Organocatalytic asymmetric Michael addition of α-aryl cyclopentanones to nitroolefins for construction of adjacent quaternary and tertiary stereocenters

Article abstract of DOI:10.1039/c0cc01987a

The first asymmetric Michael addition of α-aryl cyclopentanones to nitroolefins for construction of adjacent quaternary and tertiary stereocenters has been achieved with excellent diastereo-/enantioselectivity.

Full text of DOI:10.1039/c0cc01987a

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Organocatalytic asymmetric Michael addition of a-aryl cyclopentanones
to nitroolefins for construction of adjacent quaternary and tertiary
stereocentersw
Xiu-Qin Dong,a Huai-Long Teng,a Min-Chao Tong,a He Huang,a Hai-Yan Taoa and
Chun-Jiang Wang*ab
Received 21st June 2010, Accepted 16th July 2010
DOI: 10.1039/c0cc01987a
The first asymmetric Michael addition of a-aryl cyclopentanones
to nitroolefins for construction of adjacent quaternary and tertiary
stereocenters has been achieved with excellent diastereo-/
enantioselectivity.
Catalytic asymmetric construction of quaternary stereocenters,
as one of the highly desirable but challenging goals for synthetic
chemists, has attracted increasing attention in the past decades,
and several methods have been developed to address this issue
recently.1 However, for incorporation of an additional tertiary
stereocenter adjacent to the quaternary stereocenter, only limited
successful protocols have been reported to achieve high levels
of enantio- and diastereoselectivity.2–4 Although asymmetric
Michael addition between trisubstituted carbon nucleophiles
and various electron-deficient alkenes offers straightforward
access to such compounds, most of the nucleophiles employed
in this transformation are limited to carbonyl substrates bearing
electron-withdrawing groups such as CO2R,2 NO2,3 and CN4 at
the a-position. In sharp contrast to the substrates containing
two strongly electron-withdrawing groups, a-aryl substituted
carbonyl compounds have seldom been applied as nucleophiles
in asymmetric Michael addition reaction.5 To the best of our
knowledge, only one racemic version involving a-aryl cyclo-
pentanone as nucleophile and nitroolefin as electrophile has been
reported using Et3N as catalyst in 14–30 days.6 The required
longer reaction time was probably caused by the higher
pKa value of the corresponding a-protons7 or unfavored steric
hindrance. A stereoselective version of this transformation may
not only diversify the existing asymmetric Michael addition but
also be valuable in the synthesis of chiral building blocks with
two adjacent quaternary and tertiary stereogenic centers.
Fig. 1 Structures of the screened bifunctional amine-thiourea organo-
catalysts (I–VII).
transformation allowed for facile access to enantio-enriched
cyclic imine, nitrone and fused pyrrolidines.
We began our studies by evaluating the reaction of a-phenyl
cyclopentanone 1a and nitroolefin 2a with the fine-tunable organo-
catalysts I and II (Fig. 1) developed by our group recently.10 To our
delight, the reaction was finished remarkably in less than 20 h at
room temperature with catalyst I-a, yielding the desired adduct 3aa
with complete diastereoselectivity (>99 : 1), which preliminarily
verifies our hypothesis on accelerating this challenging reaction
through the synergistic hydrogen-bonding-activation of both
Michael donor and Michael acceptor. Encouraged by the
promising results, a series of fine-tunable bifunctional amine-
thiourea catalysts I and II were subsequently screened, and the
representative results are summarized in Table 1. In general, both
the reaction rate and enantioselectivity were significantly affected
by the configuration matching of the two units of the thiourea
moiety and the acidity of the third hydrogen bonding donor
(Table 1, entries 1–4 vs. 6–9). Faster reaction rate and higher
enantioselectivity were obtained with organocatalysts I, which was
ascribed to the additional stronger hydrogen bonding donor
rendered by the strong electron-withdrawing sulfonamide group.
Among the tested bifunctional amine-thiourea catalysts,
(1R,2R,10R,20R)-I-d was revealed as the best catalyst in terms of
enantioselectivity and reaction rate (Table 1, entry 4). The reaction
Considering the significant role played by bifunctional
catalysts in the tremendous asymmetric catalysis,8,9 we
envisioned that bifunctional amine-thiourea8 could efficiently
activate the a-aryl cyclopentanone and nitroolefin simul-
taneously through hydrogen bonding interactions and thereby
realize this challenging reaction. Herein, we report the first
highly stereoselective Michael addition of a-aryl cyclopentanones
to nitroolefins catalyzed by bifunctional amine-thiourea
bearing multiple hydrogen-bonding donors,10,11 and subsequent
a College of Chemistry and Molecular Sciences, Wuhan University,
430072, China. E-mail: cjwang@whu.edu.cn; Fax: +86-27-68754067
b State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin, 300071, China
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 768128–768129. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc01987a
c
6840 Chem. Commun., 2010, 46, 6840–6842
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Table
1
Screening studies of asymmetric Michael addition of
Table 2 Asymmetric Michael addition of a-substituted cyclopentanones
1 and nitroolefins 2 catalyzed by bifunctional organocatalyst I-da
a-phenyl cyclopentanone 1a and nitroolefin 2a catalyzed by bifunctional
amine-thiourea catalystsa
Entry Ar (1)
R (2)
3
Yield (%)b Ee (%)c
Entry
L
Solvent
t/h
Yield (%)b
Ee (%)c
1
2
3
4
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
3aa 90
3ab 88
3ac 92
3ad 94
3ae 83
3af 90
92 (99)d
94
94
1
2
3
4
5
6
7
8
I-a
I-b
I-c
I-d
I-e
II-a
II-b
II-c
II-d
III
IV
V
VI
VII
I-d
I-d
I-d
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
17
15
15
12
72
48
48
48
48
20
18
18
20
24
16
12
19
88
84
85
88
61
68
72
74
71
86
82
80
86
87
87
90
85
80
84
76
88
80
54
77
52
77
74
ꢀ63
ꢀ71
65
73
80
92
92
p-Cl-Ph (2b)
o-Cl-Ph (2c)
p-Br-Ph (2d)
p-F-Ph (2e)
p-Me-Ph (2f)
p-MeO-Ph (2g) 3ag 87
m-MeO-Ph (2h) 3ah 93
o-MeO-Ph (2i) 3ai 85
1-Naphthyl (2j) 3aj 89
2-Naphthyl (2k) 3ak 95
2-Furyl (2l)
Cinnamyl (2m) 3am 89
Propyl (2n)
Ph (2a)
Ph (2a)
94 (99)d
95
95
5
6e
7e
8e
9e
10e
11
95
94
94
96
94
94
96
80
91
90
90
91
91
94
95
9
10
11
12
13
14
15d
16e
17e,f
12e,f Ph (1a)
3al 93
13d
14g
15
16
17
Ph (1a)
Ph (1a)
p-Me-Ph (1b)
m-Me-Ph (1c)
p-MeO-Ph (1d) Ph (2a)
m-MeO-Ph (1e) Ph (2a)
3an 50
3ba 88
3ca 91
3da 93
3ea 90
3fa 89
3ga 95
3ha 90
18
19
p-Cl-Ph (1f)
m-Cl-Ph (1g)
p-CF3-Ph (1h) Ph (2a)
Ph (2a)
Ph (2a)
a
All reactions were carried out with 0.2 mmol of 1a, 0.21 mmol of 2a in
0.45 mL of DCM. b Isolated yield. c Enantioselectivity was determined by
chiral HPLC analysis, and >99 : 1 diastereomeric ratio was determined by
HPLC analysis. Minor diastereomer was not detected on the crude
1H NMR. d 5 mol% H2O was added. e 4A MS was added. f 5 mol%
catalyst.
20e
21e
a
b
c
d
See Table 1. See Table 1. See Table 1. Data in parentheses were
e
f
achieved after recrystallization. Run at ꢀ20 1C in 48 h. Diastereo-
g
meric ratio was 98 : 2. In 30 h.
deficient groups on the phenyl ring proved to be excellent donors
for this reaction, providing high diastereoselectivity and enantio-
selectivity (Table 2, entries 15–21).
became sluggish and the adduct 3aa was formed in only 61% yield
even in 72 h when using methylated I-e as the catalyst, which
further indicates that synergistic multiple hydrogen bonding activa-
tion plays a significant role in this transformation (Table 1, entry 5).
Other chiral bifunctional amine-thiourea catalysts derived from
1,2-diaminocyclohexane12 or cinchona alkaloid13 were also tested
in this transformation, producing the desired adducts with a little
lower enantioselectivities (Table 1, entries 10–14). Further improve-
ment of the enantioselectivity could be achieved through the
addition of 4A molecular sieves (Table 1, entry 16).14 A com-
parable result (>99 : 1 dr, 92% ee) was still achieved even when the
catalyst loading was reduced to 5 mol% (Table 1, entry 17).
Next, the scope and generality of this new asymmetric Michael
addition with respect to both electrophile and nucleophile were
investigated under the optimized experimental conditions. As
shown in Table 2, various electron-rich, electron-neutral, or
electron-deficient nitroolefins with different substitution patterns
on the aromatic ring reacted smoothly with a-phenyl cyclo-
pentanone 1a to afford the Michael adducts (3aa–3ai) with
excellent diastereoselectivities (>99 : 1) and high enantioselecti-
vities (92–95%) (Table 2, entries 1–9). Heteroaromatic nitroolefin
2l was also a viable substrate as condensed-ring nitroolefins 2j
and 2k (Table 2, entries 10–12). Remarkably, a,b-unsaturated
nitroolefin 2m was well tolerated in this transformation, and the
corresponding adduct 3am could be obtained in 89% yield and
96% ee (Table 2, entry 13). Noticeably, the less reactive alkyl
nitroolefin 2n15 also works in this reaction to give the desired
product with excellent diastereoselectivity and good enantio-
selectivity (Table 2, entry 14). For nucleophile partners, a wide
array of a-aryl cyclopentanones bearing electron-rich and electron-
Prompted by the results for a-aryl cyclopentanones, we then
investigated the more challenging nucleophile a-phenyl cyclo-
hexanone 8, for which no racemic Michael addition occurred
in the literature:6 To our delight, the reaction did take place
and the desired adduct was achieved in 20% yield and 84% ee
when the reaction temperature was improved to 50 1C.
Fortunately, all the products are solid, and enantioenriched
compounds can be easily obtained by direct crystallization of
the crude products in methanol (Table 2, entries 1 and 4). The
absolute configuration of 3ad was unequivocally determined as
(2S,3S) by X-ray diffraction analysis (See ESI).z Those of other
adducts were tentatively proposed on the basis of these results.
The optically active conjugate addition products 3aa containing
adjacent quaternary and tertiary stereogenic centers can be readily
converted into synthetically useful compounds as exemplified in
Scheme 1. The cyclic imine 4 was easily attained by reduction of the
nitro moiety with Zn/HCl at 40 1C without loss of diastereo- and
enantiomeric excess.2h Alternatively, direct hydrogenation of 3aa in
the presence of Pd/C afforded the nitrone 5 in 75% yield;15,16
further increasing the hydrogen pressure, reaction temperature and
extending the reaction time, 3aa and the above nitrone 5 can be
readily converted into fused pyrrolidine 6 with three consecutive
c
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Chem. Commun., 2010, 46, 6840–6842 6841

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4966; (g) F. Wu, R. Hong, J. Khan, X. Liu and L. Deng, Angew.
Chem., Int. Ed., 2006, 45, 4301; (h) Z. Yu, X. Liu, L. Zhou, L. Lin and
X. Feng, Angew. Chem., Int. Ed., 2009, 48, 5195.
3 For selected examples of catalytic asymmetric conjugate addition
of a-substituted b-nitrocarbonyl pronucleophiles for the construc-
tion of adjacent quaternary and tertiary stereogenic centers, see:
(a) Z. H. Chen, H. Morimoto, S. Matsunaga and M. Shibasaki,
J. Am. Chem. Soc., 2008, 130, 2170; (b) D. Uraguchi,
K. Koshimoto and T. Ooi, J. Am. Chem. Soc., 2008, 130, 10878.
4 For review and selected examples of catalytic asymmetric conjugate
addition of a-substituted b-cyanocarbonyl pronucleophiles for the
construction of adjacent quaternary and tertiary stereogenic centers,
see: (a) S. Jautze and R. Peters, Synthesis, 2010, 365; (b) M. S. Taylor
and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125, 11204;
(c) M. S. Taylor, D. N. Zalatan, A. M. Lerchner and E. N. Jacobsen,
J. Am. Chem. Soc., 2005, 127, 1313; (d) F. Marini, S. Sternativo, F. Del
Verme, L. Testaferri and M. Tiecco, Adv. Synth. Catal., 2009, 351, 1801;
(e) H. Li, J. Song and L. Deng, Tetrahedron, 2009, 65, 3139.
Scheme 1 Synthetic transformation of the Michael adduct 3aa.
Conditions: (i) Zn/HCl, 40 1C, 78% yield; (ii) Pd/C, H2 (20 atm),
50 1C, 10 h, 60% yield; (iii) Pd/C, H2 (40 atm), 80 1C, 30 h, 63% yield;
(iv) TsCl/Et3N, 91% yield.
stereocenters in
a highly diastereo-/enantioselective manner,
5 (a) W. Nerinckx and M. Vandewalle, Tetrahedron: Asymmetry, 1990,
1, 265; (b) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti,
B. Giannichi, L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur.
J., 2009, 15, 7846; (c) T. Bui, S. Syed and C. F. Barbas III, J. Am.
Chem. Soc., 2009, 131, 8758; (d) Y. Kato, M. Furutachi, Z. Chen,
H. Mitsunuma, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc.,
2009, 131, 9168; (e) M. P. Lalonde, Y. Chen and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2006, 45, 6366; (f) N. Mase,
R. Thayumanavan, F. Tanaka and C. F. Barbas III, Org. Lett.,
2004, 6, 2527; (g) J. Wang, X. Wang, Z. Ge, T. Cheng and R. Li,
Chem. Commun., 2010, 46, 1751.
6 J. Deutsch, H.-J. Niclas and M. Ramm, J. Prakt. Chem., 1995, 337, 23.
7 F. G. Bordwell and J. Harrelson, Can. J. Chem., 1990, 68, 1714.
8 For reviews on bifunctional organocatalysis, see: (a) S. B. Tsogoeva,
Eur. J. Org. Chem., 2007, 1701; (b) Y. Takemoto, Org. Biomol. Chem.,
2005, 3, 4299; (c) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418;
(d) A.-G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713;
(e) H. Miyabe and Y. Takemoto, Bull. Chem. Soc. Jpn., 2008, 81, 785.
9 For reviews on bifunctional metallic catalysis, see:
(a) S. Matsunaga and M. Shibasaki, Bull. Chem. Soc. Jpn., 2008,
81, 60; (b) M. Shibasaki, M. Kanai, S. Matsunaga and
N. Kumagai, Acc. Chem. Res., 2009, 42, 1117; (c) V. Annamalai,
E. F. DiMauro, P. J. Carroll and M. C. Kozlowski, J. Org. Chem.,
2003, 68, 1973; (d) W. Hirahata, R. M. Thomas, E. B. Lobkovsky
and G. W. Coats, J. Am. Chem. Soc., 2008, 130, 17658.
10 (a) C.-J. Wang, Z.-H. Zhang, X.-Q. Dong and X.-J. Wu, Chem.
Commun., 2008, 1431; (b) Z.-H. Zhang, X.-Q. Dong, D. Chen and
C.-J. Wang, Chem.–Eur. J., 2008, 14, 8780; (c) C.-J. Wang,
X.-Q. Dong, Z.-H. Zhang, Z.-Y. Xue and H.-L. Teng, J. Am.
Chem. Soc., 2008, 130, 8606; (d) X.-Q. Dong, H.-L. Teng and
C.-J. Wang, Org. Lett., 2009, 11, 1265.
11 For other organocatalysts having multiple hydrogen bonding
donors, see: (a) R. P. Herrera, V. Sgarzani, L. Bernardi and
A. Ricci, Angew. Chem., Int. Ed., 2005, 44, 6576;
(b) Y. Sohtome, A. Tanatani, Y. Hashimoto and K. Nagasawa,
Tetrahedron Lett., 2004, 45, 5589; (c) A. Berkessel, K. Roland and
J. M. Neudorfl, Org. Lett., 2006, 8, 4195.
which comprises a core component of various biological active
compounds.17 An X-ray analysis of a crystal of 7 revealed
(2S,3S,4S) configuration for the three consecutive stereocenters
therefore also for the corresponding moiety in 6 (See ESI).z
In conclusion, we have developed the first asymmetric Michael
addition reaction of a-aryl cyclopentanones and nitroolefins
catalyzed by bifunctional amine-thiourea catalyst bearing multiple
hydrogen bonding donors. This catalytic system performs well
over a broad scope of substrates and provides the desired adducts
containing adjacent quaternary and tertiary stereogenic centers in
excellent diastereoselectivity (>98 : 2) and high enantioselectivity
(90–96% ee), and subsequent transformations led to expedient
preparation of synthetically useful cyclic imine, nitrone and fused
pyrrolidines. Further investigations of the scope and synthetic
application of this methodology are ongoing, and the results will
be reported in due course.
This work was supported by the National Natural Science
Foundation of China (20702039, 20972117), the Fundamental
Research Funds for the Central Universities, and SRFDP
(J0730426).
Notes and references
z Crystal data for (2S,3S)-3ad: C19H18BrNO3, Mr = 388.25, T = 293 K,
orthorhombic, space group P212121, a = 8.367(4), b = 13.132(6), c =
16.078(8) A, V = 1766.6(15) A3, Z = 4, 3435 reflections measured,
2914 unique (Rint = 0.0201) which were used in all calculations. The
final wR2 = 0.0922 (all data). Flack w = 0.011(10). For (2S,3S,4S)-7:
C26H27NO2S, Mr = 417.55, T = 293 K, orthorhombic, space group
P212121, a = 7.4773(6), b = 11.8993(9), c = 25.2455(19) A, V =
2246.2(3) A3, Z = 4, 4657 reflections measured, 3641 unique (Rint
=
12 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2003, 125, 12672; (b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu
and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119.
0.0364) which were used in all calculations. The final wR2 = 0.0787
(all data). Flack w = 0.05(7). CCDC 768128 (3ad), CCDC 768129 (7).
1 For recent reviews, see: (a) Quaternary Stereocenters: Challenges and
Solutions for Organic Synthesis, ed. J. Christoffers and A. Baro,
Wiley-VCH, Weinheim, 2005; (b) B. M. Trost and C. Jiang,
Synthesis, 2006, 369; (c) C. J. Douglas and L. E. Overman, Proc.
Natl. Acad. Sci. U. S. A., 2004, 101, 5363, references cited therein.
2 For selected examples of catalytic asymmetric conjugate addition of
a-substituted b-ketoesters for the construction of adjacent quaternary
and tertiary stereogenic centers, see: (a) H. Wynberg and R. Helder,
Tetrahedron Lett., 1975, 16, 4057; (b) Y. Hamashima, D. Hotta and
M. Sodeoka, J. Am. Chem. Soc., 2002, 124, 11240; (c) F. Wu, H. Li,
R. Hong and L. Deng, Angew. Chem., Int. Ed., 2006, 45, 947;
(d) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo,
B. M. Foxman and L. Deng, Angew. Chem., Int. Ed., 2005, 44, 105;
(e) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto,
J. Am. Chem. Soc., 2005, 127, 119; (f) G. Bartoli, M. Bosco,
A. Carlone, A. Cavalli, M. Locatelli, A. Mazzanti, P. Ricci,
L. Sambri and P. Melchiorre, Angew. Chem., Int. Ed., 2006, 45,
13 (a) B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett.,
´ ´
2005, 7, 1967; (b) T. Marcelli, J. H. van Maarseveen and
H. Hiemstra, Angew. Chem., Int. Ed., 2006, 45, 7496;
(c) S. J. Connon, Chem. Commun., 2008, 2499.
14 Results of the solvent screening studies at room temperature:
CHCl3 (12 h, 89% yield, ee: 73%); EtOAc (12 h, 85% yield, ee:
71%); THF (13 h, 80% yield, ee: 66%); MeCN (15 h, 92% yield,
ee: 75%); acetone (16 h, 75% yield, ee: 76%); PhMe (19 h, 81%
yield, ee: 78%); MeOH (16 h, 83% yield, ee: 2%).
15 C. L. Cao, M.-C. Ye, X.-L. Sun and Y. Tang, Org. Lett., 2006, 8, 2901.
´ ´
16 I. H. Sanchez, M. I. Larraza, I. Rojas and F. K. Brena, Hetero-
cycles, 1985, 23, 3033.
17 (a) S. G. Pyne, A. S. Davis, N. J. Gates, J. Nicole, J. P. Hartley,
K. B. Lindsay, T. Machan and M. Tang, Synlett, 2004, 2670;
(b) S. Husinec and V. Savic, Tetrahedron: Asymmetry, 2005, 16,
2047; (c) O. Danilova, B. Li, A. K. Szardenings, B. T. Huber and
J. S. Rosenblum, Bioorg. Med. Chem. Lett., 2007, 17, 507.
c
6842 Chem. Commun., 2010, 46, 6840–6842
This journal is The Royal Society of Chemistry 2010