A highly diastereo- and enantioselective reaction for constructing functionalized cyclohexanes: Six contiguous stereocenters in one step

Article abstract of DOI:10.1002/anie.201107495

Just mix to get six: Six contiguous stereocenters, including one quaternary stereocenter, and three C-C bonds are created by a new copper-catalyzed tandem reaction (see scheme). Rigid chiral diamine ligands enabled this asymmetric tandem reaction to proceed with excellent stereoselectivity (complete diastereoselectivity and high enantioselectivity) and high yield under mild reaction conditions. Copyright

Full text of DOI:10.1002/anie.201107495

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DOI: 10.1002/anie.201107495
Asymmetric Catalysis
A Highly Diastereo- and Enantioselective Reaction for Constructing
Functionalized Cyclohexanes: Six Contiguous Stereocenters in One
Step**
Dengjian Shi, Yinjun Xie, Han Zhou, Chungu Xia, and Hanmin Huang*
Organic motifs with contiguous multiple stereocenters exist in
numerous natural and unnatural products that exhibit impor-
tant biological activity.[1] The number of possible stereoiso-
mers increases exponentially with the number of stereocen-
ters, thus the highly stereoselective synthesis of chiral com-
pounds with multiple stereocenters from simple starting
materials is a challenge. Nature has developed many efficient
ways to construct such structures from simple starting
materials, as demonstrated by the production of chiral
carbohydrates, proteins, and alkaloids. Inspired by nature,
the asymmetric domino process, which generates more than
one chemical bond concomitantly with the creation of
multiple stereocenters in a one-pot fashion, has emerged as
a promising way to achieve these aims.[2] Despite the fact that
a number of structurally diverse compounds with contiguous
multiple stereocenters have been synthesized using this
Scheme 1. Copper-catalyzed asymmetric tandem reaction for the con-
struction of the functionalized cyclohexanes.
strategy, to the best of our knowledge, a domino process
which generates six or more stereocenters by one intermo-
lecular reaction of two simple compounds in an asymmetric
fashion has not been reported.[3,4]
nitroalkene 2 by a conjugate addition to yield intermediate B.
The intermediate B would further react with nitroalkene 2 to
generate the intermediate C under appropriate reaction
conditions. Ring closure through the Henry reaction would
lead to the desired six-membered annulation product 3 with
six stereogenic centers (Scheme 1). The challenge of design-
ing such an efficient catalytic asymmetric strategy mainly
depends on the necessity of stereoselectively generating the
stable reactive species B and highly reactive intermediate C
in situ. To address this challenge, we need to identify a chiral
transition metal catalyst to generate the metal enolate A with
stereodefined geometry, thus guaranteeing that the first
conjugate Michael addition proceeds with high diastereo-
and enantioselectivity. A chiral Lewis acid catalyst with the
appropriate steric and electronic properties is crucial for the
successful implementation the above strategy. Given that a
conformationally rigid structure would have good chiral
induction abilities, we recently have designed and synthesized
a series of rigid chiral diamines 5 and 6.[9] We envisioned that
these chiral diamine ligands, which have unusually rigid
structures, would be useful for the construction of a well
oriented chiral environment around the metal center, and the
corresponding transition metal complexes derived from these
chiral diamines could efficiently promote the proposed
reaction. Herein, we report a novel copper-catalyzed asym-
metric formal [2+2+2] cycloaddition between one equivalent
of ketoester and two equivalents of nitroalkene for the
synthesis of cyclohexanes with seven substituents.[3a–c,e–k,l,10]
These compounds are not only important building blocks in
The identification of a reactive species that triggers a
domino process is a prerequisite for the successful establish-
ment of an efficient tandem reaction. As active species,
enolates are considered to be the most powerful and reliable
cornerstones for establishing many classical transforma-
tions.[5] a-Ketoesters could be recognized as latent enolates
since the keto-to-enol tautomerization could easily take place
in these compounds in the presence of suitable Lewis acids.[6]
With this in mind, we envisaged that the reactive enolate
species derived from an a-ketoester would be useful to trigger
a formal [2+2+2] cycloaddition through an asymmetric
Michael[7]/Michael/Henry[8] tandem sequence with nitroal-
kenes as electrophiles (Scheme 1). Mechanistically, a chiral
Lewis acid catalyst would activate the a-ketoester to give rise
to the intermediate enolate A which would then add to
[*] D. Shi, Y. Xie, H. Zhou, Prof. Dr. C. Xia, Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, Lanzhou, 730000 (China)
E-mail: hmhuang@licp.cas.cn
D. Shi, Y. Xie, H. Zhou
Graduate School of Chinese Academy of Sciences (China)
[**] This work was supported by the Chinese Academy of Sciences and
the National Natural Science Foundation of China (21172226 and
21133011).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107495.
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organic synthesis, but also represent a structural motif found
in a number of important natural and synthetic bioactive
products.[11] It should be noted that this tandem reaction could
be performed in the presence of 0.1 mol% of catalyst and
delivered the chiral cyclohexane frameworks with complete
diastereoselectivity and excellent enantioselectivity.
reaction at all, and only the undesired by-product 4aa was
obtained (Table 1, entries 3 and 4) with good stereoselectivity.
Other transition metals, including nickel and zinc with various
anions, were also evaluated under the identical screening
reaction conditions and gave lower yield and stereoselectivity
than the corresponding catalyst derived from Cu(OAc)2·H2O.
Again, the basic acetate anion contained in the catalysts was
essential to obtain high reactivity and selectivity (Table 1,
entries 5–8). These results indicated that the basic acetate
anion might serve as an endogenous base to generate the
metal enolate and to facilitate the Michael addition in the first
step.[6d] Without a metal, the diamine ligand 5a showed
extremely lower activity and completely no selectivity
(Table 1, entry 9). The effect of the solvent was next inves-
tigated (Table 1, entries 10–16), and it was found that the
green solvent 2-PrOH was the best for this reaction. Other
chiral diamine ligands (5b, 6a, and 6b; see Scheme 1) were
also tested and we found the ligand 5a was the most suitable
for this asymmetric reaction (Table 1, entries 17–19). The
catalyst loading can be reduced to 1 mol% (Table 1, entry 20)
without any reduction in yield and enantioselectivity,
although a reaction time of 36 h was required to reach full
conversion. Moreover, the addition of a catalytic amount of
Et3N was found to be effective and enabled the reaction to be
performed in the presence of
The tandem reaction of ketoester (1a) with nitrostyrene
(2a) was performed in 2-PrOH at room temperature with
5 mol% of metal catalyst, which was prepared in situ from
chiral diamine ligand (S,S)-5a and various transition metals
(Table 1). A preliminary investigation indicated that the
catalyst prepared with chiral ligand 5a was indeed effective
for this reaction. The catalyst prepared with Cu(OAc)2·H2O
and 5a afforded the annulation product 3aa with excellent
yield (95%) and high enantioselectivity (95% ee) as well as
absolute diastereoselectivity (Table 1, entry 1). This catalyst
was highly chemically selective, and the linear conjugate
addition by-product 4aa was not observed. Further screening
of other copper precursors that have been efficient in
different catalytic asymmetric reactions revealed that the
counteranion played an important role in this reaction, and
the copper salt containing the acetate anion gave good results
in both of reactivity and selectivity. For example, the catalysts
prepared from Cu(OTf)2 and CuBr2 did not catalyze the
Table 1: Screening of reaction conditions[a]
0.1 mol% of Cu complex with
only a slight loss of enantioselec-
tivity (Table 1, entry 21). This load-
ing of the Cu catalyst is two orders
of magnitude lower than that com-
monly used in organocatalytic
asymmetric tandem reactions.[3a–k]
Entry
MXn
Ligand
Solvent
3aa
4aa
Yield
[%][b]
d.r.[c]
ee
Yield
[%][b]
ee
Furthermore, a high yield could
still be obtained when the catalyst
loading was further decreased to
0.033 mol% of Cu complex, but a
loss in enantioselectivity was
observed (Table 1, entry 22).
[%][d]
[%][d]
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O
Cu(OAc)2
Cu(OTf)2
CuBr2
NiBr2
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
6a
6b
5a
5a
5a
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
MeOH
EtOH
nPrOH
nBuOH
iBuOH
CH2Cl2
THF
95
93
<1
<1
0
79
88
23
17
9
47
54
33
64
<1
0
93
66
70
93
94
94
>20:1
>20:1
–
95
94
–
0
0
27
39
0
–
–
84
91
–
–
–
–
–
Having identified the optimal
Ni(acac)2
>20:1
>20:1
>20:1
–
>20:1
>20:1
>20:1
>20:1
>20:1
–
49
87
–
0
–
–
set of reaction conditions, we then
investigated reactions with a vari-
ety of a-ketoesters 1a–j, which
contain R groups with different
electronic and steric properties,
and these results were summarized
in Table 2. The reaction demon-
strated a broad generality with
respect to the a-ketoesters, and
the nature of the R substitutents
had a limited influence on the
reactivities and stereoselectivities.
In all cases, the reactions pro-
ceeded smoothly at room temper-
ature under very mild reaction
conditions, and the desired func-
tionalized cyclohexanes (3aa–ja)
were consistently obtained in
good to excellent yields with com-
Ni(OAc)2·(H2O)4
Zn(OAc)2·(H2O)2
–
<1
47
13
26
36
31
42
13
34
0
77
0
9
0
–
10
11
12
13
14
15
16
17
18
19
20[e]
21[f]
22[g]
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
94
96
98
94
92
n.d.
–
94
95
91
93
–
–
–
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
85
À85
À73
95
92
85
0
–
13
20
0
0
0
À95
À75
–
–
–
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), MXn (0.01 mmol), ligand (0.0105 mmol) in
solvent (2.0 mL) at room temperature for 24 h, unless otherwise noted. [b] Yield of the isolated product.
[c] Determined by H NMR analysis of the crude products. [d] Determined by HPLC analysis using a
chiral stationary phrase. [e] Using 1.0 mol% of Cu complex, 36 h. [f] Using 0.1 mol% of Cu complex and
10 mol% of Et3N. [g] Using 0.033 mol% of Cu complex (S/C=3000) and 10 mol% of Et3N.
acac=acetoacetonate, n.d.=not determined.
1
plete
diastereoselectivity
and
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Table 2: Substrate scope of ketoesters.[a]
Table 3: Substrate scope of nitroalkenes.[a]
Prod. Yield [%][b] d.r.[c] ee [%][d]
Entry
R
Prod.
Yield [%][b]
d.r.[c]
ee [%][d]
Entry
R
Ar
1
2
3
4
5
6
7
8
9
10
C6H5CH2
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
95
83
74
80
82
81
88
85
80
85
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
94
94
95
94
94
94
95
94
93
1
2
3
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
95
92
70
81
88
80
83
85
76
90
42
80
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
95
96
95
94
96
94
94
94
60
98
94
96
4-MeC6H4CH2
3,4-diClC6H3CH2
C6H5(CH2)3
CH3CH2CH2
CH3(CH2)4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
3-ClC6H4
1-naphthyl
2-MeOC6H4
2-furyl
4[e]
5[e]
6[e]
7
CH3(CH2)6
C6H5O(CH2)3
8
9[f]
10
11
12
=
CH2 CH(CH2)2
ꢀ
TMSC C(CH2)2
3ja
3aj
=
C6H5CH CH 3ak
2-furyl 3al
[a] Reaction conditions: ketoester 1 (0.2 mmol), nitroalkene 2
=
CH2 CH-
(0.6 mmol), Cu(OAc)2·H2O (0.01 mmol), and (S,S)-5a (0.0105 mmol) in
2-PrOH (2.0 mL) at 208C for 24 h, unless otherwise noted. [b] Yield of the
isolated product. [c] Determined by 1H NMR analysis of the crude
products. [d] Determined by HPLC analysis using a chiral stationary
phase. TMS=trimethylsilyl.
(CH2)2
[a] Reaction conditions: ketoester 1 (0.2 mmol), nitroalkene 2
(0.6 mmol), Cu(OAc)2·H2O (0.01 mmol), and (S,S)-5a (0.0105 mmol) in
2-PrOH (2.0 mL) at 208C for 24 h, unless otherwise noted. [b] Yield of the
isolated product. [c] Determined by 1H NMR analysis of the crude
products. [d] Determined by HPLC analysis using a chiral stationary
phrase. [e] 10 mol% of Et3N was added as co-catalyst. [f] With 5 mol% of
Ni(OAc)2·4H2O/6a and 10 mol% of Et3N.
excellent enantioselectivity (up to 95% ee). Notably, the
formation of the alkene- and alkyne-containing adducts (3ia
and 3ja) is attractive because those functional groups could
be easily converted into some important chiral compounds.
We also surveyed the scope of this new formal [2+2+2]
tandem annulation process with respect to the nitroalkene. As
summarized in Table 3, the annulation reaction of nitro-
alkenes with ketoesters catalyzed by the Cu-
(OAc)2·H2O/(S,S)-5a was found to be general with aromatic
nitroalkenes bearing a variety of substituents. Several sub-
stituted aromatic nitroalkenes 2a–g, containing either elec-
tron-donating groups or electron-withdrawing groups in the
para or meta position of the phenyl ring, were subjected to the
reaction conditions. In all cases, high yield and excellent
enantioselectivity with complete diastereoselectivity were
obtained. Although nitroalkene 2i, derived from an ortho-
substituted benzaldehyde, failed to deliver the annulation
product when (S,S)-5a was used as the chiral ligand, the
catalyst prepared with (S,S)-6a and Ni(OAc)2·4H2O led to a
good yield for this substrate, but with a relatively lower
enantioselectivity (3ai; Table 3, entry 9). This result may be
due to a large steric hindrance between the substrate and the
catalyst. As well as the substituted phenyl nitroalkenes, the
naphthyl- and heteroaryl-substituted nitroalkenes are also
compatible with the reaction conditions, thus generating the
corresponding functionalized cyclohexanes (3ah and 3aj) in
good yield with excellent stereoselectivity (Table 3, entries 8
and 10). Furthermore, the cinnamaldehyde-derived nitro-
alkene (2k) could also be used for this reaction to afford the
desired annulation product with excellent stereoselectivity
but only moderate yield (Table 3, entry 11). Unfortunately,
the nitroalkene derived from an aliphatic aldehyde was not
applicable in this reaction under the current reaction con-
ditions. To test the practicality of the current catalytic
reaction, the reaction of 1i with three equivalents of nitro-
alkene 2a in the presence of 0.1 mol% of Cu-
(OAc)2·H2O/(S,S)-5a and 5 mol% of Et3N was carried out
on a 5 mmol scale of 1i. The desired product 3ia was obtained
in gram scale with 77% yield and 89% ee as well as complete
diastereoselectivity.
Although there is the possibility that 64 (26) stereoisomers
would be produced with the generation of six stereocenters in
this cascade asymmetric reaction, we observed that in fact this
asymmetric annulation was highly enantioselective, forming
only one diastereomer, thus demonstrating the high efficiency
of this protocol. The reason for the high stereoselectivity is
that the chiral copper catalysts derived from the rigid chiral
diamine guarantee the first Michael addition proceeds with
high diastereo- and enantioselectivity, and the high stereose-
lectivity is kept or enhanced in the following Michael and
Henry reactions. Crystal structures were obtained for annu-
lation products 3ac and 3ia.[12] The absolute configuration of
the annulation products was determined to be
1R,2R,3R,4S,5R,6S from the single-crystal X-ray analysis of
the bromo-containing product 3ac (Figure 1). This indicated
that the initial Michael reaction takes place from the Re face
of the nitroalkene under the control of the catalyst. The
absolute configurations of C4, C5, and C6 indicate that the
second Michael addition takes place from the Si face of the
nitroalkene and the final Henry reaction takes place from
Re face of the carbonyl group, a result that suggests that the
chiral catalyst is not involved in the formation of these two
bonds.
In summary, a new enantioselective and diastereoselective
transition-metal-catalyzed asymmetric formal [2+2+2] annu-
lation between a-ketoesters and nitroalkenes has been
established that gives rise to highly functionalized cyclohex-
ane carboxylates with six stereogenic centers, including one
quaternary stereocenter. A new copper complex consisting of
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Received: October 24, 2011
Published online: December 23, 2011
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Keywords: asymmetric catalysis · contiguous stereocenters ·
copper · cyclohexane · domino reactions
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Holczbauer, M. Czugler, T. Soꢂs, Org. Lett. 2011, 13, 5416; h) Z.-
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b) B. Heasley, Eur. J. Org. Chem. 2009, 1477.
[12] CCDC 844529 (3ac) and 844530 (3ia) contain the supplemen-
tary 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.
Angew. Chem. Int. Ed. 2012, 51, 1248 –1251
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