Rhodium(II)-catalyzed enantioselective synthesis of troponoids

Article abstract of DOI:10.1002/anie.201502233

We report a rhodium(II)-catalyzed highly enantioselective 1,3-dipolar cycloaddition reaction between the carbonyl moiety of tropone and carbonyl ylides to afford troponoids in good to high yields with excellent enantioselectivity. We demonstrate that α-diazoketone-derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity. Decisive dipoles: In the rhodium(II)-catalyzed asymmetric 1,3-dipolar cycloaddition of tropone with carbonyl ylides, a programmable chemoselective reaction with the keto group or the 6 π system of tropone was controlled by the substrate (see scheme). The developed method enables the synthesis of complex products in highly enantiomerically enriched form.

Full text of DOI:10.1002/anie.201502233

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502233
German Edition: DOI: 10.1002/ange.201502233
Asymmetric Cycloaddition
Rhodium(II)-Catalyzed Enantioselective Synthesis of Troponoids**
Sandip Murarka, Zhi-Jun Jia, Christian Merten, Constantin-G. Daniliuc,
Andrey P. Antonchick,* and Herbert Waldmann*
Abstract: We report a rhodium(II)-catalyzed highly enantio-
selective 1,3-dipolar cycloaddition reaction between the car-
bonyl moiety of tropone and carbonyl ylides to afford
troponoids in good to high yields with excellent enantioselec-
tivity. We demonstrate that a-diazoketone-derived carbonyl
ylides, in contrast to carbonyl ylides derived from diazodiketo-
esters, undergo [6 + 3] cycloaddition reactions with tropone to
yield the corresponding bridged heterocycles with excellent
stereoselectivity.
medicinal importance.[4] However, catalytic enantioselective
cycloaddition reactions of tropones are rare.[5]
Dirhodium(II)-complex-catalyzed 1,3-dipolar cycloaddi-
tion reactions of diazocarbonyl compounds are powerful
transformations for the construction of complex oxapoly-
cyclic systems,[6–8] and catalytic enantioselective reactions
employing chiral RhII carboxylates have been developed.[9,10]
In contrast to non-asymmetric transformations,[11–13] enantio-
selective 1,3-dipolar cycloaddition reactions of carbonyl
ylides with heterodipolarophiles have rarely been explored.[14]
There are only three reported cases of the catalytic enantio-
selective 1,3-dipolar cycloaddition of carbonyl ylides with
aldehydes as the dipolarophile,[14] and the corresponding
cycloaddition with ketones is unprecedented. The enantiose-
lective cycloaddition of tropone with carbonyl ylides has not
yet been explored. These facts inspired us to investigate the
reactivity of tropone in rhodium(II)-catalyzed tandem car-
Biology-oriented synthesis (BIOS) serves as a guiding
principle for the design and synthesis of focused compound
collections with diverse bioactivity.[1] In particular, natural
products (NPs) provide inspiration for BIOS, since they
represent the area of chemical space explored by nature, and
hence can be regarded as “privileged” starting points for the
syntheses. NPs are frequently complex and rich in stereogenic
centers. Therefore, the development of efficient enantiose-
lective methods is highly desirable.[2] The tropone scaffold
defines the structural core of the troponoids, which comprise
numerous natural products with diverse bioactivity.[3] Tro-
pones are highly valuable and readily available seven-
membered-ring-containing compounds that can undergo
cycloaddition reactions to afford annulated products of high
bonyl-ylide-formation/1,3-dipolar-cycloaddition
reactions,
which should rapidly generate molecular complexity and
provide efficient access to structurally diverse troponoid
scaffolds (Scheme 1).
[*] Dr. S. Murarka, Z.-J. Jia, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Max-Planck-Institut fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Scheme 1. Plausible cycloaddition reactions of tropone and a carbonyl
ylide.
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
Z.-J. Jia, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Technische Universitꢁt Dortmund
Fakultꢁt Chemie und Chemische Biologie, Chemische Biologie
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Herein, we report a catalytic enantioselective intermo-
lecular cycloaddition reaction between carbonyl ylides
derived from diazodiketoesters 2 and tropone (1) as the
dipolarophile to provide a diverse range of 5-alkoxylactone
derivatives 3 (Table 2). We also demonstrate that carbonyl
ylides derived from a-diazoketones undergo higher-order
cycloaddition reactions, which is remarkable, since enantio-
selective transformations involving tropone as a 6p dipolar-
ophile are rare.[5b–e] The chemoselective reaction of carbonyl
ylides with the conjugated 6p system of tropone, instead of
the carbonyl functionality, provides efficient and facile access
to bridge-containing tricyclic heterocycles embodying four
stereogenic centers (Table 3). The observed substrate-con-
trolled chemoselective switch in reactivity provides a highly
interesting example of programmable synthesis.[15,2e]
Dr. C. Merten
Ruhr-Universitꢁt Bochum, Lehrstuhl fꢀr Organische Chemie II
Universitꢁtsstrasse 150, 44801 Bochum (Germany)
Dr. C.-G. Daniliuc
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149, Mꢀnster (Germany)
[**] Z.-J.J. thanks the International Max Planck Research School in
Chemical Biology for a fellowship. C.M. thanks the FCI for a Liebig
Fellowship and the Deutsche Forschungsgemeinschaft (DFG) for
support through the Cluster of Excellence RESOLV (“Ruhr Explores
Solvation”, EXC 1069). This research was supported by the
European Research Council under the Seventh Framework Pro-
gramme of the European Union (FP7/2007-2013; ERC Grant 268309
to H.W.) and by the Max Planck Society.
We began our studies by treating tropone (1) with
diazodiketoester 2a (1.5 equiv) in the presence of various
rhodium(II) carboxylates (1 mol%) in PhCF3 as the solvent at
room temperature (Table 1, entries 1–6). The reaction pro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502233.
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Table 1: Screening of reaction conditions for the synthesis of 3a.[a]
fused phthaloyl catalyst C5 did not increase the enantiose-
lectivity of the formation of 3a substantially (67% ee;
Table 1, entry 4), an improvement in yield and enantioselec-
tivity was observed with the 1,8-naphthalimide-tert-leucine
derived catalyst C6 (77% ee; entry 3). Gratifyingly, the
tetrachlorophthalimide-derived catalyst C3 developed by
Hashimoto and co-workers[10] delivered the cycloadduct 3a
in 74% yield and with 99% ee (Table 1, entry 5). Interest-
ingly, a sharp decline in enantioselectivity was observed upon
the replacement of C3 with the corresponding fluoro-con-
taining catalyst C4 (Table 1, entry 6). Subsequently, we
screened a variety of solvents and investigated the use of
different catalyst loadings. However, none of the solvents
tested gave better results than PhCF3 (see the Supporting
Information). At a lower temperature, the reaction did not
proceed (Table 1, entry 7). High enantioselectivity was
retained even with catalyst loadings as low as 0.05 mol%,
but yields were lower and longer reaction times were required
(see the Supporting Information). The absolute configuration
of cycloadduct 3a was established by vibrational circular
dichroism (VCD) spectroscopy, and the configuration of the
other cycloadducts was assigned by analogy (see the Support-
ing Information).
Entry
Catalyst (mol%)
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
C1 (1)
C2 (1)
C6 (1)
C5 (1)
C3 (1)
C4 (1)
C3 (1)
C3 (0.25)
C3 (0.05)
3
3
3
3
3
74
34
89
71
74
58
trace
74
26
62
13
77
67
99
50
n.d.
98
98
3
7[b]
8
12
15
24
9[c]
[a] Reaction conditions: 1 (0.1 mmol), 2a (1.5 equiv), catalyst, solvent:
PhCF3 (0.1m), room temperature. [b] The reaction was carried out at
08C. [c] The reaction did not proceed to completion. n.d.=not
determined. C1: [Rh2{(S)-pttl]}4]; C2: [Rh2{(S)-ptil]}4];
C3: [Rh2{(S)-tcpttl]}4]; C4: [Rh2{(S)-tfpttl]}4]; C5: [Rh2{(S)-bpttl]}4];
C6: [Rh2{(S)-nttl]}4].
Having optimized the reaction conditions, we explored
the scope of the transformation by treating tropone (1) with
a set of electronically and structurally diverse diazodiketo-
ester derivatives 2 (Table 2). The reaction was very versatile,
and various substitution patterns on the phenyl ring of
diazodiketoester 2 were tolerated. The 4-methyl- and 4-hexyl-
substituted phenyl diazo derivatives 2b and 2c underwent
ceeded smoothly in the presence of catalyst C1 to give
cycloadduct 3a as the sole product, instead of the expected
spirocyclic compound A (Scheme 2). The formation of 3a
proceeds via intermediate A through a cascade reaction. We
propose the formation of A by the [3 + 2] cycloaddition of
smooth transformation in
a completely chemoselective
manner to furnish the desired cycloadducts 3b and 3c in
good yield with excellent enantioselectivity (Table 2, entries 1
Table 2: Scope of the reaction.[a]
Entry
Product
R
Yield [%][b]
ee [%][c]
1
2
3b
3c
3d
3e
3 f
3g
3h
3i
4-MeC6H4
4-nHexC6H4
4-iPrC6H4
4-tBuC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2,5-Me2C6H3
3-F-4-MeOC6H3
Me
71
86
66
69
73
80
77
78
73
79
85
95
97
99
99
99
98
99
94
98
98
99
76
77
3[d]
4[d]
5[d,e]
6
Scheme 2. Proposed pathway for the formation of product 3a.
7
8
9[d,e]
10[d,e]
11
12
3j
3k
3l
a carbonyl ylide with the keto group of tropone. Subsequently,
under the reaction conditions, intermediate A is converted
into zwitterion B, which then undergoes cyclization and
rearrangement to generate lactone 3a.
Product 3a was obtained in 74% yield and with 62% ee
(Table 1, entry 1). The yield and enantioselectivity dropped
drastically upon the replacement of C1 with the isoleucine-
derived catalyst C2 (Table 1, entry 2). Although the benzene-
3m
iPr
[a] Reaction conditions: 1 (0.1 mmol), 2 (1.5 equiv), C3 (1 mol%),
solvent: PhCF3 (0.1m). [b] Yield of the isolated product. [c] The ee value
was determined by HPLC on a chiral stationary phase. [d] The reaction
was carried out with 2 mol% of C3. [e] The reaction was carried out with
2 equivalents of derivative 2.
2
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Table 3: Scope of the reaction.[a]
and 2). Furthermore, a high level of asymmetric induction was
maintained in the case of derivatives 2d and 2e, with sterically
encumbered substituents (Table 2, entries 3 and 4). Pleas-
ingly, aryl diazo derivatives 2 containing both electron-
donating and electron-withdrawing substituents reacted effi-
ciently with tropone to deliver the expected products 3 f–i in
high yield and with excellent enantioselectivity (94–99% ee;
Table 2, entries 5–8). Importantly, the reaction was tolerant of
ortho substitution in the dimethyl-substituted derivative 2j,
and the corresponding product 3j was obtained in 73% yield
with 98% ee (Table 2, entry 9). The efficacy of the reaction
remained unaltered in the case of 3-fluoro-4-methoxy deriv-
ative 2k, from which the product 3k was synthesized with
excellent stereoselectivity (Table 2, entry 10). The reaction
was found to be compatible with aliphatic diazodiketoester-
derived carbonyl ylides, and moderate enantioselectivity
(76% ee) was observed in the reaction of methyl-substituted
derivative 2l (Table 2, entry 11). Upon replacement of the
methyl substituent with a sterically more bulky isopropyl
substituent, a higher yield and a similar level of enantiose-
lectivity were observed in the formation of 3m (Table 2,
entry 12).
To further functionalize the products, we decided to
exploit the reactivity of the conjugated 8p system embedded
in products 3. Accordingly, a diastereoselective [8 + 2] cyclo-
addition of product 3i and N-phenyltriazolinedione (4)
yielded the fused-ring compound 5, with one tertiary and
two quaternary stereogenic centers (Scheme 3). The solid-
state molecular structure of 5 was determined by single-
crystal X-ray diffractional analysis, which unambiguously
revealed the absolute configuration of product 5 and reaf-
firmed the absolute configuration of compounds 3.
Entry
Product
Ar
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7a
7b
7c
7d
7e
7 f
C6H5
78
55
56
30
66
–
94
92
89
92
87
–
4-nHexC6H4
4-iPrC6H4
4-FC6H4
4-BrC6H4
4-MeOC6H4
[a] Reaction conditions: 1 (0.1 mmol), 6 (2.0 equiv), C3 (2 mol%),
solvent: C6H5CF3 (0.1m). All products were obtained with d.r. >20:1.
[b] Yield of the isolated product. [c] The ee value was determined by
HPLC on a chiral stationary phase.
reaction, we exposed tropone to a diverse set of a-diazoke-
tones 6 (2.0 equiv) in the presence of C3 (2 mol%) at room
temperature. Pleasingly, electronically diverse aryl diazo
carbonyl substrates with electron-rich and electron-with-
drawing substituents on the phenyl ring underwent efficient
transformation to yield the corresponding cycloadducts 7b–
e in moderate to good yield and with excellent diastereo-
(> 20:1) and enantioselectivity (Table 3, entries 2–5).
Unfortunately, we did not observe the formation of the
desired product when the electron-rich 4-methoxy-substi-
tuted derivative 6 f was used as the dipole precursor, possibly
À
as a result of competing C H insertion of the rhodium(II)
carbenoid into the activated aromatic ring. It is known that
À
the C H insertion of rhodium carbenoids can be a competitive
process with carbonyl-ylide formation and
cycloaddition.[11a] The absolute configura-
tion of cycloadduct 7a was established by
VCD spectroscopy, and the configuration of
the other cycloadducts was assigned by
analogy (see the Supporting Information).
In summary, we have developed a 1,3-
dipolar cycloaddition reaction of carbonyl
ylides derived from diazodiketoesters with
tropone under the catalysis of dirhodium
tetrakis[N-tetrachlorophthaloyl-(S)-tert-
leucinate] ([Rh2{(S)-tcpttl)}4], C3) that
affords the corresponding cycloadducts in
Scheme 3. Diastereoselective [8+2] cycloaddition of product 3i and N-phenyltriazolinedione
(4).
We then explored the use of carbonyl ylides derived from
a-diazoketones as dipoles in this transformation. This possi-
bility is intriguing owing to the reactivity difference arising
from the different HOMO/LUMO energy levels of carbonyl
ylides derived from diazodiketoesters and a-diazoketones.[11a]
Upon the treatment of the carbonyl ylide derived from a-
diazoketone 6a with tropone 1 in the presence of catalyst C3,
the bridged polyheterocyclic compound 7a was obtained as
a single diastereoisomer (> 20:1) with high enantioselectivity
(94% ee; Table 3, entry 1). In this case, the carbonyl ylide
underwent [6 + 3] cycloaddition with the conjugated triene
system of tropone. We found that the best yield was obtained
when the corresponding diazo compound was added over 1 h
by the use of a syringe pump. To explore the scope of the
good to high yields and with excellent enantioselectivity. We
also demonstrated that carbonyl ylides derived from a-
diazoketones undergo facile [6 + 3] cycloaddition reactions
with tropone to furnish the corresponding bridged tricyclic
compounds in moderate to good yields and with excellent
stereoselectivity. The substrate-controlled switch in reactivity
of tropone provides an opportunity for the catalytic enantio-
selective programmable synthesis of complex products.
Keywords: asymmetric catalysis · carbonyl ylides ·
cycloaddition · rhodium · tropone
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=
=
ylides to give both C C and C O addition products. The
product ratio was shown to be dependent on the solvent and
catalyst used.[12b]
Received: March 10, 2015
Published online: && &&, &&&&
4
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Cycloaddition
S. Murarka, Z.-J. Jia, C. Merten,
C.-G. Daniliuc, A. P. Antonchick,*
H. Waldmann*
&&&& — &&&&
Rhodium(II)-Catalyzed Enantioselective
Synthesis of Troponoids
Decisive dipoles: In the rhodium(II)-cat-
alyzed asymmetric 1,3-dipolar cycloaddi-
tion of tropone with carbonyl ylides,
a programmable chemoselective reaction
with the keto group or the 6p system of
tropone was controlled by the substrate
(see scheme). The developed method
enables the synthesis of complex prod-
ucts in highly enantiomerically enriched
form.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!