Asymmetric synthesis of functionalized cyclohexanes bearing five stereocenters via a one-pot organocatalytic Michael-Michael-1,2-addition sequence

Article abstract of DOI:10.1039/c4cc01885k

A highly stereoselective one-pot procedure involving an enantioselective Michael addition promoted by low loading of an amino-squaramide catalyst followed by an achiral base catalyzed domino Michael-Knoevenagel-type 1,2-addition sequence provides efficient access to fully substituted cyclohexanes bearing five contiguous stereogenic centers in good yields (68-86%) and excellent stereoselectivities (>30 : 1 dr and 96-99% ee). the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01885k

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Asymmetric synthesis of functionalized cyclohexanes
bearing five stereocenters via a one-pot
organocatalytic Michael–Michael–1,2-addition
sequence†
Cite this: Chem. Commun., 2014,
50, 6853
Received 13th March 2014,
Accepted 14th May 2014
Pankaj Chauhan, Gregor Urbanietz, Gerhard Raabe and Dieter Enders*
DOI: 10.1039/c4cc01885k
www.rsc.org/chemcomm
A highly stereoselective one-pot procedure involving an enantio- In 2010 Rodriguez et al.5 observed that two molecules of a nitro-
selective Michael addition promoted by low loading of an amino- alkene react in an organocascade asymmetric Michael–Michael–
squaramide catalyst followed by an achiral base catalyzed domino Henry sequence with 1,2-ketoamides to afford fully functionalized
Michael–Knoevenagel-type 1,2-addition sequence provides efficient cyclohexane derivatives. This process was later on extended by
access to fully substituted cyclohexanes bearing five contiguous Huang and co-workers6 by using 1,2-ketoesters instead of
stereogenic centers in good yields (68–86%) and excellent stereo- 1,2-ketoamides in the presence of a copper complex of a chiral
selectivities (430: 1 dr and 96–99% ee).
diamine. Chen and co-workers also succeeded to create as many as
six stereogenic centers on spirocyclic oxindoles in one-pot tandem
The asymmetric synthesis of complex molecular structures bearing reactions promoted by a chiral secondary amine and achiral
several different functionalities is one of the major goals of modern amines.7 Recently, our group has found that one-pot reactions of
synthetic organic chemistry as these structures exist in numerous b-ketoesters with two different electrophiles, i.e. nitroalkenes and
pharmaceutical and natural products.1 The stereocontrolled for- enals, were facilitated by an amino-thiourea catalyst and a stoichio-
mation of such complex molecules with several adjacent stereo- metric amount of an achiral base to afford fully functionalized
genic centers is regarded as a great challenge, because with an cyclohexane derivatives in high stereoselectivities.8
increase of the stereocenters the number of possible stereoisomers
It is highly desirable to extend the scope of these one-pot
also increases exponentially. Recently, organocatalytic domino or reactions beyond enals and nitroalkenes. Owing to the synthetic
cascade reactions have emerged as a powerful strategy for providing challenge of the controlled formation of many stereogenic centers
these complex molecular frameworks by employing simple and knowing the advantages associated with organocatalytic one-
and readily available precursors in a simple operational procedure.2 pot cascade reactions as well as the importance of the synthesis
The six-membered carbocycles, i.e. cyclohexane derivatives bearing of cyclohexane derivatives, we herein disclose unprecedented one-
several adjacent stereogenic centers, are common structural pot organocatalytic Michael–Michael–Knoevenagel-type 1,2-addition
features of many valuable natural products and synthetic bioactive reactions involving b-dicarbonyl compounds, nitroalkenes and
compounds, thus leading to the rapid development of the synthetic a,a-dicyanoolefins. Employing sequential organocatalysis by using
strategies for obtaining these structures.3
a low loading of a bifunctional amino-squaramide9 and a catalytic
Most of the organocatalytic strategies for the stereoselective amount of an achiral base virtually enantiopure cyclohexane deriva-
synthesis of functionalized cyclohexanes employ aliphatic aldehydes tives bearing five stereogenic centers with two vicinal tetrasubsti-
or a,b-unsaturated analogues as one of the substrates, which are tuted carbons could be obtained (Scheme 1). To achieve this we have
activated by chiral amine catalysts via enamine or iminium ion used a chiral amino-squaramide (1 mol%) derived from quinine
formation.4 The major problem associated with these transforma- as catalyst to promote the Michael addition of the b-ketoester 1a
tions is the subsequent dehydration after the aldol reaction leading to b-nitrostyrene (2a) in dichloromethane and after 24 hours the
to the loss of two chiral centers. There are only a few reports on the a,a-dicyanoolefin 3a was added followed by the addition of DBU
asymmetric synthesis of fully functionalized cyclohexane derivatives. (10 mol%) in dichloromethane.10 Further stirring the reaction for
24 hours afforded the desired cyclohexane 4a in 53% yield with 98%
ee and 430 : 1 dr (Table 1, entry 1). The excellent diastereoselectivity
of 4a may be due to a dynamic kinetic resolution of the Michael
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: enders@rwth-aachen.de
adduct via base mediated deprotonation of the acidic proton
† Electronic supplementary information (ESI) available. CCDC 990847. For ESI
followed by selective protonation (Scheme 1).11 Further optimization
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc01885k
of the reaction conditions by screening different bases and solvents
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Table 2 Substrate scopea
Entry R1
R2
R3
4/ent-4 Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt 4-FC6H4
OEt 4-ClC6H4
OEt 4-MeC6H4
OEt 3-MeOC6H4 Ph
OEt 2-Furanyl
OEt 2-Thienyl
OEt Cyclohexyl Ph
OMe Ph
Me Ph
OEt Ph
OEt Ph
Ph
4a
4b
4c
4d
4e
4f
72
76
72
74
70
84
80
80
74
73
68
70
75
68
69
69
71
99
99
99
99
99
99
99
99
99
99
99
98
99
99
99
99
99
96
97
98
98
96
99
98
99
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-MeC6H4
4-MeOC6H4 4g
2-Thienyl
Ph
Ph
Ph
Scheme 1 One-pot Michael–Michael–1,2-addition reaction for the asym-
metric synthesis of functionalized cyclohexanes bearing five contiguous
stereocenters.
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
ent-4a 70
ent-4b 77
ent-4d 75
ent-4e 77
ent-4f
ent-4h 81
ent-4i 75
ent-4k 72
Table 1 Optimizations of reaction conditionsa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph
Ph
Ph
Ph
Ph
4-FC6H4
3-ClC6H4
2-ClC6H4
4-MeC6H4
2-Thienyl
Ph
OEt Ph
OEt Ph
OEt Ph
OEt Ph
OEt 4-FC6H4
OEt 4-MeC6H4
86
Entry
Base (x mol%)
Solvent
Yieldb (%)
eec (%)
Ph
1
2
3
4
5
6
7
8
DBU (10)
DBN (10)
DABCO (10)
TEA (10)
TBD (10)
TBD (20)
TBD (30)
TBD (20)
TBD (20)
TBD (20)
TBD (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
53
31
—
35
58
71
69
62
63
56
70
98
99
—
a
Reaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol% of I
(entries 1–17) or II (entries 18–25), 0.6 mmol of 3 and 20 mol% of
89
99
99
99
99
99
99
96d
b
TBD (0.1 M in CH2Cl2). Yield of isolated product after column
c
chromatography. Enantiomeric excess of the major diastereomer
determined by HPLC analysis on a chiral stationary phase.
9
10
11
Toluene
THF
CH2Cl2
the desired cyclohexane under the optimized reaction conditions.
Further screening of different nitroalkenes showed that various
electron rich and electron deficient aromatic nitroalkenes as well as
heteroaromatic nitroalkenes also worked well under this one-pot
procedure to afford fully functionalized cyclohexanes 4i–n in 68–75%
and high stereoselectivities (430 : 1 dr and 99% ee) (entries 9–14). An
aliphatic nitroalkene was also tolerated to afford the corresponding
adduct 4o in 69% yield and excellent stereoselectivity (entry 15). Other
a
Reaction conditions: 0.2 mmol of 1a, 0.2 mmol of 2a, 1 mol% of I,
b
0.24 mmol of 3a and x mol% of base (0.1 M in solvent). Yield of
isolated 4a after column chromatography. Enantiomeric excess of the
major diastereomer (430 : 1 dr) determined by HPLC analysis on a
chiral stationary phase. ee value of ent-4a.
c
d
showed that with 20 mol% of the guanidine base triazabicyclo- b-ketoester and a b-diketone were also found to react efficiently to give
decene (TBD) in dichloromethane provides good yields of 71% and good yields and excellent stereoselectivities of the corresponding
excellent stereoselectivity (entry 6). The use of pseudo-enantiomeric products 4p and 4q (entries 16 and 17).
catalyst II leads to the opposite enantiomer of the product in 70%
yield and 96% ee with excellent diastereoselectivity (entry 11).
The synthesis of the enantiomers of the products is also possible
by employing the pseudo-enantiomeric amino-squaramide catalyst
Under optimized reaction conditions, the substrate scope was II, which afforded the enantiomers of 4a, 4b, 4d, 4e, 4f, 4h, 4i, and
evaluated at 0.5 mmol scale, which revealed that the use of various 4k in very good yields (70–86%) and excellent stereoselectivities
a,a-dicyanoolefins bearing electron withdrawing and electron- (430 : 1 dr and 96–99% ee, entries 18–25).
donating substituents provides a direct access to the corresponding
The absolute configuration of the products 4a–q synthesized
cyclohexanes 4b–g in very good yields (70–84%) and virtually by squaramide I was assigned as 1S,2S,3R,4R and 6S on the
complete enantioselectivity of 99% ee (Table 2, entries 2–7). basis of a X-ray crystallographic analysis of 4a (Fig. 1).12
A a,a-dicyanoolefin with a heteroaromatic group could be employed
Further we have tried to extend the substrate scope of this
under the standard reaction conditions, which afforded the one-pot methodology by employing olefin 5, which gave the
desired product 4h in 80% yield and 99% ee (entry 8). However, adduct 6 bearing six contiguous stereocenters in 67% yield and
a a,a-dicyanoolefin bearing a cyclohexyl group did not provide 99% ee, albeit low diastereoselectivity (Scheme 2).
6854 | Chem. Commun., 2014, 50, 6853--6855
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a series of highly substituted cyclohexane derivatives via one-pot
Michael–Michael–1,2-addition reactions in very good yields and
excellent stereoselectivities. The enantiomers of the multifunction-
alized cyclohexanes are easily accessible by employing a pseudo-
enantiomeric amino-squaramide catalyst. This method can be
scaled up without any loss of reaction efficiency.
Support from the European Research Council (ERC Advanced
Grant ‘‘DOMINOCAT’’) is gratefully acknowledged.
Fig. 1 X-ray structure of 4a [Cu-Ka radiation (l = 1.54178 Å), T = 120 K, Flack
parameter: w = 0.025(115)].
Notes and references
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Scheme 2 One-pot organocatalytic Michael–Michael–1,2-addition reaction
between 1a, 2a and 5.
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Scheme 3 One-pot stereoselective organocatalytic Michael–Knoevenagel
condensation–Michael–1,2-addition reaction.
A one-pot reaction involving the in situ formation of the
a,a-dicyanoolefin was successfully performed, which involves
the addition of benzaldehyde and malononitrile followed by
TBD (40 mol%) to the initially formed Michael adduct of 1a
with 2a catalyzed by I (Scheme 3). The corresponding product
4a was obtained in 69% yield, 430 : 1 dr and 99% ee through
this one-pot Michael–Knoevenagel condensation–Michael–1,2-
addition sequence.
A successful gram-scale reaction between 1a, 2a and 3a to
form 4a showed that the reaction efficiency was maintained,
thus highlighting the practical and preparative utility of this
one-pot process (Scheme 4).
´
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´
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12 CCDC 990847 (for 4a).
Scheme 4 Gram-scale one-pot stereoselective organocatalytic Michael–
Michael–1,2-addition reaction.
This journal is ©The Royal Society of Chemistry 2014
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