Enantioselective 1,3-dipolar cycloaddition of cyclic enones catalyzed by multifunctional primary amines: Beneficial effects of hydrogen bonding

Article abstract of DOI:10.1002/anie.200702618

(Chemical Equation Presented) Hydrogen bonding makes a difference: Multifunctional primary amine catalysts derived from cinchona alkaloids are used in the highly enantioselective 1,3-dipolar cycloaddition of cyclic enones and azomethine imines (see scheme; R = aryl, alkyl; TIPBA = 2,4,6- triisopropylbenzene-sulfonic acid). The synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for stereocontrol.

Full text of DOI:10.1002/anie.200702618

Angewandte
Chemie
DOI: 10.1002/anie.200702618
Organocatalysis
Enantioselective 1,3-Dipolar Cycloaddition of Cyclic Enones Catalyzed
by Multifunctional Primary Amines: Beneficial Effects of Hydrogen
Bonding**
Wei Chen, Wei Du, Yong-Zheng Duan, Yong Wu, Sheng-Yong Yang, and Ying-Chun Chen*
Organocatalytic asymmetric reactions provide an environ-
mentally benign approach to a variety of optically pure
compounds.[1] In particular, the development of organocata-
lysts bearing two or more activating functionalities has
provoked increasing attention, because a concerted interac-
tion among multifunctional catalyst and reactants can gen-
erally lead to more efficient catalysis and enantiocontrol.[2]
Most bifunctional organocatalysts combine a Brønsted acid
Scheme 1. Design of the second-generation primary amine catalyst.
and Lewis base in one molecule to activate an electrophile
and nucleophile, respectively. However, this strategy has not
been applied to organocatalytic cycloaddition reactions.[3]
Table 1: Screening of the organocatalytic 1,3-dipolar cycloaddition of 2-
Asymmetric [3+2] dipolar cycloaddition is one of the
most powerful protocols to synthesize chiral five-membered
heterocycles, which usually have biological importance,[4] and
MacMillan et al. developed the first elegant amine-catalyzed
1,3-dipolar cycloaddition of enals through a LUMO-lowering
strategy.[5] However, despite great progress in iminium
catalysis,[6] the organocatalytic 1,3-dipolar cycloaddition of
enones still remains to be explored, probably because of the
lack of suitable amine catalysts.[7] Recently, we established
that 9-amino-9-deoxyepicinchona alkaloids could serve as
excellent iminium catalysts for enones.[8] This finding encour-
aged us to investigate the undeveloped organocatalytic 1,3-
dipolar cycloaddition of enones.
cyclohexen-1-one (2a) and azomethine imine 3a.[a]
Entry
Catalyst
Acid
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1a
1a
1c
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1a
1b
1d
TFA
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
EtOAc
DME
iPrOH
THF
THF
THF
THF
THF
16
20
20
36
12
24
24
36
36
36
36
24
36
36
42
144
36
36
56
37
19
82
52
96
89
96
89
96
44
23
60
22
52
44
89
82
51
55
60
p-TSA
l-CSA
l-CSA
p-TSA
l-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
d-CSA
TIPBA
TIPBA
À59
78
87
89
88
89
89
78
61
95
96
51
46
90
9-Amino-9-deoxyepiquinine (1a; 10 mol%, Scheme 1) in
combination with acid (20 mol%) smoothly catalyzed the 1,3-
dipolar cycloaddition of 2-cyclohexen-1-one (2a) and azome-
thine imine[9] 3a to give the desired tricyclic product 4a with
excellent diastereoselectivity (d.r. > 99:1) at 208C. Unfortu-
9
10
11
12
13[d]
14[e]
15
16[d]
17[d,f]
18[d,f]
[*] Dr. W. Chen,W. Du,Y.-Z. Duan,Prof. Dr. Y. Wu,Prof. Dr. Y.-C. Chen
Key Laboratory of Drug Targeting of Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy
THF
À86
Sichuan University
[a] Unless otherwise noted,reactions were performed with 0.2 mmol of
2a,0.1 mmol of 3a,0.01 mmol of 1,and 0.02 mmol of acid in 0.5 mL
solvent at 208C. [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis,d.r. >99:1. [d] Addition of 10 mg 4-Š M.S. [e] Addition of
25 mg 4-Š M.S. [f] At 408C. CSA=camphor-10-sulfonic acid; TIPBA=
2,4,6-triisopropylbenzenesulfonic acid; DME=1,2-dimethoxyethane.
Chengdu 610041 (China)
Fax: (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
Prof. Dr. S.-Y. Yang,Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy
West China Hospital
Sichuan University
Chengdu 610041(China)
nately, only low to moderate ee values could be obtained
(Table 1, entries 1–3). 9-Amino-9-deoxyepiquinidine (1c;
10 mol%, Scheme 2) exhibited higher catalytic activity,
while a similar ee value was obtained (Table 1, entry 4).
We realize that 1a could activate dipolarophile 2a by the
formation of ketiminium ion, but has no direct contact with
[**] We are grateful for the financial support from the NSFC (20502018),
Ministry of Education (NCET-05-0781),Fok Ying Tung Education
Foundation (101037),and Sichuan Province Government
(07ZQ026-027).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 7667 –7670
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7667

Communications
Table 2: Asymmetric 1,3-dipolar cycloaddition of cyclic enones 2 and
azomethine imines 3.[a]
Scheme 2. Structures of amine catalysts derived from quinidine.
Entry
2
R (3)
t [h]
4
Yield [%][b] ee [%][c]
1
2
3
2a Ph (3a)
36 4a
60 4b
72 4c
18 4d
48 4e
48 4 f
36 4g
48 4g
120 4g
89
73
73
80
73
70
99
99
67
90
92[d]
95
94
92
92
92
93
93
86
95
91
92
87
90
95
93
93
1,3-dipole 3a. We envisage that the introduction of a hydroxy
group in the primary amine catalyst 1b (Scheme 1),[10,11]
which might form a hydrogen bond[12] with the carbonyl
group of dipole 3a, would be helpful for enantiocontrol, as a
synergistic interaction between the organocatalyst and the
two reactants could be created.[4j,13] Indeed, both the reac-
tivity and enantioselectivity were dramatically improved
when the reaction was catalyzed by 1b salt (Table 1,
entries 5–7), and a higher ee value was attained with d-CSA
(Table 1, entry 7). Other solvents like CH2Cl2, toluene, and
EtOAc were also tolerated (Table 1, entries 8–10), but both
reaction rate and ee values were decreased in DME or 2-
propanol (Table 1, entries 11 and 12).
As H2O would be generated during the formation of an
active iminium intermediate, the expected hydrogen-bonding
interaction might be affected. Consequently, a molecular
sieve (M.S., 4 Š) was added to remove the trace amount of
water. In this way, the ee value was raised to 95%, although
the reaction time had to be extended, probably because the
hydrolysis of the iminium salt to release the catalyst would be
retarded after the completion of cycloaddition (Table 1,
entry 13). Moreover, the reaction became very sluggish
when more M.S. was introduced to further reduce the H2O
content (Table 1, entry 14). In comparison, there were no
beneficial effects on the ee value when catalyst 1a was applied
in the presence of M.S. (Table 1, entries 15 versus 16), which
also verified that the OH group of 1b played a crucial role in
this reaction.
2a p-ClC6H4 (3b)
2a m-ClC6H4 (3c)
2a o-ClC6H4 (3d)
2a p-BrC6H4 (3e)
2a p-FC6H4 (3 f)
2a p-MeOC6H4 (3g)
2a p-MeOC6H4 (3g)
2a p-MeOC6H4 (3g)
2a 3,4-(MeO)2C6H3 (3h)
2a 2-furanyl (3i)
2a iPr (3j)
2a cyclohexyl (3k)
2a nPr (3l)
2b Ph (3a)
2b p-MeOC6H4 (3g)
2b p-BrC6H4 (3e)
2c p-MeOC6H4 (3g)
2a m-ClC6H4 (3c)
2a p-MeOC6H4 (3g)
2a cyclohexyl (3k)
2b p-MeOC6H4 (3g)
4[e]
5
6
7
8[f]
9[g]
10
11
12
13
14
15[h]
16[h]
17[h]
18
19[i]
20[i]
21[i]
22[i]
20 4h 88
96 4i
40 4j
24 4k
40 4l
60 4m 78
24 4n 91
60 4o
60 4p 76
60 4c
40 4g
40 4k
99
76
94
76
72
72
95
83
À90
À85
À85
À90
40 4n 75
[a] Unless otherwise noted,reactions were performed with 0.2 mmol of
2,0.1 mmol of 3,10 mol% of 1b,and 20 mol% of TIPBA in 0.5 mL THF
at 408C. [b] Yield of isolated product. [c] Based on chiral HPLC analysis.
[d] The absolute configuration of 4b was determined by X-ray analysis
(Figure 1),[15] and other products were assigned by analogy. [e] Without
adding M.S. [f] With 5 mol% of 1b. [g] With 2 mol% of 1b. [h] With
20 mol% of 1b. [i] With 1d as catalyst.
Inspired by recent studies on counterion-directed iminium
catalysis,[14] a more bulky additive, TIPBA, was tested and
excellent ee values were obtained even at 408C. The reaction
rate was also greatly enhanced (Table 1, entry 17). In
addition, 6’-hydroxy-9-amino-9-deoxyepiquinidine (1d) was
prepared from quinidine[10] and good results were obtained,
although the product had the opposite configuration (Table 1,
entry 18). Hence, both enantiomers of the cycloaddition
product could be attained.
Having established the optimal conditions, the scope of
the dipolar cycloaddition reaction was explored with a variety
of cyclic enones 2 and azomethine imines 3 (Table 2). In
general, better results were obtained with catalysis by 1b/
TIPBA salt at 408C with addition of 4-Š M.S.[10] Excellent
diastereoselectivity (d.r. > 99:1) was noted in all reactions.
For 2a, high enantioselectivities were achieved with azome-
thine imines bearing various aryl (Table 2, entries 2–10),
heteroaryl (Table 2, entry 11), and alkyl substituents (Table 2,
entries 12–14). Azomethine imines with an electron-donating
substituent displayed higher reactivity, and excellent results
were obtained even with 2 mol% of 1b (Table 2, entry 9).
In addition, remarkable ee values were obtained in the
cycloaddition of 2-cyclopenten-1-one (2b), although
20 mol% of catalyst was required for the achievement of
high yields (Table 2, entries 15–17). Furthermore, 2-cyclo-
hepten-1-one (2c) was tested and a high enantioselectivity
was attained (Table 2, entry 18). On the other hand, the
opposite enantiomeric cycloaddition products were prepared
with high ee values when catalyzed by 1d/TIPBA salt under
the same conditions (Table 2, entries 19–22).[16,17]
On the basis of the absolute configuration of 4b (see
Figure 1), we propose a plausible catalytic mode, albeit very
naive, for the reaction of 2a and 3b (Scheme 3). The
ketiminium cation between 1b and enone 2a might adopt a
trans conformation, and a hydrogen bond would be formed
from the OH group of 1b and the carbonyl group of 3b to
produce concerted communication. As a result of the steric
hindrance from the ion pair of the tertiary amine moiety,[8]
high endo- and re-face selectivity would be enforced to give
the desired cycloaddition product. Nevertheless, the exact
catalytic mechanism still needs more investigation.
7668 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7667 –7670

Angewandte
Chemie
Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang,
L.-Z. Gong, J. Am. Chem. Soc. 2005, 127, 9285; g) H. Huang,
E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170; h) C. Palomo,
S. Vera, A. Mielgo, E. Gômez-Bengoa, Angew. Chem. 2006, 118,
6130; Angew. Chem. Int. Ed. 2006, 45, 5984; i) S. B. Tsogoeva, S.
Wei, Chem. Commun. 2006, 1451; j) T. Kano, M. Ueda, J. Takai,
K. Maruoka, J. Am. Chem. Soc. 2006, 128, 6046; k) Y. Yamaoka,
H. Miyabe, Y. Takemoto, J. Am. Chem. Soc. 2007, 129, 6686;
l) for a review on bifunctional organometallic catalysts, see: M.
Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187.
[3] A Diels–Alder reaction promoted by a bifunctional organo-
catalyst was reported recently: Y. Wang, H. Li, Y.-Q. Wang, Y.
Liu, B. M. Foxman, L. Deng, J. Am. Chem. Soc. 2007, 129, 6364.
[4] For reviews, see: a) K. V. Gothelf, K. A. Jørgensen, Chem. Rev.
1998, 98, 863; b) K. V. Gothelf, K. A. Jørgensen, Chem.
Commun. 2000, 1449; c) C. Nµjera, J. M. Sansano, Angew.
Chem. 2005, 117, 6428; Angew. Chem. Int. Ed. 2005, 44, 6272;
for recent examples catalyzed by metal complexes, see: d) T.
Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2006, 128,
2174; e) M. P. Sibi, L. M. Stanley, C. P. Jasperse, J. Am. Chem.
Soc. 2005, 127, 8276; f) S. Cabrera, R. G. Arrayµs, J. C. Carre-
tero, J. Am. Chem. Soc. 2005, 127, 16394; g) S. Shirakawa, P. J.
Lombardi, J. L. Leighton, J. Am. Chem. Soc. 2005, 127, 9974;
h) T. Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2005,
127, 11926; i) X.-X. Yan, Q. Peng, Y. Zhang, K. Zhang, W. Hong,
X.-L. Hou, Y.-D. Wu, Angew. Chem. 2006, 118, 2013; Angew.
Chem. Int. Ed. 2006, 45, 1979; j) W. Zeng, G.-Y. Chen, Y.-G.
Zhou, Y.-X. Li, J. Am. Chem. Soc. 2007, 129, 750, and references
therein.
Figure 1. X-ray structure of enantiomerically pure 4b. Thermal ellip-
soids are set at 30% probability.
[5] a) W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan, J. Am. Chem.
Soc. 2000, 122, 9874; for limited examples of the organocatalytic
1,3-dipolar cycloaddition of enals, see: b) S. Karlsson, H.-E.
Högberg, Eur. J. Org. Chem. 2003, 2782; c) W. Chen, X.-H.
Yuan, R. Li, W. Du, Y. Wu, L.-S. Ding, Y.-C. Chen, Adv. Synth.
Catal. 2006, 348, 1818; d) S. S. Chow, M. Nevalainen, C. A.
Evans, C. W. Johannes, Tetrahedron: Asymmetry 2007, 18, 277;
e) J. L. Vicario, S. Reboredo, D. Badia, L. Carrillo, Angew.
Chem. 2007, 119, 5260; Angew. Chem. Int. Ed. 2007, 46, 5168.
[6] For selected asymmetric reactions of enones by iminium
activation: secondary amine catalysts: a) A. B. Northrup,
D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 2458; b) N.
Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2003, 115,
685; Angew. Chem. Int. Ed. 2003, 42, 661; c) A. Prieto, N.
Halland, K. A. Jørgensen, Org. Lett. 2005, 7, 3897, and
references therein; d) K. R. Knudsen, C. E. T. Mitchell, S. V.
Ley, Chem. Commun. 2006, 66; primary amine catalysts:
e) N. J. A. Martin, B. List, J. Am. Chem. Soc. 2006, 128, 13368;
f) H. Kim, C. Yen, P. Preston, J. Chin, Org. Lett. 2006, 8, 5239.
[7] For pioneering work on the organocatalytic Diels–Alder reac-
tion of enones, see reference [6a]; for the Lewis acid catalyzed
asymmetric Diels–Alder reaction of enones, see: a) R. S. Singh,
T. Harada, Eur. J. Org. Chem. 2005, 3433, and references therein;
for the [3+2] cycloaddition of enones, see: b) B. M. Trost, J. P.
Stambuli, S. M. Silverman, U. Schworer, J. Am. Chem. Soc. 2006,
128, 13328.
Scheme 3. Proposed cycloaddition mode of 2a and 3b catalyzed by
multifunctional salt of 1b.
In conclusion, we have developed the first organocatalytic
and highly enantioselective 1,3-dipolar cycloaddition of cyclic
enones and azomethine imines, by employing novel multi-
functional primary amine catalysts derived from cinchona
alkaloids. The additional and synergistic hydrogen-bonding
interaction of catalyst and 1,3-dipole is essential for enantio-
control, and excellent stereoselectivities were achieved for a
broad spectrum of substrates (d.r. > 99:1, up to 95% ee). We
hope that this work will give some hints in the development of
new multifunctional organocatalysts and asymmetric reac-
tions.
Received: June 15, 2007
Published online: September 4, 2007
Keywords: amines · cycloaddition · enantioselectivity · enones ·
.
organocatalysis
[8] a) J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C.
Chen, Y. Wu, J. Zhu, J.-G. Deng, Angew. Chem. 2007, 119, 393;
Angew. Chem. Int. Ed. 2007, 46, 389; b) J.-W. Xie, L. Yue, W.
Chen, W. Du, J. Zhu, J.-G. Deng, Y.-C. Chen, Org. Lett. 2007, 9,
413; c) W. Chen, W. Du, L. Yue, R. Li, Y. Wu, L.-S. Ding, Y.-C.
Chen, Org. Biomol. Chem. 2007, 5, 816; d) G. Bartoli, M. Bosco,
A. Carlone, F. Pesciaioli, L. Sambri, P. Melchiorre, Org. Lett.
2007, 9, 1403.
[9] For the catalytic asymmetric dipolar cycloaddition of azome-
thine imines, see: a) R. Shintani, G. C. Fu, J. Am. Chem. Soc.
2003, 125, 10778; b) A. Suµrez, C. W. Downey, G. C. Fu, J. Am.
Chem. Soc. 2005, 127, 11244; c) H. Suga, A. Funyu, A. Kakehi,
[1] For reviews, see: a) P. I. Dalko, L. Moisan, Angew. Chem. 2004,
116, 5248; Angew. Chem. Int. Ed. 2004, 43, 5138; b) B. List,
Chem. Commun. 2006, 819; c) A. Berkessel, H. Gröger,
Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005.
[2] For selected examples, see: a) Y. Iwabuchi, M. Nakatani, N.
Yokoyama, S. Hatakeyama, J. Am. Chem. Soc. 1999, 121, 10219;
b) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
125, 12672; c) W. Wang, J. Wang, H. Li, Angew. Chem. 2005, 117,
1393; Angew. Chem. Int. Ed. 2005, 44, 1369; d) K. Matsui, S.
Takizawa, H. Sasai, J. Am. Chem. Soc. 2005, 127, 3680; e) M. Shi,
L.-H. Chen, C.-Q. Li, J. Am. Chem. Soc. 2005, 127, 3790; f) Z.
Angew. Chem. Int. Ed. 2007, 46, 7667 –7670
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7669

Communications
Org. Lett. 2007, 9, 97; d) see reference [5c]; for the [3+3]
[13] a) R. P. Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew.
Chem. 2005, 117, 6734; Angew. Chem. Int. Ed. 2005, 44, 6576;
b) M. P. Sibi, K. Itoh, J. Am. Chem. Soc. 2007, 129, 8064.
[14] a) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299; Angew.
Chem. Int. Ed. 2006, 45, 4193; b) S. Hoffmann, M. Nicoletti, B.
List, J. Am. Chem. Soc. 2006, 128, 13074; c) see reference [6e];
d) J. Zhou, B. List, J. Am. Chem. Soc. 2007, 129, 7498; e) see
reference [8d].
[15] CCDC-655245 (4b) 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.
cycloaddition of azomethine imines in racemic form, see: e) A.
Chan, K. A. Scheidt, J. Am. Chem. Soc. 2007, 129, 5334; f) R.
Shintani, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 6330.
[10] See the Supporting Information for details.
[11] For the development of 6’-OH cinchona alkaloids as bifunctional
Brønsted acid–Lewis base organocatalysts, see: a) B. Wang, F.
Wu, Y. Wang, X. Liu, L. Deng, J. Am. Chem. Soc. 2007, 129, 768,
and references therein; b) S. Brandes, M. Bella, A. Kjærsgaard,
K. A. Jørgensen, Angew. Chem. 2006, 118, 1165; Angew. Chem.
Int. Ed. 2006, 45, 1147; c) J. Wang, H. Li, L. Zu, W. Wang, Org.
Lett. 2006, 8, 1391; d) T. Mandal, S. Samanta, C.-G. Zhao, Org.
Lett. 2007, 9, 943; for a highlight, see: e) T. Marcelli, J. H. van
Maarseveen, H. Hiemstra, Angew. Chem. 2006, 118, 7658;
Angew. Chem. Int. Ed. 2006, 45, 7496.
[16] Currently only a low ee value (< 30%) was obtained for acyclic
enones. Further studies on such substrates and synthetic utility of
the new heterocycles are being explored.
[12] For recent reviews, see: a) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. 2006, 118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520;
b) S. J. Connon, Chem. Eur. J. 2006, 12, 5418.
[17] The preparation, and potential cycloaddition reaction, of acyclic
azomethine imine from N-Boc-N’-benzylhydrazine (Boc = tert-
butoxycarbonyl) and benzaldehyde was unsuccessful.
7670 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7667 –7670