Asymmetric direct aldol reactions of acetoacetals catalyzed by a simple chiral primary amine

Article abstract of DOI:10.1021/jo9021259

(Chemical Equation Presented) An asymmetric direct aldol reaction of acetoacetals is described. Under the catalysis of a simple chiral primary amine, the direct aldol reactions of acetoacetals occur exclusively on the γ-position to give vinylogous-type al

Full text of DOI:10.1021/jo9021259

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reactions),1b derived from either β-dicarbonyl or R,β-unsa-
Asymmetric Direct Aldol Reactions of Acetoacetals
Catalyzed by a Simple Chiral Primary Amine
turated carbonyl compounds.5 Asymmetric direct ap-
proaches for these reactions are highly valuable in terms of
atom economy.6 However, such a reaction with high regio-,
diastereo-, and enantioselectivity remains unknown to date.
In addition, the range of vinylogous aldol donors has been
primarily limited to the ester-derived dienol ethers. Examples
with ketone or aldehyde counterparts are scarce and there is
no report on the use of β-keto aldehyde in asymmetric
vinylogous aldol reactions so far as we are aware.7
Sanzhong Luo,*,† Yupu Qiao,†
Long Zhang,‡ Jiuyuan Li,† Xin Li,† and Jin-Pei Cheng*,‡
†Beijing National Laboratory for Molecular Sciences
(BNLMS), CAS Key Laboratory of Molecular Recognition
and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, 100190, China, and ‡Department of
Chemistry and State Key Laboratory of Elemento-organic
Chemistry, Nankai University, Tianjin, 300071, China
SCHEME 1
luosz@iccas.ac.cn
Received October 2, 2009
The development of asymmetric direct aldol reactions of
β-keto aldehyde possesses a series of challenges. Besides
difficulties in controlling both diastereo- and enantioselec-
tivity, there are also issues such as chemoselectivity and
regioselectivity that requires differentiation of the two car-
bonyl groups and selective reaction on the γ-position rather
than the typical R-position as is usually observed in the
classical Knoevenagel reaction with similar substrates
(Scheme 1). Herein, we presented the first direct aldol reac-
tions of acetoacetals with high regio-, diastereo-, and en-
antioselectivity. This process was made possible by utilizing
the recently appearing chiral primary aminocatalysis,8 and
our previous finding that simple chiral primary amines such
as 1 (Table 1) were able to promote a range of direct aldol
reactions of functionalized aliphatic ketones beyond the
reach of typical secondary amines.9
An asymmetric direct aldol reaction of acetoacetals
is described. Under the catalysis of a simple chiral pri-
mary amine, the direct aldol reactions of acetoacetals
occur exclusively on the γ-position to give vinylogous-
type aldol products with high diastereo- and enantios-
electivity.
The asymmetric vinylogous aldol (AVA) reaction is a
versatile C-C bond forming reaction that has been widely
utilized in the synthesis of polyketides natural products.1 In
contrast to the well-developed asymmetric direct aldol reac-
tions,2 for which a number of asymmetric catalysts including
both chiral transition metal catalysts3 and organocatalysts4
have been developed, the success of the AVA reaction has
been largely limited to the use of preformed and activated
dienol ether donors (i.e., Mukaiyama vinylogous aldol
(5) For an example of direct aldol of 1,3-dicarbonyl compounds, see:
Rohr, K.; Mahrwald, R. Adv. Synth. Catal. 2008, 350, 2877.
(6) Trost, B. M. Science 1991, 254, 1471.
(7) For an example using R,β-unsaturate ketone aldol donor, see:
(a) Denmark, S. E.; Heemstra, J. R. J. Org. Chem. 2007, 72, 5668. For other
asymmetic direct vinylogous reactions, see: Michael addition: (b) Trost,
B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572. Mannich: (c) Liu, T.; Cui,
H.; Long, J.; Li, B.; Wu, Y.; Ding, L.; Chen, Y. J. Am. Chem. Soc. 2007, 129,
1878. Amination: (d) Bertelsen, T.; Marigo, M.; Brandes, S.; Diner, P.;
Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
(8) For a review, see: (a) Xu, L.; Luo, J.; Lu, Y. Chem. Commun. 2009,
ꢀ
1807. For recent examples, see: (b) Cordova, A.; Zou, W.; Dziedzic, P.; Ibrahem,
I.; Reyes, E.; Xu, Y. Chem.;Eur. J. 2006, 12, 5383 and references cited therein.
(c) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (d) Tsogoeva,
S. B.; Wei, S. Chem. Commun. 2006, 1451. (e) Ramasastry, S. S. V.; Zhang, H.;
Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2007, 129, 288. (f) Xu, X.-Y.;
Wang, Y.-Z.; Gong, L.-Z. Org. Lett. 2007, 9, 4247. (g) Xie, J.; Chen, W.; Li, R.;
Zeng, M.; Du, W.; Yue, L.; Chen, Y.; Wu, Y.; Zhu, J.; Deng, J. Angew. Chem., Int.
Ed. 2007, 46, 389. (h) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.;
Feng, X.; Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654. (i) Zhou, J.;
Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed. 2008, 47, 7656.
(j) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 17666. (k) Lu, X.;
Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008, 130, 8134.
(9) (a) Luo, S.; Xu, H.; Li, J. Y.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc.
2007, 129, 3074. (b) Luo, S.; Xu, H.; Zhang, L.; Li, J. Y.; Cheng, J.-P. Org.
Lett. 2008, 10, 653. (c) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett. 2008,
10, 1775. (d) Li, J.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2009, 74, 1747.
(1) For reviews, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. Rev. 2000, 100, 1929. (b) Denmark, S. E.; Heemstra, J. R.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (c) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506. (d) Brodmann, T.;
Lorenz, M.; Schackel, R.; Simsek, S.; Kalesse, M. Synlett 2009, 174.
(2) (a) Mahrwald, R., Ed. Modern aldol reactions; Wiley-VCH: Weinheim,
Germany, 2004. (b) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009,
20, 131.
(3) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. 1997, 36, 1871. (b) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12993.
(4) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000,
122, 2395. (b) For a review, see: Mukherjee, S.; Yang, J. W.; Hoffman, S.;
List, B. Chem. Rev. 2007, 107, 5471.
DOI: 10.1021/jo9021259
r
Published on Web 11/02/2009
J. Org. Chem. 2009, 74, 9521–9523 9521
2009 American Chemical Society

Luo et al.
JOCNote
TABLE 1. Selected Screening and Optimization Data a
SCHEME 2. Screening of Vinylogous Donors
entry
cat.
solvent
yield (%)b
ee (%)c
49% yield and 86% ee. Subsequent optimization indicated a
dramatic solvent effect. While the reactions in polar solvents
such as H2O and DMSO were generally sluggish affording
low yields (Table 1, entries 11-13), the use of nonpolar
solvents such as Et2O and hexane provided significant rate
enhancement (Table 1, entries 14 and 15), of which hexane
was found to be the optimal solvent. Moreover, the reaction
in hexane could be further improved by the addition of a
second weak acid additive, m-nitrobenzoic acid (Table 1,
entry 16).9a,11 Under these optimal conditions, the reaction
of 7a provided 85% yield and 90% ee.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
1a/DNBS
1b/DNBS
1c/DNBS
1d/DNBS
1e/DNBS
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
H2O
DMSO
DMF
Et2O
hexane
hexane
31
26
50
49
8
67
74
83
86
27
42
racemic
10
5
3/DNBS
4
77
15
trace
63
34
35
24
73
79
85
5/DNBS
6/DNBS
1d/DNBS
1d/DNBS
1d/DNBS
1d/DNBS
1d/DNBS
1d/DNBS
19
90
87
88
86
89
90
With the optimal conditions in hand, the scope of the
direct aldol reaction was next explored with respect to both
the acetoacetal donors and aldehyde acceptors in the pre-
sence of 1d/DNBS. The reactions of 7a with various aromatic
aldehydes gave the desired vinylogous aldol products in
moderate to excellent yields with high enantioselectivity
(Table 2, entries 1-8). Notably, the reactions worked well
with γ-substituted acetoacetal donors such as 7b-d. In cases
of 7b, the reactions occurred regioselectively on the γ-posi-
tion to give the desired vinylogous aldol products in good
yields favoring the syn-diastereomers with excellent enan-
tioselectivity (Table 2, entries 9-11). Remarkably faster
reactions were achieved with γ-hydroxyl acetoacetals 7d. In
these reactions, the syn-diol vinylogous aldol products
11-13 were obtained in high yields with excellent diastereo-
(syn/anti 5:1-12:1) and enantioselectivity (70-96% ee)
(Table 2, entries 13-18). It is noted that the reactions also
worked well with some activated carbonyl compounds such
as 2,2-dimethoxyacetaldehyde and ethyl glycoxylate
(Table 2, entries 17 and 18). In addition, the observation of
improved reaction rate and stereoselectivity with 7d over that
with benzyl protected 7c suggested a favorable participation
of the free hydroxyl group in the reaction coordinate via
intra/inter hydrogen-bonding interactions. A similar effect
has also been observed in the direct aldol reactions of
R-hydroxyketones.10b Last, a large-scale reaction (2 mmol)
has also been tried to give consistent results, demonstrating
the practicality of this reaction (Table 2, entry 2).
aThe reactions were carried out with 0.25 mmol of aldehyde, 1.0 mmol
of 7a in 100 μL of solvent at rt. isolated yield. Determined by chiral
HPLC. d5 mol % of m-nitrobenzoic acid was added. DNBS: 2,4-di-
nitrobenzenesulfonic acid.
b
c
Acetoacetals, the common precursors for Danishefsky’s
dienes,10 were initially selected as the targeted direct aldol
donors. It was envisioned that a properly protected acetal
group would address the chemo- and regioselectivity issues
via both electronic and steric tuning. To our delight, cyclic
acetoacetals derived from propane-1,3-diol such as 7a were
identified, after trials, as the optimal donors affording a facile
and clean reaction with exclusively γ-regioselectivity and good
stereoselectivity. Other derivatives of 7a such as the dimethyl
acetal, dithiane analogue, and vinylogous amide or ester
demonstrated lower or even no reactivity (Scheme 2).
The reaction of acetoacetal 7a and p-nitrobenzaldehyde
was selected as a model reaction and some selected screening
and optimization data were collected in Table 1. Among a
range of chiral primary amines examined, primary-tertiary
vicinal diamines such as 1 were found to be the optimal
catalysts for this type of aldol reaction (see the SI for full
details on screening and optimization). Other types of pri-
mary amines such as primary amine-thiourea 2 or primary
amine-amide 3, L-phenylalaninol 4, primary amine-pyridine
5, or primary-secondary diamines 6 were either inactive or
with low stereoselectivity (Table 1, entries 6-10), highlight-
ing the critical nature of primary-tertiary vicinal diamines for
direct aldol catalysis. Overall, the combination of a new
chiral primary amine 1d and 2,4-dinitrobenzenesulfonic acid
was identified to be the optimal catalytic system producing
In all cases examined, the reaction occurred dominantly
on the γ-position and no R-regioisomers were observed.
Furthermore, the reactions were generally clean even in cases
with deactivated aldehydes though long reaction times were
normally employed. No acetal ring-opening products were
(11) In the presence of 25 mol % of DNBS, the reaction gave 76% yield
and 89% ee.
(10) Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
9522 J. Org. Chem. Vol. 74, No. 24, 2009

Luo et al.
JOCNote
TABLE 2. Asymmetric Direct Aldol Reactions of Acetoacetalsa
SCHEME 3. Synthetic Applications of the Aldol Productsa
entry
donor
R0
time
yield (%)b
drc
ee (%)d
aReagents and conditinos: (a) TFA, CH2Cl2, rt, 6 h; (b) 8a, NaBH4,
THF, rt, 82%, anti/syn = 3:1; (c) TFA, MeOH, 87%, β/R = 1:2.
1
2 e
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17g
18
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7c
7d
7d
7d
7d
7d
7d
4-NO2Ph
4-NO2Ph
2-NO2Ph
3-NO2Ph
4-CNPh
2-ClPh
48 h
48 h
72 h
72 h
72 h
4 d
5 d
4 d
4 d
4 d
5 d
48 h
6 h
8 h
6 h
2 h
8a/85
8a/81
8b/91
8c/73
8d/64
8e/77
8f/27
8g/66
9a/74
9b/69
9c/60
10a/84
11a/92
11b/90
11c/93
11d/92
12/72
13/54
90
90
86
84
87
84/95f
86
85
97
97
93
90
96
95
94
96
86
70
In summary, we have developed unprecedented regio-,
diastereo-, and enantioselective direct aldol reactions of
acetoacetals catalyzed by a simple chiral primary amine.
The current reaction represents a rare example of direct aldol
reaction of β-ketoaldehyde affording vinylogous-type aldol
adducts.
2-Napt
2-BrPh
4-NO2Ph
3-NO2Ph
4-CNPh
4-NO2Ph
4-NO2Ph
2-NO2Ph
4-CNPh
4-CF3Ph
CH(OMe)2
CO2Et
3:1
3:1
4:1
2:1
9:1
9:1
9:1
12:1
10:1
5:1
Experimental Section
General Experimental Procedure. To a given anhydrous ke-
tone (1 mmol) in 0.1 mL of hexane was added the corresponding
aldehyde (0.25 mmol), m-nitrobenzoic acid (0.0125 mmol),
and catalyst 1d-DNBS (0.05 mmol) (prepared in CH2Cl2 with
1 equiv of 1d and 1 equiv of DNBS). The resulting mixture was
stirred at room temperature for the indicated reaction time and
then purified by flash chromatography on silica gel to afford the
pure products.
24 h
72 h
aThe reactions were carried out with 0.25 mmol of aldehyde, 1.0 mmol
of 7a, and m-nitrobenzoic acid (5 mol %) in 100 μL of hexane at rt.
bIsolated yield. cDetermined by 1H NMR. dDetermined by chiral HPLC.
e2 mmol of p-nitrobenzaldehyde, 8 mmol of 7a, and m-nitrobenzoic acid
8a: starting from p-nitrobenzaldehyde (38 mg, 0.25 mmol) to
f
(5 mol %) in 800 μL of hexane at rt. ee after one recrystallization.
give 8a as a colorless solid (63 mg, 85% yield). [R]20 -13.6
g1 equiv of anhydrous Na2SO4 was added. DNBS: 2,4-dinitrobenzene-
sulfonic acid.
D
(c 1.0, CH3OH). IR (KBr, cm-1) 3402, 3356, 3044, 2979, 2951,
2921, 28572, 1720, 1600.63, 1519, 1469, 1458, 1352, 860, 815. 1H
NMR (300 MHz, CDCl3) δ 8.20 (2H, d, J=8.7 Hz), 7.54 (2H, d,
J=8.7 Hz), 5.27 (1H, s), 4.95 (1H, t, J=5.1 Hz), 4.09 (2H, dd,
J=10.8 Hz, 5.1 Hz), 3.78 (2H, m), 3.66 (1H, s), 2.91 (2H, t, J=
7.5 Hz), 2.76 (2H, d, J=5.1 Hz), 2.14-1.97 (1H, m), 1.37 (1H,
dt, J = 13.5 Hz, 1.2 Hz). 13C NMR (75 MHz, CDCl3) δ 207.1,
150.1, 147.3, 126.5, 123.7, 98.5, 68.9, 67.0, 52.2, 48.9, 25.4.
observed under the present conditions. Unfunctionalized
aliphatic aldehydes are currently not workable substrates
in the present reaction due to their low activity and the
accompanying by-pathways. The reactions of R,β-unsatu-
rated aldehyde also showed low activity in the present
reaction. The absolute and relative configurations of the
vinylogous aldol products, as determined unambiguously by
X-ray crystallography of adduct 8e (see Supporting Infor-
mation for details)12 and NMR analysis of compound 14b,
respectively, suggested the reaction would occur through
Z-enamine-type transition state with Re-Si attack to the
aldehyde, being consistent with the model proposed pre-
viously (Figure 1).9
þ
HRMS calcd for C14H17NO6 295.1056, found 295.1060. En-
antiomeric excess was determined to be 90% ee (determined by
HPLC on a Chiralpak AD-H column, 254 nm, 2-propanol/
hexane 20:80, 25 °C, 0.5 mL/min, tR =37.13 min (major), tR=
41.17 min (minor)).
9a: starting from p-nitrobenzaldehyde (38 mg, 0.25 mmol) to
give 9a as a pale yellow solid (57.2 mg, 74% yield). [R]20D þ16.4
(c 1.0, CH3OH). IR (KBr, cm-1) 3455, 3081, 2964, 2925, 2857,
1712, 1604, 1519, 1347, 1133, 854. 1H NMR (300 MHz, CDCl3)
δ 8.14 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 5.26 (1H, s),
4.92 (1H, t, J=5.2 Hz), 4.06-4.01 (2H, m), 3.73-3.69 (2H, m),
3.35 (1H, br s), 2.88-2.67 (3H, m), 2.09-1.98 (1H, m), 1.31 (1H,
dt, J = 13.5, 1.20 Hz), 0.90 (3H, d, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3) δ 211.3, 149.0, 147.2, 126.7, 123.5, 99.0, 71.4,
67.1, 53.1, 47.0, 25.4, 8.5. HRMS calcd for C15H19NO6Naþ
332.1110, found 332.1105. Enantiomeric excess was determined
to be 97% ee (syn) (determined by HPLC on a Chiralpak AD-H
column, 254 nm, 2-propanol/hexane 10:90, 25 °C, 0.8 mL/min,
tR =40.44 min (minor), tR =45.30 min (major)).
FIGURE 1. The proposed transition state.
Given the multifunctionalized nature of vinylogous aldol
products, versatile synthetic applications are conceivable. As
a demonstration, the products 8a and 9a could be readily
transformed into pyran-4-one 14 and tetrahydropyranol 15
in excellent yields and high enantioselectivities (Scheme 3).
Acknowledgment. The project was supported by the Natu-
ral Science Foundation (NSFC 20702052 and 20972163),
MOST (2008CB617501 and 2009ZX09501-018), and CAS.
Supporting Information Available: Experimental details,
characterizations of new compounds, and X-ray crystallogra-
phy of 8e. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) CCDC 749280 contains the supplementary crystallographic data for
compound 8e. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data-request/cif.
J. Org. Chem. Vol. 74, No. 24, 2009 9523