General Enantioselective C?H Activation with Efficiently Tunable Cyclopentadienyl Ligands

Article abstract of DOI:10.1002/anie.201611981

Cyclopentadienyl (Cp) ligands enable efficient steering of various transition-metal-catalyzed transformations, in particular enantioselective C?H activation. Currently only few chiral Cp ligands are available. Therefore, a conceptually general approach to

Full text of DOI:10.1002/anie.201611981

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611981
German Edition: DOI: 10.1002/ange.201611981
À
C H Activation
Hot Paper
À
General Enantioselective C H Activation with Efficiently Tunable
Cyclopentadienyl Ligands
Zhi-Jun Jia, Christian Merten, Rajesh Gontla, Constantin G. Daniliuc, Andrey P. Antonchick,*
and Herbert Waldmann*
Abstract: Cyclopentadienyl (Cp) ligands enable efficient
steering of various transition-metal-catalyzed transformations,
À
in particular enantioselective C H activation. Currently only
few chiral Cp ligands are available. Therefore, a conceptually
general approach to chiral Cp ligand discovery would be
invaluable as it would enable the discovery of applicable Cp
ligands and to efficiently and rapidly vary and tune their
structures. Herein, we describe the three-step gram-scale
synthesis of a structurally diverse and widely applicable
chiral Cp ligand collection (JasCp ligands) with highly variable
and adjustable structures. Their modular nature and their
amenability to rapid structure variation enabled the efficient
discovery of ligands for three enantioselective RhIII-catalyzed
À
C H activation reactions, including one unprecedented trans-
formation. This novel approach should enable the discovery of
efficient chiral Cp ligands for various further enantioselective
transformations.
T
he cyclopentadienyl (Cp) ligand and its pentamethyl
analogue (Cp*) have emerged as versatile anionic ancillary
ligands broadly applicable in transition-metal catalysis.[1]
Despite this importance, highly efficient chiral Cp ligands
for asymmetric catalysis had remained elusive for a long time
and are in high demand.[2,3] Recently, inspired by the rapid
III
À
development of Cp*Rh -catalyzed C H activation, in two
complementary strategies, Ward and Rovis et al.[4a] and
Cramer and co-workers[4b,c] (Figure 1a) developed the first
classes of chiral Cp ligands, leading to a remarkable develop-
[*] Z.-J. Jia, Dr. R. Gontla, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Max-Planck-Institut fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
Figure 1. Concept for the discovery and synthesis of a new class of
chiral JasCp ligands and the corresponding [CpJRh(C2H4)2] complexes.
Z.-J. Jia, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Technische Universitꢁt Dortmund
Fakultꢁt Chemie und Chemische Biologie, Chemische Biologie
Otto-Hahn-Strasse 4a, 44227 Dortmund (Germany)
ment in this field.[5] However, both ligand types face
limitations.[3] On the one hand, the proteinaceous ligands
developed by the groups of Ward and Rovis can be modified
and optimized rapidly by means of molecular biology
techniques, but may not be broadly applicable owing to the
limitations imposed by the protein, such that only one
successful example has been reported to date.[4a] On the
other hand, the synthetic organic ligand type developed by
the groups of Cramer[4b,c] and You[5k] is broadly applicable but
limited in structural variability, and thereby its adaptation to
different transformations is difficult owing to its lengthy
preparation. As explicitly pointed out by Cramer et al.,[3b]
novel chiral Cp ligand types that combine the advantages of
Dr. C. Merten
Ruhr-Universitꢁt Bochum
Lehrstuhl fꢀr Organische Chemie II
Universitꢁtsstrasse 150, 44801 Bochum (Germany)
Dr. C. G. Daniliuc
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢀnster (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611981.
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both current approaches, that is, efficient modification of the
ligand structure and wide applicability under different con-
ditions for rapid adaptation to different transformations, are
highly desirable. Herein, we describe the development and
implementation of a general strategy for the synthesis of
a new class of chiral Cp ligands (JasCp ligands) and their
À
application in enantioselective C H activation reactions
(Figure 1a). The chiral JasCp ligands embody four adjustable
positions and can be accessed efficiently in three steps on
gram scale from commercially available starting materials
with an enantioselective [6+3] cycloaddition as the key step,
as previously reported by our group.[6] To demonstrate and
validate the generality of the concept and the efficiency of the
ligand development, a library of corresponding RhI catalysts
was synthesized and employed for the highly enantioselective
catalysis of two reactions previously described with the
complementary chiral cyclopentadienyl ligands mentioned
above[4b,c] and an unprecedented transformation yielding
axially chiral biaryl compounds.
For the implementation of a general and efficient strategy
for catalyst discovery and development, a variety of chiral Cp
ligands must be readily accessible in a few steps and in high
enantiopurity, and the Cp ligands must be equipped with
stereogenic centers and functional groups that can both be
flexibly varied to allow for catalyst optimization depending on
the transformation to be steered enantioselectively. In light of
these requirements, we employed enantioselective [6+3]
cycloadditions of imino esters with fulvenes to efficiently
access chiral Cp derivatives (Figure 1b).[6] The modular
nature of these Cp derivatives enables rapid structural
variation by employment of different amino acids, aldehydes,
and fulvenes. Different chiral Cp (JasCp) derivatives are
available through enantioselective endo- and exo-selective
transformations (L1, L2; see the Supporting Information for
details). By means of this robust asymmetric synthesis
methodology, a wide range of chiral Cp ligands were prepared
using commercial catalysts for the [6+3] cycloadditions (see
the Supporting Information, Table S1). We prepared the
corresponding [CpJRh(C2H4)2] complexes and divided them
into two categories (1 and 2) based on mono- or disubstitution
with R1 (Figure 1c and Table S2). A notable feature of the
developed [CpJRh(C2H4)2] complexes is the presence of
a nucleophilic nitrogen atom in their structure.
Figure 2. Enantioselective synthesis of isoquinolinones.[10] Bz=ben-
zoyl.
purity of the employed Cp catalyst and the enantiopurity of
the products of the targeted reaction is assumed.[8] The
validity of this assumption was subsequently confirmed by
successful catalyst optimization (Figure S1). For ligand opti-
mization, a standard reaction was employed with R1 sub-
stituents originating from different ketones or aldehydes
(Table S3, entries 1–6). The methyl group was identified to be
optimal for disubstitution with R1, and the corresponding RhI
complex 1a gave the desired product with 68% CT in 90%
yield. Other groups, such as ethyl, cyclobutyl, or cyclohexyl
moieties, resulted in either lower reactivity or lower enantio-
selectivity. Sequentially, intensive screening of R2 was con-
ducted by making use of commercially available aldehydes,
including aromatic substitutions with different electronic
properties on all positions (Table S3, entries 7–9). The R2
group was identified to be critical for the enantioselectivity
and the 2-naphthyl group turned out to be optimal. Further-
more, investigations of the possible effect of R3 on the ester
group revealed that big groups such as ethyl resulted in lower
reactivity for this specific reaction although the enantiose-
lectivity remained comparable (Table S3, entry 10). The
corresponding ligand in optically pure form can be prepared
To explore the potential of the novel catalysts, we
À
investigated the C H functionalization of hydroxamates
with alkenes catalyzed by RhIII (see Figure 2) that was
initially reported by the groups of Glorius[7a] and Fagnou,[7b]
and for which the first chiral version was developed by Ward
and Rovis et al.[4a] and the Cramer group[4b] employing chiral
Cp ligands (see Figure 1a). To develop an efficient, stream-
lined process for catalyst optimization, we chose commercial
catalysts for the synthesis of the chiral JasCp ligands by
asymmetric [6+3] cycloaddition[6a,b] with moderate to excel-
lent enantioselectivity. As the JasCp ligands were not
obtained as pure enantiomers in these cycloadditions, the
concept of chirality transfer (CT) was introduced to rapidly
evaluate the efficiency of chirality induction by a given ligand
(Table S3). In this concept, enantiomerically enriched ligands
are employed and a linear relationship between the enantio-
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by using preparative HPLC on a chiral stationary phase for
racemate separation on gram scale or by using a known
enantioselective [6+3] cycloaddition.[6c] With this optically
pure ligand in hand, we investigated the importance of the
protective group on the secondary amine. Several N-alkylated
ligands were readily synthesized by reductive amination with
various aldehydes. Among those, the N-methylated catalyst 1i
afforded the desired product in 90% yield and with 83% ee.
Further enhancement of steric hindrance by introduction of
an ethyl or an isobutyl substituent led to a decrease in both
reactivity and enantioselectivity (Table S3, entries 11–13).
The structure and absolute configuration of catalyst 1i were
unambiguously determined by crystal-structure analysis (Fig-
ure S3).[9]
Having an optimized catalyst (1i) in hand, we optimized
the reaction conditions (Table S4). The solvent had no
obvious effect on the enantioselectivity, but significantly
influenced the reactivity. Moreover, up to 90% ee could be
reached by lowering the temperature to À108C (Figure 2 and
Table S4, entry 3). Having established optimized reaction
conditions, the substrate scope was explored. As shown in
Figure 2, various styrenes, even those with heterocyclic
substituents or cyclic alkenes, are tolerated in this enantiose-
lective transformation, yielding the desired products with
excellent regio- and enantioselectivity (see 5a–5j and 5k–5m,
respectively). Aryl hydroxamates with substituents with
different electronic and steric properties proved to be suitable
for this reaction and yielded the desired products 5n–5v. The
absolute configuration of product 5m was assigned by
vibrational circular dichroism (VCD) spectroscopy (Fig-
ure S4).[10]
Figure 3. Enantioselective allylation of benzamides.[10] Method J: Ben-
zamides 6 (0.12 mmol, 1.20 equiv) and allenes 7 (0.10 mmol,
1.00 equiv) were used with 0.5 mL of DCM/TFE mixture as the solvent.
Method K: Benzamides 6 (0.10 mmol, 1.00 equiv) and allenes 7
(0.12 mmol, 1.20 equiv) were used. Method L: 0.1 mL of DCM/TFE.
reaction and decreased enantioselectivity (Table S5,
entry 11). Ultimately, catalyst 2l turned out to be best.
Subsequent optimization of the reaction conditions revealed
that the solvent has a dramatic effect on the reactivity, but
only a slight influence on the enantioselectivity (Table S6). A
4:1 combination of dichloromethane (DCM) and trifluoro-
ethanol (TFE) proved to be optimal, affording the desired
product in 85% yield and with 90% ee within 18 h at À208C
(Figure 3). Examination of the possible difference between
the two diastereomers of the RhI complex surprisingly
revealed that both diastereomers of catalyst 2l yielded the
product with the same stereoselectivity. This finding was
confirmed for catalyst 2n (Figure S2). Therefore, RhI com-
plex 2l was employed as a mixture of two diastereomers in all
further transformations. Evaluation of the substrate scope
(Figure 3) showed that benzamides bearing different substi-
tution patterns were well tolerated, affording products 8a–8h
with good to excellent ee values and yields. Furthermore,
various allenes can be employed in this reaction (8i–8k).
To confirm that our approach also enables the discovery
To demonstrate the generality of the approach and the
flexible applicability of our ligand library, we investigated the
À
asymmetric C H allylation of benzamides (Figure 3) that had
previously been rendered enantioselective by Cramer and co-
workers with chiral binaphthyl-substituted Cp ligands.[4c] This
seminal work showed that the cyclohexyl-substituted chiral
Cp ligands successfully applied in the synthesis of isoquino-
linones[4b] (Figure 2) failed to induce high enantioselectivity in
this transformation.[4c] A preliminary experiment showed that
only 24% ee could be achieved with catalyst 1i, which had
proven best in steering the reaction described above (Figure 2
and Table S5, entry 3). Gratifyingly, screening with our ligand
collection rapidly revealed that catalyst 2a, which is based on
a chiral Cp ligand obtained from exo-selective [6+3] cyclo-
addition and equipped with two aryl groups, is very efficient
in this process, yielding up to 86% CTwithout diminishing the
reactivity (Table S5, entry 6). Although RhI complex 2a was
obtained as a 60:40 mixture of diastereomers owing to the
face selectivity of Rh complexation (Table S2), we decided to
directly use this mixture of RhI complexes for further ligand
optimization to streamline the catalyst screening process.
Systematic variation of the R1 and R2 groups in the ligand
demonstrated that excellent enantioselectivity was observed
if ligands with para- or meta-substituted aryl groups were used
(Table S5). The R3 group did not have a significant effect on
the enantioselectivity (Table S5, entries 8, 17, and 18). In
sharp contrast to catalyst 1i, which performed best in the
isoquinolinone synthesis (Figure 2), R4 = Me led to a sluggish
À
of chiral catalysts for unprecedented reactions, a novel C H
activation reaction was realized that yields valuable axially
chiral biaryl compounds with excellent enantioselectivity
(Figure 4). Despite the prevalence of atropisomerism in
natural products,[11] pharmaceuticals,[12] and chiral catalysts/
ligands,[13] the corresponding catalytic enantioselective
approaches have not reached the state of the art for the
establishment of chirality established for other compound
classes, and novel methods are in high demand.[14] Especially
in the field of asymmetric transition-metal catalysis enabled
by chiral Cp ligands, only two classes of transformations have
been documented.[2d-f,5c,k] In contrast, biaryl compounds have
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To rationalize the observed regio- and enantioselectivity,
computational studies[17] were performed for the isoquinoli-
none synthesis (Figure 2; for details, see the Supporting
Information). There are four possible stereoisomers based on
two regioisomers with the phenyl group at the 3- and 4-
positions, of which only the 3-substituted regioisomer 5a with
S configuration was found experimentally. The excellent
regioselectivity can be rationalized by our calculations as all
pathways to the 4-substituted regioisomers feature transition-
state barriers that are approximately 2 kcalmolÀ1 higher in
energy than those leading to the 3-substituted regioisomers
(Figure S6 and Table S7). Hence, from a kinetic perspective
and in agreement with the experimental findings, the path-
ways leading to the 4-substituted regioisomer can be excluded
from the analysis. Regarding the enantioselectivity of the
formation of the 3-substituted regioisomers, previous mech-
anistic considerations suggested a preferred structure for the
rhodacycle intermediate in which the Boc protective group is
located on the sterically less hindered side, and styrene
approaches the rhodacycle intermediate from the open side
with the phenyl group pointing away from the Cp ligand to
avoid unfavorable steric interactions.[4b] Accordingly, in the
present case, the Boc moiety would point towards the
2-naphthyl group (substituent R2) bearing side of the ligand
to avoid unfavorable steric interactions with the methyl group
(substituent R1; intermediate B, Figure 5). Styrene should
Figure 4. Synthesis of axially chiral compounds.[10]
À
efficiently been synthesized through direct C H arylation
enabled by rhodium(III) complexes with achiral Cp and Cp*
ligands.[15] Although such strategies represent one of the most
efficient approaches to construct aryl–aryl bonds, a catalytic
enantioselective version has not been reported thus far. Based
on this consideration, we envisioned that the chiral JasCp
ligands could also enable the synthesis of axially chiral biaryls
À
by direct C H arylation. Benzamides 6 and diazonaphtho-
quinones 9 were chosen as promising coupling partner
candidates (Figure 4).[16] Aside from their considerable reac-
tivity, diazo compounds 9 can provide two ortho substituents
adjacent to aryl–aryl bonds in the resulting biaryl products 10,
thus contributing to the stabilization of the axial chirality.
After preliminary optimization, the reaction of benzamide 6l
and 9a afforded the desired substituted product 10a in 74%
yield with up to 91% ee using 2l as the catalyst (Figure 4).
Subsequent investigation of the substrate scope revealed that
various electron-rich substituents in the meta position of the
benzamide were tolerated well, affording chiral biaryl com-
pounds 10b–10i in good to excellent yields and enantiose-
lectivities. To prohibit further coupling of biaryl product 10
with diazonaphthoquinone 9, various ortho substituents, such
as methyl, bromo, and iodo groups, were installed on the
benzamide, and also found to be compatible with this
transformation. Furthermore, reactions with 9 bearing vari-
ous substituents proceeded well and provided compounds
10j–10n with high enantioselectivity. The absolute configu-
ration of 10a was assigned by vibrational circular dichroism
(VCD) spectroscopy (Figure S5).[10]
Figure 5. Stereochemical model for the isoquinolinone synthesis.
approach in the same way (intermediate D, Figure 5) while
the other orientation of styrene would be less favorable
(intermediate C, Figure 5). For the calculations, we also
considered that the hydroxamate is in its presumably less
favored orientation with the Boc group pointing towards the
methyl groups (substituents R1, intermediate A, Figure 5). In
addition, we took into account two different orientations of
the Boc carbonyl group (Figure S8), so that in total four
conformers of the rhodacycle intermediate were investigated.
Furthermore, two opposite ways for the approach of styrene
to the rhodacycle intermediate were also taken into consid-
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In conclusion, we have developed a conceptually novel
general approach to chiral Cp ligand discovery that unites the
advantages of previously developed ligand classes, namely
wide applicability and the possibility for rapid structural
variation. The chiral JasCp ligands can be readily synthesized
in three steps on gram scale from commercially available
starting materials, and both their structures and configura-
tions can be efficiently adjusted by means of flexible
enantioselective [6+3] cycloaddition reactions. Further modi-
fication of the secondary amine embodied in the [6+3]
cycloadducts enlarges the ligand pool significantly, and more
importantly proves to be critical for the enantiocontrol of
different reactions. Investigation of a chiral JasCp ligand
collection with modular nature, and therefore with highly
variable and adjustable structures and absolute and relative
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III
À
ligands for different enantioselective Rh -catalyzed C H
activation reactions. Our results suggest that this approach
should enable the discovery of efficient chiral JasCp ligands
for various further enantioselective transformations.
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Acknowledgements
Z.-J.J. thanks the International Max-Planck-Research School
in Chemical and Molecular Biology for a fellowship. C.M.
thanks the FCI for a Liebig Fellowship and the Deutsche
Forschungsgemeinschaft (DFG) for support through the
Cluster of Excellence RESOLV (“Ruhr Explores Solvation”,
EXC 1069). This research was supported by the European
Research Council under the Seventh Framework Programme
of the European Union (FP7/2007–2013; ERC Grant 268309
to H.W.) and by the Max Planck Society.
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Conflict of interest
The authors declare no conflict of interest.
À
Keywords: asymmetric synthesis · C H activation ·
cycloadditions · cyclopentadienyl ligands · rhodium
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Communications
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Manuscript received: December 9, 2016
Final Article published: && &&, &&&&
6
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Activation
The discovery of chiral Cp ligands that
unite the advantages of previously devel-
oped ligand classes is enabled by a novel
approach. They can be readily synthe-
sized on gram scale, and both their
structures and configurations can be
efficiently adjusted by means of flexible
enantioselective [6+3] cycloaddition
reactions. With these ligands, three
Z.-J. Jia, C. Merten, R. Gontla,
C. G. Daniliuc, A. P. Antonchick,*
H. Waldmann*
&&& — &&&
À
General Enantioselective C H Activation
with Efficiently Tunable Cyclopentadienyl
Ligands
À
rhodium(III)-catalyzed C H activation
reactions were rendered highly enantio-
selective.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!