Asymmetrie Michael addition of γ,γ-disubstituted α,β-unsaturated aldehydes to nitroolefins via dienamine catalysis

Article abstract of DOI:10.1021/ol901939b

The first chemo- and α-regioselective asymmetric Michael addition of γ,γ,-disubstituted α,β-unsaturated aldehydes to nitroolefins has been presented in excellent diastereo- and enantloselectivities (dr up to >99:1, 93-96% ee) via dienamine catalysis. The

Full text of DOI:10.1021/ol901939b

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4660-4663
Asymmetric Michael Addition of
γ,γ-Disubstituted r,ꢀ-Unsaturated
Aldehydes to Nitroolefins via Dienamine
Catalysis
Bo Han,† You-Cai Xiao,† Zhao-Quan He,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug DeliVery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan UniVersity, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received August 20, 2009
ABSTRACT
The first chemo- and r-regioselective asymmetric Michael addition of γ,γ-disubstituted r,ꢀ-unsaturated aldehydes to nitroolefins has been
presented in excellent diastereo- and enantioselectivities (dr up to >99:1, 93-96% ee) via dienamine catalysis. The Michael adducts have been
efficiently converted to a number of optically pure cyclic frameworks with versatile scaffold diversity.
The discovery of effective synthetic methodologies that can
access chiral compounds with multifunctionalities is in
increasing demand owing to the rapid development of chiral
drugs.1 It would be quite attractive if the obtained products
could be further transformed to a broad spectrum of optically
pure compounds with scaffold diversity in a highly economic
way.2 Over the past decade, asymmetric aminocatalysis has
made great progress through a variety of activation modes
for carbonyl compounds.3 Among them, the direct Michael
addition of saturated aldehydes or ketones to nitroolefins via
enamine catalysis has triggered extensive interest because
of the synthetic versatility of the bifunctional adducts.4,5 In
sharp contrast, the direct Michael addition of R,ꢀ-unsaturated
aldehydes to nitroolefins, in which the inversion of the
inherent electrophilicity of R,ꢀ-unsaturated aldehydes will
be involved by dienamine activation,6 has not been developed
yet, probably because the rather challenging manipulations
on chemo-, regio-, and stereoselectivities must be simulta-
neously fulfilled in a complex reaction system. Although a
Baylis-Hillman-type reaction of R,ꢀ-unsaturated aldehydes
and nitroolefins has been reported by a proline-Lewis base
cocatalysis,7 unfortunately, almost no enantioselectivity was
(3) For selected reviews on asymmetric aminocatalysis, see: (a) Erkkila,
A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416. (b) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (c)
Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47, 42. (d) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(e) Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360. (f) Bertelsen, S.;
† West China School of Pharmacy.
‡ West China Hospital.
(1) Caner, H.; Groner, E.; Levy, L. Drug DiscoVery Today 2004, 9, 105.
(2) For a highlight on scaffold diversity synthesis, see: Galloway,
W. R. J. D.; Dia´z-Gavila´n, M.; Isidro-Llobet, A.; Spring, D. R. Angew.
Chem., Int. Ed. 2009, 48, 1194.
Jørgensen, K. A. Chem. Soc. ReV. 2009, 38, 2178
.
10.1021/ol901939b CCC: $40.75
Published on Web 09/15/2009
 2009 American Chemical Society

obtained.8 Encouraged by our recent findings in an inverse-
electron-demand aza-Diels-Alder reaction of N-Tos-1-aza-
1,3-butadienes and R,ꢀ-unsaturated aldehydes,9 we hope to
develop the first direct chemo-, regio-, and stereoselective
Michael addition of R,ꢀ-unsaturated aldehydes to nitroolefins
via dienamine catalysis.
Nevertheless, the self-dimerization of R,ꢀ-unsaturated
aldehyde was preferably observed in the reaction mixture
of a linear enal and nitroolefin catalyzed by a secondary
amine,6a,c which was ascribed to iminium-dienamine co-
activation of R,ꢀ-unsaturated aldehyde [Scheme 1, (a)]. We
chemoselective Michael addition of 4-methyl-2-penten-1-al
2a to ꢀ-nitrostyrene 3a could be realized by the catalysis of
R,R-diphenylprolinol O-TMS ether 110 and AcOH in toluene
at room temperature. Furthermore, an exclusive R-regiose-
lectivity was noted, and the allylic alkylated product 4a was
obtained,11 which was more easily isolated and analyzed as
the corresponding alcohol 5a. Gratifyingly, both diastereo-
and enantioselectivities were remarkable (Table 1, entry 1).
Table 1. Screening Studies of Organocatalytic Direct Michael
Addition of R,ꢀ-Unsaturated Aldehyde 2a to Nitroolefin 3aa
Scheme 1. Switching Reactivity in Different R,ꢀ-Unsaturated
Aldehyde and Nitroolefin Reaction Systems
entry
solvent
yieldb (%)
drc
eec
1
2
3
4
toluene
THF
DCM
52
<10
68
<10
<10
78
91:9
-
75:25
-
94
-
82
-
DMF
envisaged that the self-dimerization process would be
significantly prohibited if a more bulky γ,γ-disubstituted R,ꢀ-
unsaturated aldehyde was applied. As a result, the intermo-
lecular conjugate addition of an in situ formed dienamine
intermediate to electrophilic nitroolefin might be enforced
[Scheme 1, (b)]. In fact, we were pleased to find that the
5
DMSO
MeCN
MeCN
MeCN
-
-
6d
7e
8f
92:8
89:11
94:6
96
95
96
41
67
a Unless otherwise noted, reactions were performed with 0.4 mmol of
2a, 0.2 mmol of 3a, 0.2 mmol of 1, and AcOH in 0.5 mL of solvent, for
24 h. b Isolated yield of 5a for two steps. c By HPLC analysis. d For 12 h.
e Without AcOH. f With PhCOOH.
(4) For selected examples of Michael addition of saturated carbonyl
compounds to nitroolefins by enamine catalysis, see: (a) List, B.; Pojarliev,
P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (b) Betancort, J. M.; Barbas,
C. F., III. Org. Lett. 2001, 3, 3737. (c) Alexakis, A.; Andrey, O. Org. Lett.
2002, 4, 3611. (d) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am.
Chem. Soc. 2004, 126, 9558. (e) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji,
M. Angew. Chem., Int. Ed. 2005, 44, 4212. (f) Mase, N.; Watanabe, K.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 4966. (g) Palomo, C.; Vera, S.; Mielgo, A.; Go´mez-Bengoa, E.
Angew. Chem., Int. Ed. 2006, 45, 5984. (h) Luo, S.; Mi, X.; Zhang, L.;
Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093. (i)
McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599. (j) Liu, K.; Cui,
H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (k)
Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545. (l) Belot,
S.; Sulzer-Mosse´, S.; Kehrli, S.; Alexakis, A. Chem. Commun. 2008, 4694.
(m) Ruiz, N.; Reyes, E.; Vicario, J. L.; Bad´ıa, D.; Carrillo, L.; Uria, U.
Chem.sEur. J. 2008, 14, 9357. (n) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.;
Zhong, G. Org. Lett. 2009, 11, 1927.
Subsequently, a variety of solvents were screened (entries
2-6), and higher efficacy was gained in CH3CN (entry 6).
Lower reaction rate was observed in the absence of AcOH
(entry 7). In addition, similar good results were attained when
PhCOOH was used (entry 8).
Consequently, a variety of nitroolefins were explored in
the reaction with γ,γ-disubstituted R,ꢀ-unsaturated aldehydes
catalyzed by 1 and AcOH in acetonitrile. As summarized in
Table 2, for 4-methyl-2-penten-1-al 2a, excellent enantiose-
lectivities were obtained for an array of nitroolefins bearing
ꢀ-aryl groups with diverse electron-withdrawing or -donating
substitutions, while the diastereoselectivities were good to
excellent (Table 2, entries 1-7). A modest dr ratio was
obtained for a heteroaryl-substituted nitroolefin, but the ee
value was still high (entry 8). In addition, ꢀ-alkyl-substituted
nitroolefins could be successfully utilized, and the results
were also outstanding (entries 9 and 10). Moreover, a racemic
4-phenyl-2-penten-1-al 2b was synthesized and tested. To
our gratification, the complete E-configuration was observed
in the newly generated CdC bond of product 5k, and
excellent diastereo- and enantioselectivities were attained
(entry 11).
(5) For a review on the Michael addition of nitroolefins, see: Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(6) For limited examples on dienamine catalysis, see: (a) Ramachary,
D. B.; Ramakumar, K. K. Tetrahedron Lett. 2005, 46, 7037. (b) M. Hong,
B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8, 2217. (c)
Bertelsen, S.; Marigo, M.; Brandes, S.; Dine´r, P.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 12973. (d) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Huang, G.-F.; Su, C.-F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (e) Hong,
B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007, 63, 2840. (f) de
Figueiredo, R. M.; Fro¨hlich, R.; Christmann, M. Angew. Chem., Int. Ed.
2008, 47, 1450. (g) Marque´s-Lo´pez, E.; Herrera, R. P.; Marks, T.; Jacobs,
W. C.; Ko¨nning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett. 2009,
11, 4116.
(7) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2007, 46, 1878.
(8) Vesely, J.; Rios, R.; Co´rdova, A. Tetrahedron Lett. 2008, 49, 1137.
(9) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen,
Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474.
(11) The absolute configuration of 4a was assigned based on an X-ray
structure of the derivative 6e (see Figure 1). Thus, the origin of the
stereoselectivity in this dienamine catalysis by catalyst 1 is similar to that
observed in its enamine catalysis (see ref 3f).
(10) For reviews on R,R-diarylprolinol ethers catalysis, see: (a) Palomo,
C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876. (b) Yu, X.; Wang,
W. Org. Biomol. Chem. 2008, 6, 2037.
Org. Lett., Vol. 11, No. 20, 2009
4661

Table 2. Asymmetric Direct Michael Addition of R,ꢀ-Unsaturated Aldehydes 2 to Nitroolefins 3a
entry
2
R1
5
yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
78
76
80
72
75
69
62
71
58
52
68
92:8
96:4
93:7
95:5
96:4
85:15
84:16
75:25
98:2
92:8
>99:1
96
95
95
93
96
94
94
94
95
95
94
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-BrC6H4
m-MeOC6H4
3,4-(MeO)2C6H3
thienyl
c-Hexyl
n-Propyl
o-BrC6H4
9
10
11
5j
5k
a Unless otherwise noted, reactions were performed with 0.4 mmol of 2, 0.2 mmol of 3, 0.2 mmol of 1, and AcOH in 0.5 mL of CH3CN at rt. b Isolated
c
yield of 5 for two steps. By H NMR and HPLC analysis. d By HPLC analysis.
1
With the multifunctional Michael adducts 4 in hand, we
then conducted a cascade reaction with another R,ꢀ-unsatur-
ated aldehyde by the tandem iminium-enamine catalysis of
1, similar to that reported by Enders and co-workers.12 The
presence of additional base catalyst diisopropylethylamine
(DIPEA) was crucial for the reaction conversion. As il-
lustrated in Scheme 2, the densely functionalized 1-cyclo-
enantiopurity in moderate to good yields. The absolute
configuration of 6e was confirmed by an X-ray crystal-
lographic analysis (Figure 1). The alcohol 7 was obtained
Scheme 2. Cascade Reaction to Densely Substituted
1-Cyclohexene-1-carboxaldehydes
Figure 1. X-ray structure of enantiopure 6e.
by NaBH4 reduction of the corresponding 1-cyclohexene-
1-carboxaldehyde from the cascade reaction of two molecules
of 2a with 3a.
On the other hand, the highly diastereoselective nitro-
Mannich reaction could be performed with aldehyde 4a and
N-Tos aryl or alkyl imines by the catalysis of an achiral base
tetramethylguanidine (TMG). The hemiaminals 8 were
generated by a domino intramolecular cyclization process,
which were further transformed to diverse chiral piperidine
derivatives 9-11 (Scheme 3).13 It should be noted that such
nitro group-containing piperidine compounds are very valu-
able intermediates for the synthesis of novel Farnesyltrans-
ferase inhibitors14 or selective dipeptidyl peptidase IV
inhibitors for the treatment of type 2 diabetes.15
hexene-1-carboxaldehydes 6a-6e with multiple chiral cen-
ters could be directly isolated with almost complete
(12) (a) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature
2006, 441, 861. (b) Enders, D.; Hu¨ttl, M. R. M.; Runsink, J.; Raabe, G.;
Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467.
(13) (a) Han, B.; Li, J.-L.; Ma, C.; Zhang, S.-J.; Chen, Y.-C. Angew.
Chem., Int. Ed. 2008, 47, 9971. (b) Hayashi, Y.; Gotoh, H.; Masui, R.;
Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012. (c) Zu, L.; Xie, H.;
Li, H.; Wang, J.; Yu, X.; Wang, W. Chem.sEur. J. 2008, 14, 6333.
(14) (a) Nara, S.; Tanaka, R.; Eishima, J.; Hara, M.; Takahashi, Y.; Otaki,
S.; Foglesong, R. J.; Hughes, P. F.; Turkington, S.; Kanda, Y. J. Med. Chem.
2003, 46, 2467. (b) Tanaka, R.; Rubio, A.; Harn, N. K.; Gernert, D.; Grese,
T. A.; Eishima, J.; Hara, M.; Yoda, N.; Ohashi, R.; Kuwabara, T.; Soga,
S.; Akinaga, S.; Naraa, S.; Kanda, Y. Bioorg. Med. Chem. 2007, 15, 1363.
(15) Pei, Z.; Li, X.; von Geldern, T. W.; Longenecker, K.; Pireh, D.;
Stewart, K. D.; Backes, B. J.; Lai, C.; Lubben, T. H.; Ballaron, S. J.; Beno,
D. W. A.; Kempf-Grote, A. J.; Sham, H. L.; Trevillyan, J. M. J. Med. Chem.
2007, 50, 1983.
4662
Org. Lett., Vol. 11, No. 20, 2009

Scheme 3
.
Synthesis of Chiral Piperidine Derivatives
Scheme 4. Synthesis of Five-Membered Heterocycles
We have further explored the synthetic utilities of the
Michael adducts to afford some five-membered heterocycles.
As outlined in Scheme 4, the chiral pyrrolidine compound
12 with a side olefin functionality could be efficiently
prepared from 4e,4m which might allow more transformations
for molecular complexity.9 Furthermore, a chiral tetrahy-
drofuran framework 13 was smoothly obtained from 5a by
an iodine-mediated cyclization reaction.
In conclusion, we have developed the first direct chemo-
and regioselective Michael addition of γ,γ-disubstituted R,ꢀ-
unsaturated aldehydes to nitroolefins via dienamine catalysis.
In general, excellent enantioselectivities and diastereoselec-
tivities have been obtained for a spectrum of substrates (dr
up to >99:1, 93-96% ee). Moreover, we have demonstrated
that the obtained multifunctional Michael adducts are very
versatile synthons for further organic transformations. Some
valuable cyclic frameworks with scaffold diversity, which
might have synthetic significance in medicinal chemistry,
have been efficiently prepared. Currently, more studies on
asymmetric reactions via dienamine catalysis are being
investigated in our laboratory.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (20772084) and Sichuan University.
Supporting Information Available: Experimental pro-
cedures, structural proofs including NMR spectra and HPLC
chromatograms, and CIF file of 6e. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL901939B
Org. Lett., Vol. 11, No. 20, 2009
4663