Squaramide-tertiary amine catalyzed asymmetric cascade sulfa-Michael/ Michael addition via dynamic kinetic resolution: Access to highly functionalized chromans with three contiguous stereocenters

Article abstract of DOI:10.1021/ol400025a

An efficient asymmetric cascade sulfa-Michael/Michael addition reaction catalyzed by a chiral bifunctional squaramide-tertiary amine catalyst has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chromans with three contiguous stereocenters, including one quaternary center. In addition, a novel cascade sulfa Michael/retro-sulfa- Michael/sulfa-Michael/Michael reaction process, involving dynamic kinetic resolution, is described.

Full text of DOI:10.1021/ol400025a

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1190–1193
SquaramideÀTertiary Amine Catalyzed
Asymmetric Cascade Sulfa-Michael/
Michael Addition via Dynamic Kinetic
Resolution: Access to Highly
Functionalized Chromans with Three
Contiguous Stereocenters
Wen Yang, Yi Yang, and Da-Ming Du*
School of Chemical Engineering and Environment, Beijing Institute of Technology,
Beijing 100081, People’s Republic of China
dudm@bit.edu.cn
Received January 4, 2013
ABSTRACT
An efficient asymmetric cascade sulfa-Michael/Michael addition reaction catalyzed by a chiral bifunctional squaramideÀtertiary amine catalyst
has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chromans with three contiguous
stereocenters, including one quaternary center. In addition, a novel cascade sulfa Michael/retro-sulfa-Michael/sulfa-Michael/Michael reaction
process, involving dynamic kinetic resolution, is described.
Chroman is a fundamental heterocyclic skeleton found
in a large family of natural products and medically syn-
thetic molecules that exhibits a wide spectrum of signifi-
cant biological activities.1 Inthiscontext, great efforts have
been devoted to the synthesis of chiral chromans, and
numerous effective catalytic asymmetric approaches have
been established.2 Among these methods, organocatalytic
cascade reactionswereconsidered asa straightforwardand
powerful process to construct the chiral chroman frame-
work. Several impressive examples for the synthesis of chiral
chromans with multiple stereocenters were reported.3 In
2009, Wang’s group reported a highly enantioselective
cascade oxa-Michael/Michael reaction of 2-hydroxycin-
namaldehydes with nitroalkenes catalyzed by a chiral
diphenylprolinol TMS ether.3a In 2010, Xiao and co-
workers developed a chiral thiourea-catalyzed highly
enantioselective sulfa-Michael/Michael cascade reaction
of thiols with nitroalkene enoates.3b Subsequently, they
used anilines as donors to develop an efficient organocatalytic
aza-Michael/Michael cascade reaction.3c Very recently,
Peng et al. reported a chiral thiourea-catalyzed highly
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J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2010, 49, 8379. (c) Wang,
X.-F.; An, J.; Zhang, X.-X.; Tan, F.; Chen, J.-R.; Xiao, W.-J. Org. Lett.
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Prog. Chem. 2008, 20, 518. (c) Shen, H. C. Tetrahedron 2009, 65, 3931.
r
10.1021/ol400025a
Published on Web 03/06/2013
2013 American Chemical Society

asymmetric oxa-Michael/aza-Henry cascade reaction of
salicylaldimines with nitroalkenes.3d Despite a few suc-
cesses, the development of efficient new cascade reactions
or catalytic systems is still highly desirable.
In recent years, the emerging field of organocatalytic
cascade reactions has attracted considerable attention, and
great progress has been made.4 Organocatalysts for cas-
cade reactions mainly include proline and its derivatives,
cinchona alkaloid-based primary amines, thioureas, and
phosphoric acids. Squaramides are a class of good hydro-
gen-bonding organocatalysts and have been increasingly
utilized in organocatalysis.5,6 Nevertheless, they are still
rarely employed in cascade reactions.7 Recently, our group
also reported some asymmetric Michael addition reactions
catalyzed by squaramides.8 In addition, a large number of
methods on asymmetric Michael addition of nitroalkenes
have been reported.9 Herein, we document an efficient
squaramide-catalyzed asymmetric cascade sulfa-Michael/
Michael addition of thiosalicylates with nitroalkene
enoates for the construction of highly functionalized chro-
mans containing three contiguous stereocenters.
Figure 1. Squaramide catalysts.
12 h. Pleasingly, the asymmetric cascade sulfa-Michael/Michael
addition proceeded smoothly to afford the desired chroman
3aa in 83% yield with good diastereoselectivity and enantio-
selectivity (88:12 dr and 87% ee) (Table1, entry 1). How-
ever, the sulfa-Michael adduct 4aa was also obtained in
10% yield. After trials, temperature was found to benefit the
cascade reaction. The reaction was complete at 40 °C in 4 h
and only afforded the corresponding chroman 3aa in
excellent yield with almost the same good diastereoselec-
tivity and enantioselectivity (Table 1, entry 2). Encouraged
by the initial result, we then investigated the effect of solvent
and temperature for the optimal reaction conditions. The
results are presented in Table 1.The solvent optimization
disclosed that MeCN was the best reaction medium
(Table 1, entry 6). Variation of the solvents had little effect
on the reaction. The solvents such as ClCH2CH2Cl, CHCl3,
and toluene gave the comparable results as CH2Cl2, and the
solvents THF and i-PrOH provided lower enantioselectiv-
ities (78% ee and 73% ee, respectively) (Table 1, entries
3À5, 7, and 8). When reactions were performed at higher
temperature (60 or 80 °C), high diastereoselectivity and
enantioselectivity were maintained (Table 1, entries 9 and
10). Finally, we chose 60 °C as the optimal reaction
temperature.
With the optimal reaction conditions in hand, we screened
a small library of squaramide catalysts IÀX (Figure 1). The
results are summarized in Table 2. Squaramide II with 4-CF3
on the aromatic ring gave slightly lower diastereoselectivity
and enantioselectivity (88:12 dr, 86% ee) (Table 2, entry 2).
Squaramides III and IV derived from quinidine afforded the
desired adducts with similar results, but with opposite con-
figuration (Table 2, entries 3 and 4). We then turned our
attention to these squaramides VÀIX derived from chiral
1,2-diaminocyclohexane (Table 2, entries 5À9). Among
them, squaramides VII and IX gave higher diastereoselec-
tivity and enantioselectivity, but squaramide IX provided the
adduct 3aa in lower yield because of the formation of sulfa-
Michael adduct 4aa. C2-symmetric quinine-derived squar-
amide X were also examined, and lower diastereoselectivity
and enantioselectivity was obtained (Table 2, entry 10).
Therefore, squaramide VII was selected as the best catalyst.
Subsequently, the effect of catalyst loading was investigated.
The catalyst loading affected reaction rate, but rarely did the
We commenced our study with methyl thiosalicylate 1a
and nitroalkene enoate 2a as the model substrates. The model
reaction was performed in the presence of 5 mol % of
squaramide catalyst I (Figure 1) in CH2Cl2 at 15 °C for
(4) For reviews of organocatalytic cascade reactions, see: (a) Enders,
D.; Grondal, C.; Huttl, M. R. Angew. Chem., Int. Ed. 2007, 46, 1570.
(b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Alba, A.-N.;
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(e) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237.
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L. H. Chem. Soc. Rev. 2011, 40, 2330. (b) Aleman, J.; Parra, A.; Jiang,
H.; Jørgensen, K. A. Chem.;Eur. J. 2011, 17, 6890.
(6) For selected examples of asymmetric reactions using squara-
mides, see: (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem.
Soc. 2008, 130, 14416. (b) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew.
Chem., Int. Ed. 2010, 49, 153. (c) Xu, D. Q.; Wang, Y.-F.; Zhang, W.;
Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem.;Eur. J. 2010, 16,
4177. (d) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H.
Chem. Commun. 2010, 46, 3004. (e) Konishi, H.; Lam, T. Y.; Malerich,
J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028. (f) Pansare, S. V.; Paul,
E. K. Chem. Commun. 2011, 47, 1027. (g) Min, C.; Han, X.; Liao, Z. Q.;
Wu, X. F.; Zhou, H.-B.; Dong, C. Adv. Synth. Catal. 2011, 353, 2715.
(h) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.;
Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196. (i) Wang,
C.; Yang, X.; Loh, C. C. J.; Raabe, G.; Enders, D. Chem.;Eur. J. 2012,
18, 11531. (j) Noole, A.; Jaerving, I.; Werner, F.; Lopp, M.; Malkov, A.;
Kanger, T. Org. Lett. 2012, 14, 4922.
(7) For examples of squaramide-catalyzed asymmetric cascade reac-
tions, see: (a) Wang, X.; Yao, W.; Yao, Z.; Ma, C. J. Org. Chem. 2012,
77, 2959. (b) Ling, J.-B.; Su, Y.; Zhu, H.-L.; Wang, G.-Y.; Xu, P.-F. Org.
Lett. 2012, 14, 1090. (c) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R.
Chem.;Eur. J. 2012, 18, 6737. (d) Duan, S.-W.; Li, Y.; Liu, Y.-Y.; Zou,
Y.-Q.; Shi, D.-Q.; Xiao, W.-J. Chem. Commun. 2012, 48, 5160.
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Du, D.-M. Adv. Synth. Catal. 2011, 353, 1241. (c) Yang, W.; Du, D.-M.
Chem. Commun. 2011, 47, 12706. (d) Yang, W.; Jia, Y.; Du, D.-M. Org.
Biomol. Chem. 2012, 10, 332. (e) Yang, W.; Du, D.-M. Org. Biomol.
Chem. 2012, 10, 6876. (f) Yang, W.; Wang, J. S.; Du, D.-M. Tetrahedron:
Asymmetry 2012, 23, 972.
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Tetrahedron: Asymmetry 2007, 18, 299. (b) Enders, D.; Luttgen, K.;
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Org. Lett., Vol. 15, No. 6, 2013
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with different R1 substitution were tested, and the corre-
sponding adducts were obtained in excellent yields with high
diastereoselectivities and enantioselectivities (95:5 dr, 90% ee)
(Table 3, entries 2 and 3). The results show that R1
substitution has no effect on the stereoselectivity. Maybe it
is because R1 substitution is far from asymmetric induction
position. Then an array of nitroalkene enoates 2bÀj derived
from various salicylaldehydes reacted smoothly with methyl
thiosalicylates 1a to afford the corresponding adducts in high
yields with good to high diastereoselectivities and enantios-
electivities (Table 3, entries 4À12). Among them, 3,5-di-
chloro- and 3,5-dibromosalicylaldehyde-derived nitroalkene
enoates 2f and 2g gave lower diastereoselectivities and
enantioselectivities, and nitroalkene enoate 2h exhibited
lower reactivity. Further substrate scope was investigated.
When thiophenol 1d was employed, the desired adduct 3da
was obtained in moderate yield (60%) with high diastereo-
selectivity and good enantioselectivity (>95:5 dr, 87% ee)
(see the Supporting Information). A linear aliphatic ni-
troalkene enoate ((2E,7E)-ethyl 8-nitronona-2,7-dienoate)
was examined, but no cascade process was observed. The
Table 1. Optimization of Reaction Conditionsa
loading
(mol %)
temp time yieldb
eec,d
entry solvent
(°C)
(h)
(%)
drc (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
5
5
5
5
5
5
5
5
5
5
15
40
40
40
40
40
40
40
60
80
12
4
4
4
4
4
4
4
2
1
83 88:12 87
97 89:11 88
93 89:11 85
97 89:11 89
96 87:13 88
PhMe
MeCN
96 93:7
88
THF
90 88:12 78
iPrOH
MeCN
84 93:7
96 93:7
95 92:8
73
89
88
10 MeCN
a Reactions were carried out with 1a (0.12 mmol) and 2a (0.1 mmol)
in solvent (0.5 mL). b Isolated yield of 3aa. c Determined by chiral HPLC
analysis. d Enantiomeric excess of the major diastereomer.
Table 3. Squaramide-Catalyzed Asymmetric Cascade Sulfa-
Michael/Michael Addition of Thiosalicylates 1 to Nitroalkene
Enoates 2a
diastereoselectivity and enantioselectivity (Table 2, entries
11À13). Considering the yield and reaction time, 1 mol % of
catalyst loading was our appropriate choice.
Table 2. Screening of Squaramide Catalytsa
entry
catalyst
yieldb (%)
drc
eec,d (%)
1
I
96
93
94
92
90
89
95
90
81
91
98
95
78
93:7
88:12
93:7
89:11
95:5
90:10
94:6
91:9
95:5
88:12
94:6
95:5
96:4
89
86
89h
86h
79
62
90
84
90
86
90
90
91
2
II
3
III
IV
V
4
5
6
VI
VII
VIII
IX
X
7
8
9
10
11e
12f
13g
VII
VII
VII
a Reactions were carried out with 1 (0.24 mmol) and 2 (0.2 mmol) in
MeCN (1.0 mL) at 60 °C. b Isolated yield. c Determined by chiral HPLC
analysis or 1H NMR. d Enantiomeric excess of the major diastereomer
by chiral HPLC analysis. e Reaction was performed for 32 h.
a Reactions were carried out with 1a (0.12 mmol) and 2a (0.1 mmol)
in MeCN (0.5 mL) at 60 °C for 2 h. b Isolated yield. c Determined by
chiral HPLC analysis. d Enantiomeric excess of the major diastereomer.
e 10 mol % of VII for 2 h. f 1 mol % of VII for 5 h. g 0.5 mol % of VII for 8
h. h Opposite enantiomer.
absolute configuration of 3ae was determined to be 2S,3S,4S
by X-ray analysis (Figure S1, Supporting Information), and
those of other adducts were assigned by analogy.
The sulfa-Michael adduct 4aa observed in our initial
investigation is a reactive intermediate, which offers us a
Having established the optimal reaction conditions, we
explored the scope of the squaramide-catalyzed asymmetric
cascade sulfa-Michael/Michael addition reaction. The re-
sults are shown in Table 3. First, thiosalicylates 1b and 1c
1192
Org. Lett., Vol. 15, No. 6, 2013

Table 4. Study on the Cascade Reaction Pathwaya
Scheme 1. Proposed Cascade Reaction Pathway
loading time yieldb
eec,d
(%)
entry
reactant
(mol %)
(h)
(%)
drc
1
2
3
4
anti-4aa (49% ee)
syn-4aa (93% ee)
rac-anti-4aa
2
10
2
36
60
36
60
92
92
93
96
95:5
94:6
94:6
95:5
90
90
91
91
Scheme 2. Gram-Scale Preparation of 3aa and Its Transformation
rac-syn-4aa
10
a Reactions were carried out with 4aa (0.1 mmol) in MeCN
(1.0 mL) at 60 °C. b Isolated yield. c Determined by chiral HPLC
analysis. d Enantiomeric excess of the major diastereomer.
good opportunity to realize the cascade reaction pathway.
The adducts anti-4aa (49% ee) and syn-4aa (93% ee)
were prepared with very different enantioselectivities in
the presence of 2 mol % of VII at À20 °C, but they were
converted to the desired chroman 3aa with almostthe same
results (Table 4, entries 1 and 2). The results were the same
as that of the cascade reaction of methyl thiosalicylate 1a
and nitroalkene enoate 2a. The unexpected observation
signifies that the transformation from 4aa to 3aa is not by
a direct Michael addition but may be by a retro-sulfa-
Michael/sulfa-Michael/Michael process. To verify the hy-
pothesis, racemic anti-4aa and syn-4aa were treated under
the same reaction conditions. As expected, similar results
were achieved (Table 4, entries 3 and 4). Based on the
observed results and relative reports, we proposed a sulfa-
Michael/retro-sulfa-Michael/sulfa-Michael/Michael pro-
cess, involving dynamic kinetic resolution, for the asym-
metric cascade reaction (Scheme 1).10
As shown in Scheme 2, to highlight the synthetic value of
this methodology, the gram-scale preparation of 3aa and its
transformation were performed. The model cascade reaction
was readily gram-scaled without significant changes in yield,
diastereoselectivity, or enantioselectivity. The chroman 3aa
underwent reduction and transesterification to afford 5,
which was easily converted into γ-lactam 6 by heating in
argon. The chroman 3aa was also transformed into the
corresponding 2H-chromenes (7 or 8) by eliminating a
nitrous acid, but with complete loss of enantioselectivity.
The result indicated the transformation first underwent the
formation of 4H-chromenes as intermediates.
reactions with 1 mol % of squaramide VII proceeded well
to furnish the corresponding chromans in high yields with
high diastereoselectivity and enantioselectivity (up to 95:5
dr, 95% ee). This approach provides easy access to highly
functionalized chromans with three contiguous stereo-
centers, including one quaternary center. In addition, a
novel cascade reaction pathway (sulfa-Michael/retro-sul-
fa-Michael/sulfa-Michael/Michael process), involving
dynamic kinetic resolution, is described. Futher studies
on asymmetric cascade reactions catalyzed by squara-
mides are ongoing in our laboratory.
Acknowledgment. This project was supported by the Na-
tional Natural Science Foundation of China (Grant No.
21272024), the Science and Technology Innovation Program
of Beijing Institute of Technology (Grant No. 2011CX01008),
and the Development Program for Distinguished Young and
Middle-Aged Teachers of Beijing Institute of Technology.
Supporting Information Available. Experimental proce-
1
dures and characterizations, copies of H NMR and 13C
In conclusion, we have developed an efficient squaramide-
catalyzed asymmetric cascade sulfa-Michael/Michael ad-
dition for the synthesis of chiral chromans. The cascade
NMR of new compounds, X-ray crystal structure of 3ae
(CIF), and HPLC chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang, W. Angew. Chem., Int.
Ed. 2008, 47, 4177.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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