Asymmetric Nazarov Cyclizations Catalyzed by Chiral-at-Metal Complexes

Article abstract of DOI:10.1002/adsc.201701546

The application of Lewis acidic chiral-at-metal complexes of iridium(III) and rhodium(III) as catalysts for the asymmetric polarized Nazarov cyclization of dihydropyran- and indole-functionalized α-unsaturated β-ketoesters is reported (overall 24 examples). For both substrate classes, catalyst loadings of 2 mol% were found to be sufficient for achieving high yields and high stereoselectivities. The cyclized dihydropyran products were isolated in 85–98% yield, with 89%–>99% ee, and trans/cis ratios of 15:1–50:1 (9 examples). The cyclized indole products were typically isolated in more than 70% yield and in up to 93% yield, typically with more than 90% ee and in up to 97% ee, and trans/cis ratios of 12:1–28:1 (15 examples). (Figure presented.).

Full text of DOI:10.1002/adsc.201701546

Title: Asymmetric Nazarov Cyclizations Catalyzed by Chiral-at-Metal
Complexes
Authors: Thomas Mietke, Thomas Cruchter, Vladimir Larionov, Tabea
Faber, Klaus Harms, and Eric Meggers
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701546
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Nazarov Cyclizations Catalyzed by Chiral-at-
Metal Complexes
Thomas Mietke,a Thomas Cruchter,a Vladimir A. Larionov,a,b Tabea Faber,a Klaus
Harmsa and Eric Meggersa*
a
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
phone: +49-6421-2821534, fax: +49-6421-2822189, email: meggers@chemie.uni-marburg.de
Department of Inorganic Chemistry, People’s Friendship University of Russia (RUDN University), Miklukho-Maklaya
b
St. 6, 117198 Moscow, Russian Federation
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
iron(II),[12] and cobalt(III),[12] have been among the
Abstract. The application of Lewis acidic chiral-at-metal
complexes of iridium(III) and rhodium(III) as catalysts for most popular ones for asymmetric Nazarov
cyclizations. Furthermore, nickel(II) phosphine,[9]
the asymmetric polarized Nazarov cyclization of
salen,[13]
and nickel(II)
palladium(0)
bisimino-
dihydropyran- and indole-functionalized α-unsaturated β-
chromium(III)
phosphoramidite,[15]
ketoesters is reported (overall 24 examples). For both
substrate classes, catalyst loadings of 2 mol% were found
to be sufficient for achieving high yields and high
stereoselectivities. The cyclized dihydropyran products
were isolated in 85–98% yield, with 89%–>99% ee, and
trans/cis ratios of 15:1–50:1 (9 examples). The cyclized
indole products were typically isolated in more than 70%
yield and in up to 93% yield, typically with more than 90%
ee and in up to 97% ee, and trans/cis ratios of 12:1–28:1
(15 examples).
bisquinoline[17] complexes have been reported as
chiral catalysts for asymmetric Nazarov cyclizations.
However, with regard to asymmetric Nazarov
cyclizations, the combination of low catalyst loadings,
high enantioselectivities, high diastereoselectivities,
and high yields is still a formidable challenge, even
for favorably activated substrates.
Relevant to this study, Frontier and Eisenberg
reported highly reactive dicationic constitutionally
and configurationally well-defined iridium(III)
Keywords: Nazarov cyclization; chiral Lewis acid;
asymmetric catalysis; chiral-at-metal; iridium; rhodium.
complexes for catalyzing
a
polar Nazarov
cyclization[20] and
a
tandem Nazarov/Michael
addition sequence[21] with impressive reaction rates
although the products were formed racemic. The high
catalytic activity was traced back to the unusual
electrophilicity of the iridium(III) complexes
combined with a two-point activation of the
substrates at two adjacent coordination sites of the
iridium(III) catalyst.
The Nazarov cyclization represents a powerful
method to generate five-membered carbocycles,
namely highly substituted cyclopentenones, which
are a frequently occurring structural motif in natural
products and bioactive compounds and their
precursors.[1-3] In recent years, significant efforts have
been devoted to the development of catalytic methods
for asymmetric Nazarov cyclizations.[4] Typically,
either a chiral Brønsted acid or a chiral Lewis acid
(LA) coordinates to a divinyl ketone or aryl vinyl
ketone substrate and triggers a conrotatory 4-
electrocyclization of an intermediate pentadienyl
cation, which is followed by a deprotonation /
reprotonation sequence to provide the final chiral
cyclopentenone (Figure 1, A).[5-19] The asymmetric
induction in this process takes place during the key
electrocyclization step or during the final
reprotonation step.[7,10,18b,19] With respect to chiral
Lewis acidic catalysts, chiral bis-oxazoline,[6,8,14,16]
We
octahedral iridium(III) and rhodium(III) complexes
bearing two cyclometalated 5-tert-butyl-2-
recently
introduced
hexacoordinated,
phenylbenzoxazoles or the analogous benzothiazole
ligands in addition to two exchange-labile
acetonitriles as a new class of asymmetric catalysts
(Figure 1, B).[22] With all ligands being achiral,
chirality is induced upon the asymmetric assembly of
the cyclometalated ligands around the stereogenic
metal center. This arrangement is configurationally
stable, providing either
a
left-handed (-
configuration) or a right-handed (-configuration)
propeller, which is responsible for the asymmetric
induction.[23] Over the past few years, we[22] and
others[24,25] have demonstrated the versatility of this
class of catalysts for a variety of asymmetric
reactions. However, in the majority of the so far
pyridine-2,6-bisoxazoline,[5-7,10,12]
and
tris-
oxazoline[11] complexes of copper(II),[6,8,11,14,16] but
also of other metals, such as scandium(III),[5,7,10]
1
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
reported applications, N,O-bidentate coordinating
rhodium(III) complex Δ-RhO[29] (entry 3) provided
desired cyclopentenone product 2a with high
enantioselectivities at 50 °C at catalyst loadings of 10
mol% (entries 1-3). Rhodium catalyst Δ-RhO was
found to be slightly superior compared to iridium
congeners Λ-IrS and Λ-IrO with respect to
enantioselectivity and moreover was found to be
superior in terms of catalytic activity, which allowed
us to perform the reaction at room temperature
(compare entries 4-6).
substrates
were
employed,
particularly
and
2-
2
acylimidazoles,
N-acylpyrazoles,
acylpyridines.[26] Herein, we now demonstrate that
these
bis-cyclometalated
iridium(III)
and
rhodium(III) complexes are also excellent catalysts
for the asymmetric Nazarov cyclization of
dihydropyran- (1) and indole-functionalized (3) -
unsaturated -ketoesters, which are supposed to be
activated via O,O-bidentate coordination. With
catalyst loadings of merely 2 mol%, high yields and
high stereoselectivities were achieved (Figure 1, B).
Table 1. Initial Experiments with Dihydropyran Substrate
1aa)
Entry Cat.
t (h) T (°C) Conv.b)
ee (%)c)
1
2
3
4
5
6
24 50
24 50
24 50
44 r.t.
44 r.t.
12 r.t.
near complete 91 (5R,6S)
near complete 91 (5R,6S)
-IrO
-IrS
-RhO
-IrS
-IrO
-RhO
full
-93 (5R,6S)
n.d.d)
partial
partial
full
n.d.
-93 (5S,6R)
a)Reaction conditions: Substrate 1a (16.5 µmol) and the
catalyst (1.65 µmol) in 1,2-dichloroethane at c = 0.05 M
and at the indicated temperature. E/Z ratio of substrate 1a
of 20:1 determined by 1H-NMR. b)Estimated by a
combination of TLC and HPLC analysis. c)Determined
from the crude product mixtures by HPLC analysis on
chiral stationary phase; exclusively determined for the
main trans diastereomer. d)n.d. = not determined.
Due to the satisfactory results obtained with IrS and
in consideration of the easier synthesis and
availability of IrS compared to RhO,[26,28,29] we
decided to continue our study with catalyst -IrS and
screened for optimal reaction conditions. When we
increased the concentration of substrate 1a in 1,2-
dichloroethane (DCE) from 0.05 M (Table 1) to 0.3
M (Table 2) and slightly reduced the temperature
from 50 °C to 40 °C while maintaining a catalyst
loading of 10 mol%, the enantioselectivity for 2a
increased from 91% ee to 93% ee (Table 2, entry 1).
The addition of 10% (v/v) water did not change the
outcome in terms of conversion and stereoselectivity
(entry 2). Furthermore, the use of dry solvent and the
execution under inert gas atmosphere had no effect
on selectivity and yield (entry 3), which indicates that
dry solvents are neither necessary nor beneficial. To
our delight, we could decrease the catalyst loading
from 10 mol% to 2 mol% without a drop in
performance (entry 4). When we replaced solvent
DCE with hexafluoro-2-isopropanol (HFIP), the
enantioselectivity slightly declined but the reaction
was significantly accelerated (entry 5). Eventually, a
mixture of DCE and 1 equivalent of HFIP (with
respect to substrate 1a) was found to give virtually
the same enantioselectivity as pure DCE but
Figure 1. A) General mechanism of Lewis-acid-catalyzed
Nazarov cyclizations. B) Lewis-acid-catalyzed Nazarov
cyclizations with chiral-at-metal complexes IrO, IrS, and
RhO, which are presented in this work. LA = Lewis acid.
We wondered if our recently developed chiral-at-
metal Lewis acids would be suitable catalysts for
asymmetric Nazarov cyclizations of dienone
substrates and therefore started with investigating the
Nazarov cyclization of dihydropyran substrate 1a
(Table 1). To our delight, both bis-cyclometalated
iridium(III) complexes Λ-IrO[27] (entry 1) and Λ-
IrS[26,28] (entry 2) as well as bis-cyclometalated
2
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
accelerated the reaction significantly and was hence
selected as the solvent mixture of choice. Under these
conditions, the reaction was completed within 7 h at
40 °C at a catalyst loading of 2 mol% Λ-IrS, and
cyclopentenone product 2a was provided with 93%
ee with respect to the major trans diastereomer (entry
6). Other investigated solvents turned out to be less
suitable (entries 7-14).
substrate containing the heteroaromatic substituent R
= thiophen-2-yl (product 2g). In this case, full
conversion was found after 23 h and the product was
isolated in 98% yield with 89% ee (trans
diastereomer) and a trans/cis ratio of 50:1. Finally,
we investigated substrates with electron-deficient
substituents R = p-Br-Ph (product 2h) and R = p-F-
Ph (product 2i), which also gave good results (85%
and 91% yield; >99% ee and 96% ee (trans
diastereomers); trans/cis ratios of 20:1 and 15:1; full
conversion after 23 h and 14 h).[11] It is important to
note that for all reactions substrates were employed
as E/Z-mixtures with E/Z-ratios ranging from 3:1 to
>30:1 although the Nazarov cyclization products
were obtained in all cases with high diastereo- and
enantioselectivities. For example, product 2b was
obtained with 97% ee and 19:1 dr although the
dienone substrate featured a low E/Z-ratio of just 3:1,
thus demonstrating a stereoconvergent reaction. This
can be traced back to well-established Lewis acid and
transition metal catalyzed E/Z-isomerizations of the
dienone substrates.[30-34]
Table 2. Optimization of Reaction Conditions for
Dihydropyran Substrate 1a with -IrS catalyst.a)
Entry -IrS
1
2
Solvent
10 mol% DCE
10 mol% DCE /10% H2O 13 full
t (h) Conv.b) ee (%)c)
13 full
93
93
93
93
90
93
3
4
5
10 mol% DCE
2 mol% DCE
2 mol% HFIP
13 full
13 full
7
full
6
2 mol% DCE/1 eq HFIP 7
full
7
8
9
10
11
12
13
14
2 mol% CHCl3
2 mol% EtOAc
2 mol% DME
2 mol% MeCN
2 mol% toluene
2 mol% THF
14 ca. 95% 92
14 low
14 low
14 low
80
30
30
30
20
20
3
7
7
7
low
low
low
2 mol% MTBE
2 mol% MeOH
14 low
a)Reaction conditions: Substrate 1a (14.5–56.0 µmol) and
Λ-IrS (0.70–1.45 µmol) in the indicated solvent at c = 0.3
M, at a temperature of 40 °C, and for the indicated time
under standard atmosphere. E/Z ratio of substrate 1a of
1
20:1 determined by H-NMR. b)Reaction was performed
under an inert gas atmosphere in a dry solvent. c)Estimated
by
a
combination of TLC and HPLC analysis.
d)Determined from crude product mixtures by HPLC
analysis on chiral stationary phase; exclusively determined
for the trans diastereomer.
With optimized reaction conditions in hand (Table 2,
entry 6), we then investigated the scope for the
dihydropyran-functionalized
α-unsaturated
β
ketoesters (1; Scheme 1). For substrates with
electronically neutral aromatic substituents R = Ph
(product 2b), R = 1-naphthyl (product 2c), and R = 2-
naphthyl (product 2d), full conversion was found
after reactions times of 12-15 h and products 2b–d
were isolated in yields of 92-96% with ee values
ranging from 92-97% (ee values for the trans
diastereomers) and dr values in the range of 19:1–
29:1 (trans/cis). Substrates with electron-rich
aromatic substituents p-MeO-Ph (product 2a), p-Me-
Ph (product 2e), and o-Me-Ph (product 2f) gave
comparable results (86-95% yields; 93-95% ee (trans
diastereomers); trans/cis 18:1-28:1; full conversion
found for all three after 14 h). We also tested a
Scheme 1. Scope for the Nazarov cyclization of
dihydropyran-functionalized α-unsaturated β-ketoesters.
Reaction conditions: E/Z-mixture of substrate 1 (1.0
equiv.; approx. 80-90 µmol) with catalyst Λ-IrS (2 mol%)
in a mixture of DCE with 1.0 equiv. HFIP (1 equiv. with
respect to substrate 1) at c = 0.3 M in a rubber-sealed,
screw-capped vial kept at 40 °C for the indicated time.
E/Z-ratios of substrates were ranging from 3:1 to >30:1
(see SI for more details). Isolated yields provided. The dr
values (trans/cis) were determined by 1H NMR analysis of
the crude product mixtures. The ee values were determined
3
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
for the trans diastereomers from isolated products by
HPLC analysis on chiral stationary phase.
for Nazarov cyclizations has been reported for
iridium catalysts and binol phosphates as
organocatalysts,[18a,20b] whereas other metal-based
Lewis acid catalysts are commonly known for
providing the trans product.[7,11,14] However, after
prolonged reaction times with catalyst IrS (or RhO)
the trans diastereomers became predominant
(thermodynamic product). As the trans/cis
equilibration was found to be very slow under the
applied cyclization conditions, which led to partial
decomposition of the products, we relied in case of
all indole products (4) on a modified trans/cis
equilibration protocol from Rueping and coworkers,
which was applied after the actual cyclization:[18a]
The crude cyclized indole products were dissolved in
CH2Cl2 and simply stirred with basic aluminum oxide
as weak insoluble base for 24 h at room temperature
(details in the experimental section). With optimized
reaction conditions (Table 3, entry 11) and the
described trans/cis equilibration protocol in hands, we
next investigated the scope for the indole-
functionalized α-unsaturated β-ketoesters. The results
of this scope screening are shown in Scheme 2.
Encouraged by these promising results with the
dihydropyran-functionalized
α-unsaturated
β-
ketoesters, we next decided to study indole-
functionalized α-unsaturated β-ketoesters (3). The
reaction conditions optimization for these substrates
are shown in Table 3. Interestingly, compared to
dihydropyran substrate 1a (Table 2), the Λ-IrS-
catalyzed Nazarov cyclization with indole substrate
3a displayed a distinct solvent dependance (Table 3):
DCE, as well as a variety of other common solvents,
were found to be completely unsuitable for this
reaction (entries 1-9). In contrast, a 1:1 mixture of
DCE and HFIP provided desired cyclization product
4a with 90% ee (entry 10; ee of the major trans
diastereomer). Eventually, pure HFIP turned out to be
the solvent of choice, which provided full conversion
after 24 h at 50 °C and an enantioselectivity of 93%
for product 4a (entry 11).
For most of the indole-functionalized substrates,
we obtained, apart from a few exceptions (products 4i,
4n, and 4o), comparable results in terms of
stereoselectivity (88-97% ee) compared to the
dihydropyran-functionalized substrates. Moreover,
the indole-functionalized products were, apart from
one exception (product 4o), obtained in good albeit
slightly lower yields than the dihydropyran-
functionalized products (70-93% yield). The
observed dr values were, after the aluminum oxide
induced cis/trans equilibration, in the same range as
the dr values of the dihydropyran-substituted
products (trans/cis 12:1-28:1). In terms of isolated
yields, p-MeO-Ph substituted products 4d and 4h, 2-
thiophenyl substituted product 4e, p-Br-Ph
substituted product 4f, p-Me-Ph substituted product
4g, p-F-Ph substituted product 4j, o-(N-carbazolyl)
Ph substituted product 4l, 3,4-Me2-Ph substituted
product 4m, and p-NMe2-Ph substituted product 4n
were all obtained in >80% yield. Ph substituted
products 4a and 4k, 2-naphthyl substituted product
4b, and 1-naphthyl substituted product 4c were
obtained with yields in the range of 70–80%. In terms
of selectivity, ee values of more than 95% were found
for 1-naphthyl substituted product 4c, p-Br-Ph
substituted product 4f, p-F-Ph substituted product 4j,
phenyl substituted product 4k, and o-(N-carbazolyl)
Ph substituted product 4l. It is remarkable that the
cyclization of sterically congested product 4l worked
so well. Enantioselectivities of 90–95% were found
for Ph substituted 4a, 2-naphthyl substituted 4b, 2-
thiophenyl substituted 4e, p-Me-Ph substituted 4g and
3,4-Me2-Ph substituted 4m. For p-MeO-Ph
substituted 4d and 4g, ee values of 88% were found
in both cases. Cyclohexyl substituted 4i was obtained
with modest 58% ee with both catalysts Λ-IrS and Δ-
RhO, which is, however, a notable result for an
alkylated Nazarov product in consideration of
previous literature reports.[11,14] As expected, Δ-RhO
Table 3. Optimization of Reaction Conditions for Indole
Substrate 3a with Λ-IrS as Catalyst.a)
Entry Solvent
T (°C) Conv.
ee (%)
1
2
3
4
5
6
7
8
DCE
DCE
CHCl3
MeNO2
DMF
40
50
60
60
60
60
60
60
60
none
trace
none
trace
trace
none
none
trace
trace
n.a.
n.d.
n.a.
n.d.
n.d.
n.a.
n.a.
n.d.
n.d.
THF
toluene
EtOAc
dioxane
9
10
11
DCE/HFIP 1:1 50
HFIP 50
ca. 95% 90 (1R,2S)
full 93 (1R,2S)
a) Reaction conditions: Substrate 3a (28.5 µmol) and Λ-IrS
(0.6 µmol) in the indicated solvent at c = 0.3 M and at the
indicated temperature for 24 h under standard atmosphere
in a screw-capped vial. E/Z ratio of substrate 3a of 20:1
was determined by 1H-NMR. b)Estimated by a combination
of TLC and HPLC analysis. c)Determined from crude
product mixtures by HPLC analysis on chiral stationary
phase; exclusively determined for the trans diastereomer.
d)n.a. = not applicable. e)n.d. = not determined.
Notably, we observed during our experiments with
indole substrate 3a that the cis diastereomer product
was initially predominant in the reaction mixture
(kinetic product). In case of other indole-
functionalized α-unsaturated β-ketoesters (3), we
observed for short reaction times also at least initially
low trans/cis ratios (Scheme 2). Such a cis selectivity
4
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
catalyzed this reaction faster than Λ-IrS: full
conversion was reached after 170 h with Λ-IrS and
after 98 h with Δ-RhO. Also, p-NMe2-Ph substituted
4n was obtained with modest 60% ee. Finally, 2-furyl
substituted 4o was obtained in 46% yield with an ee
of 50%. In this respect, it is noteworthy that we
observed the formation of a considerable amount of
side products in case of product 4o, which we did not
observe in case of all other products 4a-n.[14]
reaction time. E/Z-ratios of substrates were ranging from
7:1 to >30:1 (see SI for more details). Isolated yields
1
provided. The dr values (trans/cis) were determined by H
NMR analysis of the crude product mixtures. Values in
brackets are the dr values observed before Al2O3-induced
equilibration. The ee values were determined for the trans
diastereomers from isolated products by HPLC analysis on
chiral stationary phase.
The proposed mechanism, which is based on
published work on the mechanism of the Nazarov
cyclization[1] and the established properties of our
chiral-at-metal catalysts,[22] is shown in Figure 2. An
O,O-bidentate coordination[20b] of the -unsaturated
-ketoesters to the iridium- or rhodium-based Lewis
acids (substrate/catalyst complex A) leads to an
electronic activation (resonance structure B) and
induces a conrotatory 4-cyclization to afford a
catalyst-bound cyclopentadienyl cation (C), in which
the asymmetric induction is provided by the helical
chirality of the bis-cyclometalated C2-symmetrical
Lewis acid. A subsequent deprotonation (D) and
reprotonation generate the catalyst bound Nazarov
product (E). Upon release of the product, a new
catalytic cycle can be initiated. For the indole
substrates, the kinetic product is the cis diastereomer,
which then either slowly epimerizes to the
thermodynamically more stable trans diastereomer
under the reaction conditions or faster upon treatment
with base. The benefit of hexafluoroisopropanol
(HFIP) can be rationalized with its function as a weak
acid which facilitates the release of the catalyst-
bound product and thereby suppresses product
inhibition.
Scheme 2. Scope for the Nazarov cyclization of indole-
functionalized α-unsaturated β-ketoesters. Reaction
conditions for step 1: E/Z-mixture of substrate 3 (1.0
equiv.; approx. 70−90 µmol) with catalyst Λ-IrS (or Δ-
RhO; each 2 mol%) in HFIP at c = 0.3 M in a rubber-
sealed, screw-capped vial kept at 50 °C for the indicated
5
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
Figure 2. Proposed mechanism for the Nazarov cyclization
including activation, asymmetric induction and
diastereocontrol shown for -IrS.
bidentate coordination of the substrate to the catalyst
restricts the substrate scope to divinyl and aryl vinyl
ketones with an additional coordinating ester group in
β-position, the versatility of the ester group for
further functional group interconversions in
In summary, attractive key features of the here
presented Nazarov cyclizations with chiral-at-metal
catalyst IrS and for selected examples with IrO and
RhO are 1.) the low catalyst loadings of just 2 mol%,
2.) no requirement for expensive counteranions such
combination
with
the
observed
high
stereoselectivities should render this method
attractive for synthetic applications.
–
–
as BArF–, NTf2 or SbF6 , 3.) dry solvents and inert
gas atmosphere are neither required nor beneficial,
and 4.) Nazarov cyclizations with two different
substrates, namely dihydropyran- (1) and indole-
functionalized (3) α-unsaturated β-ketoesters, were
both performed with one single catalyst Λ-IrS in
short reaction times and with satisfactory selectivities
and yields.[11,14,17] Even though the presented method
just requires 2 mol% of catalyst Λ-IrS, the reaction
times for the dihydropyran substrates (1) remained <
Experimental Section
Representative Nazarov cyclization for dihydropyran
substrate: A vial (1.5 mL) was charged with an E/Z-
mixture of dihydropyran-functionalized α-unsatured β-
ketoester 1a (25.2 mg, 83.5 µmol, 1.00 equiv.), catalyst Λ-
IrS (1.6 mg, 1.7 µmol, 2 mol%), and a stock solution of
DCE (280 µL) containing 1 equiv. of HFIP with respect to
substrate 1a. The vial was then tightly capped with a
rubber-sealed screw cap, homogenized by sonication (1
min), and kept at 40 °C for 14 h after which TLC analysis
indicated full conversion. The solvent was removed under
1
24
h
while providing excellent yields and
reduced pressure and the dr value determined by H NMR
analysis of the crude product: trans/cis 18:1. Finally, the
crude product was purified by flash chromatography (n-
hexane/EtOAc 3:1) to give desired Nazarov cyclization
product 2a as a colorless viscous oil (21.7 mg, 71.8 µmol,
86%). Enantiomeric excess of the trans diastereomer of the
isolated product determined by chiral HPLC analysis: 93%
ee (Chiralpak AD-H column (5 µm; 25 cm x 4.6 mm), λ =
238 nm, n-hexane / isopropanol 70:30, 0.8 mL/min,
column temp.: 25 °C; tR (major) = 10.0 min, tR (minor) =
12.8 min).
enantio¬selectivities, even for more challenging
products such as p-Br-Ph substituted 2h and p-F-Ph
substituted 2i (Scheme 1). In contrast, 20 mol% of a
copper(II) bis-oxazoline catalyst was required as
recently reported by Tang and coworkers to provide
2h and 2i after > 24 h with comparable selectivities
but lower yields (Tang et al.: 2h after 57 h with 76%
yield and 96% ee; 2i after 30 h with 69% yield and
96% ee).[11] Furthermore, we obtained with 2 mol%
of catalyst Λ-IrS comparable yields and
enantioselectivities as Rueping and coworkers with a
recently reported copper(II) bis-oxazoline catalyst,
which they usually employed in a loading of 5 mol%,
for indole-functionalized Nazarov products 4.[14] In
this respect, it is also remarkable that sterically
congested indole product 4l could be obtained with
just 2 mol% of Λ-IrS with excellent yield and high
stereoselectivity (Scheme 2). Accordingly, the here
reported Lewis acidic chiral-at-metal complexes may
be employed as catalysts for challenging asymmetric
Nazarov cyclizations.
27
[α]D = –228 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): δ = 7.05 (d, J = 8.6 Hz, 2H, HAr), 6.87 (d, J = 8.6
Hz, 2H, HAr), 4.22–4.09 (m, 3H, HAliph), 3.79 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 3.29 (d, J = 2.2 Hz, 1H, CH),
2.28–2.07 (m, 2H, HAliph), 2.02–1.83 (m, 2H, HAliph) ppm;
13C NMR (75 MHz, CDCl3): δ = 193.2, 169.0, 159.3, 149.8,
147.8, 131.9, 128.5, 114.7, 67.2, 59.6, 55.5, 52.9, 47.1,
22.4, 21.5 ppm; IR (ATR): v ̃ = 2952 (w), 2929 (w), 2845
(w), 1739 (m), 1713 (s), 1648 (w), 1611 (w), 1511 (w),
1437 (w), 1400 (w), 1301 (w), 1249 (m), 1166 (w), 1121
(w), 1066 (w), 1032 (w), 978 (w), 915 (w), 836 (w), 567
(w) cm–1; HRMS (ESI): m/z calcd. for C17H18O5Na1
[M+Na]+: 325.1046; found: 325.1048.
In conclusion, we have applied chiral-at-metal
iridium and rhodium catalysts to 24 different dienone
Representative
Nazarov-cyclization
for
indole
Nazarov
cyclization
substrates,
namely
9
β-
substrate: A vial (1.5 mL) was charged with an E/Z-
mixture of indole-functionalized α-unsatured β-ketoester
3a (26.0 mg, 85.2 µmol, 1.00 equiv.), catalyst Λ-IrS (1.6
mg, 1.7 µmol, 2.0 mol%) and HFIP (280 µL). The vial was
then tightly capped with a rubber-sealed screw cap,
homogenized by sonication (1 min), and kept at 50 °C for
7 h after which TLC analysis indicated full conversion.
The solvent was removed under reduced pressure and the
dihydropyran-functionalized
α-unsaturated
ketoesters and 15 indole-functionalized α-unsaturated
β-ketoesters. The majority of the desired Nazarov
cyclization products were obtained in good to
excellent yields and enantioselectivities as well as
with satisfactory trans/cis ratios. Dry solvents and
inert gas atmosphere are not required which allows a
highly convenient reaction setup. Moreover, all 24
Nazarov cyclizations could be performed with a
catalyst loading of just 2 mol% within < 24 h for all
dihydropyran substrates and within ≤ 24 h with
respect to the actual cyclization step for most of the
indole substrates. These low catalyst loadings in
combination with the inexpensive (achiral) ligands in
the ligand sphere of the chiral iridium and rhodium
catalysts should offset the higher cost for iridium and
rhodium. Furthermore, although the requirement for a
1
dr of the crude product determined by H NMR analysis:
trans/cis 1:1.8. The crude product was then dissolved in
CH2Cl2 (7 mL), basic Al2O3 powder (140 mg; Sigma
Aldrich, 58 Å pore size, pH 9.5 ± 0.5 in water) added, and
the mixture stirred at r.t. for 24 h. Next, the crude mixture
was passed through a short plug of silica gel with
EtOAc/MeOH (removal of the powdered Al2O3), the
solvent removed under reduced pressure, and the dr of the
crude, equilibrated product determined by 1H NMR
analysis: trans/cis 15:1. Finally, the crude product was
purified by flash chromatography (n-hexane / EtOAc 3:1)
to give desired Nazarov cyclization product 4a as a
colorless solid (19.4 mg, 63.5 µmol, 75%). Enantiomeric
excess of the trans diastereomer of the isolated product
determined by chiral HPLC analysis: 93% ee (Chiralpak
6
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10.1002/adsc.201701546
Advanced Synthesis & Catalysis
AD-H column (5 µm; 25 cm x 4.6 mm), λ = 254 nm, n-
hexane / isopropanol 90:10, 0.6 mL/min, column temp.:
25 °C; tR (major) = 23.0 min, tR (minor) = 32.1 min).
[9] I. Walz, A. Togni, Chem. Commun. 2008, 4315–4317.
[10] K. Yaji, M. Shindo, Synlett 2009, 2524–2528.
27
[α]D = –102 (c 1.0, CH2Cl2); 1H NMR (300 MHz,
[11] P. Cao, C. Deng, Y.-Y. Zhou, X.-L. Sun, J.-C. Zheng,
Z. Xie, Y. Tang, Angew. Chem. Int. Ed. 2010, 49,
4463–4466.
CDCl3): δ = 9.29 (br s, 1H, NH), 7.55–7.48 (m, 1H, HAr),
7.45–7.21 (m, 8H, HAr), 7.14–7.05 (m, 1H, HAr,), 5.08 (d, J
= 2.9 Hz, 1H, HAliph), 3.92 (d, J = 2.9 Hz, 1H, HAliph), 3.85
(s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ = 186.8,
169.6, 148.0, 144.6, 140.9, 137.2, 129.2 (2C), 128.3, 127.6,
127.5 (2C), 123.1, 122.4, 121.4, 113.8, 67.9, 52.9, 44.2
ppm; IR (ATR): v = 3266 (br m), 3067 (w), 3028 (w),
2950 (w), 1733 (m), 1676 (s), 1620 (w), 1541 (w), 1486
(w), 1438 (w), 1370 (w), 1320 (m), 1246 (m), 1158 (m),
1101 (w), 1063 (w), 1016 (w), 910 (w), 851 (w), 743 (m),
702 (m), 618 (w), 506 (w), 430 (w) cm–1; HRMS (ESI):
m/z calcd. for C19H15N1O3Na1 [M+Na]+: 328.0944; found:
328.0944.
[12] M. Kawatsura, K. Kajita, S. Hayase, T. Itoh, Synlett
2010, 1243–1246.
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6288–6291.
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2015, 2, 811–814.
Acknowledgements
[17] T. Takeda, S. Harada, A. Nishida, Org. Lett. 2015, 17,
5184–5187.
This
work
was
supported
by
the
Deutsche
Forschungsgemeinschaft (ME 1805/11-1 and ME 1805/13-1) and
by a LOEWE research cluster (SynChemBio) of the State of
Hesse, Germany. V. A. L. thanks the RUDN University Program
5-100 for support.
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see: a) M. Rueping, W. Ieawsuwan, A. P. Antonchick,
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8
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Advanced Synthesis & Catalysis
COMMUNICATION
Asymmetric Nazarov Cyclizations Catalyzed by
Chiral-at-Metal Complexes
Adv. Synth. Catal. Year, Volume, Page – Page
Thomas Mietke, Thomas Cruchter, Vladimir A.
Larionov, Tabea Faber, Klaus Harms, Eric
Meggers*
9
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