Enantioselective Pallada-Electrocatalyzed C?H Activation by Transient Directing Groups: Expedient Access to Helicenes

Article abstract of DOI:10.1002/anie.202003826

Asymmetric pallada-electrocatalyzed C?H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C?H activations were realized with high position-, diastereo-, and enantio-control

Full text of DOI:10.1002/anie.202003826

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Accepted Article
Title: Enantioselective Palladaelectro-Catalyzed C–H Activations by
Transient Directing Groups: Expedient Access to Helicenes
Authors: Uttam Dhawa, Cong Tian, Tomasz Wdowik, João C. A.
Oliveira, Jiping Hao, and Lutz Ackermann
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Angewandte Chemie International Edition
10.1002/anie.202003826
RESEARCH ARTICLE
Enantioselective Palladaelectro-Catalyzed C–H Activations by
Transient Directing Groups: Expedient Access to Helicenes
Uttam Dhawa,[a] Cong Tian,[a] Tomasz Wdowik,[a] João C. A. Oliveira,[a] Jiping Hao[a] and Lutz
Ackermann*[a,b]
[
a]
U. Dhawa, C. Tian, Dr. T. Wdowik, Dr. J. C. A. Oliveira, J. Hao and Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
Prof. Dr. L. Ackermann
[
b]
Wöhler Research Institute for Sustainable Chemistry (WISCh)
Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Göttingen (Germany)
Homepage: http://wisch.chemie.uni-goettingen.de/
Supporting information for this article is given via a link at the end of the document.
Abstract: Asymmetric palladaelectro-catalyzed C–H olefinations
were achieved through the synergistic cooperation with transient
directing groups. The electrochemical, atroposelective C–H
activations were realized with high position-, diastereo-, and enantio-
control under mild reaction conditions to obtain highly
enantiomerically-enriched biaryls and fluorinated N–C axially chiral
scaffolds. Our strategy provided expedient access to, among others,
novel chiral BINOLs, dicarboxylic acids and helicenes of value to
asymmetric catalysis. Mechanistic studies by experiment and
computation provided key insights into the catalyst’s mode of action.
progress, the synthesis of axially-chiral biaryls largely requires
stoichiometric amounts of often toxic oxidants, which lead to the
formation of undesired byproducts. In sharp contrast,
enantioselective C–H activations that employ electricity as formal
redox-equivalents are as of yet unprecedented. Within our
program on sustainable C–H activation,[
23]
we have now
unraveled the first electrochemical enantioselective synthesis of
axially-chiral biaryls with the aid of a transient directing groups
(TDG, Figure 1),[24] on which we report herein. Notably, our
strategy set the stage for the assembly of highly enantio-enriched
[
n]helicenes. Additional salient features of our findings include a)
first enantioselective electrochemical organometallic C–H
activation, b) unprecedented use of transient directing groups in
electrochemical C–H activations, c) electro-catalytic access to
axially-chiral biaryls, d) mechanistic insights by computation e)
assembly of N–C axially-chiral compounds, and f) late-stage
diversification towards chiral BINOLs, helicenes and dicarboxylic
acids.
Introduction
In recent years, organic electrosynthesis has undergone a
remarkable renaissance, with notable advances in homogeneous
electrocatalysis.[1] Significant momentum was particularly gained
by the merger of electrosynthesis with organometallic C–H
activation,[ enabling the use of electrons as sustainable redox
equivalents towards improved resource economy.[3] While major
progress was thus represented by elegant studies from inter alia
Jutand, and Mei via strong N-directing groups in palladium
2]
catalysis,[ Ackermann, Mei,
4]
[5]
[1a, 1g]
Lei, and Xu among others,
[6]
[7]
made progress towards electrochemical C–H activation using
both N-chelation assistance[8] or weak O-coordination.[9] Despite
these indisputable advances, full selectivity control in terms of
enantioselective[10] electrochemical C–H activations[11] are thus
far unfortunately unknown. This can be attributed to the major
challenges in asymmetric metallaelectro-catalysis, including a)
cathodic catalyst reduction, b) electrochemical degradation of
chiral ligands, and c) unfavorable interactions of the electrolyte
within the enantio-determining transition state. Hence, it is
noteworthy that asymmetric electrochemical transformation[11]
generally continue to be underdeveloped.[11,12]
Figure 1. Enantioselective electrocatalytic C–H activation enabled by TDGs.
Results and Discussion
Axially-chiral biaryls feature prominently as key structural motifs
in privileged catalysts,[13] ligands,[14] and natural products[15] as
well as in material sciences.[16] Since an early, albeit moderately
selective report on rhodium(I)-catalyzed C–H alkylations of
arylpyridines,[ atroposelective syntheses of axially-chiral biaryls
have been established, most notably by You,[18] Wencel-
Delord/Colobert,[19] Yang[20] and Shi,[21] among others. In this
context, Shi elegantly exploited transient directing groups for the
synthesis of axially chiral biaryls.[22] Yet, despite of considerable
We initiated our studies by evaluating TDGs[24] for the envisioned
atroposelective electrocatalyzed C–H olefination of biaryls 1a with
n-butyl acrylate (2a) (Table 1 and Table S-1 in the supporting
information).[25] We were delighted to observe that initial
experimentation with L-valine provided the desired olefinated
product 3aa indeed in 35% yield and 48% ee (entry 1). Initial
optimization studies indicated that the redox mediator
benzoquinone did not improve the performance. Probing
17]
1
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RESEARCH ARTICLE
alternative TDGs failed to provide a significant improvement in
chemical and optical yields (entries 2–6). Pleasingly, L-tert-
leucine afforded a 53% yield with 97% ee (entry 7). Other
electrolyte additives, such as NaOAc, KOAc, NaOPiv and
9[f]
1
L-tert-leucine
LiOAc
AcOH
---
---
[
(
a] Reaction conditions: Undivided cell, 1a (0.20 mmol), 2a (0.60 mmol), [Pd]
10 mol %), TDG (20 mol %), additive (2.0 equiv), solvent (4.5 mL), 60 °C,
constant current at 1.0 mA, 14 h, graphite felt (GF) anode, Pt-plate cathode,
isolated yields. [b] 20 h. [c] 2a (2.0 equiv). [d] Under N . [e] Without electricity.
4 6
nBu PF showed inferior efficiency as compared with LiOAc
2
(
entries 8–11), emphasizing tight interplay of the additive serving
[25]
[
f] No palladium. TFE = 2,2,2-Trifluoroethanol.
both as electrolyte and for carboxylate-assisted strong bond
cleavage (vide infra). Notably, other reaction media did not
improve the catalyst’s performance (entries 12–13). Slightly
prolonging the reaction time delivered the desired product 3aa
with synthetically useful 71% yield and 97% ee (entries 14 and
With the optimized reaction conditions in hand, we explored the
versatility of the enantioselective palladaelectro-catalysis
(
Scheme 1). A number of biaryls containing electron-rich (1d, 1e)
1
5), while the metallaelectro-catalysis also occurred in the
absence of air, albeit with reduced efficacy (entry 16). It is
noteworthy that, in contrast to the use of chemical oxidants,[22e]
and electron-withdrawing groups (1f) provided the desired axially
chiral biaryls 3 with excellent enantioselectivities.
a
redox mediator was not required for efficient metallaelectro-
catalysis. Control experiments confirmed the necessity of the
TDG, the electricity and the palladium catalyst (entries 17–
1
9).The mass balance was accounted for by unreacted starting
material 1.[
25]
Table 1. Optimization of the atroposelective electrocatalyzed C–H olefination.[a]
Entry
TDG
Additive
Solvent
Yield
%]
ee
[%]
[
Scheme 1. Atroposelective electro-catalyzed C–H olefination of biaryls 1.[25]
1
2
3
4
5
6
7
8
9
L-valine
L-phenylalanine
L-proline
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
NaOAc
KOAc
NaOPiv
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFE
35
43
47
23
21
45
53
47
45
50
48
---
48
18
20
28
68
24
97
99
98
96
99
---
Next, a wide range of alkenes 2 was explored (Scheme 2). Here,
fluoro- (2i), bromo- (2j), nitro- (2k) and carbonyl (2l) substituents
on the arene were well tolerated in the electrochemical
atroposelective C–H olefination, which should prove instrumental
for further late stage modification. Moreover, vinyl sulfone (2e)
and vinyl phosphonate (2f) were efficiently converted, delivering
the desired products 3ae and 3af, respectively, with good yields
and excellent enantioselectivites. The reaction proceeded
likewise well with methyl vinyl ketone (2g) and acrylamide (2m) to
furnish the axially chiral biaryls 3 with very high levels of enantio-
induction.
L-aspartic acid
L-tryptophan
L-histidine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
L-tert-leucine
---
10
11
12
13
4 6
nBu PF
---
---
TFE/AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
46
71
66
43
---
99
97
97
97
---
1 [
4
b]
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
1
5[b,c]
6[b,d]
1
17
1
8[e]
L-tert-leucine
25
97
2
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Scheme 2. Atroposelective palladaelectro-catalysis with alkenes 2.[25]
Scheme 3. Atroposelective palladaelectro-catalyzed C–H olefination of N-aryl
pyrroles.
The palladaelectro-catalysis was not limited to the conversion of
biaryls. Indeed, the strategy also set the stage for the synthesis
of N–C[22a, 26] axially-chiral motifs by palladaelectro-catalysis.
Under otherwise identical reaction conditions, we were able to
access N–C axially-chiral N-aryl pyrroles in a site- and enantio-
selective fashion. We were delighted to realize unprecedented C–
H perfluoroalkenylations in a highly enantioselective fashion to
deliver the synthetically useful axially-chiral fluorinated
heterobiaryls 5an-5ao. Likewise, vinyl sulfone (5ae), vinyl
phosphonate (5af) and cholesterol derivative (5ap) mirrored the
versatility towards N–C axially chiral scaffolds (Scheme 3).
[25]
Intrigued by the outstanding efficacy of the atroposelective
palladaelectro-catalyzed C–H activation, we became attracted to
unravelling its mode of action. First, H/D scrambling was not
observed when AcOD was used as the reaction media (Scheme
4a). Second, kinetic studies with isotopically-labeled substrates
revealed a KIE value of ≈1.8 (Scheme 4b). These experiments
are suggestive of the C–H activation being the rate-determining
step. Third, we did not observe a non-linear-effect (NLE), being
indicative of the enantio-determining step involving a metal to
ligand ratio of 1:1 (Scheme 4c).
3
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Subsequently, we probed the catalyst’s mode of action by means
of
TZVP+SMD(AcOH)//PBE0-D3BJ/def2-SVP level of theory
Figure 2).[25] A detailed analysis of the C–H activation process
computational
studies
at
the
PW6B95-D4/def2-
(
revealed that the intermediate that leads to the formation of the
seven-membered intermediate I-17 is 12.0 kcal mol-1 more
favorable than the formation of the five-membered intermediate I-
15
. Interestingly, this stabilization is dominated by attractive non-
covalent interactions between the tert-butyl group of the TDG and
the substrate’s naphthalene moiety as well as the arene π-system
and the palladium (Figure 3). These secondary dispersive forces
thus allow for a favorable square-planar coordination geometry.
The migratory insertion of the alkene gives preference to the
formation of the linear product in lieu of the branched product by
4
.7 kcal mol-1 (TS4-5).
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
ee of the ligand
Scheme 4. Summary of key mechanistic findings.
Figure 2. Computed relative Gibbs free energies (ΔG333.15
)
in kcal mol−1 for the key C–H activation and -H elimination elementary steps at the
PW6B95-D4/def2-TZVP-SMD(AcOH)//PBE0-D3BJ/def2-SVP level of theory. Superscripts 5 and 7 relate to structures, which lead to the formation of the
7-membered versus the 5-membered cyclometallated intermediates. B and L correspond to the branched and linear products.
4
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RESEARCH ARTICLE
7
5
Figure 3. Visualization of the non-covalent interactions calculated with the help of the NCIPLOT program, for the intermediates I-1 and I-1 . In the plotted surfaces,
red correspond to strong repulsive interactions, while green and blue correspond to weak and strong attractive interactions, respectively.
Finally, we explored the late-stage diversification of the thus-
obtained highly enantiomerically-enriched biaryls towards chiral
helicene. While significant advances in the synthesis of chiral
helicenes have been noted,[27] asymmetric C–H activation-based
electrocatalysis has thus far not been employed in the assembly
of enantiopure helicenes. Upon performing a kinetic resolution on
conformationally stable aldehyde 1h under the optimized reaction
condition, the olefinated product 3ha was obtained with 95% ee.
Further modification provided the [5]helicene 6 with overall high
chemical and optical yield (Scheme 5a). The synthesis of
The recovered starting material 1i was next submitted to the
asymmetric palladaelectro-catalysis, giving the other enantiomer
(-)3ia with 96% ee (Scheme 5b). The synthetic utility of our
approach was further reflected by providing the chiral dialdehyde
7. Dialdehyde 7 was itself converted through a Pinnick oxidation
into chiral dicarboxylic acid 9, whilst Baeyer-Villiger-oxidation
gave the chiral BINOL 10 (Scheme 5c). These new chiral
molecules should find multiple applications as privileged ligands
for asymmetric catalysis.
[
6]helicene 8 and [6]helimers ent-8 was accomplished likewise.
5
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Scheme 5. Electrochemical access to chiral Helicenes. (a) K
2
OsO .
Cl , MW, 95 °C.
4 2 4 2 3
2H O (15 mol %), NaIO (10 equiv), THF/H O (2/1), 50 °C, 24 h; (b) MePPh Br (3.8 equiv), nBuLi
(3.2 equiv), THF, -78 °C to rt, 1 h; (c) Grubbs II (10 mol %), CH
2
2
characterized by high enantioselectivites under mild reaction
conditions[ for the synthesis of enantioenriched axially-chiral
biaryls and heterobiaryls being devoid of chemical oxidants.
Experimental, kinetic and computational studies on the
metallaelectro-catalysis unraveled key elements of the catalyst’s
working mode. Our strategy also set the stage for the efficient
assembly of novel enantio-enriched BINOLs, dicarboxylic acids
and helicenes.
28]
Conclusion
In summary, we have reported on the first asymmetric
metallaelectro-catalyzed C–H activation. The atroposelective
organometallic C–H activation was realized by a transient
directing group manifold. The palladelectro-catalysis was
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award
and SPP 1807), the DAAD (fellowship to U.D.), and the CSC
(
scholarships to C.T. and J.H.) is gratefully acknowledged.
Keywords: asymmetric C–H activation
•
biaryls
•
electrochemistry • helicene • palladium • transient directing group
6
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Entry for the Table of Contents
EE: Enantioselective Electro-catalysis was realized in terms of
asymmetric C–H activation through transient directing group
(
TDG)-enabled palladaelectro-catalysis. Experiments and
calculations rationalize the key transition states, while the
asymmetric electrocatalysis provided step-economical access to
axially-chiral bi(hetero)aryl diols, diacids and helicines.
Institute and/or researcher Twitter usernames: aztul
9
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