Asymmetric Organocatalytic Michael/Michael/Henry Sequence to Construct Cyclohexanes with Six Vicinal Stereogenic Centers

Article abstract of DOI:10.1055/s-0036-1588940

An efficient, asymmetric, catalytic, triple-cascade reaction between α-keto esters and nitroalkenes to construct cyclohexanes with six vicinal stereogenic centers in good yields and with high enantioselectivities has been established. A bifunctional guani

Full text of DOI:10.1055/s-0036-1588940

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
Y. Chen et al.
Letter
Synlett
Asymmetric Organocatalytic Michael/Michael/Henry Sequence to
Construct Cyclohexanes with Six Vicinal Stereogenic Centers
Yushuang Chen
Xiaohua Liu*
Weiwei Luo
Lili Lin
Ph
Ph
O
N
HN SO2Ar
H
t
N
t
CO2 Bu
HO CO2 Bu
R2
NO2
Cy = c-hexyl
Ar = 4-iPrC6H4
N
R2
Xiaoming Feng
Cy
NH
O
+
Cy
Key Laboratory of Green Chemistry and Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, P. R. of China
liuxh@scu.edu.cn
(10 mol%)
R1
R1
4 Å MS, THF, 0 ºC
NO2
NO2
R1
up to 99% yield, > 20:1 d.r., and 95% ee
23 examples
Received: 18.11.2016
Accepted after revision: 31.12.2016
Published online: 30.01.2017
achieved.6c,d,f,g–j,l,m Although a Michael/Michael/Henry se-
quence between aldehydes and nitroalkenes has been used
to synthesize hexasubstituted cyclohexanes, two kinds of
organocatalyst are needed to complete the cyclization
(Scheme 1, a).6l A similar process between an α-keto ester
and a nitroalkene might generate a cyclohexane with six
stereocenters, including a quaternary center, in one pot.7
Such asymmetric catalysis was first realized by the use of a
chiral Lewis acid catalyst, assisted by an organic base as the
cocatalyst in some cases (Scheme 1, b).7a However, no single
chiral organocatalyst has been employed in this cascade re-
action.
DOI: 10.1055/s-0036-1588940; Art ID: st-2016-w0778-l
Abstract An efficient, asymmetric, catalytic, triple-cascade reaction
between α-keto esters and nitroalkenes to construct cyclohexanes with
six vicinal stereogenic centers in good yields and with high enantiose-
lectivities has been established. A bifunctional guanidine–amide or-
ganocatalyst proved to be useful for the Michael/Michael/Henry se-
quence through Brønsted base and hydrogen-bonding cooperative
catalysis.
Key words asymmetric catalysis, cascade reaction, cyclohexanes, or-
ganocatalysis, keto esters, nitroalkenes
In the past few years, our group has developed a series
of bifunctional chiral guanidine catalysts that are effective
in Michael reactions, Mannich-type reactions, Henry reac-
tions, and others.8 In most cases, vicinal stereocenters can
be constructed with high diastereo- and enantioselectivi-
ties. These primary contributions suggested that a combi-
nation of Brønsted base catalysis and hydrogen-bonding ca-
talysis with a guanidine-based catalyst would be of particu-
lar interest in triple-cascade extensions. We found that the
guanidine unit of the chiral guanidine–amide catalysts pro-
motes the deprotonation of α-keto ester and nitroalkane in-
termediates, generating the corresponding carbon nucleo-
philes. Meanwhile, the amide unit activates the electrophile
by forming a hydrogen bond, thereby inducing a triple pro-
cess actively and stereoselectively (Scheme 1,c). Here, we
describe a new chiral organocatalyst for the asymmetric se-
quential Michael/Michael/Henry reaction that permits the
consecutive formation of hexasubstituted cyclohexane de-
rivatives with one quaternary stereocenter in good yield,
excellent diastereoselectivity, and high enantioselectivity.
Starting from α-keto ester 1a and nitroalkene 2a, and
employing the bifunctional guanidine catalyst G-1 in tolu-
ene as the solvent, we obtained the desired cyclohexane de-
The field of asymmetric organocatalysis is a rapidly ex-
panding and important field in organic chemistry.1 In part,
organocatalytic cascade or domino reactions constitute an
efficient and powerful synthetic tool for the construction of
molecular complexity.2 For example, the iminium–enamine
combination in the field of amine-catalyzed cascade reac-
tions permits double, triple, or even quadruple processes
for the synthesis of complex and valuable synthetic build-
ing blocks.3 Other activation modes, such as hydrogen
bonding, protonation, and umpolung, have also been estab-
lished, but are generally limited to the promotion of simple
cascade reactions.4 Bifunctional or multifunctional organo-
catalysts possess multiple activation modes, which can be
envisaged to participate in a broad variety of possible cas-
cade reactions.5
Recently, organocatalytic cascade approaches to enan-
tiomerically enriched multisubstituted cyclohexane deriva-
tives have attracted a great deal of attention, owing to the
prevalence of such motifs in pharmaceutical compounds
and complex natural products.6 Organocatalytic asymmet-
ric domino reactions for concise syntheses of tetra- or pen-
tasubstituted
cyclohexane
derivatives
have
been
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Y. Chen et al.
Letter
Synlett
ing the amount of the solvent (entry 11). Note that the or-
der of addition of the two reactants had an obvious influ-
ence on the result (entry 12): when α-keto ester 1a and cat-
alyst G-5 were mixed beforehand, with subsequent addition
of nitroalkene 2a at 0 °C, a yield of 93% with 90% ee was ob-
tained.
(a) Previous relay catalysis
OH
O
NO2
R2
R1
R2
NO2
R2
R1
R2
cat* 2
cat* 1
+
NO2
R1
NO2
NO2
R2
CHO
Ph
Table 1 Optimization of the Reaction Conditionsa
CF3
H3CO
Ph
OTMS
N
N
S
H
HO CO2tBu
N
H
O
N
cat* 1
G* (10 mol%)
H
Bn
Ph
NO2
CF3
Ph
Ph
CO2tBu
NO2
N
solvent, 0 ºC
cat* 2
Ph
2a
1a
(b) Previous Lewis acid catalysis
NO2
CO2R2
NO2
3aa
HO
R1
O
NO2
NO2
L*Xn–1Cu
Ph
Ph
Ph
N
Ph
O
R3
R3
R1
CO2R2
O
N
O
S
+
L*:
O
N
NH
R3
R3
N
HN
H
HN
S
H
O
O
NO2
R
G-2 R = H
N
N
HN
G-3 R = 4-Me
G-4 R = 4-MeO
G-5 R = 4-iPr
NH
NH
(c) Cooperative catalysis (this work)
HO CO2R2
G-6 R = 4-tBu
G-7 R = 2,4,6-iPr3
G-1
chiral
organocatalyst
R1
NO2
NO2
NO2
O
Ar
*
*
*
R1
+
CO2R2
O
*
Ar
Ar
*
Entry
Catalyst
Solvent
Yieldb (%) drc
eed (%)
Ar
*
NO2
1
2
G-1
G-1
G-1
G-2
G-3
G-4
G-5
G-6
G-7
G-5
G-5
G-5
toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
37
34
49
55
72
60
54
10
69
71
80
93
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
77
83
84
81
87
87
90
90
65
90
90
90
O
N
N
N
H
N
H
N
3
N
Cy
N
H
NCy
H
O
4
H
O
CyHN
CyN
N
H-bonding
H
O
5
R1
Brønsted base
bifunctional guanidine-amide catalyst
O
6
Ar
OR2
7
Scheme 1 Asymmetric catalytic Michael/Michael/Henry sequence for
8
the synthesis of hexasubstituted cyclohexanes
9
10e
11f
12g
rivative 3aa in 37% yield, >20:1 dr, and 77% ee (Table 1, en-
try 1). Further investigations focused on the solvent, and we
found that THF gave good results in terms of reactivity and
enantioselectivity (entries 1–3). Subsequently, we exam-
ined the substituent on the sulfonamide unit of the chiral
guanidine catalyst (entries 3–9). The results showed that
the sulfonamide substituent had obvious effects on both
the reactivity and enantioselectivity. The introduction of a
substituent at the para-position of the benzenesulfonamide
benefited the enantioselectivity, but the reactivity de-
creased as the steric hindrance of the substituent increased
(entries 4–8). When guanidine G-6 bearing a 4-tert-butyl-
benzenesulfonamide unit was used, only 10% yield of the
desired product 3aa was obtained, without loss of enanti-
oselectivity (entry 8). Embedding a sterically hindered
2,4,6-triisopropylbenzenesulfonamide into catalyst G-7
gave a sharp drop in enantioselectivity (entry 9). The use of
guanidine G-5 in the presence of 4 Å molecular sieves gave
the cascade product in an improved yield of 71% without a
decrease in the enantiomeric excess (entry 10); this was
subsequently optimized to 80% yield and 90% ee by reduc-
a Reaction conditions: G (10 mol%), 1a (0.1 mmol), 2a (3.0 equiv), solvent
(1.0 mL), 0 °C, 3 d.
b Isolated yield.
c Determined by 1H NMR.
d Determined by chiral HPLC.
e 4 Å MS (20 mg) were added.
f 4 Å MS (20 mg) and THF (0.5 mL) were used.
g G-5 (10 mol%), 4 Å MS (20 mg), and 1a (0.10 mmol) were stirred in THF
(0.5 mL) at 0 °C for 30 min, then 2a (3.0 equiv) was added.
With the optimal conditions, we next studied the scope
of the reaction (Table 2). In general, the reactions occurred
with various β-aryl-substituted nitroalkenes bearing elec-
tron-withdrawing or -donating substituents at various po-
sitions, yielding the corresponding products 3 in good
yields (56–99%) and with excellent stereoselectivities (84–
95% ee, >20:1 dr; entries 1–11). The electronic nature of the
substituent on the benzyl group had an obvious effect on
the outcome, with electron-donating substituents giving
higher yields than electron-withdrawing substituents (en-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Y. Chen et al.
Letter
Synlett
tries 8–11). Notably, slightly better enantioselectivities
were obtained when ortho-substituted β-nitrostyrenes
were subjected to the formal [2+2+2] tandem annulation
process (entries 2, 8, and 9). These results are a useful com-
plement to a previously reported reaction in which a chiral
Lewis acid catalyst gave a 76% yield and 60% ee of product
3ai.7a Both 3-furyl- and 2-furyl-substituted substrates were
tolerated in the reaction, and the corresponding cycloaddi-
tion products 3al and 3am were obtained in 94% and 93%
yield, respectively, and with 85% and 83% ee, respectively
(entries 12 and 13). Furthermore, a 1-naphthyl-substituted
nitroalkene afforded the corresponding product 3an in a
higher yield and better enantioselectivity than did a 2-
naphthyl-substituted nitroalkene (entries 14 and 15).
and 3). Meanwhile, a chained alkene group or linear or
branched alkyl chains in the α-keto ester had no obvious ef-
fect on the enantioselectivity, and the corresponding hexa-
substituted cyclohexane isomers were obtained in satisfac-
tory yields and enantioselectivities (74–92% yield, 88–90%
ee; entries 4–8).
Table 3 Substrate Scope of the α-Keto Estersa
HO CO2tBu
O
G-5 (10 mol%)
R
NO2
Ar
R
+
CO2tBu
NO2
THF, 4 Å MS, 0 °C
Ar
Ar
1
2k
Ar = 4-MeOC6H4
NO2
3
Entry
R
Product
Yieldb (%) drc
eed (%)
Table 2 Substrate Scope of the Nitroalkenesa
1
2
3
4
5
6
7
8
4-FC6H4CH2
Ph(CH2)2
Ph(CH2)3
CH2=CHCH2
CH2=CH(CH2)2
Bu
3bk
3ck
3dk
3ek
3fk
99
99
83
79
88
87
92
74
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
90
89
88
90
88
90
90
88
HO CO2tBu
O
Bn
R
NO2
G-5 (10 mol%)
R
CO2tBu
+
Ph
NO2
THF, 4 Å MS, 0 °C
R
2
1a
3
NO2
Entry
R
Product
Yieldb (%) drc
eed (%)
3gk
3hk
3ik
i-Bu
1
2
Ph
3aa
3ab
3ac
3ad
3ae
3af
93
95
88
73
77
84
56
91
99
88
96
94
93
99
86
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
90
92
88
90
91e
88
84
95
91
90
92
85
83
90
87
Me(CH2)4
2-FC6H4
a All reactions were performed with 1 (0.1 mmol) and 2k (0.3 mmol) under
the standard conditions.
3
4-FC6H4
b Isolated yields.
4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
c Determined by 1H NMR.
5
d Determined by chiral HPLC.
6
In summary, we have developed an organocatalyzed
Michael/Michael/Henry cascade strategy for the simple
construction of cyclohexane structures containing six vici-
nal stereocenters.9,10 The reaction proceeds with high to ex-
cellent diastereo- and enantioselectivities (more than 20:1
dr and up to 95% ee). The accessibility of the starting α-keto
esters and the easy manipulation of the organocatalytic sys-
tem make this system attractive. Further work aims to ex-
pand this concept to the asymmetric synthesis of more-
complex useful molecular structures.
7
3,4-Cl2C6H3
2-Tol
3ag
3ah
3ai
8
9
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-furyl
10
11
12
13
14
15
3aj
3ak
3al
2-furyl
3am
3an
3ao
1-naphthyl
2-naphthyl
a All reactions were performed with 1a (0.1 mmol) and 2 (0.3 mmol) under
the standard conditions (Table 1, entry 12).
b Isolated yield.
Acknowledgment
c Determined by 1H NMR.
We thank the National Natural Science Foundation of China
(21625205, and 21332003), the Fok Ying Tung Education Foundation
(141115), and the Top-Notch Young Talents Program of China for fi-
nancial support.
d Determined by chiral HPLC.
e The absolute configuration of 3ae was determined to be
(1R,2R,3R,4S,5R,6S) by comparison with the authentic compound.7a
Next, we applied the catalytic system to various α-keto
esters to define the scope of the one-pot procedure. As
shown in Table 3, the reaction between α-keto ester 1b
bearing a 4-fluorophenyl substituent and nitroalkene 2k
proceeded well to give product 3bk in 99% yield and 90% ee
(entry 1). When 3-phenylpropyl or 4-phenylbutyl α-keto
esters were employed in the reaction, 99% and 83% yields
with 89% and 88% ee were obtained, respectively (entries 2
References and Notes
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(9) Hexasubstituted Cyclohexanes 3aa–3ik; General Procedure
Guanidine G-5 (10 mol%), α-keto ester 1 (0.1 mmol), and 4 Å MS
(20 mg) were weighed into a test tube under N2. THF (0.5 mL)
was added and the solution was stirred for 0.5 h at 0 °C.
Nitroalkene 2 (0.3 mmol) was then added at 0 °C, and the
resulting mixture was stirred for 3 d at 0 °C to give the product
3, which was purified by flash chromatography.
(10) tert-Butyl
(1R,2R,3R,4S,5R,6S)-2-Benzyl-1-hydroxy-4,6-
dinitro-3,5-diphenylcyclohexanecarboxylate (3aa)
White solid; yield: 51.7 mg (93%, 90% ee, >20:1 dr); mp 162 °C;
29
[α]D +45.3 (c 0.47, CH2Cl2); HPLC: [Daicel CHIRALCEL IA;
hexane–i-PrOH (85:15); flow rate = 1.0 mL/min; λ = 210 nm]: tR
= 7.33 min (minor), 12.59 min (major). 1H NMR (400 MHz,
CDCl3): δ = 7.35–7.08 (m, 13 H), 6.78 (d, J = 7.2 Hz, 2 H), 5.22–
5.16 (m, 1 H), 5.10 (dd, J = 12.4, 6.4 Hz, 1 H), 4.49 (t, J = 12.4 Hz,
1 H), 4.18 (s, 1 H), 3.54 (t, J = 6.4 Hz, 1 H), 2.95 (s, 1 H), 2.54–2.36
(m, 2 H), 1.59 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 171.5,
137.4, 134.9, 132.1, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3
127.0, 92.7, 90.3, 86.6, 77.7, 47.1, 45.7, 40.3, 33.7, 27.9. HRMS
(ESI-TOF): m/z [M + Na]+ calcd for C30H32N2NaO7+: 555.2102;
found: 555.2101.
tert-Butyl
(1R,2R,3R,4S,5R,6S)-2-Benzyl-1-hydroxy-4,6-
dinitro-3,5-bis(2-tolyl)cyclohexanecarboxylate (3ah)
White solid; yield: 53.0 mg (91%, 95% ee, >20:1 dr); mp 140 °C;
26
[α]D +72.6 (c 1.26, CH2Cl2); HPLC: [Daicel CHIRALCEL IA;
hexane–i-PrOH (85:15); flow rate = 1.0 mL/min; λ = 210 nm]: tR
= 10.21 min (minor), 16.58 min (major). 1H NMR (400 MHz,
CDCl3): δ = 8.53 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.24–
7.08 (m, 8 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.74 (d, J = 6.0 Hz, 2 H),
5.27 (t, J = 12.0 Hz, 2 H), 4.88 (t, J = 12.0 Hz, 1 H), 4.35 (s, 1 H),
4.16 (t, J = 6.4 Hz, 1 H), 3.26 (s, 1 H), 2.65–2.53 (m, 1 H), 2.50 (s,
3 H), 2.49–2.32 (m, 1 H), 1.64 (s, 9 H), 1.32 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 171.6, 140.0, 139.3, 137.0, 133.2, 131.7,
131.3, 131.2, 131.1, 129.0, 128.8, 128.1, 128.0, 126.9, 126.3,
126.2, 124.0, 93.1, 90.8, 86.5, 77.8, 45.2, 39.8, 34.8, 33.5, 27.9,
19.5, 19.3. HRMS (ESI-TOF): m/z [M
C
+
Na]+ calcd for
32H36N2NaO7+ : 583.2415; found: 583.2415.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D