A novel ligand for the enantioselective ruthenium-catalyzed olefin metathesis

Article abstract of DOI:10.1002/anie.201007673

A bridge connects and efficiently transfers the chirality from the backbone of a N-heterocyclic carbene (NHC) to the metal center. The result is excellent enantioselectivities in the ruthenium-catalyzed, asymmetric ring-opening cross-metathesis of norborn

Full text of DOI:10.1002/anie.201007673

DOI: 10.1002/anie.201007673
Asymmetric Catalysis
A Novel Ligand for the Enantioselective Ruthenium-Catalyzed Olefin
Metathesis**
Axel Kannenberg, Daniel Rost, Stefan Eibauer, Sascha Tiede, and Siegfried Blechert*
Recently the interest for chiral olefin metathesis catalysts
with respect to the synthesis of enantioenriched molecules, as
well as enhanced product selectivities, has increased signifi-
cantly.[1] For these kind of transformations, a range of
molybdenum-catalysts containing one stereogen metal
center have been very successful.[2] However, in comparison
to these catalysts, ruthenium metathesis catalysts offer
improved handling and stability.[3]
A challenge with such catalysts is an efficient transfer of
chirality from the N-heterocyclic carbene (NHC) to the metal
center without substitution of the chlorine ligands, which are
important for the reactivity.[4] Recently, we introduced chiral
ruthenium metathesis catalysts of type 1,[5] which, compared
to the catalysts of Grubbs et al. (e.g. 2), have a different
orientation of the stabilizing N-aryl groups (Scheme 1) which
arises from the monosubstitution in the NHC-backbone.[6]
The C3 substituent in the NHC twists the framework and
hinders rotation of the N-aryl substituent, while at the same
time the absence of the C4 substitution allows a planar
orientation for the mesitylene moiety. The resulting highly
active catalyst was used for asymmetric ring-opening cross-
metathesis providing excellent results.[5]
Herein, we report a new type of chiral NHC-ligand in
which rotation around the chirality transferring N-aryl bond is
no longer possible, and the corresponding ruthenium meta-
thesis catalysts. We decided to use a 2-substituted tetrahy-
droquinoline as the source of chirality, which is easy
accessible via quinaldic acid 4. After esterification of 4 and
hydration to rac-5, a kinetic enzymatic resolution leads to the
desired key structure ent-5 in an overall yield of 41% (ꢀ
99% ee) (Scheme 2).[7]
Protection of amine ent-5 (route A), ester saponification
and subsequent amide coupling and deprotection, afforded
amide 6. A further reduction with BH3·SMe2 led to the
formation of diamine 7 in good yields. During this reaction a
partial racemization and fluctuating ee-values were detected
Scheme 1. Chiral ruthenium metathesis (pre)catalysts.
Scheme 2. Preparation of catalysts: a) SOCl2/MeOH, 97%; b) PtO2/H2
(60–70 bar), MeOH, quant.; c) a-chymotrypsine, Sꢀrensen-buffer
(pH 7.4, 0.1m), 41% (>99% ee); d) Na2CO3, ethyl chloroformate,
H2O/ CH2Cl2, quant.; e) NaOH, THF/H2O, quant.; f) pyridine, NEt3,
CH2Cl2, PivCl, mesidine, 68%; g) [Pd(PPh3)4], PPh3, dimedone, THF,
quant.; h) BH3·SMe2, THF, 98%; i) LiAlH4, THF, quant.; j) SOCl2,
pyridine, CH2Cl2, 85%; k) 2 mol% RuCl3·H2O, NaIO4, SiO2, ethyl
acetate, H2O, 91%; l) NaH, Boc-mesidine, DMF, CH2Cl2, TFA (trifluoro
acetic acid), 80% (99% ee); m) triethyl orthoformate, H2CO2H,
[*] A. Kannenberg, D. Rost, S. Eibauer, S. Tiede, Prof. S. Blechert
Technische Universitꢁt Berlin, Institut fꢂr Chemie, Sekr. C3
Strasse des 17. Juni 135, 10623 Berlin (Germany)
Fax: (+49)303-142-9745
E-mail: blechert@chem.tu-berlin.de
[**] We acknowledge support from the Cluster of Excellence “Unifying
Concepts in Catalysis” coordinated by the Technische Universitꢁt
Berlin.
=
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007673.
NH4BF4, toluene, 92%; n) KO(CH3)2CH2CH3, hexane, [(PCy3)2Cl2Ru
CHPh], 82%; o) 1-isopropoxy-2-vinyl-benzene, 3a, CH2Cl2, 56%.
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Table 1: Test of catalysts in AROCM with styrene as the cross-partner.[a]
(90–97% ee). For this reason we developed synthetic route B.
Reduction of ent-5 with LiAlH4 to the amino alcohol,[7]
cyclization with SOCl2 to the sulfamidite, and oxidation
with RuCl3·H2O/NaIO4 on wet silica afforded crystalline
sulfamidate 8 in 80% overall yield.[8] The subsequent ring
opening with Boc-protected mesidine led to formation of 7
without partial racemization (99.4% ee), which was easily
transformed into the carbene precursor. The green micro-
crystalline complex 3a was obtained by a phosphine–NHC
exchange of the Grubbs I catalyst. A second phosphine
exchange on 3a afforded 3b and recrystallization from n-
hexane/CH2Cl2 resulted in single crystals.
Entry Substrate
Catalyst (mol%) t [h] Conv. [%][c] ee [%][b]
(E:Z)[d]
1
2
3a (7)
3b (2.5)
16[e] 78 (17:1)
16[f] 83 (13:1)
86
75
3
3a (6)
16[e] 36 (3:1)
85
4
5
3a (5)
3b (5)
24[e] 97 (8:1)
24[e] 96 (11:1)
80
71
The crystal structure of 3b (Figure 1) provided an insight
into the steric influence of the ligand on the metal centre. The
C2 bridge at the chirality center causes a large twist of 458
around the N-aryl bond and forces the carbon atom C13 into
the coordination sphere of the ruthenium center. The short
interatomic distance between Ru1–C13 of 3.131(6) ꢀ results
in an agostic Ru-H-C-interaction, that is reflected in a
6
7
8
2 (1)
3b (2.5)
3a (2.5)
1[f]
>96 (1:1)[6] 57
72[f] 99 (11:1)
18[e] 98 (9:1)
91
92
[a] Conditions: 5 equiv styrene, CH2Cl2, 0.04m with respect to substrate.
[b] E-Isomer, determined by chiral HPLC. [c] Determined by 1H NMR
spectroscopy. [d] Determined by GC. [e] Reaction temperature 408C.
[f] Reaction temperature 258C.
1
diminished J (C13,H13) coupling constant of 154 Hz. Also
the reactivity is lower but the selectivities are
however significantly higher (Table 1, entries 6
and 8).[6]
The most commonly used cross-partners in
AROCM are styrenes. These are however limited
in their usefulness for further reactions. Hence we
focused on the AROCM of norbornenes with
allyltrimethylsilane, which to our knowledge, has
not been investigated to date. The substituted
allyltrimethylsilanes obtained should offer diverse
synthetic possibilities.
We investigated the solvent dependency of the
enantioselectivity in the reaction of allyltrimethyl-
silane and 10 with 3a (Table 2). In the process a
clear solvent influence on the ee-values and surpris-
ingly on the E/Z-ratios was observed. For instance, in MTBE
or toluene the E-isomer was preferentially formed, whereas in
CH2Cl2 the Z-isomer prevailed (Table 2, entries 1, 2, and 5).
Figure 1. Two views of the crystal structure of 3b.[13]
1
notably herein is the downfield shifted H13 signal in the H-
spectra at d = 9.23 ppm. The metal coordination environment
is no longer a square-pyramid, but rather a distorted
octahedron.[9]
As a result of twist there is a strong steric interaction
Table 2: Solvent effects on AROCM of 10 with catalyst 3a.[a]
À
between the ligand and chlorine atom Cl1. The Ru Cl bond
lengths of 2.350(3) ꢀ are significantly shortened and the Cl1-
Ru1-Cl2 bond angle of 158.57(6)8 is increased. Consistent
with our expectations, the mesitylene group is orthogonally
oriented to the styrene ether moiety. The 1H-NMR spectrum
for 3a shows splitting for a multiplicity of proton signals at
08C, which disappear at room temperature, which suggests
the presence of rotameres.[10] Since no splitting of the proton
signals was observed for 3b even at À508C, the rotameres in
3a are presumably caused by different orientations of the
benzylidene unit.
To compare the efficiency of 3a/b with other chiral
ruthenium catalysts, we chose the asymmetric ring-opening
cross-metathesis (AROCM) of meso-norbornenes with sty-
rene as the model reaction (Table 1). The new complexes
furnish good ee-values with up to 92% ee, combined with
pronounced E-selectivity. In contrast to the Grubbs catalyst,
Entry
Solvent
Conv. [%][b]
E:Z[c]
ee [%] E (Z)[c]
1
2
3
4
5
6
CH2Cl2
>99
>99
>99
>99
>99
92
1:1.5
2:1
1:1
2:1
2:1
75 (78)
58 (39)
63 (66)
53 (36)
57 (36)
69 (50)
MTBE[d]
THF
benzene
toluene
trifluorotoluene
1.5:1
[a] Conditions: 2 equiv allyltrimethylsilane, CH2Cl2, 0.05m with respect to
substrate, 12 h, room temperature, 3 mol% 3a. [b] Determined by
1H NMR spectroscopy. [c] Determined by chiral HPLC. [d] methyl-tert-
butylether.
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Angew. Chem. Int. Ed. 2011, 50, 3299 –3302

Solvent-dependent changes in the ee-values for the E/Z-
isomers are also remarkable, for example in toluene 57% ee
for the E- and 36% ee for the Z-product, whereas in CH2Cl2
the difference is relatively low, 75% ee and 78% ee,
respectively (Table 2, entries 1 and 5).
Once CH2Cl2 was recognized as the solvent of choice, we
investigated the influence of temperature. As expected the
enantiomeric excess increased at low temperature (Table 3,
provides high enantioselectivities. In 2 however there is the
possibility of a partial N-aryl rotation giving rise to a more
flexible reaction pocket, resulting in a lower enantioselectiv-
ity. Owing to its properties, we believe that this novel carbene
ligand is also of particular interest for a range of applications
in metal-catalyzed enantioselective reactions.
entries 1–4) as did the amount of Z-product. Ruthenium- Experimental Section
Typical procedure for AROCM: 10 (28.9 mg; 0.10 mmol, 1 equiv) and
catalyzed Z-selective cross-metathesis is rare and to our
allyltrimethylsilane (22.8 mg; 0.2 mmol, 2 equiv) were dissolved in
dry CH2Cl2 (0.04m) under nitrogen atmosphere at room temperature.
The mixture was degassed by “freeze-pump-thaw” cycle. 3a (2.08 mg;
2.5 mol%, 2.5 mmol) was added and the mixture stirred for 2 h at
room temperature. Ethyl vinyl ether was added in excess and the
volatile compounds were removed under vacuum. The residue was
purified by column chromatography (SiO2, c-hexane:EtOAc, 25:1)
and 36.0 mg of a clear oil were isolated (0.09 mmol, 89%).
Table 3: Test of the catalyst in AROCM with allyltrimethylsilane as the
cross partner.[a]
Entry Substr.
Catalyst t [h] Conv.[c]
(mol%)
ee [%] E (Z)[b]
(E:Z)[b]
1
2
3
4
5
6
3a (2.5)
3a (2.5)
3a (2.5)
3a (2.5) 48
3b (2.5) 18
1
2
2
>99 (1:1.5) 75 (75) (408C)
>99 (1:1.5) 75 (78)
>99 (1:2)
>99 (1:2)
>99 (1:1)
>99 (3:1)
79 (85) (08C)
79 (87) (À108C)
73 (71)
Received: December 7, 2010
Keywords: agostic interactions · asymmetric catalysis ·
2 (2.5)
2
34 (8)
.
N-heterocyclic carbenes · olefin metathesis · ruthenium
7
8
3a (2.5)
3a (2.5)
2
6
>99 (2:1)
>99 (2:1)
80 (75)[d]
82 (82)[d] (08C)
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9
3a (2.6) 72
87 (2:1)
72 (n.d.)
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11
12
3a (3.0) 96[e] 96 (2:1)
98 (92)
95 (91)
35 (15)
3b (3.0) 96
2 (2.0) 18
>99 (2:1)
>99 (2:1)
[a] Conditions: 2 equiv allyltrimethylsilane, CH2Cl2, 0.04m with respect to
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knowledge only described with acrylonitrile as the cross
partner.[11] In our case the preferred Z-product formation is
caused by the catalyst, because the same reaction catalyzed
with the chiral Grubbs-complex 2 led to the preferred
formation of E-product (Table 3, entry 6).
A particularly notable feature of these reactions is the
significant difference in the enantioselectivity. The C2-sym-
metric carbene ligand with partially rotatable N-aryl groups in
ruthenium complex 2 led to very low ee values in the
AROCM with the allylsilane and as already observed with
other reaction partners, the enantioselectivity for the Z-
product was again significantly lower (Table 3, entries 6 and
12). The fixed, non-rotatable N-aryl unit in our ligand causes a
considerably higher enantioselectivity that is of similar
magnitude for both stereoisomers of the olefins. These results
are in accordance with the calculations of Cavallo et al.[12] who
found that the steric demand of the NHC-ligand in the
ruthenium coordination sphere is an important factor. Our
ligand forms a well-defined rigid reaction pocket, which
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Angew. Chem. Int. Ed. 2011, 50, 3299 –3302
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[13] Crystallographic data for 3b: C30H34Cl2N2ORu, Mr = 610.56, P21,
a = 8.9101(4), b = 15.7385(6), c = 9.8022(4), a = g = 908, b =
94.402(4)8, V= 1370.52(10) ꢀ3, Z = 2, 1calcd = 1.480 gcmÀ3, m =
0.793 mmÀ1, T= 150 K, qmax = 25.008, Rint = 0.0512, R = 0.0417,
Rw = 0.0475. CCDC 795016 (3b) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
3302
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