Chiral-at-metal octahedral iridium catalyst for the asymmetric construction of an all-carbon quaternary stereocenter

Article abstract of DOI:10.1002/anie.201306997

Metal-templated organocatalysis: The enantioselective formation of an all-carbon quaternary stereocenter is catalyzed by the ligand sphere of an inert bis-cyclometalated iridium complex (see picture). In this complex, the metal-centered chirality serves as the sole source for the effective asymmetric induction. Copyright

Full text of DOI:10.1002/anie.201306997

Angewandte
Chemie
DOI: 10.1002/anie.201306997
Asymmetric Catalysis
Chiral-at-Metal Octahedral Iridium Catalyst for the Asymmetric
Construction of an All-Carbon Quaternary Stereocenter**
Liang-An Chen, Xiaojuan Tang, Jianwei Xi, Weici Xu, Lei Gong,* and Eric Meggers*
Asymmetric catalysts, whether metal complexes with chiral
ligands, chiral organometallics, or chiral organic compounds
(organocatalysts), achieve asymmetric induction by trans-
ferring chiral information from the catalyst to the sub-
strate(s).[1] The source of the catalystꢀs chirality therefore
plays a crucial role for its mode of action, and is typically
derived from one or more tetrahedral stereogenic centers
(mostly carbon atoms, but also heteroatoms, such as sulfur or
phosphorus), axial chirality, planar chirality, or a combination
thereof (Scheme 1). In contrast, only few reports exist of
asymmetric catalysts that derive their chirality exclusively
from an octahedral stereocenter.[2–4] This seems surprising,
considering the prevalence of the octahedral coordination
geometry in chemistry and its ability to support the gener-
ation of structures with high complexity and, as a result of
ligand crowding and chelate effects, often low conformational
flexibility.[5] We recently demonstrated the use of chiral-at-
metal octahedral complexes for the tailored design of a highly
efficient asymmetric noncovalent catalyst that requires low
catalyst loading by reporting an inert iridium(III)-based
catalyst for the conjugate asymmetric transfer hydrogenation
of b,b-disubstituted nitroalkenes.[6] However, excellent
metal-, bio-, and organo-catalysts already exist for this
Scheme 1. Sources of chirality in asymmetric catalysts. See Ref. [6] (L-
Ir1) and the Supporting Information (L-Ir2 and L-Ir3) for the synthesis
of the enantiopure iridium catalysts. BArF24ꢀ =tetrakis[(3,5-di-trifluoro-
methyl)phenyl]borate.
transformation,[7] and we were therefore wondering whether
an octahedral chiral-at-metal catalyst could be developed for
a more challenging asymmetric conversion. In this respect,
the asymmetric conjugate addition of carbon nucleophiles to
b,b-disubstituted nitroalkenes constitutes a highly attractive
reaction as it permits the construction of a stereogenic carbon
atom bound to four other carbon substituents (all-carbon
quaternary stereocenter).[8] Only a handful of studies are
available dealing with this particular reaction, thereby
presumably reflecting the involved challenge of overcoming
a significant steric repulsion between the incoming carbon
nucleophile and the carbon substituents of the nitroalkene
electrophile. Nevertheless, Hoveyda and co-workers intro-
duced a Cu-catalyzed dialkylzinc conjugate addition,[9] Arai
and co-workers reported a Cu-catalyzed addition of indoles to
isatin-derived nitroalkenes,[10] Jia and co-workers disclosed
a Ni-catalyzed addition of indoles to b-CF3-b-disubstituted
nitroalkenes,[11] Ricci and co-workers reported a phase-trans-
fer asymmetric organocatalytic conjugate addition of cyanide
to b,b-disubstituted nitroalkenes, albeit with only modest
enantioselectivities,[12] Melchiorre and co-workers introduced
the asymmetric vinylogous Michael addition of cyclic enones
to nitroalkenes catalyzed by natural cinchona alkaloids,
including one reaction using a b,b-disubstituted nitroal-
kene,[13] and finally Kastl and Wennemers introduced a pro-
line-peptide-catalyzed asymmetric addition of aldehydes to
b,b-disubstituted nitroalkenes under formation of g-nitro-
aldehydes.[14] The restricted scope of dialkylzinc reagents and
the high catalyst loadings of 10 mol% or more required for
the remaining methods confirm the significant difficulty of
[*] L.-A. Chen, X. Tang, J. Xi, W. Xu, Prof. L. Gong, Prof. E. Meggers
Key Laboratory for Chemical Biology of Fujian Province and
Department of Chemical Biology, College of Chemistry and
Chemical Engineering, Xiamen University
Xiamen 361005 (P.R. of China)
E-mail: gongl@xmu.edu.cn
meggers@xmu.edu.cn
Prof. E. Meggers
Fachbereich Chemie, Philipps-Universitꢀt Marburg
Hans-Meerwein-Straße, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
[**] This work was supported by the National Natural Science
Foundation of P.R. China (21272192, 21201143), the Program for
Changjiang Scholars and Innovative Research Team of P.R. China
(PCSIRT), the National Thousand Talents Program of P.R. China,
and the 985 Program of the Chemistry and Chemical Engineering
disciplines of Xiamen University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306997.
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this conversion. Herein, we wish to report the highly efficient
catalysis of the conjugate addition of indoles to a-substituted-
b-nitroacrylates under the enantioselective construction of an
all-carbon quaternary stereocenter using an inert only-chiral-
at-metal iridium(III) complex. Although it functions as
a nonbonding catalyst, promoting merely three hydrogen
bonds, the iridium complex can be employed routinely with
catalyst loadings of not more than 1 mol%, while retaining
high ee values of up to 98%.
amide instead of the hydroxymethyl group of L-Ir1.[16,17]
Interestingly, 5 mol% of L-Ir2 catalyzed the reaction 1a!
(S)-2a with a conversion of 87% after 24 hours and a vastly
improved ee value of 96% (Table 1, entry 2). Even a reduced
catalyst loading of 2 mol% afforded (S)-2a, still with 93% ee
in 58 hours (Table 1, entry 3). Replacing the 3,5-dimethyl-
phenyl group by a carbazolyl moiety finally resulted in the
further improved catalyst L-Ir3 (Scheme 1). L-Ir3 provides
(S)-2a with a high ee of 98% at 2 mol% catalyst loading
(Table 1, entry 4). Optimization of the reaction conditions
(Table 1, entries 5–7) by increasing the concentration of 1a
(2m) and indole (5 equiv) further speeded up the reaction so
that with 1 mol% of L-Ir3 full conversion is afforded within
just 12 h at room temperature (Table 1, entry 7). It is
noteworthy that Ricciꢀs thiourea catalyst OC1[15]
(Scheme 1), at a catalyst loading that is 20 times higher
(20 mol%), catalyzes the conversion 1a!(S)-2a only with
a modest 42% ee (Table 1, entry 8). The related carboxamide
thiourea catalyst OC2[18] (Scheme 1) displayed an even
weaker performance with just 10% ee at 20 mol% catalyst
loading (Table 1, entry 9).
We started our study with the previously developed
asymmetric
transfer
hydrogenation
catalyst
L-Ir1
(Scheme 1).[6] We envisioned that L-Ir1 might be capable of
catalyzing the addition of indoles to b,b-disubstituted nitro-
alkenes by simultaneously activating the nitroalkene electro-
phile (double hydrogen bond with the amidopyrazole moiety)
and the indole nucleophile (single hydrogen bond between
the indole-NH and an oxygen lone pair of an OH group),
according to a mechanism recently proposed by Ricci and co-
workers for the addition of indoles to b-monosubstituted
nitroalkenes catalyzed by a bifunctional thiourea.[15] In fact,
the reaction of (Z)-1-phenyl-2-nitro-isopropylacrylate (1a)
with indole catalyzed by 5 mol% L-Ir1 at room temperature
afforded the expected conjugate-addition product (S)-2a with
a conversion of 71% after three days, but created the all-
carbon quaternary stereocenter with a disappointing enan-
tiomeric excess of just 70% (Table 1, entry 1). We speculated
that the performance of the catalyst might be improved by
replacing the hydroxy group with a stronger hydrogen-bond
acceptor and therefore designed the carboxamide-containing
catalyst L-Ir2 (Scheme 1), which bears an N,N-diethylcarbox-
We next investigated the scope of the reaction of nitro
substrates with iridium catalyst L-Ir3. Table 2 shows that the
reactions of a variety of 1-aryl-2-nitroacrylates (1a–i) with
indole in the presence of 1 mol% L-Ir3 provided the products
2a–i containing the quaternary carbon center in high yields
(87–97%) and with excellent enantioselectivities (93–
98% ee) within 11–15 hours at room temperature (Table 2,
Table 2: Nitroalkene substrate scope of the alkylation of indole with
iridium catalyst L-Ir3 generating a quaternary carbon center.[a]
Table 1: Development of a chiral-at-metal iridium(III) complex for the
enantioselective Friedel–Crafts alkylation of indole with the b,b-disub-
stituted nitroalkene 1a.[a]
Entry Substrate (R1, R2)
Product t [h]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1a (Ph, iPr)
1b (Ph, nHex)
1c (Ph, Me)
1d (4-ClC6H4, iPr)
1e (4-ClC6H4, Et)
1 f (4-MeOC6H4, iPr) (S)-2 f
1g (3-MeOC6H4, Et) (S)-2g 12
1h (3-ClC6H4, Et)
1i (2-thienyl, Et)
1j (iPr, Et)
1k (cyclohexyl, Et)
1l (Me, Et)
(S)-2a 12
(S)-2b 12
97
95
92
93
94
87
92
95
94
82
72
96
96
95
95
95
97
96
93
98
94
93
Entry Catalyst
Conditions
t
[h]
Conv. ee
(S)-2c
11
[%][b] [%][c]
(S)-2d 13
(S)-2e 12
1
2
3
4
5
6
7
8
9
L-Ir1 (5 mol%) 1a (1m), indole (2 equiv)
L-Ir2 (5 mol%) 1a (1m), indole (2 equiv)
L-Ir2 (2 mol%) 1a (1m), indole (2 equiv)
L-Ir3 (2 mol%) 1a (1m), indole (2 equiv)
L-Ir3 (1 mol%) 1a (2m), indole (2 equiv)
L-Ir3 (1 mol%) 1a (1m), indole (5 equiv)
L-Ir3 (1 mol%) 1a (2m), indole (5 equiv) <12 100
OC1 (20 mol%) 1a (2m), indole (5 equiv)
OC2 (20 mol%) 1a (2m), indole (5 equiv)
72 71
70
96
93
98
96
96
96
42
10
24 87
58 77
36 97
24 93
24 98
15
(S)-2h 12
9
(R)-2i
(S)-2j
12
40
10
11
12
(S)-2k 72
(S)-2l
(S)-2a 24
24 84
24 71
11 (36)[d] 91 (84)[d] 76 (92)[d]
95 93
13[e] 1a (Ph, iPr)
[a] Reaction conditions: Nitroalkene 1a (0.10 mmol), indole (0.20 mmol
or 0.50 mmol), and iridium catalyst L-Ir1-3 (1–5 mol%) in anhydrous
toluene (0.050 mL or 0.10 mL) were stirred at 208C for the indicated time
under argon atmosphere and reduced light. [b] Conversion determined
by 1H NMR spectroscopy. [c] Enantiomeric excess determined by HPLC
on a chiral stationary phase.
[a] Reaction conditions: Nitroalkenes 1a–1l (0.10 mmol), indole
(0.50 mmol), and iridium catalyst L-Ir3 (0.0010 mmol) in anhydrous
toluene (0.050 mL, 2.0m) were stirred at 208C for the indicated time
under argon atmosphere and reduced light. [b] Yields of isolated
products. [c] Enantiomeric excess determined by HPLC on a chiral
stationary phase. [d] Performed at ꢀ208C. [e] L-Ir3 at 0.5 mol%.
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entries 1–9). To our delight, L-Ir3 also efficiently converts 1-
alkyl-2-nitroacrylates (1j–l) to their respective products (S)-
2j–l containing the quaternary carbon center under optimized
conditions (Table 2, entries 10–12, 72–84% yield, 92–
94% ee), although 1-methyl-2-nitroacrylate 1l requires
a reduction of the reaction temperature to ꢀ208C in order
to achieve a high ee value (Table 2, entry 12). Furthermore,
chiral-at-metal iridium catalyst L-Ir3 tolerates electron-
acceptor- and electron-donor-substituted indoles 3–8, as
shown in Table 3 (entries 1–7) with the exception of the N-
Table 3: Indole substrate scope of the alkylation of indoles with iridium
catalyst L-Ir3 generating a quaternary carbon center.[a]
Figure 1. a) Proposed hydrogen-bonded ternary complex composed of
catalyst L-Ir3 (beige), nitroalkene 1a (yellow), and indole (green)
leading to the transitions state. The distance between C3 of the indole
(carbon nucleophile) and the carbon atom in b position of the nitro-
alkene (carbon electrophile) is 3.8 ꢁ. The ternary complex was built
with the molecular modeling software Scigress (Fujitsu) and repre-
sented with The PyMOL Molecular Graphics System, Version 1.3
Schrçdinger, LLC. b) ORTEP representation of a crystal structure of
(S)-2a with thermal ellipsoids at 50% probability. Solvent molecules
are omitted for clarity.
Entry
Substrate (R)
Product
t [h]
Yield [%][b]
ee [%][c]
1
2
3 (5-CH3)
4 (5-OCH3)
5 (5-Br)
6 (6-OCH3)
7 (6-Cl)
(S)-2m
(S)-2n
(S)-2o
(S)-2p
(S)-2q
(S)-2r
(S)-2s
12
13
48
17
25
12
24
95
94
78
94
84
96
79
97
93
95
96
97
97
76
can be rationalized with a preferred hydrogen-bonding
arrangement of the nitroalkene in which the bulky carboxylic
ester is pointing away from the carbazole moiety in addition
to a preference for the Si face in the addition of the indole to
the nitroalkene directed by the hydrogen bonding between
the amide of the iridium catalyst and the indole NH. The
importance of this single hydrogen bond is confirmed by the
observed low enantioselectivity upon N methylation of the
indole, which prevents a formation of this hydrogen bond
(Table 3, entry 7). Furthermore, the amide catalysts L-Ir2 and
L-Ir3 are significantly more active and provide the addition
product (S)-2a with higher enantioselectivity compared to L-
Ir1 (Table 1), thus demonstrating the superiority of the N,N-
diethylcarboxamide over the hydroxymethyl group as a hydro-
gen-bond acceptor in this catalysis. This result can be
rationalized with a superior hydrogen-bond affinity of the
carboxamide over the hydroxy group,[16] in combination with
a preferred conformation of the amide group rotated out of
conjugation with the benzoxazole moiety because of steric
reasons,[21] thereby placing the amide oxygen atom in an ideal
position for hydrogen bonding with the indole nucleophile. It
is intriguing that the reaction 1a!(S)-2a still provides high
enantioselectivities (93% ee) with just 0.5 mol% L-Ir3
(Table 2, entry 13). With the assumption that under these
conditions the undesired enantiomer (R)-2a is formed
predominately from the uncatalyzed background reaction,
one can calculate a rate acceleration with catalyst L-Ir3 by
a factor of 2.7 ꢁ 103.[22] This rate acceleration is even more
impressive taking into account that L-Ir3 catalyzes a challeng-
ing asymmetric formation of a quaternary carbon center by
forming just three hydrogen bonds, and we hypothesize that it
is the limited flexibility of the iridium scaffold that keeps the
key functional groups in the right orientation, thereby
lowering the entropic penalty paid for the highly ordered
transition state.
3[d]
4[d]
5[d]
6
8 (7-CH3)
9 (N-CH3)
7
[a] Reaction conditions: Nitroalkene 1a (0.10 mmol), indoles
(0.50 mmol), and iridium catalyst L-Ir3 (0.0010 mmol) in anhydrous
toluene (0.050 mL, 2.0m) were stirred at 208C for the indicated time
under argon atmosphere and reduced light. [b] Yields of isolated
products. [c] Enantiomeric excess determined by HPLC on a chiral
stationary phase. [d] Nitroalkenes used at lower concentration (0.10 mL,
1.0m).
methylated derivative 9, which provides (S)-2s only in 79%
yield and 76% ee. It is worth noting that the catalyst loading
can be further reduced while retaining high enantiomeric
excess. For example, just 0.5 mol% L-Ir3 catalyzed the
conversion 1a!(S)-2a within 24 hours in 95% yield with
93% ee (Table 2, entry 13).
A proposed hydrogen-bonded ternary complex composed
of catalyst L-Ir3, nitroalkene 1a, and indole (Figure 1a) is
based on the mechanistic understanding of bifunctional
thiourea catalysis in general,[19,20] the proposed mechanism
by Ricci and co-workers for the addition of indoles to b-
monosubstituted nitroalkenes in particular,[15] and is consis-
tent with our experimental results of affording the S enan-
tiomer of product 2a with a quaternary carbon center
(Figure 1b). Accordingly, the b,b-disubstituted nitroalkene
forms two hydrogen bonds with the trifluoroacetamidopyr-
azole moiety, whereas the NH group of the indole nucleophile
forms hydrogen bonds with the carbonyl oxygen atom[15] of
the amide moiety. Overall, these three hydrogen bonds lower
the activation barrier by rendering the nitroalkene more
electrophilic and the indole more nucleophilic, and by
bringing electrophile and nucleophile in the proper position
In conclusion, we herein reported an inert iridium-based
catalyst that draws its chirality exclusively from an octahedral
ꢀ
for the following C C bond formation. The enantioselectivity
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stereocenter and highly efficiently catalyzes the challenging
construction of a stereogenic all-carbon quaternary stereo-
center by merely forming three hydrogen bonds. Beyond
demonstrating the scope of hydrogen-bonding catalysis, this
work demonstrates the power of inert metal complexes as
templates for asymmetric organocatalysis. In this respect, it is
our opinion that cyclometalated iridium(III) complexes are
especially suitable metal-based scaffolds because of their high
substitutional inertness and configurational stability,[23,24] as
well as the ability to conveniently access stereoisomers in
a nonracemic fashion.[25,26]
Received: August 9, 2013
Revised: September 9, 2013
Published online: November 8, 2013
Keywords: asymmetric catalysis · chirality · hydrogen bonds ·
.
iridium · quaternary stereocenter
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[18] S. E. Reisman, A. G. Doyle, E. N. Jacobsen, J. Am. Chem. Soc.
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[19] For leading reviews on hydrogen-bonding catalysis, see: a) P. R.
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Org. Biomol. Chem. 2005, 3, 4299 – 4306; c) M. S. Taylor, E. N.
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38, 1187 – 1198; h) R. R. Knowles, E. N. Jacobsen, Proc. Natl.
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[20] For an early example of the asymmetric activation of nitro-
alkenes with a bifunctional thiourea catalyst, see: T. Okino, Y.
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[21] N,N-Disubstituted arylamides adopt a twisted conformation. For
=
example, the torsional angle between the amide C O and the
plane of the phenyl group in N,N-diethylbenzamide has been
estimated using 13C NMR spectroscopy to be 578 in CDCl3
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Angewandte
Chemie
(C. W. Fong, H. G. Grant, Aust. J. Chem. 1981, 34, 957 – 967),
thus being in the range of torsional angles observed in X-ray
structures of N,N-diethylbenzamide derivatives (e.g., S. N.
Calderon, R. B. Rothman, F. Porreca, J. L. Flippen-Anderson,
R. W. McNutt, H. Xu, L. E. Smith, E. J. Bilsky, P. Davis, K. C.
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J. C. Warner, Cryst. Growth Des. 2005, 5, 407 – 411).
[23] No racemization was observed upon keeping L-Ir3 dissolved in
CH2Cl2 or MeCN at 208C for 7 days (see the Supporting
Information). However, as a precaution to prevent any light-
induced catalyst racemization, all catalysis reactions were
performed under reduced light in brown glass vials.
[24] The catalyst can be recycled several times without any significant
loss of catalytic activity, as determined for the conversion 1a!
(S)-2a with L-Ir3 (1 mol%) starting with a 1 mmol scale:
cycle 1 = 96% yield, 97% ee; cycle 2 = 95% yield, 97% ee;
cycle 3 = 98% yield, 96% ee. See the Supporting Information
for more details.
[22] Calculated rate accelerations for the higher catalyst loadings of
1 mol% (entry 1 of Table 2, calculated rate acceleration of 2.4 ꢁ
103) and 2 mol% (entry 4 of Table 1, calculated rate acceleration
of 2.5 ꢁ 103) are consistent with the assumption that the
formation of the minor R enantiomer is due to the uncatalyzed
background reaction.
[25] D. L. Davies, K. Singh, S. Singh, B. Villa-Marcos, Chem.
Commun. 2013, 49, 6546 – 6548.
[26] M. Helms, Z. Lin, L. Gong, K. Harms, E. Meggers, Eur. J. Inorg.
Chem. 2013, 4164 – 4172.
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