Enantioselective Synthesis of Five-Membered-Ring Atropisomers with a Chiral Rh(III) Complex

Article abstract of DOI:10.1021/acs.orglett.0c03355

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C-H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.

Full text of DOI:10.1021/acs.orglett.0c03355

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Letter
Enantioselective Synthesis of Five-Membered-Ring Atropisomers
with a Chiral Rh(III) Complex
Saad Shaaban, Houhua Li, Felix Otte, Carsten Strohmann, Andrey P. Antonchick,*
and Herbert Waldmann*
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ABSTRACT: Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and
efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered
aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an
enantioselective C−H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types
that can be accessed from three different five-membered-ring heterocycles.
aromatic compounds with alkynes forming axially chiral 4-
xially chiral atropisomers have found widespread applica-
Ation in diverse areas of investigation, in particular arylisoquinolones catalyzed by chiral RhJasCp complexes,12 and
Li et al. recently reported the use of chiral RhCpx complexes in
asymmetric synthesis and medicinal chemistry, and conse-
the synthesis of axially chiral biindolyls.13 To the best of our
quently, methods for their efficient synthesis are in high
demand.1 Attention has been mostly focused on six-
knowledge, there is no general enantioselective method that
membered-ring biaryl axis atropisomers,2 but atropisomers
enables the construction of atropisomers containing a five-
membered aromatic ring (furans, thiophenes, and pyrroles).
Herein, we report the RhJasCp-catalyzed enantioselective
synthesis of these five-membered-ring atropisomers via direct
C−H functionalization with 1-diazonaphthoquinones (Scheme
1c, bottom).
To establish the methodology, we investigated coupling of 2-
amido-benzothiophene 1a14 and 1-diazonaphthoquinone 2a as
model substrates using various RhJasCp catalysts. As shown in
Table 1, Rh1 led to the formation of desired product 3a in low
yield and poor enantiomeric ratio (entry 1), whereas Rh2 gave
the corresponding product in higher yield and better
enantiomeric ratio (entry 2). Screening of a variety of solvents
demonstrated that 1,4-dioxane was the best (entries 2−7), and
variation of the catalysts with strict temperature control (entries
8−12) showed that Rh3 gave the desired product in excellent
formed from five-membered rings have been infrequently
explored (Scheme 1a). In these cases, the lower barrier for
rotation among the biaryl axis limits both their asymmetric
synthesis and their applicability.3 Carbazole-, indole-, and
pyrrole-derived atropisomers with mostly a C−N axis, but also
C−C axis, have been isolated from natural sources (Scheme
1b).4 A few synthesized chiral five-membered-ring atropisomer
ligands have also been employed in asymmetric catalysis
(Scheme 1b). Five-membered-ring atropisomers have been
synthesized by means of transition metal-catalyzed cross
coupling reactions5 (Scheme 1c, left), organo-catalyzed
asymmetric arylations6 (Scheme 1c, right), and the establish-
ment of the biaryl axis via construction of one of the rings.7 In
addition, enantioselective C−H functionalization using chiral
Cpx ligands has been employed as an alternative strategy to
access atropisomers.8 Thus, Heller et al. reported a Co-catalyzed
enantioselective synthesis of axially chiral biaryls by means of
[2+2+2] cycloaddition reactions,9 You et al. described an
enantioselective dehydrogenative Heck coupling of biaryls with
alkenes,10 and Cramer et al. achieved an Ir-catalyzed synthesis of
axially chiral biaryl phosphines using diazonaphthoquinones.11
We have described an intramolecular C−H functionalization of
Received: October 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03355
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 1. (A) Comparison between Five-Membered-Ring
and Six-Membered-Ring Atropisomers, (B) Selected
Examples of Natural Products and Synthetic Chiral Ligands,
and (C) General Approaches for Biaryl Synthesis and a
Proposed Strategy Using Chiral RhJasCp Complexes
Table 1. Optimization of Conditions for the Enantioselective
Synthesis of Five-Membered-Ring Atropoisomeric
Benzothiophene 3a
a
temp
(°C)
yield
(%)
enantiomeric ratio
(er)
entry catalyst
solvent
1
2
3
4
5
6
7
8
Rh1
Rh2
Rh2
Rh2
Rh2
Rh2
Rh2
Rh3
Rh4
Rh5
Rh3
Rh3
1,4-dioxane
1,4-dioxane
MeOH
DCM
toluene
23
23
23
23
23
23
23
23
23
23
17
0
64
85
39
75
69
41
85
92
79
85
90
35
76:24
90.5:9.5
72:28
87:13
85.5:14.5
79.5:21.5
71:29
MeCN
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
91:9
9
87.5:12.5
90.5:9.5
92.5:7.5
91:9
10
11
12
a
Reactions were run for 36 h. Yields were determined for isolated
products. Values of ee were determined using chiral HPLC.
Scheme 2. Scope of the Enantioselective Synthesis of Five-
Membered-Ring Atropoisomeric Thiophenes and
Benzothiophenes
yield and with very good enantiomeric ratio (entry 11). It should
be noted that the temperature moderately influences the
enantioselectivity (entries 8, 11, and 12).
After having identified suitable reaction conditions, we
investigated the scope for the transformation of thiophenes
and benzothiophenes (Scheme 2). A substituent at position C-4
of the benzothiophenes led to an increase in enantioselectivity.
Thus, 4-fluoro and chloro substituents (3c−3g) afforded the
corresponding biaryl derivatives in high yields and excellent
enantiomeric ratios. In addition, the presence of electron-
donating (3f) and electron-withdrawing (3b) groups was
tolerated and the desired products were formed in good yields
and very appreciable enantioselectivities. Thiophene (3i) was
obtained in high yield; however, the compound racemized very
quickly. We attributed this to the lack of steric hindrance
allowing the rotation barrier to remain low. To overcome this
problem, sterically demanding substituents were incorporated at
position C-4 of the thiophene coupling partner, and the
corresponding thiophene atropisomers were formed in very
good yields and high enantiomeric excesses (3k−3p). We note
that bromo derivative (3n) may open up further opportunities
to elaborate structure, e.g., via Pd(0) chemistry. Slow
evaporation of product 3p afforded crystals suitable for X-ray
diffraction analysis, which allowed us to unambiguously confirm
the structure. Measuring several crystals provided the same
absolute configuration (aR) (CCDC 1994612; see the
Supporting Information for more details).
B
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To further explore the applicability of the method, the scope
for analogous transformations employing benzofurans and
furans was investigated (Scheme 3). Benzofuran afforded
Scheme 4. Scope of the Enantioselective Synthesis of Five-
Membered-Ring Atropoisomeric Indoles
Scheme 3. Scope of the Enantioselective Synthesis of Five-
Membered-Ring Atropoisomeric Furans and Benzofurans
Scheme 5. Proposed Reaction Mechanism
desired product 3q in good yield albeit with lower
enantioselectivity. Increasing the steric bulk at position C-4
led to formation of the desired benzofuran biaryl atropisomers in
good yields and high enantioselectivities (3t−3w). We note that
high reactivity with good enantioselectivity was also observed
with a bromo-substituted furan derivative (3x).
The orienting exploration of indoles and pyrroles in this
transformation revealed that indoles with an unprotected NH-
group and a directing group at position C-2 are not reactive
under the employed conditions. Introduction of a variety of
substituents at the nitrogen atom did not substantially improve
this situation (see the Supporting Information for more details).
Fortunately, installation of the directing group on the nitrogen15
afforded the desired products in very good yield and moderate to
high ee values under the optimized reaction conditions.
Exploration of the reaction scope revealed that indoles bearing
both electron-donating and electron-withdrawing groups were
tolerated and yielded the desired 2-indolo-naphthaline
atropisomers (4b−4h) in good yields and good enantioselectiv-
ities (Scheme 4).
odology may find widespread interest and application in various
areas of science.
On the basis of previous studies, the mechanism shown in
Scheme 5 for rationalizing the observed transformation appears
to be plausible.16 The reaction begins with an oxidative addition
of active Rh(III) complex I to give five-membered-ring
rhodacyle II. Insertion of the diazonaphthoquinone affords
intermediate III, which upon loss of nitrogen (N2) yields Rh−
carbene intermediate IV. This intermediate undergoes 1,2-
migration, followed by subsequent reductive elimination
yielding chiral compound VI. Finally, aromatization (point to
axis chirality transfer) furnishes final biaryl atropisomer 3.
In conclusion, we have developed an enantioselective C−H
functionalization method giving access to the biaryl atropisomer
types that can be accessed from three different five-membered-
ring heterocycle classes. The method enabled a straightforward
synthesis of (benzo)furano, (benzo)thiopheno, and indolo
atropoisomers in high yields and high enantioselectivity. In light
of the challenging synthesis of these five-membered-ring
atropoisomeric products in general, we anticipate that this
practical, enantioselective direct C−H functionalization meth-
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03355.
Experimental procedures and characterization data for all
new compounds and computational details (PDF)
Accession Codes
CCDC 1994612 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
C
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Letter
(6) (a) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F.
Angew. Chem., Int. Ed. 2017, 56, 116. (b) Qi, L.; Mao, J.; Zhang, J.; Tan,
B. Nat. Chem. 2018, 10, 58. (c) Zhu, S.; Chen, Y.-H.; Wang, Y.-B.; Yu,
P.; Li, S.-Y.; Xiang, S.-H.; Wang, J.-Q.; Xiao, J.; Tan, B. Nat. Commun.
2019, 10, 4268. (d) Chatterjee, S.; Bhattacharjee, P.; Butterfoss, G. L.;
Achari, A.; Jaisankar, P. RSC Adv. 2019, 9, 22384. (e) Zheng, S.; Wang,
Q.; Zhu, J. Angew. Chem., Int. Ed. 2019, 58, 1494. (f) Zheng, S.; Wang,
Q.; Zhu, J. Angew. Chem., Int. Ed. 2019, 58, 9215. (g) Jiang, F.; Chen, K.-
W.; Wu, P.; Zhang, Y.-C.; Jiao, Y.; Shi, F. Angew. Chem., Int. Ed. 2019,
58, 15104. (h) Lu, S.; Ong, J.-Y.; Yang, H.; Poh, S.-B.; Liew, X.; Seow, C.
S. D.; Wong, M.; Zhao, Y. J. Am. Chem. Soc. 2019, 141, 17062.
(7) (a) Wang, D.; Tong, X. Org. Lett. 2017, 19, 6392. (b) Raut, V. S.;
Jean, M.; Vanthuyne, N.; Roussel, C.; Constantieux, T.; Bressy, C.;
Bugaut, X.; Bonne, D.; Rodriguez, J. J. Am. Chem. Soc. 2017, 139, 2140.
(8) (a) Newton, C. G.; Kossler, D.; Cramer, N. J. Am. Chem. Soc. 2016,
138, 3935. (b) Yoshino, T.; Satake, S.; Matsunaga, S. Chem. - Eur. J.
2020, 26, 7346. (c) Shaaban, S.; Davies, C.; Waldmann, H. Eur. J. Org.
Chem. 2020, 6512 DOI: 10.1002/ejoc.202000752.
AUTHOR INFORMATION
Corresponding Authors
■
Andrey P. Antonchick − Max-Planck-Institute of Molecular
Physiology, Department of Chemical Biology, 44227
Dortmund, Germany; Technical University Dortmund,
Faculty of Chemical Biology, 44227 Dortmund, Germany;
orcid.org/0000-0003-0435-9443;
Email: andrey.antonchick@mpi-dortmund.mpg.de
Herbert Waldmann − Max-Planck-Institute of Molecular
Physiology, Department of Chemical Biology, 44227
Dortmund, Germany; Technical University Dortmund,
Faculty of Chemical Biology, 44227 Dortmund, Germany;
orcid.org/0000-0002-9606-7247;
Email: herbert.waldmann@mpi-dortmund.mpg.de
Authors
(9) (a) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.;
Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew. Chem.,
Int. Ed. 2004, 43, 3795. (b) Hapke, M.; Kral, K.; Fischer, C.;
Spannenberg, A.; Gutnov, A.; Redkin, D.; Heller, B. J. Org. Chem. 2010,
75, 3993.
(10) (a) Zheng, J.; You, S.-L. Angew. Chem., Int. Ed. 2014, 53, 13244.
(b) Zheng, J.; Cui, W.-J.; Zheng, C.; You, S.-L. J. Am. Chem. Soc. 2016,
138, 5242.
Saad Shaaban − Max-Planck-Institute of Molecular Physiology,
Department of Chemical Biology, 44227 Dortmund, Germany
Houhua Li − Max-Planck-Institute of Molecular Physiology,
Department of Chemical Biology, 44227 Dortmund, Germany
Felix Otte − Technical University Dortmund, Department of
Inorganic Chemistry, 44227 Dortmund, Germany
Carsten Strohmann − Technical University Dortmund,
Department of Inorganic Chemistry, 44227 Dortmund,
Germany
́
(11) Jang, Y.-S.; Wozniak, Ł; Pedroni, J.; Cramer, N. Angew. Chem.,
Int. Ed. 2018, 57, 12901.
(12) (a) Jia, Z.-J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick,
A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2017, 56, 2429. (b) Shan,
G.; Flegel, J.; Li, H.; Merten, C.; Ziegler, S.; Antonchick, A. P.;
Waldmann, H. Angew. Chem., Int. Ed. 2018, 57, 14250. (c) Li, H.; Yan,
X.; Zhang, J.; Guo, W.; Jiang, J.; Wang, J. Angew. Chem., Int. Ed. 2019,
58, 6732.
(13) (a) Tian, M.; Bai, D.; Zheng, G.; Chang, J.; Li, X. J. Am. Chem.
Soc. 2019, 141, 9527. (b) Wang, F.; Qi, Z.; Zhao, Y.; Zhai, S.; Zheng, G.;
Mi, R.; Huang, Z.; Zhu, X.; He, X.; Li, X. Angew. Chem., Int. Ed. 2020,
59, 13288.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03355
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Max-Planck-Gesellschaft. S.S.
thanks the Alexander von Humboldt Foundation for funding.
H.L. is grateful to the Swiss National Science Foundation
(SNSF) for an Early Postdoc. Mobility fellowship
(P2GEP2_168250).
(14) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 7190.
(15) Chen, X.; Yang, S.; Li, H.; Wang, B.; Song, G. ACS Catal. 2017, 7,
2392.
(16) (a) Chan, W.; Lo, S.; Zhou, Z.; Yu, W. J. Am. Chem. Soc. 2012,
134, 13565. (b) Liu, Z.; Wu, J.; Yang, S. Org. Lett. 2017, 19, 5434.
(c) Ghosh, B.; Biswas, A.; Chakraborty, S.; Samanta, R. Chem. - Asian J.
2018, 13, 2388.
REFERENCES
■
(1) (a) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M.
J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(b) LaPlante, S. R.; Fader, L. D.; Fandrick, K. R.; Fandrick, D. R.;
Hucke, O.; Kemper, R.; Miller, S. P. F.; Edwards, P. J. J. Med. Chem.
2011, 54, 7005. (c) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.;
Sivaguru, J. Chem. Rev. 2015, 115, 11239.
(2) (a) Loxq, P.; Manoury, E.; Poli, R.; Deydier, E.; Labande, A. Coord.
Chem. Rev. 2016, 308, 131. (b) Wang, Y.; Tan, B. Acc. Chem. Res. 2018,
51, 534. (c) Mancinelli, M.; Bencivenni, G.; Pecorari, D.; Mazzanti, A.
Eur. J. Org. Chem. 2020, 2020, 4070.
(3) (a) Bonne, D.; Rodriguez, J. Chem. Commun. 2017, 53, 12385.
(b) Bonne, D.; Rodriguez, J. Eur. J. Org. Chem. 2018, 2018, 2417. (c) Li,
T.-Z.; Liu, S.-J.; Tan, W.; Shi, F. Chem. - Eur. J. 2020, DOI: 10.1002/
chem.202001397.
(4) (a) Norton, R. S.; Wells, R. J. J. Am. Chem. Soc. 1982, 104, 3628.
(b) Hughes, C. C.; Prieto-Davo, A.; Jensen, P. R.; Fenical, W. Org. Lett.
2008, 10, 629. (c) Schneider, P.; Schneider, G. Chem. Commun. 2017,
53, 2272.
(5) (a) He, C.; Hou, M.; Zhu, Z.; Gu, Z. ACS Catal. 2017, 7, 5316.
(b) Yamaguchi, K.; Yamaguchi, J.; Studer, A.; Itami, K. Chem. Sci. 2012,
3, 2165. (c) Nishimoto, Y.; Kondo, H.; Yamaguchi, K.; Yokogawa, D.;
Yamaguchi, J.; Itami, K.; Irle, S. J. Org. Chem. 2017, 82, 4900.
(d) Zhang, S.; Yao, Q.-J.; Liao, G.; Li, X.; Li, H.; Chen, H.-M.; Hong, X.;
Shi, B.-F. ACS Catal. 2019, 9, 1956. (e) Nguyen, Q.; Guo, S.; Royal, T.;
Baudoin, O.; Cramer, N. J. Am. Chem. Soc. 2020, 142, 2161.
D
https://dx.doi.org/10.1021/acs.orglett.0c03355
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