Enantioselective organocatalytic Michael addition of malonates to α,β-unsaturated aldehydes in water

Article abstract of DOI:10.1016/j.tetlet.2008.03.051

The Michael addition of malonates to α,β-unsaturated aldehydes catalyzed by O-TMS protected diphenylprolinols and acetic acid in water occurs at 0 °C to rt. In most cases, the reaction runs to completion in less than 24 h. A wide range of aldehydes includ

Full text of DOI:10.1016/j.tetlet.2008.03.051

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3075–3077
Enantioselective organocatalytic Michael addition
of malonates to a,b-unsaturated aldehydes in water
Anqi Ma, Shaolin Zhu, Dawei Ma *
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 2 February 2008; revised 10 March 2008; accepted 11 March 2008
Available online 14 March 2008
Abstract
The Michael addition of malonates to a,b-unsaturated aldehydes catalyzed by O-TMS protected diphenylprolinols and acetic acid in
water occurs at 0 °C to rt. In most cases, the reaction runs to completion in less than 24 h. A wide range of aldehydes including b-aryl,
b-alkyl and b-alkenyl acroleins are found to be compatible with these conditions, providing the corresponding adducts in good yields and
with good to excellent enantioselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
The catalytic asymmetric Michael addition is one of the
most powerful and reliable tools for the stereocontrolled
formation of carbon–carbon and carbon–heteroatom
bonds.1 Over the past years, significant progress in this area
has been made using organocatalysts.1 When a,b-unsatu-
rated aldehydes were employed as Michael acceptors,
chiral secondary amines such as O-TMS protected
diarylprolinols 1, 2, and imidazolidinone 3 were proven
to be effective catalysts by activating them through an imin-
ium-ion mechanism.2 Jørgensen and co-workers reported
that the asymmetric Michael addition of malonates to aro-
matic a,b-unsaturated aldehydes could be achieved with
good yields and enantioselectivities by using O-TMS pro-
tected diarylprolinol 1a as catalyst, which provided a very
useful approach to chiral lactones and lactams.3 However,
this reaction requires a long time (usually 4 days) and a rel-
atively higher catalyst loading (10 mol %). Furthermore,
the use of aliphatic a,b-unsaturated aldehydes as substrates
was unsuccessful in this case due to predominant side reac-
tions with the solvent ethanol.3 Recently, we observed that
the Michael addition of aldehydes to nitroalkenes could be
greatly accelerated with improved stereochemical outcome
by using O-TMS protected diphenylprolinol 2 and benzoic
acid as catalytic system and water as the reaction medium.4
Gratifyingly, application of these conditions to the Michael
addition of malonates to a,b-unsaturated aldehydes gave
similar effects. Both aromatic and aliphatic a,b-unsaturated
aldehydes were found to be compatible with these reaction
conditions. Herein, we wish to disclose our results.5
O
Me
Ar
Ar
Ph
Ph
N
N
N
H
OTMS
H
Bn
Bu-t
OTMS
N
H
1a: Ar = 3,5-(CF3)2C6H3
1b: Ar = Ph
2
3
As indicated in Table 1, a model reaction between
dimethyl malonate and cinnamaldehyde was used to evalu-
ate the results under different conditions. A very good yield
was obtained at room temperature with the additive
PhCO2H using 10 mol % catalyst 2 within only 3 h (entry
1). We tried to reduce the amount of catalyst to 1 mol %,
but the reaction became too slow to give reasonable yields
even after 2 days (entry 2). Consequently, the amount of
catalyst 2 was set to 5 mol % and it was found that the
reaction ran smoothly now (entry 3). Further attempts
demonstrated that the ee value could be slightly increased
when the reaction was first kept at 0 °C for 1 h (entry 4).
*
Corresponding author. Tel.: +86 2164163300; fax: +86 2164166128.
E-mail address: madw@mail.sioc.ac.cn (D. Ma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.051

3076
A. Ma et al. / Tetrahedron Letters 49 (2008) 3075–3077
Table 1
Table 2
Influence of additives on the addition of dimethyl malonate 5a to
cinnamaldehyde 4a catalyzed by O-TMS protected diphenylprolinol 2a
Enantioselective Michael addition of malonates 5 to b-aryl acroleins 4
catalyzed by O-TMS protected diphenylprolinol 2 and acetic acida
CHO
CHO
CHO
+
CHO
CO2Me
CO2R'
catalyst 2, additive
5 mol% 2, 20 mol% HOAc
CO2Me
CO2R'
CO2R'
+
Ph
R
H2O, 0 oC-rt
H2O
CO2Me
CO2R'
Ph
R
CO2Me
4a
6a
4
6
5a
5
Entry
R
R0
Time (h)
Product/yieldb (%)
eec (%)
Entry
Compound 2
(mol %)
Time
(h)
Additive
Yieldb
(%)
eec
(%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Me
Bn
Me
Bn
Me
Bn
Me
Me
Bn
6
5
3
3
4
4
2
4
4
6a/90d
6b/93
6c/92
96
95
88
90
91
96
97
94f
92f
90f
92
1
2
3
4
5
6
7
a
10
1
5
5
5
3
48
12
8
24
48
24
PhCO2H
PhCO2H
PhCO2H
PhCO2H
NaOAc
91
<10
81
73d
85d
<5d
96d
91
—
91
97
96
—
95
2-Furyl
2-Furyl
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
2-BrC6H4
4-NO2C6H4
6d/85d
6e/81e
6f/88e
6g/78e
6h/75d
6i/95
5
5
CF3CO2H
HOAc
6j/74d
6k/78d
Reaction conditions: 4a (1.0 mmol), 5a (0.5 mmol), 10 mol % acetic
10
11
a
Me
Me
12
3
acid, 0.25 mL of water, rt.
b
Isolated yield.
c
Reaction conditions: 4 (1.0 mmol), 5 (0.5 mmol), 5 mol % 2, 20 mol %
acetic acid, 0.25 mL of water, 0 °C for 1 h, then rt for the indicated time.
Determined by chiral HPLC analysis of the isolated product.
Reaction was carried out at 0 °C for 1 h, then rt for the indicated time.
d
b
Isolated yield.
c
Determined by chiral HPLC analysis of the isolated product.
The reaction was carried out with 0.5 mmol of 4 and 1.0 mmol of 5.
The reaction was carried out with 0.75 mmol of 4 and 0.5 mmol of 5.
Determined by chiral HPLC analysis of the corresponding methyl ester
d
Screening other additives including salt (entry 5) and acids
(entries 6 and 7) revealed that they had an effect on the pro-
cess. Because of the decomposition of the catalyst, there
was barely any product when CF3CO2H (TFA) was used
(entry 6). The use of acetic acid gave the best result with
the highest yield and excellent enantioselectivity (entry 7).
With the optimized reaction conditions at hand, we
examined a number of aromatic a,b-unsaturated aldehydes
and two different malonates, and the results are summa-
rized in Table 2. Generally, these reactions were complete
in less than 12 h, and better yields and enantioselectivities
were obtained compared to Jørgensen’s conditions.3 The
electronic nature of the substituents at the aromatic ring
seems to have little influence on this reaction process as evi-
dent from the fact that both substrates with a strong elec-
tron-donating group and a strong electron-withdrawing
group gave similar results (compare entries 5 and 11).
However, steric hindrance could greatly slow down this
reaction, as indicated by the longer reaction time required
in the case of the 2-bromophenyl substituted acrolein
(entry 10). Noteworthy is that the excess amounts of alde-
hydes (entries 2, 3, 5–7, and 9) or malonates (entries 1, 4, 8,
10, and 11) had to be used to ensure better yields because
incomplete conversion was met in most cases if equal molar
amounts of the two partners were added (data not shown).
Based on Jorgensen’s report3, we assumed that using
(R)-2 as catalyst would afford (S)-configurated products.
In order to confirm this hypothesis and demonstrate the
practical application of this reaction, we decided to synthe-
size piperidine 9, a known key intermediate for the assem-
bly of antidepressant (ꢀ)-paroxetine.3,6 As depicted in
Scheme 1, we tried to use only 1 mol % catalyst 1b to pro-
mote the reaction of b-(4-fluorophenyl) acrolein 4d with
dimethyl malonate 5a. To our delight, this reaction worked
well on a 20 mmol scale to provide 77 in 67% yield with
e
f
that was obtained by oxidation and esterification of the adduct.
CHO
CO2Me
CO2Me
CHO
CO2Me
1 mol% 1b, 20 mol% HOAc
+
H2O, 0 oC-rt, 14 h
67% yield, 96% ee
CO2Me
F
F
4d
5a
7
Bn
Bn
N
N
LAH
BnNH2
NaBH(OAc)3
97%
82%
O
CO2Me
F
OH
F
9
8
Scheme 1.
96% ee. Next, reductive amination of 7 and benzylamine
mediated with NaBH(OAc)3 followed by condensative
cyclization delivered lactam 8 in 97% yield. No cis-isomer
was determined by 1H NMR, indicating that the diastereo-
selectivity in this step was greater than 97%. Finally, the
reduction of 8 with LAH afforded 9, whose optical rotation
was identical to that previously reported, thereby indi-
cating that intermediate 7 has the (R)-configuration.
Having achieved excellent results in the Michael addi-
tion of malonates to aromatic a,b-unsaturated aldehydes,
we next explored the use of aliphatic a,b-unsaturated alde-
hydes as substrates since their products should be more
useful for organic synthesis. As expected, these substrates
were also compatible with our conditions, although rela-
tively low yields and enantioselectivities were observed as
illustrated in Table 3. Interestingly, b-alkyl substituted

A. Ma et al. / Tetrahedron Letters 49 (2008) 3075–3077
3077
Table 3
References and notes
Enantioselective Michael addition of malonates 5 to b-alkyl or alkenyl
acroleins 4 catalyzed by O-TMS protected diphenylprolinol 2 and acetic
acida
´
1. For recent reviews, see: (a) Vicario, J. L.; Badıa, D.; Carrillo, L.
Synthesis 2007, 2065; (b) Enders, D.; Grondal, C.; Huttl, M. R. M.
¨
´
Angew. Chem., Int. Ed. 2007, 46, 1570; (c) Guillena, G.; Ramon, D. J.;
CHO
Yus, M. Tetrahedron: Asymmetry 2007, 18, 693; (d) Enders, D.;
CHO
CO2Bn
´
Luttgen, K.; Narine, A. A. Synthesis 2007, 959; (e) Sulzer-Mosse, S.;
¨
5-20 mol% 2, 50 mol% HOAc
CO2Bn
+
R
H2O, 0 oC-rt
Alexakis, A. Chem. Commun. 2007, 3123; (f) Pellissier, H. Tetrahedron
2007, 63, 9267.
CO2Bn
R
CO2Bn
4
6
5b
2. For selected examples, see: (a) Austin, J. F.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 1172; (b) Paras, N. A.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 7894; (c) Carlone, A.; Marigo, M.;
North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun. 2006, 4928;
(d) Marigo, M.; Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 5475; (e) Chen, Y. K.; Yoshida, M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 9328; (f) Ibrahem, I.; Rios, R.;
Entry
R
Time (h)
Product/yieldb (%)
eec (%)
1
2
Me
i-Pr
27
48
6l/55d,e
6m/70d,e
79
95
(CH2)2
C2H5
3
4
40
27
6n/44e
6n/62d,e
73
83
´
Vesely, J.; Zhao, G.-L.; Cordova, A. Chem. Commun. 2007, 849; (g)
´
Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew.
5
20
20
6o/62
6p/67
82
82
H3C
Chem., Int. Ed. 2007, 46, 778; (h) Zu, L.; Li, H.; Xie, H.; Wang, J.;
Jiang, W.; Wang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732;
(i) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang,
W. Org. Lett. 2007, 9, 965; (j) Bertelsen, S.; Diner, P.; Johansen, R. L.;
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536.
6
n-C5H11
a
Reaction conditions: 4 (1.0 mmol), 5b (0.5 mmol), 5 mol % 2, 50 mol %
acetic acid, 0.25 mL of water, 0 °C for 1 h, then rt for the indicated time.
´
b
Isolated yield.
´
3. Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K. A.
c
Determined by chiral HPLC analysis of the isolated product.
The reaction was carried out with 2.0 mmol 4 and 0.5 mmol 5b.
The reaction was carried out with 20 mol % catalyst 2.
Angew. Chem., Int. Ed. 2006, 45, 4305.
d
4. Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
5. During the preparation of this manuscript, Palomo and co-workers
reported a similar improvement by using their newly developed
catalysts. However, only two aromatic a,b-unsaturated aldehydes were
discussed. See: Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.;
e
acroleins showed a strongly reduced reactivity so that
increased catalyst and aldehyde loadings were required to
get satisfactory yields (entries 1 and 2). An unconjugated
b-alkenyl substituted acrolein showed a similar behavior
(entry 3), while two conjugated dienals displayed a reactiv-
ity similar to b-aryl acroleins (entries 5 and 6). These differ-
ences might arise from the bigger p-conjugated system that
makes the imine intermediates more stable. The best
enantioselectivity was obtained in the case of i-propyl as
the b-substituent (entry 2). This implies that a bulkier
b-substituent is favorable for asymmetric induction.
In conclusion, we have developed a new procedure for
the asymmetric Michael addition of malonates to a,b-
unsaturated aldehydes, which afforded the adducts in good
yields with good to excellent enantioselectivities. Both aro-
matic and aliphatic a,b-unsaturated aldehydes worked in
this process, thereby broadening the scope of this syntheti-
cally useful reaction. The short reaction time used here is
also remarkable. These advantages presumably result from
the combination of Brønsted acids as promoters8 and water
as the reaction medium.9
´
Puente, A.; Vera, S. . Angew. Chem., Int. Ed. 2007, 46, 8431.
6. For articles on the synthesis of (ꢀ)-paroxetine, see: (a) Yu, M. S.;
Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41,
5647; (b) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.;
Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org.
´
Chem. 2000, 65, 3074; (c) Czibula, L.; Nemes, A.; Sebo¨k, F.; Szantay,
C., Jr.; Mak, M. Eur. J. Org. Chem. 2004, 2004, 3336; (d) Greenhalgh,
D. A.; Simpkins, N. S. Synlett 2002, 2074; (e) Cossy, J.; Mirguet, O.;
Pardo, D. G.; Desmurs, J.-R. Eur. J. Org. Chem. 2002, 2002,
3543.
´
7. Selected data for 7: 1H NMR (300 MHz, CDCl3) d 9.59 (t, J = 1.8 Hz,
1H), 7.26–7.18 (m, 2H), 7.00–6.95 (m, 2H), 4.03–4.00 (m, 1H), 3.73 (s,
3H), 3.70 (d, J = 9.3 Hz, 1H), 3.51 (s, 3H), 2.95–2.86 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 199.5, 168.2, 167.7, 161.9, 135.5, 129.6,
115.6, 57.2, 52.7, 52.5, 47.3, 38.6; HRMS calcd for C14H15O5FNa
25
(M+Na)+ 305.0796, found 305.0794; ½aꢁD ꢀ30.5 (c 1.0, CHCl3, 96%
ee).
8. For the acceleration effect of Brønsted acids, see: (a) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260; (b) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58,
8167; (c) Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int.
´
Ed. 2004, 43, 2420; (d) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460;
(e) Diner, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2007, 46, 1983.
´
9. For organocatalytic asymmetric reactions in water, see: (a) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C.
F., III. J. Am. Chem. Soc. 2006, 128, 734; (b) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int.
Ed. 2006, 45, 958; (c) Blackmond, D. G.; Armstrong, A.; Coombe, V.;
Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798; (d) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J.
Am. Chem. Soc. 2006, 128, 4966.
Acknowledgement
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of China
(Grants 20321202, 20572119) for their financial support.