Enantioselective cascade Oxa-michael-michael reactions of 2-hydroxynitrostyrenes with enones using a prolinol thioether catalyst

Article abstract of DOI:10.1002/adsc.201301114

The efficient simultaneous activation of cyclohexenones or simple alkyl acyclic enones and 2-hydroxynitrostyrenes was realized by using a prolinol thioether catalyst. Thus, a highly chemo-, diastereo- and enantioselective synthesis of functionalized tetrahydroxanthenones and chromanes with up to three contiguous stereocenters was developed.

Full text of DOI:10.1002/adsc.201301114

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DOI: 10.1002/adsc.201301114
Enantioselective Cascade Oxa-Michael–Michael Reactions of
2-Hydroxynitrostyrenes with Enones Using a Prolinol Thioether
Catalyst
Ai-Bao Xia,+a Chao Wu,+a Tao Wang,a Yan-Peng Zhang,a Xiao-Hua Du,a
Ai-Guo Zhong,b Dan-Qian Xu,a,* and Zhen-Yuan Xua,*
a
Catalytic Hydrogenation Research Centre, State Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Zhejiang University of Technology, Hangzhou 310014, Peopleꢀs Republic of China
Fax : (+86)-0571-8832-0066; phone: (+86)-0571-88320609; e-mail: chrc@zjut.edu.cn or greenchem@zjut.edu.cn
Department of Pharmaceutical and Chemical Engineering, Taizhou College, Linhai Zhejiang 317000, Peopleꢀs Republic
b
of China
+
These authors contributed equally to this work.
Received: December 10, 2013; Revised: January 29, 2014; Published online: April 9, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301114.
Abstract: The efficient simultaneous activation of
cyclohexenones or simple alkyl acyclic enones and
2-hydroxynitrostyrenes was realized by using a proli-
nol thioether catalyst. Thus, a highly chemo-, dia-
stereo- and enantioselective synthesis of functional-
ized tetrahydroxanthenones and chromanes with up
to three contiguous stereocenters was developed.
products synthesis (Scheme 2). Given their structural
complexity and intriguing biological activities, signifi-
cant attention has been given to the efficient and se-
lective construction of these cores. In this work, the
asymmetric reaction of enones, especially simple alkyl
acyclic enones, and 2-hydroxynitrostyrenes[6] which
serve as a suitable substrate bearing both acceptor
and donor components for reaction with aldehydes,[7]
ketones,[8] a,b -unsaturated aldehydes,[9] is examined
to construct functionalized tetrahydroxanthenones
and chromanes.
Keywords: asymmetric catalysis; domino reactions;
functionalized chromanes; functionalized tetrahy-
droxanthenones; organocatalysis
The reaction of 2-hydroxynitrostyrene 1a and cyclo-
hexenone 2a was used as the test reaction (Table 1).
Initially, to determine the suitable reaction conditions,
Over the last decade, asymmetric organocatalysis has
become one of the most important research areas.[1]
However, in contrast to the widely reported iminium
ion-catalyzed simple enal acceptor reaction systems
[Scheme 1, Eq.(1)], fewer examples are known to
deal with the organocatalytic transformation of
enones[2] particularly in the case of simple alkyl acy-
clic enones[3] with complex reaction substrates that
possess both acceptor and donor components. Certain
challenging problems remain unresolved in this field,
possibly because of the complexity of the reaction of
the activated intermediate and the difficulty in simul-
taneously activating both substrates [Scheme 1,
Eq.(2)].
Tetrahydroxanthenones[4] and chromanes[5] are
abundant in natural products and pharmacologically
active compounds and are used as versatile intermedi-
Scheme 1. Challenges arising from the amino catalysis of
ates for further transformation in drugs and natural simple alkyl acyclic enones.
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Scheme 2. Selected examples of pharmacologically active xanthenones and chromanes.
the ability of typical secondary amine catalysts 3a–3f with respect to both 2-hydroxynitrostyrenes and cy-
in catalyzing the domino reaction was investigated clohexenone components in saturated aqueous NaCl
(Table 1, entries 1–6). Using multifunctional prolinol solution. Table 2 shows that in the cascade process,
thioether catalyst 3a as a catalyst, moderate conver- the reactions produced moderate to high yields (60%
sion, excellent diastereoselectivity, and enantioselec- to 98%) with excellent levels of diastereoselectivity
tivity were achieved (Table 1, entry 1). In the case of (>20:1 dr) and enantioselectivity (90% to 99% ee) in
multifunctional catalyst 3b, the domino reaction pro- all cases. The study revealed that the electronic
ceeded with 99% conversion within 6 h to yield the nature and position of substituents on the aromatic
functionalized tetrahydroxanthenone 5a with excel- ring of 1 minimally affected the reaction efficiencies
lent diastereoselectivity (36:1 dr) and excellent enan- in terms of diastereoselectivity and enantioselectivity
tioselectivity (96% ee) (Table 1, entry 2). Further- (Table 2, entries 1–15). However, the 2-hydroxynitros-
more, the classic amine catalysts 3c–3f cannot effi- tyrenes bearing substitutions at the C-3, C-4, and C-5
ciently promote the cascade process (Table 1, entries positions on the aromatic ring achieved higher yields
3–6). Accordingly, prolinol thioether catalyst 3b was than those substituted at the C-6 position (Table 2,
selected for further optimization of the reaction con- entries 1–14 vs. entry 15). Less reactive 3-methylcyclo-
ditions. A survey of different acidic additives 4 re- hex-2-enone can efficiently participate in the cascade
vealed that an acidic additive was necessary to the process to produce the desired product 5p possessing
catalyst system to achieve high catalytic performance a quaternary stereogenic center in good yield (60%)
(Table 1, entries 7–14). Using 4-trifluoromethylbenzo- and excellent dr and ee values (>20:1 and 94%, re-
ic acid as the acidic additive yielded the adduct 5a spectively). However, the reaction rate was low
with 98% conversion, 98:1 dr, and 96% enantiomeric (Table 2, entry 16). 4,4-Dimethyl-substituted cyclohex-
excess (Table 1, entry 9). To further optimize the cata- 2-enone was also a suitable substrate for the domino
lytic system to achieve higher ee, saturated aqueous reaction (Table 2, entry 16). The absolute configura-
NaCl solution was used as the solvent, and the reac- tion of 5d prepared under the optimized conditions
tion time was shortened from 6 h to 3 h with similar was determined to be (R,R,R) by means of single
ee but sharply diminished dr (Table 1, entry 15). crystal X-ray diffraction.[10,11]
When the reaction temperature was set at 58C, the re-
After establishing the novel approach to the prepa-
action was completed with the same conversion and ration of functionalized tetrahydroxanthenones
slightly increased enantioselectivity within 18 h through an organocatalytic oxa-Michael–Michael pro-
(Table 1, entry 16). Decreasing the additive 4/catalyst cess, the cascade reactions of 2-hydroxynitrostyrenes
3 molar ratio to 0.5:1 resulted in higher conversion (> with simple alkyl acyclic enones for the preparation
99%) and higher ee (98%) but lower dr (28:1) in 3 h of functionalized chromans were examined. The
(Table 1, entry 17). However, further reduction in the above optimized approach was then adopted in the
amount of catalyst loading to 10 mol% prolonged the asymmetric domino reaction of 1a and 6a in brine
reaction time with no positive change in both diaste- and water. The functionalized chroman 7a was ob-
reoselectivity
entry 18).
and
enantioselectivity
(Table 1, tained in 95% to 96% ee and >20:1 dr, but only 30%
to 40% yield (Table 3, entries 1–3). After further opti-
Subsequently, under the optimum reaction condi- mizing the reaction conditions in organic solvents,
tions, the scope of this domino reaction was examined functionalized chroman 7a was obtained in 85% yield,
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Table 1. Screening of catalysts and optimization of conditions for the reaction of 1a with 2a.[a]
Entry
Catalyst 3
Additive 4
Time [h]
Conversion [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b
3c
3d
3e
3f
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
C6H5CO2H 4a
C6H5CO2H 4a
C6H5CO2H 4a
C6H5CO2H 4a
C6H5CO2H 4a
C6H5CO2H 4a
none
6
6
70
99
6
trace
trace
trace
trace
88
98
99
80
98
61
67
99
99
35:1
36:1
n.d[d]
n.d[d]
n.d[d]
n.d[d]
n.d[d]
24:1
98:1
19:1
41:1
16:1
9:1
13:1
62:1
98:1
28:1
24:1
27:1
28:1
96
96
48
48
48
48
48
6
6
6
6
6
6
6
3
18
3
18
3
3
n.d[d]
n.d[d]
n.d[d]
n.d[d]
n.d[d]
95
2-CF3C6H4CO2H 4b
4-CF3C6H4CO2H 4c
4-FC6H4CO2H 4d
4-NO2C6H4CO2H 4e
4-CH3C6H4CO2H 4f
96
95
96
92
74
95
95
96
98
96
95
87
[e]
2-C10H7SO3 4g
CH3CO2H 4h
15[f]
16[f,g]
17[f,h]
18[f,i]
19[f,h,j]
20[f,h,k]
4-CF3C6H4CO2H 4c
4-CF3C6H4CO2H 4c
4-CF3C6H4CO2H 4c
4-CF3C6H4CO2H 4c
4-CF3C6H4CO2H 4c
4-CF3C6H4CO2H 4c
>99
96
61
45
[a]
Unless otherwise noted, the reactions were conducted in water (0.5 mL) using 2-hydroxynitrostyrene 1a (0.4 mmol) and
cyclohexenone 2a (1.6 mmol) in the presence of 20 mol% catalyst 3 and 20 mol% benzoic acid at room temperature with
vigorous stirring.
Conversion to the product as determined by GC-MS.
Determined by HPLC analysis on a Chiralcel AS-H column.
Not determined.
2-Naphthalenesulfonic acid.
Saturated aqueous NaCl solution as the solvent.
Reaction was carried out at 58C.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
Using 20 mol% catalyst and 10 mol% additive.
Using 10 mol% catalyst and 5 mol% additive.
0.8 mmol cyclohexenone 2a was used
[j]
[k]
0.48 mmol cyclohexenone 2a was used
>20:1 dr and 96% ee within 24 h at 608C in para- excellent diastereoselectivities (>20:1 dr), and excel-
cymene (Table 3, entry 10).[11]
lent enantioselectivities (93% to 96% ee). Both the
Under the optimized conditions, the scope of the electronic nature and position of substituents on the
enantioselective tandem oxa-Michael–Michael reac- phenyl ring of 2-hydroxynitrostyrenes minimally influ-
tion between 2-hydroxynitrostyrenes and alkyl acyclic enced the diasteroselectivity and enantioselectivity of
enones was next evaluated. Scheme 3 shows that this the cascade reaction. The 2-hydroxynitrostyrenes
reaction system exhibits a broad substrate spectrum. bearing substitution at the C-4 position on the aro-
When a series of substituted 2-hydroxynitrostyrenes is matic ring achieved lower yields than those with sub-
reacted with (E)-hex-4-en-3-one, the desired products, stitutions at other positions (Scheme 3, 7c vs. 7a, 7b,
the functionalized chromans 7a–7h, can be smoothly 7d–7h). Further exploration of the substrate scope fo-
obtained in moderate to good yields (41% to 85%), cused on alkyl acyclic enones (Scheme 3, 7i–7r). The
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Table 2. Scope of the cascade reaction of 1 with 2 promoted by catalyst 3b in brine.[a]
Entry
R1, R2, R3
Product
Time [h]
Conversion [%][b]
Yield [%][c]
dr[d]
ee [%][d]
1
2
3
4
5
6
7
8
H, H, H
5-F, H, H
5-Cl, H, H
5-Br, H, H
3-Cl-5-Cl, H, H
3-Br-5-Cl, H, H
3-Br-5-Br, H, H
3-Me-5-Cl, H, H
3-OMe-5-Br, H, H
3-MeO, H, H
3-EtO, H, H
4-MeO, H, H
5-Me, H, H
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
3
3
3
3
3
3
3
3
3
3
3
3
3
3
8
12
12
>99
>99
98
>99
>99
>99
>99
>99
96
96
98
98
>99
97
98
96
94
97
95
92
94
93
91
90
92
93
93
90
64
60
97
28:1
98
96
96
96
93
96
96
96
99
97
96
92
97
96
96
94
98
>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
>20:1
9
10
11
12
13
14
15
16
17
5-MeO, H, H
6-MeO, H, H
H, Me, H
66
91
98
H, H, Me
[a]
Unless otherwise noted, the reactions were conducted in saturated aqueous NaCl solution (0.25 mL) using 1 (0.2 mmol)
and 2 (0.8 mmol) in the presence of 20 mol% 3b and 10 mol% 4c at room temperature with vigorous stirring.
Conversion to the product as determined by GC-MS.
Yield of isolated product 5 after column chromatography.
Determined by HPLC analysis.
[b]
[c]
[d]
Table 3. Screening of the solvent and temperature for the cascade reaction between 1a and 6a.[a]
Entry
Solvent
Temperature [oC]
Time [h]
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
9
brine
brine
water
toluene
isopropyl alcohol
isopropyl ether
trichloromethane
xylene
toluene trifluoride
para-cymene
25
60
60
60
60
60
60
60
60
60
72
72
48
48
48
48
48
48
48
24
30
40
36
48
38
48
48
61
61
85
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
96
95
95
95
90
94
93
95
94
96
10
[a]
Unless otherwise noted, the reactions were conducted in solvent (0.5 mL) using 1a (0.4 mmol) and 6a (1.6 mmol) in the
presence of 20 mol% 3b and 10 mol% 4c at the set temperature with vigorous stirring.
Yield of isolated product 7a after column chromatography.
[b]
[c]
Determined by HPLC analysis.
corresponding products were obtained in moderate to diastereoselectivities (5:1 to >99:1 dr) and enantiose-
high yields (43% to 85%), as well as high to excellent lectivities (83% to 99% ee). Structural variations in
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Enantioselective Cascade Oxa-Michael–Michael Reactions
Scheme 3. Generality of the cascade reaction of 1 with alkyl acyclic enones 6 in para-cymene. Unless otherwise stated, reac-
tions were conducted in para-cymene (0.25 mL) using 1 (0.2 mmol) and 6 (0.8 mmol) in the presence of 20 mol% 3b and
10 mol% 4c at 608C with vigorous stirring.
the alkyl acyclic enone component including long- or enantioselectivities (7p–7r; 43% to 67% yield, >
chain alkyl (7j and 7k), branched alkyl (7l), as well as 20:1 dr, 85% to 99% ee).
functionalized thio-ether (7m), alkene (7n), aromatic
According to our previous studies about the proli-
ring (7o), ester (7p), cyclohexyl (7q), and carbamate nol thioether catalyst,[12] we believe that the excellent
(7r) are possible. Importantly, sterically demanding stereochemical outcome observed in the cascade reac-
alkyl acyclic enones [R4 =ethyl formic ester (7p), cy- tion is mainly due to the ability of the bifunctional
clohexyl (7q), and 4-piperidinyl (7r)] were also ac- prolinol thioether catalyst 3b to activate both the re-
commodated with little effect on diastereoselectivities actants, and a logical activation mode was proposed.
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Scheme 4. Proposed catalytic cycle.
As depicted in Scheme 4, the enone was activated by syntheses of complex natural products are ongoing in
3b to form the reactive chiral iminium ion 8, whereas our laboratory.
2-hydroxynitrostyrene was simultaneously activated
through a hydrogen-bonding interaction between the
nitro group and the protonated thiopyridine group of Experimental Section
3b. An ideal transition state (TS) formed with the two
substrates being effectively approached and oriented. General Information
Then the intermolecular oxa-Michael reaction pro-
ceeded through Si-face attack to give the postulated
NMR data were obtained on Bruker AVANCE III at
1
500 MHz for H and at 125 MHz for 13C with TMS as the in-
intermediate enamine 9, followed by the intramolecu-
lar Michael addition through Si-face attack. The re-
sulting postulated intermediate 10 was subsequently
hydrolyzed to afford the oxa-Michael–Michael adduct
and release the organocatalyst 3b.[11] Furthermore, the
ESI mass spectra showed the signals for the key inter-
mediates (8 and 9) and the results were further con-
firmed by accurate mass data using Fourier-transform
ion cyclotron resonance mass spectrometry (see the
Supporting Information, Figure S1 and Table S3).
In summary, an unprecedented efficient asymmetric
organocatalytic cascade oxa-Michael–Michael reac-
tion of 2-hydroxynitrostyrenes with enones has been
established. This protocol tolerates a diverse scope of
functional groups in both the 2-hydroxynitrostyrenes
and the enones, including cyclohexenones and simple
alkyl acyclic enones, furnishing functionalized tetrahy-
droxanthenones and chromans with up to three con-
tiguous stereocenters in excellent chemoselectivity,
moderate to excellent diastereoselectivity, and high to
excellent enantioselectivity. Such processes are rare
ternal standard. HR-MS data were measured on an Agilent
6120 LC/TOF-MS with ESI source or a Waters Premier GC/
TOF-MS with EI source. In each case, the enantiomeric
ratio was determined on a chiral column in comparison with
authentic racemates by chiral HPLC, using a JASCO LC-
2000 Plus system consisting of an MD-2010 HPLC diode
array detector. GC-MS experiments were performed on
a Trace GC ultra system with a DSQ II mass selective detec-
tor. Column chromatography and flash chromatography ex-
periments were conducted using silica gel GF254 (200–
300 mesh) eluting with ethyl ether and petroleum ether.
TLC experiments were carried out on glass-backed silica
plates. Unless otherwise noted, chemicals were used without
purification as commercially available. 2-Hydroxynitrostyr-
enes 1, the alkyl acyclic enones 6 and organocatalysts 3a, 3b
were synthesized according to literature procedures (see the
Supporting Information).
Typical Experimental Procedures for the Asymmetric
Cascade Reactions
A: In the case of cyclohexenones: To the solution of the or-
and further studies about their applications in total ganocatalyst 3b (20 mol%) and the acid 4b (10 mol%) in sa-
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turated aqueous NaCl solution (0.5 mL) were added sequen-
tially cyclohexenone 2 (1.6 mmol) and the respective 2-hy-
droxynitrostyrene 1 (0.4 mmol) at room temperature with
vigorous stirring. The reaction conversion was monitored by
GC-MS. After completion, the reaction mixture was extract-
ed with EtOAc (3ꢂ10 mL), washed with water, dried and
concentrated. The residue was purified by flash chromatog-
raphy to give product 5. The enantiomeric ratio was deter-
mined by HPLC analysis on a chiral column. The racemic
products were prepared using pyrrolidine as catalyst and
benzoic acid as co-catalyst in DCM.
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B: In the case of alkyl acyclic enones: To the solution of
the organocatalyst 3b (20 mol%) and the acid 4b (10 mol%)
in para-cymene (0.5 mL) were added sequentially alkyl acy-
clic enone 6 (1.6 mmol) and the respective 2-hydroxynitro-
ACHTUNGTRENNUNGstyrene 1 (0.4 mmol) at 608C with vigorous stirring. The re-
action conversion was monitored by GC-MS. After comple-
tion, the reaction mixture was diluted with EtOAc (30 mL),
washed with water, dried and concentrated. The residue was
purified by flash chromatography to give product 7. The
enantiomeric ratio was determined by HPLC analysis on
a chiral column. The racemic products were prepared using
pyrrolidine as catalyst and benzoic acid as co-catalyst in tol-
uene.
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Acknowledgements
Financially supported by the NSFC (21202149), the Zhejiang
Natural Science Foundation (Y4110348), the Foundation of
Zhejiang Education Committee (Y201225109) and the Foun-
dation of Zhejiang Key Course of Chemical Engineering and
Technology.
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