Dual organocatalytic ion-pair assemblies: A highly efficient approach for the enantioselective oxa-michael-mannich reaction of salicylic aldehydes with cyclohexenones

Article abstract of DOI:10.1002/chem.200902540

A study was conducted to demonstrate a novel type of bifunctional catalyst generated by the self-assembly of pyrrolidines and readily available primary amino acids. It was demonstrated that the protonation of the aromatic nitrogen atom of pyrrolidines by amino acids spontaneously led to ion-pair assemblies. The self-assembled catalysts possessed dual activation centers and enabled the catalysis of the electrophilic and nucleophilic substrates similar to catalysis by enzymes. The simultaneous activation of cyclohex-2-enone and salicylic aldehyde by pyrrolidines and amino acids generated the transient ion pairs through iminiums and imines. The resultant assemblies ensured that the enantioselective domino oxa-Michael addition and intramolecular Mannich reaction proceeded to afford the corresponding products upon hydrolysis.

Full text of DOI:10.1002/chem.200902540

COMMUNICATION
DOI: 10.1002/chem.200902540
Dual Organocatalytic Ion-Pair Assemblies: A Highly Efficient Approach for
the Enantioselective Oxa-Michael–Mannich Reaction of Salicylic Aldehydes
with Cyclohexenones
Ai-Bao Xia, Dan-Qian Xu,* Shu-Ping Luo, Jun-Rong Jiang, Jie Tang,
Yi-Feng Wang, and Zhen-Yuan Xu*[a]
Organocatalysis has made great progress in recent years.[1]
However, developing novel types of catalysts and organoca-
talytic strategies to achieve high activity and enantioselectiv-
ity is still a big challenge in asymmetric catalysis.[2] Recently,
the synergistic activation by the self-assembly of two or
more organocatalysts has been introduced as a useful strat-
egy for high-performance asymmetric catalysis.[3] In compar-
ison with the conventional covalent-bonded multifunctional
catalysts, the highly modular nature of the assembly should
allow a more convenient optimization of the catalyst, there-
by facilitating the achievement of excellent catalytic activity
and enantioselectivity.[4] Herein, we present a novel type of
bifunctional catalyst generated by the self-assembly of pyr-
rolidines 1 and readily available primary amino acids 2.[5–6]
As shown in Scheme 1, the protonation of the aromatic ni-
trogen atom of pyrrolidines 1 by amino acids 2 spontaneous-
ly leads to ion-pair assemblies.[7] Notably, the self-assembled
catalysts possess dual activation centers and thus, similar to
catalysis by enzymes, enable the catalysis of the electrophilic
and nucleophilic substrates simultaneously.
The tricyclic structure moiety of xanthones is found in a
variety of natural products with interesting biologic activi-
ties.[8] Tetrahydroxanthenones are common motifs in the
family of xanthones and are used as versatile intermediates
for further transformation in organic and natural product
synthesis, and thus their synthesis has attracted considerable
attention.[9] Recently, Cꢀrdova and co-workers reported the
first catalytic asymmetric synthesis of tetrahydroxanthe-
nones from cyclohexenones and salicyclic aldehydes by an
oxa-Michael–aldol reaction using a chiral pyrrolidine with
moderate yields and up to 91% ee.[9g]
We envisaged that the bifunctional catalysts mentioned
above should facilitate this asymmetric transformation by a
domino oxa-Michael–Mannich reaction. As shown in
Scheme 2, the simultaneous activation of cyclohex-2-enone
and salicylic aldehyde by pyrrolidines 1 and amino acids 2,
respectively, generates the transient ion pairs through imini-
ums 6 and imines 7. The resultant assemblies ensure that the
enantioselective domino oxa-Michael addition and intramo-
lecular Mannich reaction proceeded to afford, upon hydrol-
ysis, the corresponding products 8 and release the pyrroli-
dines 1. Finally, elimination of the resulting Mannich bases
leads to the desired tetrahydroxanthenone, concurrently re-
generating the amino acids 2.
Scheme 1. Proposed self-assembly and applied precatalyst modules.
To assess the viability of this domino process, the investi-
gation was started by reacting salicylic aldehyde with cyclo-
hex-2-enone in the presence of various precatalyst modules
1/2. As shown in Table 1, after six days of stirring in MeCN
at ambient temperature, less than 5% conversions were ob-
served when 1a was used alone or in combination with con-
ventional carboxylic acids (Table 1, entries 1–3). In contrast,
the assembly of 1a with 2a (or l-2b, l-2c) gave 18–24%
[a] Dr. A.-B. Xia, Prof. Dr. D.-Q. Xu, Dr. S.-P. Luo, Dr. J.-R. Jiang,
J. Tang, Y.-F. Wang, Prof. Dr. Z.-Y. Xu
State Key Laboratory Breeding Base of
Green Chemistry-Synthesis Technology
Zhejiang University of Technology, Hangzhou (China)
Fax : (+86)571-8832-0066
E-mail: greenchem@zjut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902540.
Chem. Eur. J. 2010, 16, 801 – 804
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
801

conversions after only 1.5 days (Table 1, entries 4–6). Fur-
ther experiments revealed that the enantiomers of amino
acids 2 showed strong matching and mismatching effects
with pyrrolidines 1. Though similar enantioselectivies were
observed, l-2d and l-2e together with 1a, respectively, ex-
hibited superior activities to their d-enantiomers, leading to
increased conversions of 35% and 17% (Table 1, entries 7
and 9 vs. entries 8 and 10). Whereas in the case of the as-
sembly of 1b with 2d, d-2d gave the superior results
(Table 1, entry 11 vs. entry 12). Notably, all assemblies
tested afforded the desired tetrahydroxanthenone 5a with
the same R configuration,[10] implying that the modules 1 in
the assembly play a leading role in the enantioselectivity of
the oxa-Michael addition step.
With regard to the various assemblies 1/2, the assembly of
1b with d-2d appeared to be the most suitable for this trans-
formation in terms of conversion and enantioselectivity, and
functioned most effectively in 1,4-dioxane as solvent to
afford almost complete conversion and 88% ee after three
days (Table 1, entries 12–19). The domino reaction proceed-
ed also smoothly in lower catalyst loading (Table 1, en-
tries 20–22). In contrast, even when the reaction was carried
out in dioxane, poor catalytic performance was observed
when 1b or d-2d were used alone, or when 1b and d-2d
were N-Boc-protected (Table 1, entries 23–26). In addition,
the combination of 1b and the methyl ester of d-2d gave
the desired product in very low yields (Table 1, entry 27).
These results clearly indicated the importance of the dual
activation and catalyst assembly.
Scheme 2. Proposed catalytic cycle and transition states for the domino
reaction.
Table 1. Reaction of salicylic aldehyde with cyclohex-2-enone catalyzed
by the assemblies 1/2.[a]
Entry
1
2
Solvent
t
C[b]
ee[c]
A
[%]
[%]
1
2
1a
1a
none
CH3COOH
MeCN
MeCN
6
6
trace
1
–
72
71
75
74
72
82
80
73
75
84
86
74
72
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
4-NO2C6H4CO2H MeCN
6
<5
24
18
24
35
2
17
2
3
A range of salicylic aldehydes were then surveyed to de-
termine the scope of the methodology. As shown in Table 2,
the assembly of 1b and d-2d was highly effective in promot-
ing the domino reaction of cyclohexenone with a variety of
2a
l-2b
l-2c
l-2d
d-2d
l-2e
d-2e
l-2d
d-2d
d-2d
d-2d
d-2d
d-2d
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DMSO
PhMe
CH2Cl2
Et2O
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
3
3
3
3
3
3
2
2
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[f]
23
24
25
26
27
Table 2. The enantioselective reaction of salicylic aldehydes with cyclo-
hexenones promoted by the assembly of 1b/d-2d in dioxane.[a]
37
10
20
>99 76
>99 79
>99 75
>99 80
>99 88
d-2d
d-2d
d-2d
d-2d
THF
Entry
R1
R2
Prod
t
C[b]
[%]
Yield[c]
[%]
ee[d]
[%]
1b
1b
1b
1b
Diox[d]
Diox
[h]
96
96
93
trace
48
trace
43
88
92
89
–
60
–
d-2d
Diox
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
Me
5a
5b
5c
5d
5e
5 f
5g
5h
5i
48
40
20
12
12
12
12
12
12
12
72
96
97
89
90
95
95
95
91
86
89
87
86
88
92
95
92
91
93
93
93
98
97
97
80
d-2d
Diox
2
6
6
2
2
6
3-MeO
5-MeO
3-F
5-F
5-Cl
none
1b
d-2d
Diox
>99
>99
>99
>99
95
94
94
95
95
none
Diox
Boc-1b[g]
1b
d-2d
Diox
Diox
Diox
Boc-d-2d[h]
d-2d-ester[i]
85
31 (S)
1b
<5
5-Br
3-MeO-5-Br
3,5-DiCl
3,5-DiBr
3-MeO-5-Br
[a] Unless otherwise indicated, all reactions were conducted in solvent
(1 mL) using salicylic aldehyde 3a (1 mmol) and cyclohex-2-enone 4a
(3.5 mmol) in the presence of 30 mol% 1 and 30 mol% 2 at room tem-
perature with stirring. [b] Conversion of 3a to the product, less than 5%
conversion of 4a to the self Michael addition product was found, as de-
termined by GC-MS. [c] Determined by HPLC analysis on a chiralcel
OD-H column. [d] 1,4-Dioxane. [e] 20 mol% each of 1b and d-2d was
used. [f] 15 mol% each of 1b and d-2d was used. [g] N-Boc-protected
1b. [h] N-Boc-protected d-2d. [i] The methyl ester of d-2d.
9
10
5j
5k
11[e]
[a] All reactions were conducted in 1,4-dioxane (1 mL) using 3 (1 mmol)
and 4 (3.5 mmol) in the presence of 20 mol% 1b and 20 mol% d-2d at
room temperature. [b] Conversion to the product, as determined by GC-
MS. [c] Isolated yield. [d] Determined by HPLC analysis on a chiralcel
OD-H column or chiralcel AD-H column. [e] Reacted at 308C.
802
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Chem. Eur. J. 2010, 16, 801 – 804

Dual Organocatalytic Ion-Pair Assemblies
COMMUNICATION
Table 3. High-resolution mass data of detected intermediates 6–8.
salicylic aldehydes (Table 2, entries 1–10). It appeared that
the electronic property and the position of the substituents
on the phenyl ring of salicylic aldehydes had a very limited
influence on the enantioselectivity of the reaction, and the
desired tetrahydroxanthenones 5 were obtained with 91–
98% ee. Likewise, the assembly was also reactive for 4-di-
methylcyclohex-2-enone to give 88% yield and 80% ee
within 72 h (Table 2, entry 11).
Results of mass spectrometry experiments confirmed the
proposed catalytic cycle.[11] As shown in Figure 1 and
Figure 2, the ESI mass spectra showed the signals for the
key transition states 6–8 involved in this domino reaction.
These results were further confirmed by accurate mass data
using Fourier-transform ion cyclotron resonance mass spec-
trometry in Table 3.
In summary, we have developed a highly efficient ap-
proach for the asymmetric oxa-Michael–Mannich reaction
of salicylic aldehydes with cyclohexenones to generate ver-
satile tetrahydroxanthenones in up to 98% ee. The special
feature of the approach is the first application of bifunction-
al catalysts formed from the ion-pair assembly of pyrroli-
dines and readily available primary amino acids, which si-
multaneously activate the two substrates. The key intermedi-
ates in this domino reaction were fully characterized by
Species Formula
Mass (measured) Mass (calculated) Error [ppm]
6
7
8
C16H21N2S 273.1415
C13H16NO3 234.1140
C19H24NO4 330.1711
273.1420
234.1130
330.1705
1.8
4.3
1.8
using mass spectrometry. We believe that the present strat-
egy will aid the development of future asymmetric transfor-
mations.
Experimental Section
Typical experimental procedure for the oxa-Michael–Mannich reaction of
salicylic aldehydes 3 and cyclohexenones 4 (Table 1, entry 21): 2-Hydrox-
ybenzaldehyde (112 mg, 1 mmol) and the amino acid d-2d (26.2 mg,
0.2 mmol) were added to 1,4-dioxane (1 mL) at room temperature with
vigorous stirring. After the d-2d had dissolved in the solution, cyclohex-
2-enone (336 mg, 3.5 mmol) and pyrrolidine 1b (38.8 mg, 0.2 mmol) were
added to the solution. The reaction conversion was monitored by GC-
MS. After reaction at room temperature for 2 days, the reaction mixture
was extracted with EtOAc (3ꢂ10 mL), washed with water, dried, and
concentrated. The residue was purified by flash chromatography, eluted
with ether/petroleum ether to give the desired oxa-Michael-Mannich
product 5a. The enantiomeric ratio was determined by HPLC analysis on
Daicel Chiralpak OD-H; hexane/2-
propanol (90:10, 1.0 mLminÀ1); re-
tention time: 11.92 (minor), 9.07-
1
N
d=7.44 (d, J=2.0 Hz, 1H), 7.28–7.22
(m, 2H), 6.98–6.95 (m, 1H), 6.90–
6.88 (d, J=8.5 Hz, 1H), 5.03–4.99 (m,
1H), 2.54–2.50 (m, 1H), 2.43–2.41
(m, 1H), 2.35–2.28 (m, 1H), 2.05–
1.99 (m, 1H), 1.97–1.89 (m, 1H),
1.68–1.58 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d=197.5, 155.9,
132.0, 131.5, 130.4, 129.8, 122.1(ꢂ2),
116.0, 74.6, 38.8, 29.7, 18.0 ppm; GC-
MS: m/z: 200.1, 199.1, 197.1, 144.1-
AHCTUNGTERG(NNUN 100), 115.1; HRMS: (EI+) m/z
calcd for [C13H12O2]+ 200.0837, found
200.0846.
Figure 1. ESI mass spectrum (positive mode) of the domino reaction, 2 h after the start of the reaction.
Acknowledgements
We gratefully acknowledge the Na-
tional Natural Science Foundation of
China (No. 20772110) and the Pro-
gram for Changjiang Scholars and In-
novative Research Teams in the Uni-
versities of China and Graduate In-
novative Research Project in Zhe-
jiang Province.
Keywords: asymmetric
synthesis · dual activation ·
organocatalysis · oxa-Michael–
Mannich reaction
assembly
·
self-
Figure 2. ESI mass spectrum (negative mode) of the domino reaction, 2 h after the start of the reaction.
Chem. Eur. J. 2010, 16, 801 – 804
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: September 15, 2009
Published online: November 27, 2009
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