Catalytic Aerobic Oxidation and Tandem Enantioselective Cycloaddition in Cascade Multicomponent Synthesis

Article abstract of DOI:10.1002/chem.201500125

An efficient multicomponent cascade transformation for the highly diastereo- and enantioselective synthesis of complex natural product inspired polycyclic products from simple starting materials is described. The cascade is initiated by copper-catalyzed a

Full text of DOI:10.1002/chem.201500125

DOI: 10.1002/chem.201500125
Communication
&
Cascade Reactions
Catalytic Aerobic Oxidation and Tandem Enantioselective
Cycloaddition in Cascade Multicomponent Synthesis
Marco Potowski,[a, b] Christian Merten,[c] Andrey P. Antonchick,*[a, b] and
Herbert Waldmann*[a, b]
have rarely been explored and the development of novel se-
Abstract: An efficient multicomponent cascade transfor-
mation for the highly diastereo- and enantioselective syn-
thesis of complex natural product inspired polycyclic
products from simple starting materials is described. The
cascade is initiated by copper-catalyzed aerobic CÀH oxi-
dation of cyclopentadiene to cyclopentadienone followed
by double catalytic asymmetric 1,3-dipolar cycloaddition
of azomethine ylides. The cascade synthesis efficiently
yields structurally complex 5,5,5-tricyclic products with
eight stereocenters with good yields and excellent diaster-
eo- and enantiocontrol using one catalyst.
lective transformations is in high demand.[4]
Herein we describe an asymmetric multicomponent cascade
reaction consisting of the aerobic copper-catalyzed oxidation
of cyclopentadiene to cyclopentadienone followed by subse-
quent enantioselective catalytic double 1,3-dipolar cycloaddi-
tion of azomethine ylides resulting in complex natural product
inspired products with eight stereocenters. The notable feature
of the developed process is the unprecedented application of
a chiral copper complex as catalyst in two mechanistically dif-
ferent catalytic cycles in one multicomponent cascade reac-
tion.
Biology-oriented synthesis (BIOS) employs biological rele-
vance is employed as key parameter to inspire the design and
synthesis of focused compound libraries.[5,6] Natural products
and their underlying scaffolds are biologically relevant because
they define the areas of chemical space explored by nature
during evolution.[5,6] Natural product scaffolds and compound
collections inspired by them are frequently structurally and ste-
reochemically complex and the development of efficient enan-
tioselective methods for their synthesis is in high demand and
at the heart of BIOS.
Cascade reactions enable the formation of several bonds in se-
quence without isolation of intermediates, change of reaction
conditions or addition of reagents and are powerful methods
for the efficient, rapid and economic synthesis of complex mol-
ecules.[1] The major challenge to design and develop novel
enantioselectively catalyzed cascade reactions has recently
been met by enantioselective organocatalysis.[2] Over the past
decades, progress has been made in the development of
metal-catalyzed cascade transformations. Recently, remarkable
advances in the development of cascade reactions were ach-
ieved using two metal catalysts in one pot.[3] Those processes
gained increasing interest for the rapid synthesis of complex
products. Nevertheless, the combination of several catalysts in
one multicomponent reaction dramatically increases the sys-
tem’s complexity leading to undesired side reactions, catalyst
deactivation and difficulties in chemoselectivity of the transfor-
mation. Enantioselective metal-catalyzed cascade reactions
Recently, using biology-oriented synthesis (BIOS) of focused
compound libraries, we developed a novel programmable syn-
thesis of a 5,6,5-tricyclic scaffold by highly enantioselective
tandem cycloadditions (Scheme 1).[7] Inspired by these results
we became interested in the 5,5,5-tricyclic scaffold. The 5,5,5-
tricyclic scaffold is found in more than 160 natural products
(for selected examples see Figure 1) rich in bioactivity.[8] The tri-
cyclic core is predominantly cis-fused and carries multiple ste-
reogenic centers.
For the synthesis of a focused 5,5,5-tricyclic compound col-
lection, inspired by the leading natural products we envisaged
that a target scaffold approaching the complexity of the natu-
ral product structures and in which two carbon atoms would
be replaced by two nitrogen atoms might be accessible by
[a] M. Potowski, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Max-Planck-Institut fꢀr Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Fax: (+49) 231-133-2499
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
[b] M. Potowski, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Fakultꢁt Chemie und Chemische Biologie
Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
[c] Dr. C. Merten
Fakultꢁt fꢀr Chemie und Biochemie
Ruhr-Universitꢁt Bochum
Universitꢁtsstrasse 150, 44799 Bochum (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500125.
Figure 1. Structures of natural compounds with a 5,5,5-tricyclic scaffold.
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double 1,3-dipolar cycloaddition of azomethine ylides (1) with
cyclopentadienone (2) (Scheme 1).[9–11] Azomethine ylides (1)
are readily available from commercial amino acid esters and al-
dehydes. However, cyclopentadienone (2) is only accessible by
means of multistep procedures[12] and the low stability of dien-
one 2 severely complicates its use.[13] Intrigued by a recent
finding of Kumar et al.[14] for bioinspired oxygenation of acti-
vated CÀH bonds, we considered that an efficient in situ syn-
thesis of 2 could be achieved by means of CÀH bond oxidation
of the cyclopentadiene methylene group. The CÀH bonds in
the methylene group of 3 have relatively low bond dissocia-
tion energy such that the desired keto group could be selec-
tively installed by oxidation of 3. It would be desirable to
employ oxygen as an environmentally benign, highly atom-
economical oxidant, and for an aerobic oxidation, the high ac-
tivation energy of oxygen a catalyst is required.[15] Copper-
based catalysts were successfully used in the aerobic oxidation
of CÀH bonds with molecular oxygen, and notably, copper
salts may also serve as catalysts of the enantioselective 1,3-di-
polar cycloaddition of azomethine ylides (1) and various dipo-
larophiles. In light of these preconditions we envisaged the de-
velopment of a cascade reaction in which a chiral copper cata-
lyst is used for the aerobic oxidation of cyclopenta-
Scheme 1. Cascade enantioselective cycloaddition.
while application of P,N- or P,P-bidentate ligands was not suc-
cessful. With the exception of Cu(OAc)2 all tested copper salts
(including copper(I) and copper(II) sources) resulted in compa-
rable results with respect to enantioselectivity (Table 1, entries
13–15). Copper(II) triflate led to product 4a formation with
lower yield. Interestingly, also with AgOAc the desired product
4a was obtained with 92% enantioselectivity, (Table 1, entry
16), however, in only 36% yield. Decreasing the catalyst load-
diene (3) to cyclopentadienone (2) followed by
double enantioselective 1,3-dipolar cycloaddition of
azomethine ylides (1) to form the 5,5,5-tricyclic prod-
uct (4) (Scheme 1).
Table 1. Screening of reaction conditions.[a]
To establish the proposed cascade, we initially in-
vestigated the reaction of glycine ester imine 1a and
cyclopentadiene 3 in the presence of triethylamine
under air using a complex of copper(I) with (R)-Fesul-
phos[16] 5a as catalyst. To our delight we obtained
the desired double cycloaddition product 4a with
moderate yield (50%) but excellent diastereo- and
enantioselectivity (ee 97%, Table 1, entry 1). It is nota-
ble, that a S,P-ligand, such as (R)-Fesulphos, can be
successfully employed in the cascade reaction, be-
cause the aerobic oxidation of CÀH bonds usually re-
quires dinitrogen-based ligands. Furthermore, over-
oxidation of the desired product 4a was not detect-
ed. Under an argon atmosphere (Table 1, entry 2) the
yield of the double cycloaddition product 4a sub-
stantially decreased while under an oxygen atmos-
phere (Table 1, entry 3) the yield increased to 74%
without altering the enantioselectivity.
Entry
Catalyst
Ligand
Solvent
atm
d.r.[b]
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
7
8
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuBF4
CuPF6
CuOAc2
CuOTf2
AgOAc
CuBF4
5a
5a
5a
5a
5a
5a
5a
5b
CH2Cl2
CH2Cl2
CH2Cl2
THF
air
Ar
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
>95:5
>95:5
>95:5
n.d.
n.d.
>95:5
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>95:5
n.d.
>95:5
>95:5
n.d.
50
20
74
traces
traces
58[e]
n.d.
n.d.
n.d.
traces
traces
n.d.
69
traces
50
97
97
97
n.d.
n.d.
95
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
94
PhMe
MeOH
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
5 c
5d
10
11
12
13
14
15
16
17[f]
(R)-BINAP
(R)-SEGPHOS
Encouraged by these results, we investigated vari-
ous solvents for the cascade reaction (Table 1, entries
3–7). While in toluene and THF traces of the desired
product 4a were observed after 16 hours, in acetoni-
trile no conversion occurred (Table 1, entries 4–5, 7).
In methanol a high reaction rate was observed and
full conversion with respect to a-iminoester 1a
within one hour was detected. However, the yield of
the desired product 4a was lower than in CH2Cl2
(Table 1, entry 6). Investigation of different chiral li-
gands were (Table 1, entries 8–12) revealed that, no-
tably, again (R)-Fesulphos 5a yielded the best results
5a
5a
5a
5a
5a
n.d.
96
92
36
traces
n.d.
[a] Reaction conditions: chiral ligand 5 (5.5 mol%), catalyst (5 mol%), Et3N (50 mol%),
glycine ester imine 2a (1 equiv, 0.20 mmol) and cyclopentadiene 3 (0.70 mmol) in sol-
vent (0.05m) at ambient temperature. [b] Determined by 1H NMR spectroscopy of
crude reaction mixture. [c] Yield of isolated pure product 4a after chromatography on
silica gel. [d] Determined by HPLC analysis on a chiral stationary phase. [e] Isolated
after 1 h. [f] Using 2.5 mol% of catalyst and 2.75 mol% of ligand 5a. n.d. = not deter-
mined; CuBF4 = Cu(CH3CN)4BF4; CuPF6 = Cu(CH3CN)4PF6.
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ing resulted in lower conversion and only traces of the double
cycloaddition product 4a were detected (Table 1, entry 17).
Thus, the optimal reactions conditions are 5 mol% of
Cu(CH3CN)4BF4 as catalyst, 5.5 mol% of (R)-Fesulphos 5a as
chiral ligand in CH2Cl2 in the presence of Et3N as base under
oxygen atmosphere at ambient temperature.
Table 2. Scope of the cascade reaction.[a]
With the optimized reaction conditions in hand, we investi-
gated the scope of the cascade reaction using various glycine
ester imines (Table 2). The reaction proceeds with halogenated
a-iminoesters to give the cycloaddition products with good
yield (69–76%) and high diastereo- and enantioselectivity (>
95:5 d.r. and 95–98% ee, Table 2, entries 1–4). The position of
substituents (ortho, meta or para) does not influence yield or
enantioselectivity (Table 2, entries 2–4). However, the use of
methyl and ester substituents in the phenyl ring of the imines
led to decreased yields (35–47%) without any influence to the
excellent diastereo- and enantioselectivity (Table 2, entries 6–
8). Increasing catalyst loading to 10 mol% overcame this prob-
lem and higher yields (68–71%) were recorded for the desired
products 4g–4i (Table 2, entries 6–8). It is notable, that various
imines derived from polysubstituted aromatic aldehydes can
be successfully employed in the developed cascade multicom-
ponent reaction to give the desired products with similar per-
formance (Table 2, entries 9–13). Unfortunately, the reaction of
glycine ester imines obtained from heteroaromatic or aliphatic
aldehydes did not result in the formation of the desired prod-
ucts 4o and 4p (Table 2, entries 14–15). An alanine-derived
imine gave the desired product 4q with 64% yield but only
moderate enantioselectivity (Table 2, entry 16). To our delight,
scale-up experiments were successful and resulted in slightly
higher yields without any effects on the excellent diastereo- or
enantioselectivity (Table 2, entries 9–10). The application of cy-
clohexa-1,4-diene instead of cyclopentadiene resulted in the
formation of a complex inseparable product mixture.
Entry
1
Product
R1
R2
Yield [%][b]
72
ee [%][c]
4b
H
97
2
3
4c
H
H
71
69
95
98
4d
4
4e
H
76
60
98
5
6
4 f
H
H
95
98
35
(68)[d]
4g
43
(71)[d]
7
8
4h
4i
H
H
98
99
47
(72)[d]
74
(78)[e]
9
4j
H
H
98
97
68
(73)[e]
10
4k
Supported by analogy to a previous report[17] and our previ-
ous experience with the stereochemical course of 1,3-dipolar
cycloadditions of azomethine ylides and Fesulphos as cata-
lyst,[7] the regioselectivity and the absolute configuration were
determined using vibrational circular dichroism (VCD) spectros-
copy (see Supporting information for details).
11
12
4l
H
H
67
54
96
95
4m
45
(73)[d]
13
14
15
4n
4o
4p
H
H
H
98
The proposed mechanism and the transition states of the
cascade reaction sequence are shown in Scheme 2. The cas-
cade reaction is initialized by formation of peroxo-complex 6
in a reaction of Cu(CH3CN)4BF4 with (R)-Fesulphos 5a in the
presence of molecular oxygen.[18] Complex 6 abstracts hydro-
gen at the allylic position of 3 to form radical 7 which then
reacts with oxygen to give peroxy-radical 8. The reaction of 8
with 3 leads to formation of hydroperoxycyclopentadiene (9)
and regenerates radical 7. The following copper catalyzed elim-
ination of water from 9 by cleavage of the OÀO bond leads to
cyclopentadienone (2).[18] Subsequently, cyclopentadienone (2)
undergoes 1,3-dipolar cycloaddition with the azomethine ylide
derived from glycine ester imine (1). Glycine ester imine (1),
Cu(CH3CN)4BF4 and the bidentate chiral ligand (R)-Fesulphos
5a form complex A with tetrahedral coordination of CuI. De-
protonation of the complex by base leads to formation of an
azomethine ylide, which undergoes the first cycloaddition with
n.d.
n.d.
n.d.
n.d.
41
(64)[d]
16
4q
Me
73
[a] Reaction conditions: chiral ligand 5a (5.5 mol%), Cu(CH3CN)4BF4
(5 mol%), Et3N (50 mol%), glycine ester imine 1a (0.20 mmol) and cyclo-
pentadiene 3 (0.70 mmol) in CH2Cl2 (0.05m) under oxygen atmosphere at
ambient temperature. [b] Yield of isolated pure product 4 after chroma-
tography on silica gel. [c] Determined by HPLC analysis on a chiral sta-
tionary phase. d.r. > 95:5, determined by 1H NMR spectroscopy of crude
reaction mixture. [d] 10 mol% of catalyst and 11 mol% of chiral ligand 5a
were used. [e] Yield for scale up experiment using 1 mmol of imine. n.d.
= not determined.
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previously generated cyclopentadienone 2 to form compound
10. The attack proceeds via an endo transition state from the
front side (Re face with respect to C=N) to avoid unfavorable
interactions with the tBu group (Si face with respect to C=N)
of the chiral ligand 5a. The first cycloaddition product 10
serves in the second cycloaddition as dipolarophile with com-
plex A. Again, due to the steric hindrance caused by the tBu
group of ligand 5a, the attack occurs from the front (Re face
with respect to C=N). Due to destabilizing steric interactions
between the phenyl group of (R)-Fesulphos 5a and the aryl
substituent of the single cycloaddition product 10, the stereo-
selective formation of product 4 is favored.
Acknowledgements
M.P. thanks the Fonds der Chemischen Industrie for a fellow-
ship. C.M. thanks the FCI for a Liebig fellowship and the Deut-
sche Forschungsgemeinschaft (DFG) for support through the
Cluster of Excellence RESOLV (“Ruhr Explores Solvation”, EXC
1069). This work was funded by Max-Planck-Gesellschaft and
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013) (ERC Grant
no. 268309).
Keywords: aerobic oxidation
·
asymmetric catalysis
·
azomethine · cycloaddition · ylides alkylation
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action which allows the highly diastereo- and enantioselective
synthesis of complex natural product inspired polycyclic prod-
ucts with eight stereocenters from simple starting materials. A
notable feature of the developed process is aerobic copper-
catalyzed oxidation of cyclopentadiene 3 to cyclopentadienone
2 followed by catalytic asymmetric double cycloaddition with
azomethine ylides 1 to provide natural product inspired com-
pounds. The developed cascade process is catalyzed by
a single catalyst and five novel bonds and eight stereogenic
centers are formed during the reaction.
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Received: January 12, 2015
Published online on && &&, 2015
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Cascade Reactions
M. Potowski, C. Merten, A. P. Antonchick,*
H. Waldmann*
&& – &&
Catalytic Aerobic Oxidation and
Tandem Enantioselective
Cycloaddition in Cascade
Multicomponent Synthesis
A new cascade reaction for the synthe-
sis of complex products with eight ste-
reocenters was developed. The reaction
cascade proceeds with excellent diaster-
eo- and enantioselectivity from simple
starting chemicals such as aromatic al-
dehydes, amino acid esters, cyclopenta-
diene and molecular oxygen (see
scheme).
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!