Asymmetric aldol reactions catalyzed by new spiro diamine derivatives

Article abstract of DOI:10.1016/j.tetasy.2006.01.010

Two new organocatalysts derived from l-proline and a novel chiral spiro diamine bearing a C₂ symmetric backbone, were introduced for an asymmetric aldol reaction in moderate to good asymmetric induction in up to 76% ee and high yields.

Full text of DOI:10.1016/j.tetasy.2006.01.010

Tetrahedron: Asymmetry 17 (2006) 384–387
Asymmetric aldol reactions catalyzed by new spiro
diamine derivatives
Man Jiang,a Shou-Fei Zhu,b Yun Yang,b Liu-Zhu Gong,c
Xiang-Ge Zhoua,* and Qi-Lin Zhoub,*
aInstitute of Homogeneous Catalysis, College of Chemistry, Sichuan University, Chengdu 610064, China
bState Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
cChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
Received 9 December 2005; accepted 13 January 2006
Available online 20 February 2006
Abstract—Two new organocatalysts derived from L-proline and a novel chiral spiro diamine bearing a C2 symmetric backbone, were
introduced for an asymmetric aldol reaction in moderate to good asymmetric induction in up to 76% ee and high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
diamine14 named (S)-1,10-spirobiindane-7,70-diamine
6 to form two catalysts with L-proline for an aldol
reaction.
The asymmetric aldol reaction, which is a basic C–C
bond-forming method, constitutes a great challenge in
synthetic chemistry. Among the different kinds of cata-
lysts used, organocatalysis have contributed one of the
most exciting advances in recent years.1
O
CO2Et
OH
CO2Et
N
N
H
NH
N
N
H
H
Proline has been found to be efficient in many asymmet-
ric catalysis, such as dehydration, a-amination of alde-
hydes, Baylis–Hillman reaction, Michael addition, and
a-alkylation of aldehydes.2–9 In the case of the aldol
reaction, List first reported the utility of this amino acid
catalyst in 2000 with the highest ee of 96% for acetone
with 2-methylpropanal. Similar to the reported enamine
based mechanism with aldolase antibodies,8 L-proline
activates both the donor and acceptor, which are a
ketone and aldehyde, respectively, during the reaction.
High catalytic efficiency obtained indicates a conver-
gence of biological and chemical approaches.1 Mean-
while, many other organocatalysts containing a similar
structure to proline or its derivatives have been devel-
oped, some of which exhibited high chiral inductions
of 99%, 95%, and 83% ee with catalysts 1,10,11 2,12 and
3,13 respectively. In a continuation of our studies on
transition metal catalyzed synthetic transformation, we
herein report a new chiral source bearing a rigid spiro
1
(S)-2
(S)-3
2. Results and discussion
2.1. Preparation of organocatalysts 4 and 5
The procedure for the synthesis of the catalysts 4 and 5
is shown in Scheme 1 according to the reported
method10 but with the exception that the amino alcohol
was replaced by the new chiral diamine. As expected,
these two new catalysts could be obtained individually
in one pot with the ratio determined by the amount of
reactants used; increasing the amount of proline used,
benefited the formation of catalyst 8. Furthermore,
when the ratio of reactants N-(tert-butoxy carbonyl)-L-
proline and diamine 6 remained constant at 2:1, the
ratio of products 7 and 8 relied on the reaction time
and temperature. The formation of 8 was dominant if
the reaction was kept for a further 3 h under refluxing
conditions. Furthermore, using our procedure, acyl
*
Corresponding authors. Tel./fax: +86 28 85412026 (X.-G.Z.);
e-mail: zhouxianggescu@126.com
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.010

M. Jiang et al. / Tetrahedron: Asymmetry 17 (2006) 384–387
385
H
Boc
O
N
COOH
H
H
H2N
Boc
H
N
+
N
NH2
N
N
H
NH2
ClCOOC2H5, Et3N
H
H
N
Boc
O
O
Boc
8
6
7
O
H
H
NH
MeOH, CH3COCl
H
H
N
N
+
N
H
N
NH2
H
H
HN
O
O
4
5
Scheme 1.
chloride in methanol was used instead of the Pd/C
reagent to remove the BOC group.
ee were found with either polar or apolar solvents (en-
tries 1–7). Thus, the ensuing reactions were performed
without solvents.
2.2. Optimization of reaction conditions
For the effects of reaction temperature, a lower temper-
ature seemed to benefit the results.1 For example,
enantioselectivities increased from 33%, 38%, 45% to
52% when the reaction temperature decreased from 25,
0, ꢀ15 to ꢀ25 °C, respectively (entries 7–10). A lower
temperature of ꢀ40 °C seemed to be unnecessary due
to the unchanged results obtained, while longer reaction
time was needed (entry 11). On the other hand, under
the same reaction temperature, similar results were
found when the catalyst loadings were decreased from
20%, 10%, 5%, 2% to 1% (entries 10, 12–15). It indicated
the high catalytic activity of this new catalyst, while 20%
The influences of reaction conditions such as tempera-
ture, solvents, and amount of catalyst used were
optimized in the catalytic aldol reaction of p-nitrobenz-
aldehyde and acetone, and the results are listed in Table
1.
In general, the reactions proceeded smoothly with
higher yields than using the reported L-prolinamides.10
Furthermore, in our case, it proved that solvents were
not good for asymmetric induction as reported. In fact,
33% ee was obtained without solvents, while only 7–14%
Table 1. Asymmetric aldol reaction of p-nitrobenzaldehyde with acetone catalyzed by 4 or 5
OH
O
CHO
O
Cat. 4 or 5
+
O2N
O2N
Entry
Solvent
Temp (°C)
Time (h)
3
Cat.
Cat. loading (%)
10
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
CH3CN
DMF
CH2Cl2
Toluene
DMSO
Dioxane
None
None
None
None
None
None
None
None
None
None
None
25
4
75
70
73
70
70
70
92
90
88
87
82
87
85
81
80
70
75
14
12
11
8
8
7
33
38
45
52
55
53
52
51
51
48
52
0
ꢀ15
ꢀ25
ꢀ40
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
3.5
4
4.5
5
9
10
11
12
13
14
15
16
17
4.5
20
5
2
1
1
5
1
a Isolated yield based on aldehyde.
b Ee values were determined by HPLC, and the configuration was assigned as R by comparison of retention time reported.10

386
M. Jiang et al. / Tetrahedron: Asymmetry 17 (2006) 384–387
catalyst was needed to be used in the literature. Catalyst
5 was also synthesized and applied in this reaction to
give similar results (entries 16 and 17).
4. Experimental
4.1. Instrument and materials
2.3. Asymmetric Aldol reactions with other aldehydes
1H NMR spectra were recorded on a Bruker-300 MHz
spectrometer with CDCl3 as solvent. MS spectra were
recorded on a Finnigan MAT 95 mass spectrometer.
Elemental analysis was carried out using Carlo Erba-
1106 Analyzer. Optical rotations were measured on
Auto V Polarimeter at k = 589 nm. Melting points were
determined on a Yanaco microscopic melting point
instrument without adjustment. HPLC analysis was per-
formed on Waters-Breeze (2487 Dual k Absorbance
Detector and 1525 Binary HPLC Pump), Chiralpak
AS, AD columns were purchased from Daicel Chemical
Industries Ltd. Acetone was purified by KMnO4 and
then dried over anhydrous K2CO3. Petroleum ether
and ethyl acetate for column chromatography were dis-
tilled before use. Other materials were purchased from
Aldrich or Acros. The procedure for the asymmetric
aldol reaction was carried out according to a described
Asymmetric aldol reactions with other aldehydes were
carried out under the optimized reaction conditions by
4. As shown in Table 2, moderate to good selectivities
were obtained for aromatic aldehydes with better results
for alkyl analogues. The highest ee of 76% was observed
for the reaction of cyclohexanecarboxaldehyde with ace-
tone (entry 7).
3. Conclusion
C2 Symmetric spirocyclic chiral rigid diamine was intro-
duced to form two new organocatalysts with L-proline
for the intermolecular asymmetric direct aldol reaction
in moderate enatiomeric selectivity (76% ee).
Table 2. Asymmetric aldol reaction of acetone with other aldehydes catalyzed by 4a
OH
*
O
O
1 mol% catalyst 4
RCHO
CHO
+
R
-25 ºC, 4.5 h
Product
Entry
1
Aldehyde
Yield (%)b
68
ee (%)c
48
OH
OH
OH
O
NC
NC
O
2
3
68
63
46
32
F3C
Br
CHO
CHO
F3C
Br
O
OH
OH
O
4
5
87
70
27
25
Cl
CHO
Cl
F
O
F
CHO
OH
OH
O
6
7
72
56
19
76
CHO
CHO
O
OH
O
8
50
73
CHO
a The reactions were carried out under ꢀ25 °C for 4.5 h in the presence of 1 mol % catalyst 4.
b Isolated yield based on aldehyde.
c The ee values were determined by HPLC. An (R)-configuration was assigned by comparison of the retention time.

M. Jiang et al. / Tetrahedron: Asymmetry 17 (2006) 384–387
387
method and the products were determined to be identi-
cal with those reported.10
(0.005 mmol) and the reaction mixture stirred at
ꢀ25 °C for 4.5 h. The reaction mixture was then treated
with saturated ammonium chloride solution, and the
aqueous layer was extracted with ethyl acetate. The
combined organic layer was dried over anhydrous
MgSO4. After removal of solvent, the residue was puri-
fied through flash column chromatography on silica gel
(eluent: PET–ethyl acetate = 2:1) to give pure products.
4.2. Preparation of organocatalysts
Compound 7: N-(tert-Butoxy carbonyl)-L-proline (0.43 g,
2 mmol) and triethylamine (0.28 mL, 2 mmol) were dis-
solved in THF (10 mL). The solution was cooled down
to 0 °C. To the mixture was added ethyl chloroformate
(0.19 mL, 2 mmol) dropwise for 15 min. After stirring
for 30 min, chiral diamine 6 (0.25 g, 1 mmol) was added.
The resulting mixture was stirred at room temperature
for 5 h, and then diluted with ethyl acetate. After filtra-
tion and removal of solvent under reduced pressure,
the crude product of 7 was obtained as a solid without
further purification for next step. MS: 447 (M+).
Acknowledgments
The Project was sponsored by the Scientific Research
Foundation for the Returned Overseas Chinese Schol-
ars, State Education Ministry of China.
Compound 8 was prepared according to the same
method described for 7 except that the final reaction
temperature was 65 °C and the reaction time changed
to 12 h. The crude product was also obtained with mass
spectrum of 644 (M+).
References
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Compound 4 (S,S)-1,10-spirobiindane-7-amine-70-(pyr-
rolidine-2-carboxylic acid amide): 7 was added to a
methanol solution containing a few drops of acyl chlo-
ride at 0 °C, the mixture was kept stirring at room
temperature overnight. Methanol was then removed
under reduced pressure, and the residue dissolved in ethyl
acetate, after washing with saturated sodium carbonate
solution. The organic solvent was dried over anhydrous
Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel
(dichloromethane–methanol = 80:1) to give white solid
25
organocatalyst 4. Yield: 85%. Mp 168–170 °C. ½aꢁD
¼
1
ꢀ123:7 (c 0.27, CH2Cl2). H NMR d (ppm) 1.25–1.68
(m, 4H), 2.12–2.27 (m, 6H), 2.59 (m, 1H), 2.93–3.03
(m, 4H), 3.30 (br s, 2H), 3.54 (m, 1H), 6.41 (d, J =
7.5 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 7.02 (t, J =
7.8 Hz, 2H), 7.24 (m, 1H), 8.13 (d, J = 8.1 Hz, 1H),
9.31 (br s, 1H). MS (EI): 347 (M+Å). Anal. Calcd for
C22H25N3O: C, 76.08; H, 7.20; N, 12.10. Found: C,
75.82; H, 7.48; N, 11.76.
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dine-2-carboxylic acid amide): 5 was prepared according
to the same method described for 4, except that 8 was
used instead of 7 to give white solid. Yield 92%. Mp
234–236 °C. ½aꢁD ¼ ꢀ92:2 (c 0.27, CH2Cl2). H NMR
d (ppm) 1.33–1.65 (m, 8H), 2.01 (m, 4H), 2.22 (m,
4H), 2.55 (m, 2H), 2.98 (m, 4H), 3.51 (m, 2H), 7.03 (d,
J = 7.2 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 8.22 (d,
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Anal. Calcd for C27H32N4O2: C, 72.97; H, 7.21; N,
12.61. Found: C, 72.52; H, 7.47; N, 12.76.
25
1
4.3. General procedure for the aldol reaction
To a mixture of anhydrous acetone (1 mL) was added
the corresponding aldehyde (0.5 mmol) and catalyst