A highly stereoselective hydrogen-bond-mediated Michael-Michael cascade process through dynamic kinetic resolution

Article abstract of DOI:10.1002/anie.200800381

(Chemical Equation Presented) Oh Mickey, you're so fine: The title reaction, which is efficiently catalyzed by a cinchona alkaloid thioure affords direct access to thiochromanes in high efficiency. The reaction features a new activation mode of organocata

Full text of DOI:10.1002/anie.200800381

Angewandte
Chemie
DOI: 10.1002/anie.200800381
Cascade Reactions
A Highly Stereoselective Hydrogen-Bond-Mediated Michael–Michael
Cascade Process through Dynamic Kinetic Resolution**
Jian Wang, Hexin Xie, Hao Li, Liansuo Zu, and Wei Wang*
The ability of organocatalyzed asymmetric reactions to
promote cascade reactions has expanded their scope signifi-
cantly in the past few years, and a number of elegant cascade
reactions have been reported.[1] The predominant strategy is
the use of cascade reactions that are driven by the formation
of covalent bonds through the action of a chiral amine
catalyst.[1,2] In contrast, the use of noncovalent hydrogen
bonds as an activation force for such processes has been much
less explored, with only a handful of examples reported.[3–5]
Herein we report a novel asymmetric Michael–Michael
cascade reaction [Eq. (1)]. Notably, the cascade process is
efficiently catalyzed by a cinchona alkaloid amine thiourea at
acid ethyl ester (1a) was treated with trans-a,b-unsaturated
oxazolidinone 4 in the presence of catalyst I in CH2Cl2 at
room temperature [Eq. (2)]. Unfortunately, the process did
not lead to the desired Michael–Michael product. Instead, a
single Michael adduct 5 was obtained in 92% yield, possibly
because the steric hindrance in 5 might obstruct the second
Michael addition.
Accordingly, the less hindered trans-b-nitrostyrene (2a)
was then used for the Michael–Michael reaction with 1a in
the presence of I (5 mol%) under the same reaction
conditions as above (Table 1, entry 1). Gratifyingly, this
reaction proceeded smoothly to furnish the desired Michael
adduct 3a in 93% yield and with good selectivity (86% ee,
d.r. 15:1). Further investigation of other bifunctional organo-
catalysts revealed that I gave the best conversion and
selectivity.[6] A survey of reaction media showed that toluene
was the optimum solvent for the reaction (Table 1, entry 6). In
this case, the process was complete within 4 h and afforded
Table 1: Effects of solvent and catalyst loading on the Michael–Michael
reaction.[a]
a low catalyst loading (2 mol%) and affords one-pot access to
enantioenriched thiochromanes with the creation of three
new stereogenic centers in remarkably high efficiency and
stereoselectivity. More significantly a novel activation mode
of the chiral amine thiourea catalyzed dynamic kinetic
resolution (DKR) has been identified for this highly stereo-
selective cascade process.
[b]
Entry
Solvent
t [h]Yield [%]
ee [%][c]
d.r.[d]
15:1
27:1
18:1
1
2
3
4
5
6
CH2Cl2
6
6
93
89
92
76
81
91
90
86
88
87
86
93
91
95
94
97
97
97
95
8
To probe the feasibility of the proposed Michael–Michael
cascade reaction, trans-3-(2-mercaptophenyl)-2-propenoic
Cl(CH2)2Cl
1,4-dioxane
Et2O
PhOMe
toluene
toluene
toluene
xylenes
DMF
6
9
9
4
25:1
27:1
>30:1
>30:1
>30:1
>30:1
17:1
[*]Dr. J. Wang, H. Xie, Dr. H. Li, L.-S. Zu, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
7[e]
8[f]
9
8
15
4
10
4
E-mail: wwang@unm.edu
[a]Reaction conditions: unless otherwise specified, see the Experimental
Section. [b]Yield of the isolated product. [cD] etermined by HPLC
analysis on a chiral stationary phase (Chiralcel OD-H). [d]Determined by
1H NMR spectroscopy. [e]2 mol% catalyst loading. [f]1 mol% catalyst
loading. DMF=N,N-dimethylformamide.
[**]Financial support of this research was provided by the NSF
(CHE-0704015) and the ACS Petroleum Research Fund.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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4177

Communications
thiochromane 3a in 91% yield and with excellent selectivity
(97% ee, d.r. > 30:1). Remarkably, the reaction also pro-
ceeded efficiently with a catalyst loading of only 1 mol%
(Table 1, entry 8).
We then selected the use of I (2 mol%) in toluene at room
temperature to evaluate the generality of our cascade process
(Table 2). The results demonstrate that the cascade process
Table 2: Scope of the Michael–Michael cascade reaction catalyzed by I.[a]
Figure 1. X-ray crystal structure of 6.
[Eq. (1)]. However, we suspected that the reaction might
follow an alternative pathway because low enantioselectivity
was generally observed with I for the single conjugate
addition reaction of thiols with nitroolefins.[8] In an effort to
reconcile the unusual observation, we propose a novel DKR-
mediated Michael–retro-Michael–Michael–Michael cascade
pathway [Rauhut–Currier reaction; Eq. (3)].[9–11] We ration-
Entry
X
R
t [h]Product
(yield) [%][b]
ee [%][c] d.r.[d]
1
2
3
4
5
6
7
8
9
10
H
H
H
H
H
H
H
H
H
H
Ph
8
3a (90)
3b (92)
3c (99)
3d (98)
3e (91)
3 f (83)
3g (88)
3h (95)
3i (90)
3j (87)
97
97
97
94
97
97
97
97
99
92
>30:1
4-FC6H4
4-ClC6H4
2,6-Cl2C6H3
4-BrC6H4
3-BrC6H4
4-MeOC6H4 15
4-BnOC6H4 12
2-MeOC6H4 18
12
12
12
12
12
30:1
>30:1
16:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
3-BnO,
24
4-MeOC6H3
11
H
H
2-thiophene 12
3k (97)
98
>30:1
>30:1
>30:1
>30:1
12[e]
13
nC4H9
96
36
72
3l (32) 91[g] 93
5-Me
5-OMe Ph
Ph
3m (93)
3n (42)
99
97
14[f]
alized that the initially formed Michael adduct 7 could
undergo a DKR process in the presence of I: where
deprotonation of the highly acidic nitroalkane proton of 7
by the chiral bifunctional amine thiourea I would lead to a
reversible and highly stereoselective retro-Michael–Michael–
Michael process. The above hypothesis was confirmed by
treatment of racemic 7a with I (10 mol%) under the standard
reaction conditions, that is, in toluene at room temperature
[Eq. (4)]. Product 3a was formed in 94% yield (95% ee,
[a]Reaction conditions: unless otherwise specified, see the Experimental
Section. [b]Yield of the isolated product. [c]Determined by HPLC
analysis on a chiral stationary phase (Chiralpak AS-H, Chiralpak AD,
Chiralcel OD-H, or Chiralcel OJ-H). [d]Determined by 1H NMR spec-
troscopy. [e]10% catalyst loading. [f]5% catalyst loading. [g]Yield of the
recovered product.
catalyzed by I serves as a general approach to afford
thiochromanes with the highly efficient creation of three
new stereogenic centers. It was found that an extensive range
of nitroalkenes can effectively participate in the process
(Table 2, entries 1–12), irrespective of the electronic nature
and the substitution pattern of the aromatic system. For
example, the reaction takes place with aromatic systems that
possess electron-neutral (Table 2, entry 1), -withdrawing
(Table 2, entries 2–6), or -donating (Table 2, entries 7–10)
groups at the o, m, or p positions of the nitroalkene without
substantial loss in yield (83–98%) or selectivity (92–99% ee,
d.r. 16:1 to > 30:1). Moreover, the heteroaromatic nitroolefin
(Table 2, entry 11) can also be tolerated. A high ee value
(93%) and good diastereoselectivity (> 30:1) were obtained
with this less reactive aliphatic nitroalkene, in spite of the slow
conversion (Table 2, entry 12). Finally, the system also seems
inert to any electronic changes to the aromatic ring of 1
(Table 2, entries 13 and 14). The absolute configuration of the
products was determined by single-crystal X-ray analysis of 6
(an amide derived from 3c; Figure 1).[7]
d.r. > 30:1) and with the same 2R,3S,4S configuration that
was observed from the direct reaction of 1a with 2a (Table 2,
entry 1). Notably, however, the previous I-promoted
Michael–aldol cascade reaction did not undergo the DKR
process.[5a,12]
In conclusion, we have developed a novel and highly
stereoselective Michael–Michael cascade reaction that is
catalyzed by a cinchona alkaloid thiourea. An unprecedented
cascade process, which involved dynamic kinetic resolution, is
described. Our study, with a new activation mode, expands
the scope of organocatalyzed reactions. Further applications
Initially a Michael–Michael cascade process was proposed
for the formation of the highly stereocontrolled products 3
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Angewandte
Chemie
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Experimental Section
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[6] See Table S1 of the Supporting Information for details.
[7] CCDC 675590 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
General procedure (Table 2, entry 1): A solution of 3-(2-mercapto-
phenyl)-2-propenoic acid ethyl ester (1a; 21 mg, 0.1 mmol), trans-b-
nitrostyrene (2a; 15 mg, 0.1 mmol), and I (3 mg, 0.002 mmol) in
toluene (0.2 mL) was stirred at room temperature for 8 h. The crude
product was purified by column chromatography on silica gel with
hexanes/EtOAc (20:1) as eluent to afford the desired product as a
clear oil (32 mg, 90% yield); d.r. > 30:1 (determined by 1H NMR
spectroscopy); 97% ee (HPLC on a Chiralcel OD-H column, eluted
with hexanes/iPrOH (70:30) at 0.5 mLminÀ1, l = 254 nm); retention
time: 14.7 min (major product) and 16.5 min (minor product); [a]D25
À88.6 degcm3 gÀ1 dmÀ1 (c = 0.90 gcmÀ3, CHCl3).
=
Received: January 24, 2008
Published online: April 17, 2008
Keywords: cascade reactions · kinetic dynamic resolution ·
.
Michael addition · organocatalysis
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Angew. Chem. Int. Ed. 2008, 47, 4177 –4179
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4179