A Planar-Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones

Article abstract of DOI:10.1002/anie.201801703

The rapid development of enantioselective C?H activation reactions has created a demand for new types of catalysts. Herein, we report the synthesis of a novel planar-chiral rhodium catalyst [(C₅H₂^tBu₂CH₂^tBu)RhI₂]₂ in two steps from commercially available [(cod)RhCl]₂ and tert-butylacetylene. Pure enantiomers of the catalyst were obtained through separation of its diastereomeric adducts with natural (S)-proline. The catalyst promoted enantioselective reactions of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones in high yields (up to 97 %) and with good stereoselectivity (up to 95 % ee).

Full text of DOI:10.1002/anie.201801703

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Planar-chiral rhodium(III) catalyst with sterically demanding
cyclopentadienyl ligand and its application for enantioselective
synthesis of dihydroisoquinolones
Authors: Evgeniya A Trifonova, Nikita M Ankudinov, Andrey A
Mikhaylov, Denis A Chusov, Yulia V Nelyubina, and Dmitry
Perekalin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801703
Angew. Chem. 10.1002/ange.201801703
Link to VoR: http://dx.doi.org/10.1002/anie.201801703
http://dx.doi.org/10.1002/ange.201801703

10.1002/anie.201801703
Angewandte Chemie International Edition
COMMUNICATION
Planar-chiral rhodium(III) catalyst with sterically demanding
cyclopentadienyl ligand and its application for enantioselective
synthesis of dihydroisoquinolones
Evgeniya A. Trifonova, Nikita M. Ankudinov, Andrey A. Mikhaylov, Denis A. Chusov,
Yulia V. Nelyubina, Dmitry S. Perekalin*
Abstract: Rapid development of enantioselective CH-activation
reactions created a demand for new types of catalysts. Herein we
report the synthesis of a novel planar-chiral rhodium catalyst
advantages: 1) it gives access to complexes with planar chirality,
which cannot be obtained from free chiral cyclopentadienyl
ligands, 2) it simultaneously gives both enantiomers of the
catalyst. Noteworthy, despite the success of planar-chiral
complexes in other catalytic reactions,[22] apparently, they have
not been previously used for enantioselective CH-activation.[12]
t
t
[(C5H2 Bu2CH2 Bu)RhI2]2 in two steps from commercially available
[(cod)RhCl]2 and tert-butyl acetylene. Pure enantiomers of the
catalyst were obtained through separation of its diastereomeric
adducts with natural proline. The catalyst promoted the
enantioselective reaction of arylhydroxamic acids with strained
alkenes giving dihydroisoquinolones in high yields (up to 97%) and
with good stereoselectivity (up to 95% ee).
In recent years cyclopentadienyl rhodium complexes have
been extensively used for CH-activation of aromatic compounds
with various directing groups.[1–3] They have opened a new way
to synthesize and explore a number of valuable molecules, such
as drugs[4] and fluorophores.[5,6] While most of the research has
been done with the commercially available catalyst [Cp*RhCl2]2,
considerable attention has also been paid to complexes with
other cyclopentadienyl ligands, which provide the control over
selectivity of transformations.[7–11] In this field, the development
of chiral catalysts is the most challenging.[12] Major progress has
been achieved by Cramer et al. and You et al., who developed a
series of cyclopentadienyl ligands with C2-symmetry and used
their rhodium complexes for asymmetric catalysis (Figure 1).[13–
18] Ward and Rovis et al. have proposed an alternative approach,
in which an achiral rhodium complex with the biotin tag is used
in combination with biochemically engineered streptavidin
proteins.[19] Very recently, Antonchik and Waldmann et al. have
synthesized a large series of rhodium complexes with chiral
cyclopentadienyl ligands, which were obtained by catalytic
enantioselective cycloaddition of imino esters to fulvenes.[20]
Although these approaches are elegant and efficient, they
involve multi-step syntheses of chiral cyclopentadienyl ligands
(or preparation of mutant streptavidin peptides) that require
expensive reagents. This motivated us to propose an alternative
approach to chiral rhodium catalysts based on separation of
racemic mixtures of complexes through crystallization of their
diastereomeric adducts with naturally available amino acids.[21]
Apart from the simple synthesis this approach has two strategic
Figure 1. Previously reported types of the chiral cyclopentadienyl rhodium
catalysts.
Driven by our interest in rhodium-catalysed transformation of
alkynes,[23] we chose a non-classical route for the synthesis of
our catalyst, namely [2+2+1]-cyclotrimerization of the terminal
alkynes in the coordination sphere of a metal.[24] The reaction of
the commercially available rhodium precursor [(cod)RhCl]2 with
tert-butylacetylene in the presence of AgPF6 gave the cationic
fulvene complex (±)-1 in 64% yield (Scheme 1).[25,26] Interestingly,
similar reactions with less hindered 1-hexyne, phenylacetylene,
or cyclopropylacetylene led to mixtures of oligomerization
products. Nucleophilic addition of a hydride from NaBH3CN to
the coordinated fulvene of (±)-1 produced the cyclopentadienyl
complex (±)-2a and its subsequent oxidation with I2 gave the
t
t
desired new catalyst [(C5H2 Bu2CH2 Bu)RhI2]2 ((±)-3a). Two latter
stages can be carried out in one pot to give (±)-3a in 63% total
yield.
Modification of the catalyst structure is possible via addition
of other nucleophiles to the fulvene complex (±)-1. For example,
its reaction with MeOH/tBuOK gave the methoxy-substituted
cyclopentadienyl complex (±)-2b which can be then transformed
into the iodide (±)-3b in 80% total yield. Noteworthy, the addition
of MeO-group proceeded with high diastereoselectivity. Such
approach can be used for introduction of chelating pendant
groups or attachment of the catalyst to a polymer support.
[*]
Dr. E. A. Trifonova, N. M. Ankudinov, Dr. A. A. Mikhaylov,
Dr. D. A. Chusov, Dr. Y. V. Nelyubina, Prof. Dr. D.S. Perekalin
Nesmeyanov Institute of Organoelement Compounds
Russian Academy of Sciences
28 Vavilova str., 119991, Moscow, Russia
E-mails: dsp@ineos.ac.ru
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801703
Angewandte Chemie International Edition
COMMUNICATION
presence of the catalyst R-3a (1 mol-%), Ag2CO3 (2.5 mol-%),
and CsOAc (25 mol-%) to give product 6a in 81% total yield and
93% ee. Ag2CO3 acts as iodide-abstracting agent, while CsOAc
is the source of acetate anion, which facilitates the abstraction of
the ortho-hydrogen atom of the O-Boc-phenylhydroxamic
acid.[30] The use of the Boc group is crucial, as O-pivaloyl and O-
methyl derivatives of phenylhydroxamic acid reacted much
slower. Variation of solvents and temperature did not
significantly change the enantioselectivity (see Supporting
information). It is possible to decrease the amount of the
rhodium catalyst to 0.5 mol-%, which is notably lower than 5
mol-% typically reported in the literature.[13]
Scheme 1. Synthesis of the racemic rhodium catalysts.
Racemic complex (±)-3a reacts with the natural S-proline to
give the mixture of diastereomeric adducts 3a-Pro in high yield
91% (Scheme 2). Interestingly, the rigid cyclic structure of
proline uniquely determines the configuration of the stereocenter
at the metal atom.[27] Fortunately, it was possible to separate the
diastereomers of 3a-Pro without chromatography just by
crystallization. Single crystallization from 1,2-dichloroethane
gives the isomer RCp-3a-Pro in 35-40% yield (50% is
theoretically possible) and >98:2 diastereomeric purity. Double
crystallization of the residue from CHCl3 affords the second
isomer SCp-3a-Pro. The chirality of the diastereomers was
assigned by the X-ray diffraction analysis of the crystals of RCp
-
3a-Pro. Noteworthy, these crystals contain 1,2-dichloroethane
as solvate, which might explain the predominant crystallization
of this diastereomer from this solvent. Treatment of the adduct
RCp-3a-Pro with aqueous HI regenerates the iodide complex R-
3a in the form of a pure enantiomer in almost quantitative yield.
Scheme 2. Separation of enantiomers of the catalyst 3a.
The performance of the catalyst R-3a was tested in a
benchmark enantioselective CH-activation reaction, namely the
reaction of arylhydroxamic acids 4 with alkenes 5, which gives
dihydroisoquinolinones
conditions phenylhydroxamic acid 4 was first activated by Boc-
Figure 2. Synthesis of dihydroisoquinolinones 6 using the catalyst R-3a.
a Prepared from isolated Boc-derivative of acid; yield given for the second
(catalytic) step. b Total yield of both regioisomers is given, while ee
corresponds to the major regioisomer.
6
(Figure 2).[28,29] Under optimized
group and then reacted with norbornene in MeOH in the
This article is protected by copyright. All rights reserved.

10.1002/anie.201801703
Angewandte Chemie International Edition
COMMUNICATION
Under these optimized conditions
a
wide range of
regioselectivity (>15:1) (Scheme 3). However, the enantiose-
lectivity is moderate in this case (45-47% ee), apparently
because of insufficient steric interactions between the incoming
alkene and the cyclopentadienyl ligand. Presumably, it can be
improved by modification of the catalyst structure.
substituted arylhydroxamic acids 4a-k react with cyclic alkenes
to give products 6a-6p in 53−97% yields and with good
stereoselectivity 76−95% ee. The R-isomer of the catalyst
provides (3S,4S)-dihydroisoquinolinone scaffold as confirmed by
the X-ray diffraction analysis of the bromine-substituted
compound 6c (Figure 3). The selectivity may be explained by
the less hindered approach of an alkene to one of the sides of
the proposed metallacycle intermediate (Figure 4).[10,28]
Scheme 3. Synthesis of dihydroisoquinolinones 6 from the terminal alkenes.
In order to illustrate the practical application of our catalyst
for drug design we carried out a short synthesis of the
compound 9 as a potential nanomolar inhibitor of CDC7
kinase[34] (Scheme 4). The key step of the synthesis is the
reaction of hydroxamic acid 7 with norbornene in the presence
of the catalyst R-3a, which gives the heterocycle 8 in 92% yield
and 90% ee. Noteworthy, neither sulfur nor bromine substituent
interferes with the catalyst and only one regioisomer of the
product is formed. It is also important to note that this approach
provides rigid non-planar structures and allows for variation of
substituents in 6 and 7 positions of the thienopyridinone system,
which is difficult to achieve by traditional methods. The
pharmacophore model suggests that hydrophobic residues in
these positions should increase the selectivity of inhibition.[34]
Figure 3. The crystal structures of the catalyst adduct RCp-3a-Pro and the
reaction product 6c, which confirm their stereochemistry.
Figure 4. The proposed model for the origin of enantioselectivity.
The reaction tolerates the presence of various functional
groups in arene, except strong electron acceptors (p-CN, p-NO2).
In the case of meta-substituted aryl and 2-naphtyl hydroxamic
acids the mixtures of regioisomers are formed with 3:1-14:1
selectivity, which is similar or better to that provided by the
t
related achiral [(C5H3 Bu2)RhCl2]2 catalyst.[7] The synthesized
products 6h/6h’ are of interest, since both of them have
structures similar to narciclasine alkaloids.[31] Compounds 6n
and 6o can be also used for synthesis of alkaloids via ring-
rearrangement metathesis.[32]
The best alkene components are norbornene-type
derivatives, which are readily available via Diels-Alder addition
to cyclopentadiene and provide a variety of options for further
functionalization. Unstrained cyclic alkenes, such as
cyclohexene, react slowly with phenylhydroxamic acid 4 under
our catalytic conditions, while upon heating Lossen
rearrangement becomes the dominant process (this typical
problem has been observed previously for other rhodium
catalysts).[33] On the other hand, acyclic terminal alkenes, such
as 1-heptene, allyl alcohol or homoallyl alcohol, react smoothly
Scheme 4. Synthesis of potential CDC7 inhibitor 9 via catalytic annulation.
To conclude, we have developed
a new planar-chiral
t
t
rhodium catalyst [(C5H2 Bu2CH2 Bu)RhI2]2 (R-3a) with the
sterically demanding cyclopentadienyl ligand and demonstrated
its application for the enantioselective synthesis of dihydroiso-
with Boc-derivative of
4 to give 4-substituted dihydroiso-
quinolones 6q-s in excellent yields 89-97% and with high
This article is protected by copyright. All rights reserved.

10.1002/anie.201801703
Angewandte Chemie International Edition
COMMUNICATION
[21] For some examples of separation of chiral metal complexes via
diastereomeric derivatives see: a) J. W. Faller, P. P. Fontaine,
Organometallics 2005, 24, 4132–4138; b) A. Kina, K. Ueyama, T.
Hayashi, Org. Lett. 2005, 7, 5889−5892; c) M. Yasushi, A. Katsuhiro, U.
Mitsunari, T. Shigetoshi, Chem. Lett. 1996, 25, 887−888; d) N.
Komatsuzaki, M. Uno, H. Kikuchi, S. Takahashi, Chem. Lett. 1996,
677−678; e) M. Uno, K. Ando, N. Komatsuzaki, S. Takahashi, J. Chem.
Soc., Chem. Commun. 1992, 964−965; f) A. Schäfer, E. Karl, L. Zsolnai,
G. Huttner, H.-H. Brintzinger, J. Organomet. Chem. 1987, 328, 87−99.
[22] For recent examples of catalytic application of planar-chiral half-
sandwich complexes of platinum metals with cyclopentadienyl ligands
see: a) Y. Ishido, N. Kanbayashi, T. Okamura, K. Onitsuka,
Macromolecules, 2017, 50, 5301–5307; b) N. Kanbayashi, K. Hosoda,
M. Kato, K. Takii, T. Okamura, K. Onitsuka, Chem. Commun. 2015, 51,
10895−10898; c) N. Kanbayashi, K. Onitsuka, J. Am. Chem. Soc. 2010,
132, 1206−1207; d) Y. Matsushima, K. Onitsuka, T. Kondo, T. Mitsudo,
S. Takahashi, J. Am. Chem. Soc. 2001, 123, 10405–10406; for the
reviews on other planar-chiral catalysts see: e) G. Fu, Acc. Chem. Res.
2000, 33, 412−420; f) A. H. Hoveyda, J. P. Morken, Angew. Chem. Int.
Ed. Engl. 1996, 35, 1262−1284; Angew. Chem. 1996, 108, 1378–1401.
[23] a) D. S. Perekalin, N. V. Shvydkiy, Y. V. Nelyubina, A. R. Kudinov,
Chem. Eur. J. 2015, 21, 16344–16348; b) N. V. Shvydkiy, E. A.
Trifonova, A. M. Shved, Y. V. Nelyubina, D. Chusov, D. S. Perekalin, A.
R. Kudinov, Organometallics 2016, 35, 3025−2031.
quinolones from arylhydroxamic acids and alkenes. We think
that the approach to chiral catalysts through separation of
proline adducts can also be used for preparation of the planar-
chiral ruthenium complexes[35] [(arene)RuCl2]2, which are difficult
to obtain from the enantiomerically pure ligands.
Acknowledgements
This work was supported by the Russian Science Foundation
(grant # 17-73-20144). The X-ray diffraction data were obtained
using the equipment of the Center for Molecular Composition
Studies of INEOS RAS. We thank Dr. Maxim V. Kozlov for the
help with synthesis of the starting hydroxamic acids.
Keywords: Asymmetric catalysis • C-H-activation •
Cyclopentadienyl ligands • Rhodium
[1]
R.-Y. Zhu, M. E. Farmer, Y.-Q. Chen, J.-Q. Yu, Angew. Chem. Int. Ed.
2016, 55, 10578–10599; Angew. Chem. 2016, 128, 10734–10756.
G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651–3678.
J. Wencel-Delord, F. W. Patureau, F. Glorius, Top. Organomet. Chem.
2015, 1–27.
[2]
[3]
[24] Similar route has been effectively used previously by Severin et al. and
Tanaka et al. to obtain ruthenium and rhodium complexes with the
sterically demanding cyclopentadienyl ligands: a) S. Gauthier, E. Solari,
B. Dutta, R. Scopelliti, K. Severin, Chem. Commun. 2007, 1837–1839;
b) B. Dutta, E. Solari, S. Gauthier, R. Scopelliti, K. Severin,
Organometallics 2007, 26, 4791–4799; c) B. Dutta, R. Scopelliti, K.
Severin, Organometallics 2008, 27, 423–429; d) Y. Shibata, K. Tanaka,
Angew. Chem. Int. Ed. 2011, 50, 10917–10921; Angew. Chem. 2011,
123, 11109–11113; e) S. Yoshizaki, Y. Shibata, K. Tanaka, Angew.
Chem. Int. Ed. 2017, 56, 3590–3593; Angew. Chem. 2017, 129, 3644–
3647.
[4]
[5]
C. W. Murray, D. C. Rees, Angew. Chem. Int. Ed. 2016, 55, 488–492;
Angew. Chem. 2016, 128, 498−503.
J. H. Kim, T. Gensch, D. Zhao, L. Stegemann, C. A. Strassert, F.
Glorius, Angew. Chem. Int. Ed. 2015, 54, 10975–10979; Angew. Chem.
2015, 127, 11126−11130.
[6]
[7]
[8]
Q. Ge, Y. Hu, B. Li, B. Wang, Org. Lett. 2016, 18, 2483–2486.
T. K. Hyster, D. M. Dalton, T. Rovis, Chem. Sci. 2015, 6, 254–258.
N. Semakul, K. E. Jackson, R. S. Paton, T. Rovis, Chem. Sci. 2017, 8,
1015–1020.
[25] This reaction was briefly described previously, but no experimental
procedure was given: G. Moran, M. Green, A. G. Orpen, J. Organomet.
Chem. 1983, 250, c15–c20.
[9]
T. Piou, F. Romanov-Michailidis, M. Romanova-Michaelides, K. E.
Jackson, N. Semakul, T. D. Taggart, B. S. Newell, C. D. Rithner, R. S.
Paton, T. Rovis, J. Am. Chem. Soc. 2017, 139, 1296–1310.
[26] Interestingly, the direct reaction of RhCl3×3H2O with tert-butylacetylene
gives a different cyclopentadienyl complex, although in a low yield: G.
Kiefer, B. Dutta, E. Solari, R. Scopelliti, K. Severin, Z. Anorg. Allg.
Chem. 2012, 638, 1114–1118.
[10] M. D. Wodrich, B. Ye, J. F. Gonthier, C. Corminboeuf, N. Cramer,
Chem. Eur. J. 2014, 20, 15409–15418.
[11] S. Y. Hong, J. Jeong, S. Chang, Angew. Chem. Int. Ed. 2017, 56,
2408–2412; Angew. Chem. 2017, 129, 2448−2452.
[27] D. Carmona, M. Pilar Lamata, F. Viguri, E. San José, A. Mendoza, F. J.
Lahoz, P. García-Orduña, R. Atencio, L. A. Oro, J. Organomet. Chem.
2012, 717, 152–163.
[12] C. G. Newton, S.-G. Wang, C. C. Oliveira, N. Cramer, Chem. Rev.
2017, 117, 8908–8976.
[13] B. Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308–1318.
[14] C. G. Newton, D. Kossler, N. Cramer, J. Am. Chem. Soc. 2016, 138,
3935–3941.
[28] N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133,
6449–6457.
[29] S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2350–2353.
[15] a) B. Ye, N. Cramer, Science 2012, 338, 504–506; b) Y. Sun, N.
Cramer, Angew. Chem. Int. Ed. 2017, 56, 364–367; Angew. Chem.
2017, 129, 370–373; c) Y. Sun, N. Cramer, Chem. Sci. 2018, 9,
2981−2985.
[30] L. Ackermann, Chem. Rev. 2011, 111, 1315–1345.
[31] A. Kornienko, A. Evidente, Chem. Rev. 2008, 108, 1982–2014.
[32] S. Kotha, R. Gunta, J. Org. Chem. 2017, 82, 8527–8535.
[33] K. D. Collins, F. Glorius, Tetrahedron 2013, 69, 7817–7825.
[34] M. Lindvall, C. McBride, M. McKenna, T. G. Gesner, A. Yabannavar, K.
Wong, S. Lin, A. Walter, C. M. Shafer, ACS Med. Chem. Lett. 2011, 2,
720–723.
[16] J. Zheng, S.-L. You, Angew. Chem. Int. Ed. 2014, 53, 13244–13247;
Angew. Chem. 2014, 126, 13460−13463.
[17] S. R. Chidipudi, D. J. Burns, I. Khan, H. W. Lam, Angew. Chem. Int. Ed.
2015, 54, 13975–13979; Angew. Chem. 2015, 127, 14181–14185.
[18] During the revision of this manuscript a new convenient method for the
synthesis of chiral cyclopentadienyl ligands has been published: S.-G.
Wang, S. H. Park, N. Cramer, Angew. Chem. Int. Ed. 2018, DOI:
10.1002/anie.201802244.
[35] a) L. Ackermann, Acc. Chem. Res. 2014, 47, 281–295; b) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112,
5879−5918.
[19] T. K. Hyster, L. Knorr, T. R. Ward, T. Rovis, Science 2012, 338, 500–
503.
[20] Z.-J. Jia, C. Merten, R. Gontla, C. G. Daniliuc, A. P. Antonchick, H.
Waldmann, Angew. Chem. Int. Ed. 2017, 56, 2429–2434; Angew.
Chem. 2017, 129, 2469–2474.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801703
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
E. A. Trifonova, N. M. Ankudinov,
A. A. Mikhaylov, D. A. Chusov,
Y. V. Nelyubina, D. S. Perekalin
Page No. – Page No.
Planar-chiral rhodium(III) catalyst
with sterically demanding
cyclopentadienyl ligand and its
application for enantioselective
synthesis of dihydroisoquinolones
A surprising assembly of three alkynes into a cyclopentadienyl ligand gives a new
planar-chiral rhodium catalyst for CH-activation reactions.
This article is protected by copyright. All rights reserved.