Direct catalytic asymmetric cross-aldol reactions in ionic liquid media

Article abstract of DOI:10.1016/j.tetlet.2004.03.080

Enantioselective proline-catalyzed direct asymmetric cross-aldol reactions with aldehydes were performed in ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate media, which simplified product isolation and catalyst recycling, affording 3-hydrox

Full text of DOI:10.1016/j.tetlet.2004.03.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3949–3952
Direct catalytic asymmetric cross-aldol reactions in ionic
liquid media
*
ꢀ
Armando Cordova
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, SE-10611 Stockholm, Sweden
Received 8 December 2003; revised 3 March 2004; accepted 12 March 2004
Abstract—Enantioselective proline-catalyzed direct asymmetric cross-aldol reactions with aldehydes were performed in ionic liquid
1-n-butyl-3-methylimidazolium hexafluorophosphate media, which simplified product isolation and catalyst recycling, affording
3-hydroxy aldehydes in high yield with excellent stereoselectivity. In addition, the enhanced reactivity of the asymmetric cross-aldol
reactions in ionic liquid allowed the catalyst loading to be lowered significantly.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The employment of ionic liquids as solvents for chemical
reactions has received increased attention in recent
years.1 These solvents are reusable, enhance the reac-
tivityof chemical transformations, simplifyproduct
isolation and allow for catalyst recycling. The reduction
of the amount of solvents needed for a chemical trans-
formation enables the process to be more economical
and environmentallybenign.
excellent enantioselectivity. The enantiomerically pure
products are important building blocks for the synthesis
of several natural product derivatives.
In an initial experiment, propionaldehyde (7.4 mmol)
and a catalytic amount of (S)-proline (5 mol %) were
mixed in the ionic liquid 1-n-butyl-3-methylimidazolium
hexafluorophosphate ([bmim]PF6) (1 mL) (Eq. 1).8
Organocatalysis has recently experienced a renaissance
in catalytic asymmetric synthesis.2 Asymmetric trans-
formations mediated byamino acids and their deriva-
tives have been particularlysuccessful. In our
endeavours to mimick direct cross-aldol reactions that
are catalyzed by the natural 5-phospho-deoxyribose
aldolase,3 we have investigated the use of unmodified
aldehydes as nucleophiles and organic amino acid
derivatives as catalysts for asymmetric reactions.4 In
addition, MacMillan, Jørgensen and co-workers have
also reported elegant intermolecular cross-aldol reac-
tions.5–7 These results along with our research led us to
envisage that there would be a possibilityof performing
these organocatalytic asymmetric reactions in ionic liq-
uids. If successful, the reactions would be highlyeco-
nomical and allow for efficient reuse of the catalyst.
(S)-proline
(5 mol%)
O
OH O
O
+
H
H
H
[bmim]PF , 4 C
˚
6
ð1Þ
1
51% yield
dr = 5:1
ee = >99%
After stirring for 16 h at 4 ꢁC, the reaction was quenched
byextraction with Et O (3 · 15 mL). The combined or-
2
ganic extracts were concentrated and the crude product
purified bysilica-gel column chromatographyto afford
b-hydroxy aldehyde 1 in 51% yield with dr 5:1 and
>99% ee.9 We found that the yield could be increased to
65% if the reaction was quenched after 6 h. Hence, the
reaction was faster in the ionic liquid as compared to
conventional organic solvents. In order to increase the
yield further, we added DMF as a co-solvent to the ionic
liquid. This almost completelyinhibited the excessive
oligomerization and increased the yield of 1 to 74%
without affecting the selectivityof the reaction (Table 1,
entry 1). We also tested recycling of the catalyst
(Table 1). The reaction was readilyperformed five times
Herein, we present the first direct catalytic asymmetric
cross-aldol reactions of aldehydes in ionic liquid media
furnishing 3-hydroxy aldehydes in high yield and
* Tel.: +46-8-162479; fax: +46-8-154908; e-mail addresses:
acordova1a@netscape.net; acordova@organ.su.se
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.080

3950
A. Cꢀordova / Tetrahedron Letters 45 (2004) 3949–3952
Table 1. Catalyst recycling studies
i-valeraldehyde had been the nucleophile. However,
proline was able to catalyze the self-aldol reaction of i-
valeraldehyde affording the corresponding aldol adduct
with >99% ee (Eq. 2).
(S)-proline
(5 mol%)
O
O
OH O
+
H
H
H
[bmim]PF6:DMF-1.5:1
4 C, 15-17h
˚
1
a
Drb
Ee (%)c
(S)-proline
(5 mol%)
EnctlreyRecy Yield (%)
1
O
O
O
OH
+
74
76
71
77
73
4:1
5:1
4:1
4:1
4:1
99
99
99
99
99
H
H
H
[bmim]PF6:DMF-1.5:1
2
3
4
5
1st
4 C, 24h
˚
2nd
3rd
4th
dr > 19:1
ee > 99%
yield = 71%
a Isolated yield after silica-gel column chromatography.
b Determined byNMR.
ð2Þ
c
9
Determined bychiral-phase GC.
The reactivityof the reaction increased in ionic liquid
media without decreasing the enantioselectivityof the
reaction as compared to the cross-aldol reaction in
DMF.5 In addition, the absolute and relative configu-
ration of the products did not change. Hence, (S)-pro-
line afforded anti-(2S,3S)-2-alkyl-3-hydroxy-aldehydes.
The sustainabilityand advantages of performing the
reaction in an ionic liquid were also exhibited byper-
forming entries 1, 2 and 4 in a row with the same (S)- or
(R)-proline. In addition, the reactions were recycled
more than five times without affecting the yield or the
enantioselectivityof the cross-aldolizations.
without affecting the yield or selectivity. Noteworthy,
only1–5 mol % of the catalyst was needed as compared
to the previouslyreported 45–10 mol % used in con-
ventional organic solvents.4a;h;5;6
Next, we investigated the cross-aldol reactions between
different aldehydes in ionic liquid media (Table 2).10 The
reactions proceeded smoothlyaffording
b-hydroxy
aldehydes 1–5 in good yield with excellent enantio-
selectivity. The diastereoselectivity of the reaction
increased for the a-substituted aliphatic acceptor alde-
hydes. For example, cross-aldol products 2, 4 and 5 were
isolated with dr > 19:1 and >99% ee, respectively.9
The chemoselectivityof the transformation was high,
for example, the reaction between propionaldehyde
and i-valeraldehyde did not yield any products where
We also investigated the possibilityof performing one-
pot sequential cross-aldol reactions in ionic liquid
media, which would assemble polyketide type sugars in
a similar fashion to polyketide synthases and aldolase
enzymes (Eq. 3).11;12
Table 2. Direct catalytic cross-aldol reactions in ionic liquid media
(S)-proline
(5 mol%)
O
O
OH O
+
R
H
H
R
H
[bmim]PF6:DMF-1.5:1
R'
R'
4 C, 15-17h
˚
1
cleEntryRecy R
R
Yield (%)a
Drb
Ee (%)c
Compound
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
73
76
74
78
76
75
69
71
72
70
77
78
75
78
68
70
69
4:1
99
>99
>99
>99
>99
>99
99
1
2
2
2
2
2
3
3
3
3
4
4
4
4
5
5
5
2
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Bu
i-Bu
i-Bu
i-Bu
>19:1
>19:1
>19:1
>19:1
>19:1
3:1
3
1st
4
2nd
3rd
4th
5
6
7
8
1st
3:1
3:1
99
99
9
2nd
3rd
10
11
12
13
14
15
16
17
3:1
99
c-Hexyl
c-Hexyl
c-Hexyl
c-Hexyl
i-Pr
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>99
>99
>99
>99
>99
>99
>99
1st
2nd
3rd
n-Bu
n-Bu
n-Bu
1st
2nd
i-Pr
i-Pr
a Isolated yield after silica-gel column chromatography.
b Determined byNMR.
c
9
Determined bychiral-phase GC.

A. Cꢀordova / Tetrahedron Letters 45 (2004) 3949–3952
3951
(S)-proline
(5 mol%)
15 eq. MnO2
EtOAc, rt
R
O
OH
R
O
O
O
O
O
+
+
R
H
H
H
[bmim]PF6:DMF-1.5:1
ð3Þ
4 C, 38h
˚
OH
OH
R = Et, i-Pr
6a R = Et
6b R = i-Pr
7a R = Et
7b R = i-Pr
Table 3. Catalyst recycling studies of the direct asymmetric assembly of pyranoses
(S)-proline
R
O
OH
O
O
O
(5 mol%)
+
+
R
H
H
H
[bmim]PF6:DMF-1.5:1
4 C, 38h
˚
OH
a
cle EntryRecy R
Yield (%)
Drb
Ee (%)c
Compound
1
2
3
4
Me
Me
Me
Me
50
47
48
49
>19:1
>19:1
>19:1
>19:1
49
48
49
49
6a
6a
6a
6a
1st
2nd
3rd
a Isolated yield after silica-gel column chromatography.
b Determined byNMR.
c Determined bychiral-phase HPLC analyses after conversion to 7a.
Hence, the proline-catalyzed formation of
1
in
financial support and is grateful to Prof. Jan-Erling
€
Backvall and co-workers for sharing chemicals.
[bmim]PF6/DMF 1.5:1 (2 mL) from propionaldehyde
(7.2 mmol) was continued after 16 h byslow addition of
more propionaldehyde (21 mmol) in cold [bmim]PF6/
DMF 1.5:1 (2 mL) with a syringe pump at 4 ꢁC. The
reaction was quenched after 22 h byextraction with Et 2O
(3 · 15 mL). Concentration of the combined organic
layers and subsequent purification of the crude product
byflash-column chromatographyafforded dimer 1 in a
50% yield and pyranose 6a in a 38% yield as a single
diastereomer with an anomeric ratio of 1:2 (a:b). The
pyranose 6a was converted quantitativelyto the corre-
sponding d-lactone 7a bytreatment with ab excess MnO 2
References and notes
1. Rogers, R. D.; Seddon, K. R. Science 2003, 303, 792;
Seddon, R. Chem. Commun. 2001, 2399.
2. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
3726; List, B. Tetrahedron 2002, 58, 5573; Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481; Duthaler, R. O.
Angew. Chem., Int. Ed. 2003, 42, 975.
3. Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem.
Rev. 1996, 96, 443; Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352.
in EtOAc for 48 h. The lactone 7a had an ee of 49% as
13
determined bychiral-phase HPLC analysis.
In addi-
ꢀ
4. (a) Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org.
Chem. 2002, 67, 301; (b) Cordova, A. Synlett 2003, 1651;
tion, lactone 7b was synthesized in two steps as a single
diastereomer with 25% ee.14 Noteworthythe use of ionic
liquid improved the ee as compared to the proline-cata-
lyzed formation of 6a and 6b in DMF or dioxane.4h The
proline-catalyzed direct asymmetric sequential aldol
reactions were also recycled efficiently without affecting
the yield or enantioselectivity of the reaction (Table 3).
ꢀ
ꢀ
(c) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem.
Commun. 2002, 3034; (d) Cordova, A. Acc. Chem. Res.
ꢀ
ꢀ
2004, 37, 102; (e) Cordova, A.; Watanabe, S.-i.; Tanaka,
F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
ꢀ
124, 1866; (f) Cordova, A.; Barbas, C. F., III. Tetrahedron
Lett. 2002, 43, 7749; (g) Cordova, A.; Barbas, C. F., III.
ꢀ
Tetrahedron Lett. 2003, 44, 1923; (h) Chowdari, N. S.;
In conclusion, we have reported the first catalytic direct
asymmetric cross-aldol reactions in an ionic liquid,
which simplify product isolation and catalyst recycling.
The reactions furnish b-hydroxy aldehydes in high yield
with excellent stereoselectivity. The reactions can be
readilyscaled-up and provide a low cost entryto either
enantiomer of important building blocks for natural
product synthesis.
ꢀ
Ramachary, D. B.; Cordova, A.; Barbas, C. F., III.
Tetrahedron Lett. 2002, 43, 9591; (i) Bøgevig, A.; Sunden,
ꢀ
ꢀ
H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 1109.
5. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798.
6. Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Jørgensen,
K. A. Chem. Commun. 2002, 620.
7. For other proline-catalyzed asymmetric reactions with
aldehydes see: (a) Bøgevig, A.; Juhl, K.; Kumaraguruba-
ran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 1790; (b) List, B. J. Am. Chem. Soc. 2002,
124, 5656; (c) Kumaragurubaran, N.; Juhl, K.; Zhuang,
W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
124, 6254; Pidathala, C.; Hoang, L.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2003, 42, 2785.
Acknowledgements
The author thanks the Swedish Natural Science
Research Council and the Wennergren foundation for
8. The ionic liquid [bmim]PF6 was selected since it provided
the best results as compared to [hmim]BF4 and

3952
A. Cꢀordova / Tetrahedron Letters 45 (2004) 3949–3952
[omim]bF4. It has also been successfullyused in aldol
reactions with unmodified ketones see: Kotrusz, P.;
11. Khosla, C.; Harbury, P. B. Nature 2001, 409, 247;
Kinoshita, K.; Willard, P. G.; Khosla, C.; Cane, D. E.
J. Am. Chem. Soc. 2001, 123, 2495, and references cited
therein.
12. Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1995,
117, 2947.
ꢀ
ꢀ
ꢀ
Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E. Chem.
Commun. 2002, 2510; Loh, T.-P.; Feng, L.-C.; Yang,
H.-Y.; Yang, J.-Y. Tetrahedron Lett. 2002, 43, 8741.
9. The cross-aldol adducts were reduced quantitativelyand
the corresponding anti-1,3-diols converted to the 2,2-
dimethylpropane-1,3-diols according to Ref. 5 and the ee
determined bychiral-phase GC analysis. The racemic 2,2-
dimethylpropane-1,3-diols derived by racemic proline-
catalysis were checked as GC standards.
10. In a typical experiment, i-butyraldehyde (2 mmol) was
added to a vial containing (S)-proline (5 mol %) in
[bmim]PF6/DMF 1.5:1 (2 mL) at 4 ꢁC. Next, a cold
solution of propionaldehyde (1 mmol) in [bmim]PF6/
DMF 1.5:1 (1.0 mL) was slowlyadded bysyringe pump
at 4 ꢁC. After 16 h the reaction was quenched byextraction
with Et2O (3 · 15 mL). The remaining proline in the ionic
liquid could be effectivelyreused for another cross-aldol
13. 7a: 1H NMR (400 MHz, CDCl3): d ¼ 1:04 (t, J ¼
7:2 Hz, 3H), 1.07 (d, J ¼ 7:2 Hz, 3H), 1.27 (d
J ¼ 7:2 Hz, 3H), 1.61 (m, 1H), 1.80 (m, 2H), 1.93 (br
s, 1H), 2.67 (dq, J ¼ 7:2, 3.6 Hz, 1H), 3.74 (t,
J ¼ 3:6 Hz, 1H), 3.76 (ddd, J ¼ 10:8, 8.2, 3.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): d ¼ 9:4, 16.0, 26.1, 39.0,
41.78, 75.76, 82.61, 174.53. HRMS: C9H16O3Na
(MNaþ): calcd 195.0992, found 195, 0993. ½aꢀ ꢁ14.0
D
(c 1.0, CHCl3). The ee of d-lactones 7a and 7b was
determined byesterification of the alcohol group with
3,5-dinitro-benzoyl chloride according to Ref. 4h and
subsequent chiral-phase HPLC-analysis of the corre-
sponding 3,5-dinitrobenzoate ester.
1
reaction bysimplyadding DMF to obtain a [bmim]PF to
6
14. 7b: H NMR (400 MHz, CDCl3): d ¼ 0:96 (d, J ¼ 7:2 Hz,
DMF ratio of 1.5:1. The combined organic extracts were
concentrated and the crude product purified bysilica-gel
column chromatography(pentane/EtOAc 3:1) affording b-
hydroxy aldehyde 2 in 76% yield with dr > 19:1 and >99%
ee. All the structural and spectroscopical data were
identical to the literature. See: Ref. 5 and Mahrwald, R.;
Costrisella, B.; Guendogan, B. Synthesis 1998, 26.
3H), 1.06 (d, J ¼ 6:8 Hz, 3H), 1.07 (d J ¼ 6:8 Hz, 3H),
1.26 (d, J ¼ 6:8 Hz, 3H), 1.92 (m, 2H), 2.67 (dq, J ¼ 6:8,
4.0 Hz, 1H), 3.74 (dd, J ¼ 11:2, 2.0 Hz, 1H), 3.75 (t,
J ¼ 3:6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d ¼ 11:2,
14.6, 16.1, 20.0, 29.2, 38.8, 39.4, 75.7, 85.3, 174.7. HRMS:
C10H18O3Na (MNaþ): calcd 209.1148, found 209.1146.
½aꢀ ꢁ11.2 (c 1.5, CHCl3).
D