Enantioselective direct aza hetero-Diels-Alder reaction catalyzed by chiral Bronsted acids

Article abstract of DOI:10.1021/ol062499t

(Chemical Equation Presented) The first chiral Bronsted acid-catalyzed asymmetric direct aza hetero-Diels-Alder reaction has been described. The phosphoric acids, prepared from binol and H₈-binol derivatives, have shown catalytic ability for th

Full text of DOI:10.1021/ol062499t

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6023-6026
Enantioselective Direct Aza
Hetero-Diels Alder Reaction Catalyzed
−
by Chiral Brønsted Acids
Hua Liu,†,‡ Lin-Feng Cun,† Ai-Qiao Mi,† Yao-Zhong Jiang,† and Liu-Zhu Gong*,§
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China,
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
610041, China, and Graduate School of Chinese Academy of Sciences, Beijing, China
gonglz@ustc.edu.cn
Received October 10, 2006
ABSTRACT
The first chiral Brønsted acid-catalyzed asymmetric direct aza hetero-Diels−Alder reaction has been described. The phosphoric acids, prepared
from binol and H8-binol derivatives, have shown catalytic ability for the reaction of cyclohexenone with N-PMP-benzaldimine. A chiral phosphoric
acid, derived from 3,3-di(4-chloropheneyl)-H8-binol, exhibited superior enantioselectivity, affording fairly good yields and enantioselectivities
for the reaction of a range of aromatic aldimines with cyclohexenone.
The N-containing heterocylic compounds are of great
importance in organic synthesis. The asymmetric aza Diels-
Alder reaction is one of the most efficient transformations
to approach chiral piperidine derivatives, the precursors of
a large family of biologically important compounds such as
alkaloids, peptides, and aza-sugars.1 This importance has led
to great efforts spent on the asymmetric aza Diels-Alder
reactions.2 Thus, a number of examples of highly enantio-
selective aza Diels-Alder reactions have been described in
which active preformed dienes are used as a reaction
component in conjuction with either chiral Lewis acids or
chiral Brønsted acids as catalysts.3-8 In contrast, the direct
asymmetric aza Diels-Alder reaction, which avoids the use
of preformed dienes, has been less extensively studied. To
the best of our knowledge, only a single proline-catalyzed
direct aza Diels-Alder reaction between cyclohexenone
derivatives and imines generated from aldehydes and 4-meth-
oxyphenylamine has been described.9 Although almost
(3) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(4) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int.
Ed. 1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani,
H. J. Org. Chem. 1999, 64, 4220. (c) Kobayashi, S.; Kusakabe, K.; Ishitani,
H. Org. Lett. 2000, 2, 1225. (d) Yamashita, Y.; Mizuki, Y.; Kobayashi, S.
Tetrahedron Lett. 2005, 46, 1803.
† Chengdu Institute of Organic Chemistry.
‡ Graduate School of Chinese Academy of Sciences.
§ University of Science and Technology of China.
(1) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure, Prepara-
tion and Synthetic Applications of Piperidine and its DeriVatiVes; Elsevier:
Amsterdam, The Netherlands, 1991. (b) Bailey, P. D.; Millwood, P. A.;
Smith, P. D. Chem. Commun. 1998, 633. (c) O’Hagan, D. Nat. Prod. Rep.
2000, 17, 435. (d) Michael, J. P. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, CA, 2001; Vol. 55. (e) Boger, D. L.; Weinreb,
S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, CA, 1987.
(5) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
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Chem., Int. Ed. 1998, 37, 3121. (b) Yao, S.; Saaby, S.; Hazell, R. G.;
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45, 4796. (b) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K.
Synlett 2006, 141.
(2) For reviews, see: (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558. (b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
10.1021/ol062499t CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/24/2006

perfect enantioselectivity was observed, the use of imines
in such a direct aza Diels-Alder reaction was restricted to
formaldimines and an ethyl N-PMP-R-imino glyoxylate. To
date, there has been no report of a direct aza hetero-Diels-
Alder reaction (eq 1) of cyclohexenone (1) with comparably
sterically demanding aromatic aldimines (2).
Figure 1. Phosphoric acids evaluated in this study
An initial validation of the hypothesis commenced with
experiments of reacting cyclohexenone with benzaldimines,
derived from Various amines, in the presence of binol- and
H8-binol-derived phosphoric acids,12o leading to a finding
that aromatic aldimines with an N-PMP group are reactive
toward the cyclohexenone to afford the desired product in a
modest yield and enantioselectivity.14 The NOE spectrum
of the major product showed that endo-isomer 3a was
favorably formed (see the Supporting Information). In light
of these primary results, a survey of the ability of phosphoric
acids 9 and 10 to catalyze the direct aza Diels-Alder reaction
was performed with the reaction of cyclohexenone (1) and
2a in CH2Cl2 at 20 °C. As the data in Table 1 indicated, all
It is well-known that a carbonyl compound possessing
R-hydrogens will enolize in acid and the formed enolate will
attack carbonyl compounds and activated imines to undergo
the classical aldol and Mannich reactions. Similarly, we
reasoned that under the acidic conditions cyclohexenone (1)
would be enolized into 5, which would first attack the
protonated aldimine 6 to undergo a Mannich reaction,
generating intermediates 7 and 8, after a tandem intramo-
lecular 1,4-addition reaction to afford the predicted products
3 and 4.
Recently, chiral Brønsted acids have been frequently used
for asymmetric catalysis.10,11 In particular, chiral phosphoric
acids have emerged as a class of powerful organocatalysts
for the activation of imine functional groups, resulting in a
number of asymmetric additions of various nucleophiles to
imines.12 In light of these facts and following our consid-
eration of the proposed mechanism of Brønsted acid-
catalyzed direct aza Diels-Alder reaction (Scheme 1), we
Table 1. Catalyst Screeninga
yield
(%)b
3a/4a
(endo/ exo)c
ee
(%)d
Scheme 1. Proposed Direct Aza Diels-Alder Reaction of
entry
catalyst
Cyclohexenone with Aldimines
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
10a
10b
10c
10c
65
35
67
32
45
47
72
67
77
58
32
83/17
79/ 21
76/ 24
67/33
85/15
80/20
84/16
81/19
79/21
85/15
81/19
65
70
66
34
37
70
64
72
79
85
89e
10
11
a Unless specified otherwise, the reaction of benzaldimine (0.2 mmol)
and cyclohexanone (0.4 mmol) was performed in CH2Cl2 (1.5 mL) for 4
days. b Isolated yield of 3 and 4. c Determined by 1H NMR. d The enan-
tiomeric excess of the major product was determined by HPLC. e In the
presence of 5 mol % 10c.
further hypothesized that chiral Brønsted acids would be able
to catalyze the asymmetric direct aza Diels-Alder reaction
of cyclohexenone with aldimine without the assistance of
enamine catalysis. Herein, we report the first Brønsted acid-
catalyzed asymmetric direct aza hetero-Diels-Alder reaction
of a variety of aromatic aldimines with cyclohexenone,
yielding the adducts 3 with good enantioselectivity.13
the phosphoric acids are catalytically active and afforded the
endo-isomer 3a as a major product in varying yields and
diastereo- and enantioselectivities, depending on the structure,
particularly of the 3,3′-Ar substituents, of the catalysts.
Generally, the more highly sterically congested Ar substit-
uents had more deleterious effects on the enantioselectivity.
For example, much lower enantioselectivities were observed
with 9d and 9e, which possess bulkier p-tert-butylphenyl and
(9) Sunde´n, H.; Ibrahem, H.; Eriksson, L.; Co´rdova, A. Angew. Chem.,
Int. Ed. 2005, 44, 4877.
(10) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520. (b) Connon, S. J. Angew. Chem., Int. Ed. 2006,
45, 3909. (c) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006,
348, 999. (d) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (e) Bolm,
C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44,
1758. (f) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
6024
Org. Lett., Vol. 8, No. 26, 2006

triphenylsilyl substituents, respectively, compared with their
structural analogues 9a,b and 9f (entries 1-7). In terms of
enantioselectivity, 9f turned out to be the best catalyst among
the binol-derived phosphoric acids (entry 6). The selectivity
could be further improved by using H8-binol-derived phos-
phoric acids 10 (entries 8-12). Comparably higher enantio-
selectivity was observed with 10c (entry 10) and was
maintained even after reducing the catalyst loading from 10
mol % to 5 mol % (entry 11).
Table 3. Direct Organocatalytic Asymmetric Diels-Alder
Reaction of Cyclohexenone with Aldiminesa
yield
(%)b
3/4
(endo/ exo)c
ee
entry
Ar
(%)d
With an optimal catalyst in hand, we further optimized
the reaction conditions, such as solvents and the reaction
temperature. As revealed in Table 2, nonpolar solvents, such
1
2
3
4
5
6
7
8
9
C6H5 (2a)
76
74
82
73
72
76
81
79
81
70
84/16
81/19
82/18
81/19
80/20
82/18
82/18
81/19
83/17
83/17
87
83
85
77
85
84
85
87
83
76
3-ClC6H4 (2b)
4-ClC6H4 (2c)
2-ClC6H4 (2d)
4-FC6H4 (2e)
3-FC6H4 (2f)
4-BrC6H4 (2g)
3-BrC6H4 (2h)
4-MeC6H4 (2i)
4-CNC6H4 (2j)
Table 2. Optimization of Reaction Conditionsa
10
a Unless specified otherwise, the reaction of aldimine 2 (0.2 mmol) and
temp
(°C)
yield
(%)b
3a/4a
(endo/ exo)c
ee
(%)d
cyclohexanone (10.0 equiv) was performed in toluene (1.5 mL) for 6 days.
entry
solvent
CH2Cl2
toluene
m-xylene
ClCH2CH2Cl
THF
1
b Isolated yield of 3 and 4. c Determined by H NMR. d The enantiomeric
excess of the major product was determined by HPLC.
1
2
3
4
5
25
25
25
25
25
25
20
10
0
64
71
66
60
39
57
70
57
45
76
82/18
85/15
83/17
82/18
83/17
83/17
83/17
83/17
84/16
84/16
79
85
85
79
85
76
85
88
89
87e
those bearing either an electron-donating or electron- with-
drawing substituent (Table 3). The reactions all proceeded
smoothly to favor the formation of endo-isomer 3 in good
yields (70-82%) and with fairly good enantioselectivities
(76-87% ee) and diastereoselectivities (80/20-84/16 dr).
The one-pot, three-component asymmetric aza Diels-
Alder reaction of cyclohexenone with p-methoxyphenylamine
and a number of aromatic aldehydes catalyzed by 10c (5
mol %) were also successful, furnishing the products in
good yields with enantioselectivities similar to those observed
for the corresponding reactions with preformed aldimines
(eq 2).
6
7
8
9
CHCl3
toluene
toluene
toluene
toluene
10
20
a Unless specified otherwise, the reaction of benzaldimine (0.2 mmol)
and cyclohexanone (10.0 equiv) was performed in toluene (1.5 mL) for 4
days. b Isolated yield of 3 and 4. c Determined by 1H NMR. d The enan-
tiomeric excess of the major product was determined by HPLC. e The
reaction continued for 6 days.
as toluene and m-xylene, led to higher yields than their polar
counterparts. In addition, the use of halogenated solvents
resulted in lower enantioselectivity (entries 1, 4, and 6). Thus,
toluene is the solvent of choice in this case. Lowering
reaction temperature slightly improved the selectivity, but
sacrificed the reaction rate (entries 8 and 9). Interestingly,
the diastereoselectivity was not so sensitive to the reaction
conditions. The performance of the reaction at 20 °C could
give the desired product in 76% yield with 84/16 dr and 87%
ee (entry 10).
The resulting products are of synthetic usefulness and can
be converted into some chiral building blocks. For example,
diastereoselective reduction of 3a with sodium boronhydride
gave a γ-amino alcohol 11 in >99% yield with >99/1 dr
(eq 3).
The phosphoric acid 10c-catalyzed direct aza Diels-Alder
reaction was extended to a series of benzaldimines, including
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Org. Lett., Vol. 8, No. 26, 2006
6025

In summary, we have developed the first direct hetero-
Diels-Alder reaction catalyzed by phosphoric acids. The
presence of 5 mol % phosphoric acid 10c, derived from
H8-binol, could promote the reaction for a range of aromatic
aldimines in high yields with good enantioselectivities and
diastereomeric ratioes, and with no assistance of enamine
catalysis. The reaction actually avoids the substrate limitation
associated with proline-catalyzed direct aza Diels-Alder
reaction9 and provides a new method for the preparation of
chiral multiply substituted piperidines.
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(b) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
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J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086. (j) Uraguchi,
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Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006,
45, 2254. (l) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed.
2006, 45, 2617. (m) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 3683. (n) Mayer, S.; List, B. Angew. Chem., Int.
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Acknowledgment. We are grateful for financial support
from NSFC (203900505 and 20325 211).
Supporting Information Available: Experimental pro-
cedures, spectra data, characterization data, and copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) After submission of this paper, Rueping and Azap reported a similar
reaction: Rueping, M.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, DOI:
10.1002/anie.200603199.
(14) The use of BocNH2, TsNH2, diphenylphosphinamide, and 2-ami-
nophenol led to no reaction.
OL062499T
6026
Org. Lett., Vol. 8, No. 26, 2006