfones (À4.52 eV) in the core, at 78C. Negative
°
DDGTS values indicate selective acceleration of the disfavored over
the favored reaction.
slopes, however, were clearly different. This difference,
namely steeper slopes for less preorganized turns, provided
corroborative experimental evidence that the significance of
flexible and fixed Leonard turns, in particular, increases with
decreasing p acidity. This finding is consistent with the
increasing importance of Leonard turns with increasing
temperature (Figure 2a vs. 2b). Therefore, it can be con-
cluded that precisely engineered turns enable efficient anion–
p catalysis to take place even with relatively weak p acidity.
When the aromatic surface is strongly electron-deficient,
anion–p catalysis takes place efficiently even when substrate
placement (i.e., the constituent nature of the Leonard link) is
less than ideal.
Keywords: anion–p interactions · catalysis · enolates ·
preorganization · selectivity
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4275–4279
Angew. Chem. 2016, 128, 4347–4351
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Received: January 25, 2015
Published online: February 24, 2016
Angew. Chem. Int. Ed. 2016, 55, 4275 –4279
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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