Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π-Acidic Aromatic Surfaces

Article abstract of DOI:10.1002/anie.202000681

Anion-π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long-distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation-π biocatalysis, reported here is the anion-π-catalyzed epoxide-opening ether cyclizations of oligomers. Only on π-acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements k_auto/k_cat >10⁴ m^?1). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks-type substrate concentration dependence, entropy-centered substrate destabilization) and opens intriguing perspectives for future developments.

Full text of DOI:10.1002/anie.202000681

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.202000681
German Edition: DOI: 10.1002/ange.202000681
Cyclization
Polyether Natural Product Inspired Cascade Cyclizations:
Autocatalysis on p-Acidic Aromatic Surfaces
+
+
Miguel Paraja , Xiaoyu Hao , and Stefan Matile*
Abstract: Anion-p catalysis functions by stabilizing anionic
transition states on aromatic p surfaces, thus providing a new
approach to molecular transformation. The delocalized nature
of anion–p interactions suggests that they serve best in
stabilizing long-distance charge displacements. Aiming there-
fore for an anionic cascade reaction that is as charismatic as the
steroid cyclization is for conventional cation-p biocatalysis,
reported here is the anion-p-catalyzed epoxide-opening ether
cyclizations of oligomers. Only on p-acidic aromatic surfaces
having a positive quadrupole moment, such as hexafluoroben-
zene to naphthalenediimides, do these polyether cascade
cyclizations proceed with exceptionally high autocatalysis
4
À1
(
rate enhancements kauto/kcat > 10 m ). This distinctive char-
acteristic adds complexity to reaction mechanisms (Goldi-
locks-type substrate concentration dependence, entropy-cen-
tered substrate destabilization) and opens intriguing perspec-
tives for future developments.
Figure 1. Anion-p catalysis of epoxide-opening polyether cascade cycli-
zation of 1 and 2 into 3 and 4, respectively, via the putative transition-
state TS-3 (p-acidic surfaces in blue) compared to TS-1, leading to
steroids (with position of p-basic residues in the enzyme indicated in
red), and TS-2 leading to monensins (Cane–Celmer–Westley hypoth-
esis; 2: mixture of cis/trans isomers).
I
n this report, the catalysis of the cascade cyclization of
[
1–6]
oligoepoxides,
such as the tetramers 1 and 2, into the
oligooxolanes 3 and 4, respectively, and isomers, through
[
7]
anion–p interactions is described (Figure 1a). In nature, the
[2]
cyclization of terpenes into steroids is arguably the most
oligomers on the other (Figure 1b). Inspired by the Cane–
[
8,9]
[5]
spectacular expression of cation-p catalysis (Figure 1b). In
the enzyme, the carbocations moving along the emerging
rings are stabilized on the p surface of a cluster of p-basic
Celmer–Westley hypothesis (TS-2) and Nakanishi hypoth-
[
6]
esis for the biosynthesis of monensin- and brevetoxin-type
architectures, respectively, cascade cyclizations that follow
[8]
[13]
amino acids, as outlined in the transition-state TS-1. Perhaps
because it is counterintuitive and rare in nature, the comple-
mentary anion-p catalysis, that is the stabilization of anionic
rather than cationic transition states on p-acidic rather than
p-basic aromatic surfaces, has been unknown until recently,
and violate Baldwin rules have attracted intense scientific
[1,2]
attention (Figure 1b). Compatibility with anion-p catalysis
[14]
has been demonstrated recently with model monomers. On
aromatic surfaces, epoxide-opening monoether cyclizations
occurred with primary anion–p interactions, that is, without
the need of additional activating groups. These model studies
encouraged the move from monomer cyclizations toward the
oligomer cascades reported herein.
[10]
that is 2013. Since then, anion-p catalysis has been evolving
rapidly with regard to the number of realized catalysts and
[
11,12]
reactions.
However, the delocalized nature of anion–p
[7]
interactions called for reactions that involve long-distance
charge displacements, the anionic versions of steroid cycliza-
tions. Lessons from nature support epoxide-opening poly-
ether cascade cyclizations of polyketides as cascades of choice
With a positive quadrupole moment of Q =+ 9.5B,
zz
compared to Q = À8.5B for benzene, hexafluorobenzene
zz
(HFB; 5) is not the strongest but arguably the most popular
[
7,11]
p acid.
Dissolved in HFB at room temperature, 250 mm 1,
[
1–6]
for this purpose.
Popular examples include oligooxolanes
prepared by multistep synthesis as a mixture of all-trans
stereoisomers (see Scheme S3 in the Supporting Informa-
tion), was fully converted within 20 days. With 750 mm 1, the
cascade cyclization took one month. Epoxide opening was
like the monensins on one hand, and brevetoxin-like ladder
[
+]
[+]
[
*] Dr. M. Paraja, Dr. X. Hao, Prof. S. Matile
Department of Organic Chemistry, University of Geneva
Geneva (Switzerland)
1
clearly detectable by H NMR spectroscopy and found to be
stepwise and directional, proceeding from ring 1 to ring 4
(Figure 2a; see Figure S5). Comparison of the complex NMR
E-mail: stefan.matile@unige.ch
spectra of the main product with that of the shorter oligomers
(Figures 2b,c; see Figures S1–S4) supported the formation of
a mixture of stereoisomers of 3, that is, the existence of an
anion-p catalyzed Baldwin-selective cascade cyclization as
outlined in TS-3 (Figure 1a). The conversion times of these
Homepage: http://www.unige.ch/sciences/chiorg/matile/
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202000681.
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1
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directional, presumably stepwise and include significant
contributions from anion–p templated autocatalysis (Fig-
ure 4a). Kinetic analysis of the substrate conversion afforded
À1
a formal autocatalytic rate enhancement of kauto/kcat = 180m .
p-Bromo benzoylation provided access to chiral-phase HPLC
analysis, which for the trans dimer 7 revealed the expected
four stereoisomers and their conversion on aromatic surfaces
without any preference (see Figures S12–S14).
1
Figure 2. a) Diagnostic regions of the H NMR spectra of 1 (750 mm)
after 0, 13, 21 and 34 days in HFB (bottom to top), with distinct
signals and conversions of the epoxides 1–4. b–g) Diagnostic region of
1
the H NMR spectra of representative of product mixtures with mostly:
b) 10 (from 7 in 5), c) 3 (from 1 in 5), d) 4 (from 2 with 12 in CD Cl ),
2
2
e) 18 (from 15 with 12), f) 17 (from 14 with 12; peaks marked with
blue and red circles are assigned to the correspondingly colored
protons of 20 in Figure 3), and g) 17 (from 14 with AcOH). *Peaks
from the catalyst 12.
shorter oligomers (6—8; synthesis: see Schemes S1 and S2)
into the oxolanes 9–11 decreased with oligomer length, from
7
days for the trimer 8 to 2 days for the dimer 7 to hours for
the monomer 6 (Figure 3a; see Figures S1, S2, and S4). More
detailed studies were thus performed with the shortest
1
possible dimer, 7. Kinetic studies in HFB using H NMR
spectroscopy confirmed that the cascade cyclizations are
Figure 4. a) Conversion (h) of epoxide 1 (&) and 2 (^) of 7 (250 mm)
with time t in HFB at room temperature (compare Figure 2a).
b) Substrate conversion h41 after 41 h in HFB as a function of the
concentration of substrates 7 (&) and 14 (*). c) Conversion of 14 in
CD Cl with 20 mol% 12 (*) and 25 mol% AcOH (X). d) Substrate
2
2
conversion after 17 h as a function of the concentration of substrates
) and 14 (*, X) at constant concentration of 12 (*,
, 50 mm) and
AcOH (X, 250 mm) in CD Cl . e) Conversion of 14 with 75 mol%
7
(
&
&
2
2
AcOH (grey: 25, 100, 130 mol%). f) Conversion after 19 h for 7 (
and 14 (*, *, X) at constant concentration (250 mm) with increasing
concentration of 12 (*, ), 5 (*, &), and AcOH (X) in CD Cl (14:
mixture of cis/trans isomers used for kinetics only).
&
, &)
&
2
2
However, with the p-acidic HFB used as a catalyst in
CH Cl rather than as a solvent, 7 did not react (Figure 4 f, &).
2
2
[
15]
The same was true for naphthalenediimide
(NDI; 12)
a much more powerful anion-p catalyst given its more-
positive quadrupole moment, lower LUMO energy, and
[11,14]
higher polarizability
reactivity, a series of permethylated oligomers, 13—15 and
, was prepared by multistep synthesis (Figures 3a and 1a; see
(Figures 3b and 4d,f,
&
). To increase
[16]
2
Schemes S4–S6). Besides more specific contributions (below),
permethylation could be expected to produce more basic tert-
alcoholate nucleophiles and stronger alcoholate–p interac-
tions to compensate for poorer leaving groups, and stabilize
partial positive charges building up on the central carbon
center in the transition state (Figures 3c,d). Baldwinꢀs rules
predicted that a formal 5-exo-tet cascade cyclization into the
oligomers 16—18 and 4 should be preferred. Contrary to 7,
the pentamethylated cis dimer 14 was readily converted by
Figure 3. Oligomer series (a) explored with selected anion-p catalysts
(
b). A/B selectivity ratios are for 12 compared to AcOH (given within
parentheses; tetramers 1, 2: Figure 1; LH=Leu-hexyl). c) Transition-
state hypothesis for primary anion-p autocatalysis of epoxide-opening
polyether cascade cyclizations following the Baldwin rules (BBB).
d) Transition-state hypothesis for anti-Baldwin (A) cyclization into 20;
a–c: Directing methyl activators.
NDI. With 5 mol% NDI in CD Cl , the conversion of 1m 2
2
2
into mostly 4 was completed in 12 days. The conversion of 14
2
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[
17]
in the presence of 20 mol% NDI was formally autocatalytic
(
es S74–S78). They originated from anion-p catalysis, while the
AcOH control, which was much slower, gave almost only the
4
À1
Figure 4c, *; kauto/kcat = 3.0 ꢁ 10 m ). Compared to 7 with
[
3]
HFB as a solvent, autocatalysis for 14 with 20 mol% of the
more powerful anion-p catalyst 12 was more than 160 times
more pronounced. In sharp contrast, the conversion of 14 with
AcOH was clearly not autocatalytic, independent of catalyst
concentration, and clearly much slower (Figures 4cX,e).
Extrapolation of the model for primary anion-p autocatalysis
Baldwin dimer 17 (Figure 2g). Considering that epoxide
opening by alcoholate–p interactions accounts mostly for
anion-p catalysis, the formation of the anti-Baldwin ring 2
implied a different interaction of 14 with the p surface,
leading to a different orientation of the incoming nucleophile
with respect to the epoxide to form a chairlike transition state,
and contributions from the gem-dimethyls c to stabilize the
partial positive charge on the central carbon center (TS-5,
Figure 3d). Although impossible to specify from increasingly
complex NMR spectra with longer oligomers, access to 20
implied that anion-p catalysis will provide also access to
permethylated anti-Baldwin isomers besides the BBB trimer
18 and BBBB tetramer 4 as main products (Figures 1a, 2, and
3a).
[
14]
computed on the monomer level afforded the hypothetical
transition state TS-4 (Figure 3c). TS-4 consists of an oxolane
product next to the processed epoxide oligomer on the p-
acidic surface. This oxolane product activates the nucleophile
and the intramolecular epoxide leaving group with one
hydrogen bond each. The resulting noncovalent macrocycli-
zation should shift the entropy losses of ether cyclization from
transition to ground state and thus further contribute to
catalysis by entropic substrate destabilization, that is preor-
With this study, the dream of an anionic version of the
cation-p catalyzed steroid cyclization for anion-p catalysis
becomes reality: Epoxide-opening polyether cyclizations are
realized on p-acidic surfaces for monomers, dimers, trimers,
and tetramers (Figure 1), and examples are provided for
exclusive access to primary anion-p autocatalysis (Figures 4c–
f). Besides obvious continuation toward stereo-pure sub-
[
18]
ganization. The decisive anion–p interaction then stabilizes
the alcoholate leaving group obtained from the rate-limiting
[
1–3]
epoxide opening. Absent in the many studies on the topic
[
17]
this templation of autocatalysis of epoxide-opening poly-
ether cyclizations is so far a unique characteristic of anion-p
catalysis.
[
11]
With 12 at constant concentration, the dependence on the
concentration of 14 showed first saturation behavior, followed
by a strong decrease (Figures 4d, *; see Figure S8). Satura-
tion behavior could support the existence of substrate binding
sites, whereas post-saturation substrate inhibition could
indicate interference with product binding, that is, anion–p
strates for simpler NMR spectra and asymmetric catalysis,
[
20,21]
longer monensin- and also brevetoxin-like oligomers,
[
21]
ring contractions and expansions,
and so on, we find it
important to fully explore the unique autocatalysis of cascade
cyclizations on p-acidic surfaces. More precisely, products
added at the beginning of the reaction have already been
shown on the monomer level to shorten the lag time and thus
[
19]
templated autocatalysis. These “Goldilocks” profiles
for
[
14]
dependence on substrate concentration were significant and
general. For HFB solvent catalysis, it accounted for an
inversion of reactivity, with 7 being faster at low and 14 being
confirm the existence of autocatalysis. The optimization of
such cocatalysts will likely result in optimized cascade
oligomerizations, not only with regard to BA chemoselectivity
but particularly with regard to asymmetric anion-p catalysis.
Tantalizing also are the perspectives of cascade cyclization
control in more complex systems, particularly voltage-gated
faster at high concentration (Figure 4b,
&
and *; see
Figures S6 and S7). This inversion could be understood with
decreasing substrate recognition from 7 to 14, presumably
also reducing post-saturation interference with anion–p
templated autocatalysis. Decreasing ground-state and
increasing transition-state recognition from 7 to 14 (tertiary
vs. secondary alcoholate–p interactions; TS-4), both reducing
[
11]
anion-p catalysis on electrodes,
transport not only with monensin-like products
with the unexplored oligoepoxide substrates, anion-p cata-
and of ion binding and
[
1,4]
but also
[
22]
[23]
lysts, and both together.
[
18]
activation energy, were consistent with the much higher
reactivity of permethylated oligomers such as 2 with NDI
(
Figures 3d, 4f, * vs.
&
).
Acknowledgements
Like substrate dependence, the dependence on the
concentration of 12 with a constant concentration of 14
naturally varied strongly with reaction time (Figure 4c, *).
The linear dependence found around maximal autocatalysis
after 19 hours mostly reflected the shortening of the lag
period (Figure 4 f, *; see Figure S9), whereas after 6 hours,
before the onset of autocatalysis, increasing catalyst concen-
trations gave the expected superlinear increase in activity for
the same reason (see Figure S9).
We thank the NMR and the MS platforms for services, and
the University of Geneva, the Swiss National Centre of
Competence in Research (NCCR) Molecular Systems Engi-
neering, the NCCR Chemical Biology, and the Swiss NSF for
financial support.
Conflict of interest
[
16]
The methyl activators in oligomers such as 2 provided
not only compatibility with anion-p catalysis but also access to
the first violations of the Baldwin (B) rules. The 11% anti-
Baldwin (A) oxane 19 obtained with NDI was not signifi-
cantly higher than the 7% obtained with AcOH controls
The authors declare no conflict of interest.
Keywords: p interactions · autocatalysis · cyclization ·
polyethers · synthetic methods
(
Figure 3a). More important was the 17% BA dimer 20
obtained from 14 with NDI (Figures 2 f and 3a; see Figur-
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20] Preliminary results on the dimer level support the anion-p
Manuscript received: January 14, 2020
autocatalysis provides unique access to initial cyclization of
Version of record online: && &&, &&&&
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Communications
Cyclization
The dream of an anionic version of the
cation-p-catalyzed steroid cyclization is
realized with epoxide-opening ether cyc-
lizations of oligomers. Compared to
conventional catalysts, anion-p tem-
plated autocatalysis is shown to be the
distinctive difference, important (with
rate enhancements beyond 10 m ),
mechanistically decisive (Goldilocks pro-
files), and intriguing with regard to future
perspectives.
M. Paraja, X. Hao,
S. Matile*
&&&& — &&&&
Polyether Natural Product Inspired
Cascade Cyclizations: Autocatalysis on p-
Acidic Aromatic Surfaces
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