Optically Pure C1-Symmetric Cyclic(alkyl)(amino)carbene Ruthenium Complexes for Asymmetric Olefin Metathesis

Article abstract of DOI:10.1021/jacs.0c10705

An expedient access to the first optically pure ruthenium complexes containing C1-symmetric cyclic (alkyl)(amino)carbene ligands is reported. They demonstrate excellent catalytic performances in asymmetric olefin metathesis with high enantioselectivities (up to 92% ee). Preliminary mechanistic insights provided by density functional theory models highlight the origin of the enantioselectivity.

Full text of DOI:10.1021/jacs.0c10705

pubs.acs.org/JACS
Communication
Optically Pure C1‑Symmetric Cyclic(alkyl)(amino)carbene Ruthenium
Complexes for Asymmetric Olefin Metathesis
Jennifer Morvan, Franco̧ is Vermersch, Ziyun Zhang, Laura Falivene, Thomas Vives, Vincent Dorcet,
́
Thierry Roisnel, Christophe Crevisy, Luigi Cavallo, Nicolas Vanthuyne, Guy Bertrand,*
Rodolphe Jazzar,* and Marc Mauduit*
Cite This: https://dx.doi.org/10.1021/jacs.0c10705
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An expedient access to the first optically pure ruthenium complexes containing C1-symmetric cyclic
(alkyl)(amino)carbene ligands is reported. They demonstrate excellent catalytic performances in asymmetric olefin metathesis
with high enantioselectivities (up to 92% ee). Preliminary mechanistic insights provided by density functional theory models
highlight the origin of the enantioselectivity.
ith the discovery of the second generation Grubbs
Wcatalysts, N-heterocyclic carbenes (NHCs) have
become inescapable ligands in olefin metathesis, in both
academic and industrial research environments.1 This popular-
ity has in part been attributed to their remarkable aptitude in
generating more stable, yet extremely reactive ruthenium
catalysts. Owing to their unique and highly modular steric
environment, chiral variants of diaminocarbenes have attracted
interests in the field.2 Indeed, following reports by Grubbs and
Hoveyda, a slew of Ru complexes featuring chiral diamino-
carbene ligands have been used with varying successes in
asymmetric ring-opening cross-metathesis (AROCM)3 and
ring-closing metathesis (ARCM).4 In 2007,5 a new class of
carbenes, namely cyclic (alkyl)(amino) carbenes (CAACs),6
arose as a contender to NHCs as ligands for olefin metathesis
catalysts. Since then, CAACs have been shown to achieve over
340 000 TON in ethenolysis processes while achieving
remarkable catalytic performances in a number of other
metathesis transformations (Figure 1a).7 Interestingly, despite
these achievements, there is still no report dealing with CAAC
ligands in asymmetric metathesis. In 2019, we demonstrated
that, providing the right steric environment, a steroid derived
chiral CAAC−copper complex CholestCAAC−CuCl could
induce asymmetric conjugate borylation (ACB).8
Figure 1. (a) Selected examples of known racemic CAAC−Ru olefin
metathesis catalysts. (b) An expedient access to optically pure
CAAC−Ru complexes (this work).
Encouraged by these results, we set to demonstrate the
potency of chiral CAAC−Ru complexes in asymmetric olefin
metathesis.9 Despite the availability of the ligand, we reasoned
that the CholestCAAC or related chiral CAAC ligands derived
from naturally abundant chiral building blocks would not
provide the required structural modularity. The design of
NHC chiral ligands is arguably plagued by tedious low yielding
synthetic procedures, very often resulting in the preparation of
a single enantiomer (see Figure S1 in the Supporting
Information). Eager to streamline the screening of chiral
CAAC−ruthenium catalysts, we envisaged using preparative
high-performance liquid chromatographic resolution
used in the pharmaceutical industry for bulk enantiomer
resolution at the early stage of drug discovery.10 Consequently,
we wish to report an expedient access to enantiomerically pure
ruthenium metathesis catalysts containing C1-symmetric
Received: October 8, 2020
(
PrepHPLC), a time- and cost-effective technique extensively
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
CAAC ligands. Using PrepHPLC, optically pure (>99% ee) (R)-
and (S)-CAAC−Ru complexes were obtained in almost
quantitative yields (Figure 1b). We further demonstrate that
chiral CAACs yield active but more importantly very selective
catalysts for AROCM reactions.
Capitalizing on the high stability of Hoveyda−Grubbs
CAAC ruthenium complexes, we began our investigation
with the readily accessible air-stable chiral (rac)-Ru-1 catalyst
(Table 1).5 Because to the best of our knowledge the chiral
separation of (rac)-Ru-1 on a preparative scale (100 mg, 1 cm
diameter column, flow-rate = 5 mL·min−1) (Figure 2a and b).
Both (+)-Ru-1 (first eluted) and (−)-Ru-1 (second eluted)
enantiomers were isolated in excellent yields (46 and 45%) and
remarkable enantiomeric purities (>99% and >98% ee,
respectively). As expected, electronic circular dichroism
(ECD), furnishing chiroptical properties of the Ru complex,
showed the mirror-image spectra for both enantiomers
(+)-(R)-Ru-1 and (−)-(S)-Ru-1 (Figure 2,c). Finally, we
unambiguously confirmed the absolute configuration of both
enantiomers by X-ray diffraction (Figure 3).
Table 1. Selective Chiral Stationary Phase
chiral phase (+)-Ru-1
k1
(−)-Ru-1
k2
α
resolution
Chiralpak ID
Chiralpak IE
Chiralpak IF
Chiralpak IG
5.36
5.34
4.99
6.42
0.82
0.81
0.69
1.18
7.04
7.63
6.54
8.87
1.38
1.59
1.22
2.01
1.69
1.96
1.76
1.71
5.16
8.24
6.41
5.39
Figure 3. Solid-state structure of (+)-(R)-Ru-1 (left) and (−)-(S)-Ru-
1 (right). Ellipsoids are drawn at 30% probability. Some hydrogens
are omitted for clarity.
HPLC resolution of racemic Hoveyda−Grubbs ruthenium
complexes had never been reported,11 a range of chiral
stationary phases was screened (see Supporting Information
for details). Of the 10 columns evaluated using a mobile phase
consisting of a heptane/isopropanol/dichloromethane mixture
(70/10/20 ratio), only the amylose chiral stationary phases
substituted with chloro-phenylcarbamate allowed for separa-
tions with good enantioselectivity and excellent resolution
(Table 1). We selected Chiralpak IF due to the shorter elution
time and good loading capacity, allowing for the antipodes
The latter displayed a positive ECD-active band at 220 nm
(Δε = +22) and three negative ones at 250 (Δε = −5), 350
(Δε = −2.5), and 440 nm (Δε = −5), respectively. To confirm
the efficiency of this chiral resolution protocol, we extended
our method to Grela-type CAAC−ruthenium metathesis
complexes (Ru-2−6) (see Supporting Information, Scheme
S1 for details).12 To our delight, using the aforementioned
conditions, all complexes were successfully resolved (up to 120
mg scale), and their respective (+)- and (−)-enantiomers were
Figure 2. UV (a) and circular dichroism (b) chromatograms at 254 nm of (rac)-Ru-1 from Chiralpak IF. (c) ECD spectra in acetonitrile of
(+)-(R)-Ru-1 (blue) and (−)-(S)-Ru-1 (red).
B
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
isolated in good yields (from 37 to 47%) and excellent optical
purities, ranging from >98.5 to >99.5% ee (Scheme 1).13 Here
(85% ee) for the expected metathesis product (S,R)-P1a,
which was isolated in low 13% yield with a 80/20 E/Z ratio.
With the (S)-Ru-2 precatalyst, having an electron-withdrawing
nitro group into the reactive arylidene ligand, the reaction was
complete after 24 h (entry 2), and the (S,R)-P1a was isolated
in 53% yield with a slight improvement of both E/Z ratio and
enantioselectivity (85/15; 87% ee). Lowering the temperature
to 35 °C enabled the selectivity to improve up to 90% ee,
despite a prolonged reaction time (48 h, entry 3). Thanks to
the preparative separation methodology, we confirmed that the
opposite precatalyst enantiomer (R)-Ru-2 catalyzed the
formation of the (R,S)-P1a enantiomer with similar efficiencies
(58% yield; 92% ee; entry 4). Looking to improve the chiral
transfer from the CAAC ligand, we next investigated
precatalyst (R)-Ru-3 featuring a bulkier 2-naphthyl substituent.
Compared to (R)-Ru-2, similar catalytic performance and ee
were obtained (92% ee, entry 5 vs 3−4). Neither 3,5-
dimethylphenyl, 3,5-ditertbutylphenyl, nor cyclohexyl substi-
tution at the stereogenic center led to higher chiral inductions
(complexes (R)-Ru-4−6, entries 6−8). It is worth mentioning
that an excellent 95/5 E-selectivity was achieved with (R)-Ru-
6 despite its lower catalytic activity (entry 8).14 We also
evaluated the influence of the solvent (CH2Cl2, 2-MeTHF,
benzene, or toluene); however, no significant improvement
was observed (see Supporting Information for details).
Following this optimization, we selected (R)-Ru-2, combin-
ing high productivity and decent asymmetric induction (i.e.,
>90% ee), to examine the scope of AROCM using function-
alized styrenes with norbornenes S 1d−f and cyclopropene
S23b (Scheme 2). To our delight, (R)-Ru-2 catalyzed with
similar efficiency the AROCM of S1b,c with methoxy and
trifluoromethyl para-substituted styrenes. The resulting meta-
thesis products P1b,c were isolated in 41−62% yield and 74−
80% ee. With norbornenes S 1d−f, (R)-Ru-2 was again highly
selective providing the corresponding metathesis products P
1d−f in moderate to excellent isolated yields (50−94%) and
good to excellent enantioselectivities (74, 83 and 92% ee,
respectively). Of note, as reported in previous studies, a lower
enantioselectivity was observed for each Z-stereoisomer (23−
38% ee).15 Regarding the AROCM of cyclopropene S2 with
allyl acetate, both (R)-Ru-2 and (S)-Ru-4 gave the desired P2b
but in moderate yields and E/Z ratios. Nevertheless, good ee
values were observed for Z-P2b (78−85% ee) while a
moderate 48% ee was reached for the E-isomer.
Scheme 1. Library of Optically Pure CAAC−Ruthenium
Complexes
a
b
Isolated yield after preparative chiral resolution. Determined by
chiral-stationary phase HPLC analysis.
again, we unambiguously confirmed the absolute configuration
of second eluted Ru-2−6 complexes by X-ray diffraction study
(see Figure S2; Supporting Information). It is worth
mentioning that these complexes feature the N-aryl fragment
of the CAAC ligand in the apical position, syn to the styrenyl-
ether unit.5
Having obtained a small library of optically pure CAAC−
ruthenium complexes, we investigated their catalytic perform-
ance in asymmetric olefin metathesis transformations.9 As a
benchmark, we considered the AROCM reaction of meso-
norbornene derivative S1a.3 The reaction was performed in
THF using 5 mol % of ruthenium catalyst and 5 equiv of
styrene (Table 2). Using (S)-Ru-1 precatalyst at 50 °C, the
reaction occurred slowly with a complete disappearance of the
starting material observed after 3 days (entry 1). Nevertheless,
we were pleased to observe a significant enantioinduction
Table 2. Evaluation of Optically Pure Ru-1−6 Complexes in
a
Catalytic AROCM of Norbornene S1a
A preliminary mechanistic model for ROCM of norbornene
S1 and styrene is proposed in Scheme 3 based on DFT
calculations.16 In agreement with previous studies,3a the
formation of the p-nitro styrenylether in the reaction media
suggests a Ru-benzylidene PS as the propagating species.
Owing to the C1-symmetry of CAAC ligands, we next
considered two different geometries accessible via a metal-
lacyclobutane with inversion at the Ru center.17 PSsyn in which
the benzylidene unit is in an apical position to the quaternary
chiral center substituents (syn), and the PSanti featuring the
benzylidene in apical position to the N-Dipp moiety (trans).
Using the more stable PSsyn (see Supporting Information for
details), we envisaged the norbornene S1 addition, providing
the major (E)-P1, to be enantio- and diastereo-determining.3a
In agreement with literature precedents supporting the olefin
coordination trans to the ancillary carbenic ligand,18 and
norbornene reacting preferentially on its exo face, two
metallacyclobutanes (MCB) were considered: MCB1 leading
to (E)-(S,R)-P1 and MCB2 affording the opposite enantiomer
b
Ru-cat
T (°C)/
conv.
Ε/Ζ
ee (E)-P1a
c
d
e
entry
(mol %)
time
(yield) (%)
ratio
(%)
1
2
3
4
5
6
7
8
(S)-1 (5)
(S)-2 (5)
(S)-2 (5)
(R)-2 (5)
(R)-3 (5)
(R)-4 (5)
(R)-5 (5)
(R)-6 (5)
50/3 d
50/1 d
35/2 d
35/2 d
35/2 d
35/2 d
50/5 d
35/5 d
99 (13)
99 (53)
99 (41)
99 (58)
99 (55)
99 (49)
99 (18)
60 (45)
80/20
85/15
85/15
85/15
90/10
90/10
85/15
95/5
85 (S,R)
87 (S,R)
fg
90 (S,R) ,
92 (R,S)
92 (R,S)
89 (R,S)
47 (R,S)
79 (R,S)
a
Reaction conditions: [Ru] catalyst (5%), styrene (5 equiv), THF
(0.15 M). Conversions were monitored by H NMR spectroscopy
analysis. Isolated yields after column chromatography. E/Z ratio
determined by SFC on the crude mixture. ee determined by SFC on
a chiral stationary phase. Absolute configurations determined on the
corresponding diol (see Supporting Information for details). ee of
b
1
c
d
e
f
g
(Z)-P1a: 17%.
C
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Scheme 2. Scope of AROCM Catalyzed by Optically Pure Ru-2,4,6 Complexes
a
b
c
Reaction conditions: [Ru] catalyst (5 mol %), terminal olefin (5 equiv), THF (0.1M). Determined by 1H NMR spectroscopy analysis. Isolated
d
e
f
yields after column chromatography. Determined by SFC on the crude mixture. Determined by SFC on a chiral stationary phase. Determined on
the corresponding diol by SFC on a chiral stationary phase. Determined by GC-MS. Determined on the corresponding alcohol by SFC on a
chiral stationary phase.
g
h
Scheme 3. (a) Proposed Mechanism, Supported by DFT Calculations, for AROCM of Norbornenes S1 and Styrene Catalyzed
c
by (S)-Ru-2 and Related Olefin Approaches Providing (E)-P1 (b)
c
See Supporting Information for details.
(E)-(R,S)-P1. In line with (E)-(S,R)-P1 (Table 2; entry 3),
being unambiguously identified as the major enantiomer (see
Supporting Information for details), our DFT model supports
MCB1 to be the privileged intermediate. In fact, in transition
state B1−C1, leading to the formation of the metal
lacyclobutane MCB1, the quaternary chiral center substituents
and the norbornene substrate lie quite far one from each other;
on the contrary, transition state B2−C2 forming intermediate
MCB2 suffers from the steric clash between the two moieties
(see short distances in Scheme 3c). This model is in agreement
with the lower enantioinduction observed in the bulkier (R)-
Ru-5 (Table 2; entry 7) and supports the higher selectivity of
(S)-Ru-6 versus (S)-Ru-2 in the formation of (E)-P 1d (83 vs
74% ee, Scheme 2).
To complete our study, we finally examined the challenging
asymmetric cross-metathesis (ACM). As disclosed in Scheme
4, (S)-Ru-4 afforded P3 in 42% isolated yield and up to 50%
ee. While this result is preliminary, it already surpasses state of
art selectivity obtained with chiral diaminocarbene ligand
(GII* precatalyst, 44% ee).3a,19
In summary, an expedient access to a range of optically pure,
well-defined ruthenium complexes containing chiral CAAC
D
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Chemistry and Biochemistry, University of California, San
Diego, La Jolla, California 92093-0358, United States
Ziyun Zhang − King Abdullah University of Science and
Technology (KAUST), KAUST Catalysis Center (KCC),
Thuwal 23955-6900, Saudi Arabia
Scheme 4. Preliminary Result in Asymmetric Cross-
Metathesis
Laura Falivene − Dipartimento di Chimica e Biologia,
Università di Salerno, 84100 Fisiciano, Italy; orcid.org/
0000-0003-1509-6191
Thomas Vives − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France; orcid.org/0000-0001-6533-
0703
Vincent Dorcet − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France
Thierry Roisnel − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France
ligands was developed. It relies on an efficient resolution of
their racemic mixture via chiral prepHPLC on chiral-stationary
phase. This process allowed for the isolation of air-stable (+)-
and (−)-enantiomers in good to nearly quantitative yields and
excellent optical purity (ranging from >98 to >99.5%). Using
these catalysts, excellent performances were observed in
AROCM with high enantioselectivities (up to 92% ee).
Moreover, a promising 50% ee was reached in the more
challenging ACM, one of the highest selectivities reported so
far. This novel approach paves the way for the development of
more sophisticated CAAC transition-metal complexes and
should create new opportunities in asymmetric catalysis.
́
Christophe Crevisy − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France; orcid.org/0000-0001-5145-
1600
Luigi Cavallo − King Abdullah University of Science and
Technology (KAUST), KAUST Catalysis Center (KCC),
Thuwal 23955-6900, Saudi Arabia; orcid.org/0000-
0002-1398-338X
Nicolas Vanthuyne − Aix Marseille Université, CNRS,
Marseille 13397, France; orcid.org/0000-0003-2598-
7940
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications Web site. (PDF), (CIF) The Supporting
Information is available free of charge at https://pubs.acs.org/
doi/10.1021/jacs.0c10705.
■
sı
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10705
Notes
NMR spectra of products, GC analyses, experimental
procedures, and X-ray crystallographic data (PDF)
Crystallographic information files (ZIP)
Cartesian coordinates and internal energies in gas phase
(TXT)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
We are grateful to the CNRS, the Ecole Nationale Superieure
́
de Chimie de Rennes, the Aix-Marseille Universite, and the
University of California San Diego. This work was supported
by the Region Bretagne (ARED 2018 “Biometa” N° 601, grant
to J.M.), the Agence Nationale de la Recherche (ANR-19-
CE07-0017 ChiCAAC, R.J. and M.M.), and the U.S.
Department of Energy, Office of Science, Basic Energy
Sciences, Catalysis Science Program, under Award DE-
SC0009376 (G.B.). Umicore AG & Co. is acknowledged for
a generous gift of ruthenium complexes. M.M. and T.V. thank
Shimadzu and Chiral Technology for their support in the
separation of chiral molecules by Supercritical Fluid
Chromatography (SFC) technology. For computer time, this
research used the resources of the KAUST Supercomputing
Laboratory (KSL) at KAUST.
AUTHOR INFORMATION
Corresponding Authors
■
Marc Mauduit − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France; orcid.org/0000-0002-7080-
9708; Email: marc.mauduit@ensc-rennes.fr
Rodolphe Jazzar − UCSD-CNRS Joint Research Chemistry
Laboratory (UMI 3555), Department of Chemistry and
Biochemistry, University of California, San Diego, La Jolla,
California 92093-0358, United States; orcid.org/0000-
0002-4156-7826; Email: rjazzar@ucsd.edu
Guy Bertrand − UCSD-CNRS Joint Research Chemistry
Laboratory (UMI 3555), Department of Chemistry and
Biochemistry, University of California, San Diego, La Jolla,
California 92093-0358, United States; orcid.org/0000-
0003-2623-2363; Email: gbertrand@ucsd.edu
DEDICATION
■
Dedicated to our friend and colleague Professor Pierre Dixneuf
for his foremost contribution to ruthenium chemistry
Authors
REFERENCES
■
Jennifer Morvan − Université de Rennes, Ecole Nationale
Supérieure de Chimie de Rennes, CNRS, ISCR UMR 6226,
F-35000 Rennes, France; orcid.org/0000-0003-1210-
7975
́
(1) (a) For a recent book on NHCs, see: Díez-Gonzalez, S. N-
Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic
Tools; Royal Society of Chemistry: Cambridge, 2016. (b) Hopkinson,
M. N.; Richter, C.; Schedler, M.; Glorius, F. An Overview of N-
Heterocyclic Carbenes. Nature 2014, 510, 485−496. (c) For a review
dealing with NHC/TM in catalysis, see: Gonzalez, S. D.; Marion, N.;
Franco
̧ is Vermersch − UCSD-CNRS Joint Research
Chemistry Laboratory (UMI 3555), Department of
E
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Nolan, S. P. N-Heterocyclic Carbenes in Late Transition Metal
Catalysis. Chem. Rev. 2009, 109, 3612−3676. For review dealing with
NHC/Ru in olefin metathesis: (d) Nolan, S. P.; Clavier, H.
Chemoselective olefin metathesis transformations mediated by
ruthenium complexes. Chem. Soc. Rev. 2010, 39, 3305−3316.
(e) Vougioukalakis, G. C.; Grubbs, R. H. Ruthenium-based
heterocyclic carbene-coordinated olefin metathesis catalysts. Chem.
Rev. 2010, 110, 1746−1787. (f) Ogba, O. M.; Warner, N. C.; O’Leary,
D. J.; Grubbs, R. H. Recent advances in ruthenium-based olefin
metathesis. Chem. Soc. Rev. 2018, 47, 4510−4544.
Helically Chiral Olefin Metathesis Catalyst. Chem. - Eur. J. 2018, 24,
10994−10998.
(5) Anderson, D. R.; Lavallo, V.; O’Leary, D. J.; Bertrand, G.;
Grubbs, R. H. Synthesis and Reactivity of Olefin Metathesis Catalysts
Bearing Cyclic (Alkyl)(Amino)Carbenes. Angew. Chem., Int. Ed. 2007,
46, 7262−7265.
(6) (a) Lavallo, V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand,
G. Stable Cyclic (Alkyl)(Amino)Carbenes as Rigid or Flexible, Bulky,
Electron-rich Ligands for Transition-Metal Catalysts: a Quaternary
Carbon Atom Makes the Difference. Angew. Chem., Int. Ed. 2005, 44,
5705−5709. (b) Soleilhavoup, M.; Bertrand, G. Cyclic (Alkyl)-
(Amino)Carbenes (CAACs): Stable Carbenes on the Rise. Acc. Chem.
Res. 2015, 48, 256−266. (c) Melaimi, M.; Jazzar, R.; Soleilhavoup, M.;
Bertrand, G. Cyclic (alkyl)(amino)carbenes (caacs): recent develop-
ments. Angew. Chem., Int. Ed. 2017, 56, 10046−10068. (d) Paul, U. S.
D.; Radius, U. What wanzlick did not dare to dream: cyclic
(alkyl)(amino)carbenes (caacs) as new key players in transition-
metal chemistry. Eur. J. Inorg. Chem. 2017, 2017, 3362−3375.
(e) Jazzar, R.; Soleilhavoup, M.; Bertrand, G. Cyclic (alkyl)- and
(aryl)-(amino)carbene coinage metal complexes and their applica-
tions. Chem. Rev. 2020, 120, 4141−4168.
(2) For reviews on chiral NHC in catalysis, see: (a) Wang, F.; Liu,
L.-J.; Wang, W.; Li, S.; Shi, M. Chiral NHC-Metal-Based Asymmetric
Catalysis. Coord. Chem. Rev. 2012, 256, 804−853. (b) Janssen-Muller,
̈
D.; Schlepphorst, C.; Glorius, F. Privileged Chiral N-Heterocyclic
Carbene Ligands for Asymmetric Transition-Metal Catalysis. Chem.
Soc. Rev. 2017, 46, 4845−4854. (c) Zhao, M.; Zhang, Y.-T.; Chen, J.;
Zhou, L. Enantioselective Reactions Catalyzed by N-Heterocyclic
Carbenes. Asian J. Org. Chem. 2018, 7, 54−69. (d) Montgomery, T.
P.; Johns, A. M.; Grubbs, R. H. Recent Advancements in
Stereoselective Olefin Metathesis Using Ruthenium Catalysts.
Catalysts 2017, 7, 87. (e) Hoveyda, A. H. Evolution of Catalytic
Stereoselective Olefin Metathesis: From Ancillary Trans- formation to
Purveyor of Stereochemical Identity. J. Org. Chem. 2014, 79, 4763−
4792.
(7) Selected examples: (a) Marx, V. M.; Sullivan, A. H.; Melaimi, M.;
Virgil, S. C.; Keitz, B. K.; Weinberger, D. S.; Bertrand, G.; Grubbs, R.
H. Cyclic Alkyl Amino Carbene (CAAC) Ruthenium Complexes as
Remarkably Active Catalysts for Ethenolysis. Angew. Chem., Int. Ed.
2015, 54, 1919−1923. (b) Zhang, J.; Song, S.; Wang, X.; Jiao, J.; Shi,
M. Ruthenium-Catalyzed Olefin Metathesis Accelerated by the Steric
Effect of the Backbone Substituent in Cyclic (Alkyl)(Amino)
Carbenes. Chem. Commun. 2013, 49, 9491−9493. (c) Gawin, R.;
(3) Selected examples of AROCM: (a) Berlin, J. M.; Goldberg, S.
D.; Grubbs, R. H. Highly Active Chiral Ruthenium Catalyst for
Asymmetric Cross-Metathesis and Ring-Opening Cross-Metathesis.
Angew. Chem., Int. Ed. 2006, 45, 7591−7595. (b) Giudici, R. E.;
Hoveyda, A. H. Directed Catalytic Asymmetric Olefin Metathesis.
Selectivity Control by Enoate and Ynoate Groups in Ru-Catalyzed
Asymmetric Ring-Opening/ Cross-Metathesis. J. Am. Chem. Soc.
2007, 129, 3824−3825. (c) Kannenberg, A.; Rost, D.; Eibauer, S.;
Tiede, S.; Blechert, S. A Novel Ligand for the Enantioselective
Ruthenium-Catalyzed Olefin Metathesis. Angew. Chem., Int. Ed. 2011,
50, 3299−3302. (d) Hartung, J.; Dornan, P. K.; Grubbs, R. H.
Enantioselective Olefin Metathesis with Cyclometalated Ruthenium
Complexes. J. Am. Chem. Soc. 2014, 136, 13029−13037. (e) Paradiso,
V.; Bertolasi, V.; Costabile, C.; Grisi, F. Ruthenium olefin metathesis
catalysts featuring unsymmetrical N-heterocyclic carbenes. Dalton
́
Kozakiewicz, A.; Gunka, P. A.; Dąbrowski, P.; Skowerski, K.
Bis(Cyclic Alkyl Amino Carbene) Ruthenium Complexes: A Versatile,
Highly Efficient Tool for Olefin Metathesis. Angew. Chem., Int. Ed.
2017, 56, 981−986. (d) Gawin, R.; Tracz, A.; Chwalba, M.;
Kozakiewicz, A.; Trzaskowski, B.; Skowerski, K. Cyclic Alkyl Amino
Ruthenium Complexes Efficient Catalysts for Macrocyclization and
Acrylonitrile Cross Metathesis. ACS Catal. 2017, 7, 5443−5449.
(e) Nascimento, D. L.; Gawin, A.; Gawin, R.; Gunka, P. A.; Zachara,
J.; Skowerski, K.; Fogg, D. E. Integrating Activity with Accessibility in
Olefin Metathesis: An Unprecedentedly Reactive Ruthenium-
Indenyliden Catalyst. J. Am. Chem. Soc. 2019, 141, 10626−10631.
(f) Samkian, A. E.; Xu, Y.; Virgil, S. C.; Yoon, K.-Y.; Grubbs, R. H.
Synthesis and Activity of Six-Membered Cyclic Alkyl Amino
Carbene−Ruthenium Olefin Metathesis Catalysts. Organometallics
2020, 39, 495−499.
̈
Trans 2016, 45, 561−571. (f) Rais, E.; Florke, U.; Wilhelm, R.
Reactivity of Grubbs-Hoveyda II Complexes Including Extended N-
Heterocyclic Carbenes with a Bicyclic Camphor-Based Framework.
Synthesis 2017, 49, 2852−2864.
(4) Selected examples of ARCM: (a) Van Veldhuizen, J. J.;
Gillingham, D. G.; Garber, S. B.; Kataoka, O.; Hoveyda, A. H. Chiral
Ru-Based Complexes for Asymmetric Olefin Metathesis: Enhance-
ment of Catalyst Activity through Steric and Electronic Modifications.
J. Am. Chem. Soc. 2003, 125, 12502−12508. (b) Fournier, P.-A.;
(8) Pichon, D.; Soleilhavoup, M.; Morvan, J.; Junor, G. P.; Vives, T.;
Crevisy, C.; Lavallo, V.; Campagne, J.-M.; Mauduit, M.; Jazzar, R.;
Bertrand, G. The Debut of Cyclic (Alkyl)(Amino)Carbenes (CAACs)
in Enantioselective Catalysis. Chem. Sci. 2019, 10, 7807−7811.
(9) For a selected book chapter on Ru-AOM, see: Stenne, B.;
Collins, S. K. Enantioselective Olefin Metathesis in Olefin Metathesis:
Theory and Pratice; Grela, K., Ed.; Wiley-VCH: Weinheim, Germany,
2014.
(10) Okamoto, Y.; Ikai, T. Chiral HPLC for efficient resolution of
enantiomers. Chem. Soc. Rev. 2008, 37, 2593−2608.
(11) The chiral HPLC resolution of chiral transition-metal
complexes was scarcely reported, see: (a) Norel, L.; Rudolph, M.;
Vanthuyne, N.; Williams, J. A. G.; Lescop, C.; Roussel, C.;
́
Savoie, J.; Stenne, B.; Bedard, M.; Grandbois, A.; Collins, S. K.
Mechanistically Inspired Catalysts for Enantioselective Desymmetri-
zations by Olefin Metathesis. Chem. - Eur. J. 2008, 14, 8690−8695.
(c) Savoie, J.; Stenne, B.; Collins, S. K. Improved Chiral Olefin
Metathesis Catalysts: Increasing the Thermal and Solution Stability
via Modification of a C1-Symmetrical N-Heterocyclic Carbene Ligand.
Adv. Synth. Catal. 2009, 351, 1826−1832. (d) Paradiso, V.; Bertolasi,
V.; Grisi, F. Novel Olefin Metathesis Ruthenium Catalysts Bearing
Backbone- Substituted Unsymmetrical NHC Ligands. Organometallics
2014, 33, 5932−5935. (e) Paradiso, V.; Menta, S.; Pierini, M.; Della
Sala, G.; Ciogli, A.; Grisi, F. Enantiopure C1-symmetric N-
Heterocyclic Carbene Ligands from Desymmetrized meso-1,2-
Diphenylethylenediamine: Application in Ruthenium-Catalyzed Ole-
fin Metathesis. Catalysts 2016, 6, 177. (f) Grisi, F.; Paradiso, V.;
Caruso, T.; Bertolasi, V.; Grela, K.; Dąbrowski, M.; Costabile, C.
Expanding the Family of Hoveyda−Grubbs Catalysts Containing
Unsymmetrical NHC Ligands. Organometallics 2017, 36, 3692−3708.
́
Autschbach, J.; Crassous, J.; Reau, R.; Metallahelicenes, R. Easily
Accessible Helicene Derivatives with Large and Tunable Chiroptical
Properties. Angew. Chem., Int. Ed. 2010, 49, 99−102. (b) Hellou, N.;
́
Jahier-Diallo, C.; Basle, O.; Srebro-Hooper, M.; Toupet, L.; Roisnel,
T.; Caytan, E.; Roussel, C.; Vanthuyne, N.; Autschbach, J.; Mauduit,
M.; Crassous, J. Electronic and Chiroptical Properties of Chiral
Cycloiridiated Complexes Bearing Helicenic NHC Ligands. Chem.
Commun. 2016, 52, 9243−9246. (c) Hellou, N.; Srebro-Hooper, M.;
Favereau, L.; Zinna, F.; Caytan, E.; Toupet, L.; Dorcet, V.; Jean, M.;
Vanthuyne, N.; Williams, J. A. G.; Di Bari, L.; Autschbach, J.;
Crassous, J. Enantiopure Cycloiridiated Complexes Bearing a
Pentahelicenic N-Heterocyclic Carbene and Displaying Long-Lived
́
̌
(g) Karras, M.; Dąbrowski, M.; Pohl, R.; Rybacek, J.; Vacek, J.;
́
́
́
́
Bednarova, L.; Grela, K.; Stary, I.; Stara, I. G.; Schmidt, B. Helicenes
as Chirality-Inducing Groups in Transition-Metal Catalysis: The First
F
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Circularly Polarized Phosphorescence Angew. Angew. Chem., Int. Ed.
2017, 56, 8236−8239. (d) Kong, L.; Morvan, J.; Pichon, D.; Jean, M.;
Albalat, M.; Vives, T.; Colombel-Rouen, S.; Giorgi, M.; Dorcet, V.;
́
Roisnel, T.; Crevisy, C.; Nuel, D.; Nava, P.; Humbel, S.; Vanthuyne,
N.; Mauduit, M.; Clavier, H. From Prochiral N-Heterocyclic
Carbenes to Optically Pure Metal Complexes: New Opportunities
in Asymmetric Catalysis. J. Am. Chem. Soc. 2020, 142, 93−98.
(12) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.;
Dolgonos, G.; Grela, K. Nitro-Substituted Hoveyda−Grubbs
Ruthenium Carbenes: Enhancement of Catalyst Activity through
Electronic Activation. J. Am. Chem. Soc. 2004, 126, 9318−9325.
(13) The synthesis of Ru-2 was previously reported but in a lower
13% isolated yield, see ref 7.
(14) Blechert and coworkers reported up to >30:1 E-selectivity with
chiral monodentate NHC-Ru precatalysts. See: Tiede, S.; Berger, A.;
̈
Schlesiger, D.; Rost, D.; Luhl, A.; Blechert, S. Highly Active Chiral
Ruthenium-Based Metathesis Catalysts through a Monosubstitution
in the N-Heterocyclic Carbene. Angew. Chem., Int. Ed. 2010, 49,
3972−3975.
(15) A significant lower enantioselectivity for Z-products was already
reported by Grubbs and coworkers; see refs 3a.
(16) A full DFT study has been disclosed in the Supporting
Information and involves: (i) the initiation pathway for the formation
of the Ru-benzylidene propagating species, (ii) the possible pathways
for the interconversion of the two 14e-rotamers, and (iii) energy
profiles for AROCM of S1 catalyzed by (S)-Ru-2.
(17) (a) Bornand, M.; Chen, P. Mechanism-Based Design of a
ROMP Catalyst for Sequence-Selective Copolymerization. Angew.
Chem., Int. Ed. 2005, 44, 7909−7911. (b) Khan, R. K. M.; Zhugralin,
A. R.; Torker, S.; O’Brien, R. V.; Lombardi, P. J.; Hoveyda, A. H.
Synthesis, Isolation, Characterization, and Reactivity of High-Energy
Stereogenic-at-Ru Carbenes: Stereochemical Inversion through Olefin
Metathesis and Other Pathways. J. Am. Chem. Soc. 2012, 134, 12438−
12441.
(18) (a) Tallarico, J. A.; Bonitatebus, P. J.; Snapper, M. L. Ring-
Opening Metathesis. A Ruthenium Catalyst Caught in the Act. J. Am.
Chem. Soc. 1997, 119, 7157−7158. (b) Cavallo, L. Mechanism of
Ruthenium-Catalyzed Olefin Metathesis Reactions from a Theoretical
Perspective. J. Am. Chem. Soc. 2002, 124, 8965−8973. (c) Costabile,
C.; Cavallo, L. Origin of Enantioselectivity in the Asymmetric Ru-
Catalyzed Metathesis of Olefins. J. Am. Chem. Soc. 2004, 126, 9592−
9600. (d) Adlhart, C.; Chen, P. Mechanism and Activity of
Ruthenium Olefin Metathesis Catalysts: The Role of Ligands and
Substrates from a Theoretical Perspective. J. Am. Chem. Soc. 2004,
126, 3496−3510. (e) Romero, P. E.; Piers, W. E. Direct Observation
of a 14-Electron Ruthenacyclobutane Relevant to Olefin Metathesis. J.
Am. Chem. Soc. 2005, 127, 5032−5033. (f) Nascimento, D. L.; Fogg,
D. E. Origin of the Breakthrough Productivity of Ruthenium-Cyclic
Alkyl Amino Carbene Catalysts in Olefin Metathesis. J. Am. Chem.
Soc. 2019, 141, 19236−19240. (g) Ton, S. J.; Fogg, D. E. Origin of
the Breakthrough Productivity of Ruthenium-Cyclic Alkyl Amino
Carbene Catalysts in Olefin Metathesis. ACS Catal. 2019, 9, 11329−
11334. (h) Nelson, D. J.; Manzini, S.; Urbina-Blanco, C. A.; Nolan, S.
P. Key processes in ruthenium-catalysed olefin metathesis. Chem.
Commun. 2014, 50, 10355−10375. (i) Sanford, M. S.; Love, J. A.;
Grubbs, R. H. Mechanism and Activity of Ruthenium Olefin
Metathesis Catalysts. J. Am. Chem. Soc. 2001, 123, 6543−6554.
(19) Note that the Z-selective ACM variant (35% yield, 50% ee) has
been reported by Grubbs et al. using a cyclometalated NHC
ruthenium complexes; see ref 3d.
G
https://dx.doi.org/10.1021/jacs.0c10705
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX