Highly enantioselective aldol reactions between acetaldehyde and activated acyclic ketones catalyzed by chiral primary amines

Article abstract of DOI:10.1002/chem.201300478

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Bronsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity. Copyright

Full text of DOI:10.1002/chem.201300478

FULL PAPER
DOI: 10.1002/chem.201300478
Highly Enantioselective Aldol Reactions between Acetaldehyde and
Activated Acyclic Ketones Catalyzed by Chiral Primary Amines
Yu-Hua Deng,[a] Jin-Quan Chen,[a] Long He,[a] Tai-Ran Kang,[a] Quan-Zhong Liu,*[a]
Shi-Wei Luo,*[b] and Wei-Chen Yuan[c]
Abstract:
Highly
enantioselective
fluoromethyl carbinol in good-to-excel-
lent yields and enantioselectivities.
Structural modification of the chiral
amines from the same chiral source
switched the stereoselectivity of the
products. The utility of aldol chemistry
was demonstrated in the brief synthesis
of functionally enriched d-lactones.
Theoretical calculations on the transi-
tion-state structure indicated that the
protonated tertiary amine could effec-
tively activate the carbonyl group of a
keto ester to promote the addition
process through hydrogen-bonding in-
teraction and, simultaneously, provide
an appropriate attacking pattern for
the approach of the keto ester to the
enamine, which is formed from acetal-
dehyde and the chiral catalyst, on a
particular face, resulting in high enan-
tioselectivity.
cross-aldol reactions between acetalde-
hyde and activated acyclic ketones are
reported for the first time. Various acy-
clic ketones, such as saturated and un-
saturated keto esters, reacted with ac
ACHTUNGTRENNUNGaldehyde in the presence of a chiral
primary amine and a Brønsted acid to
afford optically enriched tertiary alco-
hols in good yields and with excellent
enantioselectivities. Trifluoromethyl ke-
tones were tolerable under the reaction
conditions, thereby affording the tri-
ACHTUNGERTNeNUNG t-
Keywords: aldol reactions · amines ·
enantioselectivity · ketones · lac-
tones
Introduction
5-deoxy-7-carbon carbohydrate derivatives in the presence
of fructose-1,6-diphosphate aldolase from rabbit muscle
(RAMA).[5] The first organocatalytic enantioselective self-
aldol reaction of acetaldehyde was reported in 2002 by using
proline as the catalyst.[6] Although good enantiomeric excess
was obtained, the yield was too low to be practical. An alter-
native solution was a Mukayama-aldol reaction that em-
ployed the silyl enol ether of acetaldehyde with triflimide or
a chiral phosphoramide as the catalyst.[7] Then, in 2008, the
catalytic asymmetric direct aldol reaction between acetalde-
hyde and other aldehydes was accomplished, catalyzed by
diarylprolinol, in moderate yields and good enantioselectivi-
ties.[8] Quite recently, Chen and co-workers reported that
chiral primary amines were effective catalysts in enantiose-
lective aldol reactions with acetaldehyde as the nucleo-
phile.[9] To date, the cross-aldol reaction between acetalde-
hyde and ketones has seldom been explored. To the best of
our knowledge, only isatin has been successfully applied in
the enantioselective cross-aldol reaction with chiral amine
catalysts.[9,10] In 2008, we developed a new family of chiral
primary amines from optically pure binaphthol and amino
acids. These chiral amines were found to be effective in
asymmetric aldol reactions between acetone and aromatic
aldehydes, keto esters, and unsaturated keto esters.[11] These
direct cross-aldol reactions between acetaldehyde and ke-
tones allowed rapid access to chiral tertiary alcohols, which
are common scaffolds in many natural products
(Scheme 1).[12] In our efforts toward achieving the cross-
aldol reaction between acetaldehyde and ketones, we found
that easily modified chiral primary amine catalysts with a bi-
naphthyl backbone were effective in the reactions between
Asymmetric aminocatalysis[1] has received much attention
and significant advancements have been made over the past
few years. Organocatalytic asymmetric aldol reactions are
À
still of use in C C formation reactions that allow rapid
access to b-hydroxycarbonyl compounds.[2] Despite this
great success, direct asymmetric aldol reactions of acetalde-
hyde, the simplest aldehyde, as the nucleophile have re-
ceived less attention[3] and the challenge of that very reac-
tive acetaldehyde, which is highly prone to polymerization,
still remains. Early in 1994, Harrie and Wong reported a
stereospecific aldol reaction of acetaldehyde that was cata-
lyzed by 2-deoxyribose-5-phosphate aldolase (DERA), but
only a low yield was obtained;[4] the aldol product reacted
further with dihydroxy ketone phosphate, thereby forming
[a] Y.-H. Deng, J.-Q. Chen, Dr. L. He, Dr. T.-R. Kang, Prof. Q.-Z. Liu
Chemical Synthesis and Pollution Control
Key Laboratory of Sichuan Province and
College of Chemistry and Chemical Engineering
China West Normal University, Nanchong 637000 (P.R. China)
E-mail: quanzhongliu@cwnu.edu.cn
[b] Prof. S.-W. Luo
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P.R. China)
E-mail: luosw@ustc.edu.cn
[c] Prof. W.-C. Yuan
Chengdu Institute of Organic Chemistry
Chengdu 610041 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300478.
Chem. Eur. J. 2013, 19, 7143 – 7150
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7143

Table 1. Enantioselective cross-aldol reactions between acetaldehyde and
unsaturated keto ester 1a.[a]
Entry
Catalyst
Yield [%][b]
ee [%][c]
1[d]
2[d]
3[d]
4[d]
5[d]
6
7
8
9
10
11
12
13
14
I
32
10
29
<5
<5
26
58
45
26
74
70
76
60
60
16
À20
À22
–
Scheme 1. Cross-aldol reactions between acetaldehyde and activated acy-
clic ketones. EWG=electron-withdrawing group.
IIA
IIB
IIC
IID
IIIA
IIIB
IIIC
IIID
IV
VA
VB
VC
VD
–
acetaldehyde and activated acyclic ketones (Scheme 1). The
structural modification of these chiral amines from the same
chiral source allowed a switching of the stereoselectivity of
the products. Herein, we report our results.
À22
4
27
33
22
87
À82.5
À55
77
Results and Discussion
[a] Unless otherwise stated, the reaction was carried out with keto ester
1a (0.1 mmol), acetaldehyde (10 equiv), catalyst (10 mol%), and tri-
fluoroacetic acid (20 mol%) in DMSO (20 mL) at room temperature.
[b] Yield of isolated product. [c] Determined by chiral HPLC after reduc-
tion of the product into the corresponding alcohol (3a). [d] No acid was
added.
Based on the successful asymmetric aldol reaction between
b,g-unsaturated keto esters and ketones,[13] keto ester 1a was
initially chosen as the activated acyclic ketone for our enan-
tioselective cross-aldol reaction with acetaldehyde. The
hetero-Diels–Alder reaction between compound 1a and ac-
ACHTUNGTRENNUNGetACHTUNGTRENNUNGaldehyde in the presence of proline-based catalysts has
been reported previously, but the aldol reaction has never
been described.[3f–h] In our investigation, proline-based or-
A
E
Very recently, cinchona-derived primary amines III have
found application in asymmetric aldol reactions.[14] However,
these catalysts provided similar results to those with cata-
lysts IIA–IID. Chiral cyclohexanediamine catalyst IV was
highly efficient in the enantioselective aldol reactions, there-
by affording the product in good yield, but again only low
enantioselectivity was obtained (74% yield, 22% ee). These
results highlighted the difficulties in the enantioselective
aldol reaction between acetaldehyde and acyclic ketones.
To our delight, the chiral amine catalysts that were devel-
oped by our group were found to be efficient in this reac-
tion. For example, when amine VA was surveyed in the
model reaction, both the enantioselectivity and yield were
greatly enhanced: The corresponding tertiary alcohol was
isolated in 70% yield and 87% ee (Table 1, entry 11). To the
best of our knowledge, this result is the first example of an
enantioselective aldol reaction between acetaldehyde and
acyclic ketones. This catalyst was the most efficient among
the organocatalysts that were surveyed in this work. Thus,
other catalysts with this structure were investigated next.
The introduction of substituents at the 3,3’-positions of the
binaphthyl motif resulted in a switch in the stereoselectivity
and the opposite configuration of the product was obtained.
When catalyst VB was used, an inversion of the stereoselec-
tivity was observed, with 82.5% ee. Thus, the stereochemical
induction of the reaction greatly depended on the binaph-
aldol product was isolated in low yields and enantioselectivi-
ties (Table 1). For example, only 16% ee was obtained when
proline was used as the catalyst. Diaryl-prolinol-based cata-
lysts, such as catalysts IIA–IID, which have exhibited excel-
lent efficiency in the asymmetric aldol reactions of alde-
hydes, even for acetaldehyde, were inefficient, thereby pro-
viding the corresponding product with only 20–22% ee.[10]
Figure 1. Catalysts that were screened in the work.
ACHTUNGTRENtNUNG hyl motif, but the ee values varied with the amine structure.
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Enantioselective Aldol Reactions Catalyzed by Primary Amines
FULL PAPER
Table 3. Effects of the acid.[a]
Further optimization of the reaction parameters, such as
solvent, acid, and temperature, was carried out. Among the
solvents that were surveyed, HMPA was the best in terms of
yield and enantioselectivity (72% yield, 87% ee; Table 2,
Table 2. Solvent screen.[a]
Entry
Acid
T [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
TFA
AcOH
p-NO2C6H4CO2H
PhCO2H
TfOH
TfOH
TfOH
TfOH
TfOH
20
20
20
20
20
20
20
10
0
70
68
66
48
81
72
78
77
81
72
87
51
72
61
88
90
89
92
92
90
5
6[d]
7[e]
8[d]
9[d]
10[d]
Entry
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
9
10
11
12
13
DMSO
HMPA
DMF
THF
Et2O
70
72
50
68
73
48
64
70
65
58
60
69
60
77
87
87
36
75
83
74
81
79
68
79
78
79
78
66
TfOH
À10
[a] Unless otherwise stated, the reaction was carried out by using keto
ester 1a (0.1 mmol) and acetaldehyde (10 equiv) in HMPA (20 mL) with
VA (10 mol%) and acid (20 mol%) as the catalyst for 12 h at the indicat-
ed temperature. [b] Yield of isolated product. [c] Determined by chiral
HPLC after reduction of the product into the corresponding alcohol.
[d] TfOH (30 mol%) was used. [e] Catalyst (20 mol%) and TfOH
1,4-dioxane
CCl4
CHCl3
CH2Cl2
benzene
toluene
n-hexane
MeCN
neat
(60 mol%) were used. TFA=trifluoroacetic acid, TfOH=trifluoro
AHCTUNGTRENNaGUN nesulfonic acid, AcOH=acetic acid.
ACHTUNGTRENNUNGmeth-
[a] Unless otherwise stated, the reaction was carried out with keto ester
1a (0.1 mmol), acetaldehyde (10 equiv), catalyst VA (10 mol%), and tri-
fluoroacetic acid (20 mol%) in DMSO (20 mL) at room temperature for
12 h. [b] Yield of isolated product. [c] Determined by chiral HPLC after
reduction of the product into the corresponding alcohol. HMPA=hexa-
was heavily dependent on the electronic nature of the keto
ester. Generally speaking, for substrates with the same sub-
stituted pattern, electron-deficient substrates provided
higher selectivities compared to electron-rich substrates. For
example, unsubstituted keto ester 1a provided the product
in 92% ee, whereas 4-methyl-substituted substrate 1b pro-
vided the product in only 87% ee (Table 4, entries 1 and 2).
For 4-substituted substrates, compounds 1c, 1d, and 1 f–1h
provided their corresponding products in higher selectivities
than compounds 1b and 1e (Table 4, entries 3, 4, and 6–9 vs.
entries 2 and 5). Other substrates (compounds 1j–1m and
1q) also showed the same trend (Table 4, entries 10–13 and
17). It should be noted that the keto ester that was substitut-
ed with a furyl group was also tolerated under these condi-
tions (Table 4, entry 16).
Although most of the aldol products (2) were oils, after
reduction, the corresponding triols 3g and 3i were crystal-
line solids. Thus, the absolute configuration of compound 3g
was determined to be R by single-crystal X-ray diffraction
analysis after recrystallization from n-hexane/Et2O
(Figure 2). The absolute configurations of other aldol prod-
ucts were tentatively assigned by analogy.
ACHTUNGTRENNUNGmethylphosphoramide.
entry 2). The reaction was relatively slow when DMSO was
used as the solvent and other solvents provided poorer re-
sults compared to those in polar aprotic solvents. Therefore,
HMPA was chosen as the solvent for further investigations.
The selectivity of the reaction greatly depended on the
strength of the acid that was used (Table 3). Among the
acids that we investigated, triflic acid provided the highest
yield and enantioselectivity (81% yield, 88% ee; Table 3,
entry 5). The amount of acid has a slight impact on the reac-
tion. Increasing the amount of acid to 30 mol% led to a
marginal increase in enantioselectivity but the yield dropped
(Table 3, entry 6). We found that the amount of catalyst had
no effect on the reaction (Table 3, entry 7). Lowering the
temperature to 08C afforded the product in higher yield and
enantioselectivity (81% yield, 92% ee; Table 3; entry 9);
the reaction proceeded very slowly at À108C, with no im-
provement in enantioselectivity.
With the optimal conditions for this reaction in hand, var-
ious keto esters were surveyed with acetaldehyde as the nu-
cleophile. Among the keto esters that were screened, the
corresponding products were obtained in good yields and
good-to-excellent enantioselectivities. The electronic nature
of aromatic ring of esters has little influence on the yield of
the reaction. However, it seemed that the enantioselectivity
This procedure can be extended to the enantioselective
aldol reaction between other activated acyclic ketones and
acetaldehyde. The presence of fluorine atoms in pharma-
ceutical compounds often enhances their pharmacological
activities.[15] With this fact in mind, trifluoromethyl-substitut-
ed keto ester 4a was investigated in the enantioselective
aldol reaction with acetaldehyde. The corresponding tertiary
alcohol (5a) was obtained in 66% yield with 92% ee
Chem. Eur. J. 2013, 19, 7143 – 7150
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Q.-Z. Liu, S.-W. Luo et al.
Table 4. Enantioselective cross-aldol reactions between acetaldehyde and
unsaturated keto esters.[a]
Entry
Ar
Keto ester
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
81
80
55
84
70
70
83
90
81
73
74
79
87
88
78
77
80
92
87
89
94
88
91
91
94
87
89
85
84
88
90
94
91
94
4-MeC6H4
4-NO2C6H4
4-CNC6H4
4-OMeC6H4
4-FC6H4
4-ClC6H4
4-CF3C6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
3-MeOC6H4
3-MeC6H4
2-MeC6H4
3,4,5-(MeO)3C6H2
furyl
9
10
11
12
13
14
15
16
17
Scheme 2. Reactions between trifluoromethyl ketones and acetaldehyde.
sponding carboxylic acid (6c) without an erosion in enantio-
selectivity. Carboxylic acid 6c has been found to be an im-
portant motif in pharmaceutical compounds[18] and was pre-
viously prepared by the diastereoselective reaction between
a trifluoromethyl ketone and a chiral enolate[19] or by the al-
kenylation of the trifluoromethyl ketone, followed by a
series of transformations, such as hydroboration and oxida-
tion.[20]
3-NO2C6H4
[a] Unless otherwise stated, the reaction was carried out with the keto
ester (0.1 mmol), acetaldehyde (10 equiv), catalyst (10 mol%), and triflic
acid (30 mol%) at 08C. [b] Yield of isolated product. [c] Determined by
chiral HPLC.
Asymmetric transformations that can produce both enan-
tiomers of a product in a specified reaction by using chiral
catalysts with different substituents are desirable from a
practical point of view. The absolute configuration of the
enantioselective cross-aldol product can be switched to the
S configuration by using catalyst VB under otherwise identi-
cal conditions (Table 5), although the ee values are slight
lower. For example, compound 1a reacted with acetalde-
hyde in the presence of 10 mol% of catalyst VB and
30 mol% of TfOH to afford compound (S)-3a in 88% yield
with 84% ee. Other substrates provided their corresponding
chiral tertiary alcohols in good yields with good enantiose-
lectivities.
Figure 2. ORTEP drawing of compound 3g; thermal ellipsoids are set at
45% probability.
To obtain insight into the stereocontrol in this enantiose-
lective nucleophilic addition reaction, theoretical calcula-
tions were performed on the plausible transition states (TS)
by using the B3LYP/6-31(d) method,[21] as implemented in
the Gaussian 03 program.[22] The located most stable TS
structures are shown in Figure 3. The nitrogen atom of the
tertiary amine in the key enamine intermediate, which is
formed from the reaction of the amine catalyst with acetal-
dehyde, should be protonated during the reaction scheme
under these conditions. The protonated amine could act as a
hydrogen-bond (HB) donor to induce the keto ester into ap-
proaching the enamine through hydrogen-bonding interac-
tions and simultaneously activate the carbonyl group of the
keto ester to promote the nucleophilic addition of the en-
(Scheme 2). Although CF3-containing unsaturated ketone
4b has been successfully employed in the asymmetric aldol
reaction of acetone catalyzed by proline or prolinamide,[16]
acetaldehyde has never been used as the nucleophile in the
aldol reaction of compound 4b. Under our conditions, com-
pound 4b reacted with acetaldehyde, thereby affording com-
pound 5b in 94% yield with 89% ee. Phenyl trifluoromethyl
ketone 4c also reacted with acetaldehyde and furnished op-
tically enriched alcohol 5c in 95% ee.[17] To the best of our
knowledge, this is the first highly efficient asymmetric cata-
lytic synthesis of a trifluoromethyl carbinol by using a tri-
fluoromethyl ketone and acetaldehyde. It should be noted
that compound 5c can be easily transformed into the corre-
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Chem. Eur. J. 2013, 19, 7143 – 7150

Enantioselective Aldol Reactions Catalyzed by Primary Amines
FULL PAPER
Table 5. Enantioselective aldol reactions between acetaldehyde and un-
AHCTUNGTRENNUNG
saturated keto esters catalyzed by catalyst VB.[a]
Entry Ar
Keto ester Yield ee
Configuration
[%][b] [%][c]
1
2
3
4
5
6
C6H5
p-MeC6H4
p-FC6H4
p-CF3C6H4
p-ClC6H4
3,4,5-(OMe)3C6H2 1o
1a
1b
1 f
1h
1g
88
81
80
90
91
71
84
84
82
81
85
87
S
S
S
S
S
S
[a] Unless otherwise stated, the reaction was carried out with the keto
ester (0.1 mmol), acetaldehyde (10 equiv), catalyst VB (10 mol%), and
triflic acid (30 mol%) at 08C. [b] Yield of isolated product. [c] Deter-
mined by chiral HPLC.
The aldol product can be easily transformed into a variety
of functionally enriched compounds. To demonstrate the
utility of this chemistry, keto ester 1r was reacted with ace-
taldehyde, thereby affording tertiary alcohol 2r in 80%
yield with 91% ee. Compound 2r was readily oxidized into
the corresponding carboxylic acid with a pendent olefin (7)
in 92% yield with 90% ee. The intramolecular substrate-
controlled iodolactonization reaction in the presence of I2
yielded a six-membered lactone (8) with 91% ee and excel-
lent diastereoselectivity (>20:1);[23] the optical purity of
compound 8 could be further increased to 99% ee after a
single recrystallization step. The configuration of compound
8 was assigned as 2S,3S,4S by X-ray diffraction. Heating a
mixture of compound 8 at reflux with azobisisobutyrontrile
(AIBN) and Bu3SnH in CH2Cl2 yielded optically pure d-lac-
tone 9 in 95% yield (Scheme 3).
Conclusion
In summary, we have developed an enantioselective cross-
aldol reaction between acetaldehyde and activated acyclic
ketones. The acyclic activated ketones reacted with acetal-
dehyde in the presence of a chiral primary amine and a
Brønsted acid, thus yielding optically enriched tertiary alco-
hols in good yields and excellent enantioselectivities. The
utility of this aldol chemistry was demonstrated in the brief
synthesis of functionally enriched d-lactones. Theoretical
calculations on the transition-state structure were carried
out to elucidate the catalytic mechanism.
Figure 3. Located transition-state structures in the enantioselective aldol
reaction by using the B3LYP/6-31(d) method; distances are in ꢁ; relative
enthalpies and Gibbs free energies [kcalmolÀ1], respectively, are as fol-
lows: a) TS-VA-R, 0.00 and 0.00; b) TS-VA-S, 5.41 and 4.93; c) TS-VB-S,
0.00 and 0.00; d) TS-VB-R, 10.90 and 10.30.
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Q.-Z. Liu, S.-W. Luo et al.
phy on silica gel (petroleum ether/EtOAc, 5:1) to afford compound 2r
(80 mg, 80% yield, including its hemiacetals) as
a pale-yellow oil.
1H NMR (400 MHz, CDCl3): d=9.77 (t, J=1.4 Hz, 1H), 7.42–7.28 (m,
5H), 6.91 (d, J=15.8 Hz, 1H), 6.26 (d, J=15.8 Hz, 1H), 4.35–4.28 (m,
2H), 3.80 (s, 1H), 3.11 (dd, J=0.4 Hz, J=16.9 Hz), 2.97 (dd, J=1.6 Hz,
J=17.2 Hz, 1H), 1.34 ppm (t, J=7.2 Hz, 3H). Owing to the instability of
compound 2r, the enantiomeric purity of 2r was determined by HPLC
analysis after reduction into its corresponding alcohol 3a.
AHCTUNGTERG(NNUN R,E)-3-(Ethoxycarbonyl)-3-hydroxy-5-phenylpent-4-enoic acid (7): To a
solution of crude compound 2r (75 mg, 0.3 mmol) in iPrOH (3 mL) was
added a 10% solution of NaH2PO4 buffer to adjust the pH to 4, followed
by the addition of a 30% aqueous solution of H2O2 (24 mL) and 80%
NaClO2 (75 mg in 0.5 mL water, 2.2 equiv). The mixture was stirred at
about 108C until the reaction had been completed (monitored by TLC).
Then, the reaction mixture was cooled to 08C and Na2SO3 (50 mg) was
added to remove the oxidant. The mixture was extracted with EtOAc
(3ꢂ5 mL) and the organic layer was dried and concentrated. The residue
was purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 1:1) to afford compound 7 (73 mg, 92% yield, 90% ee) as
a white solid. Rf =0.36 (petroleum ether/EtOAc, 1:2); M.p. 84–898C;
[a]2D5 =+28.2 (c=0.7, CHCl3; 90% ee); 1H NMR (400 MHz, CDCl3): d=
7.42–7.28 (m, 5H), 6.92 (d, J=15.8 Hz, 1H), 6.23 (d, J=15.8 Hz, 1H),
4.32 (q, J=7.2 Hz, 2H), 3.23 (d, J=16.6 Hz, 1H), 2.86 (d, J=16.6 Hz,
1H), 1.33 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
175.3, 173.4, 135.8, 131.3, 128.6, 128.2, 128.0, 126.8, 75.0, 62.8, 43.3,
14.0 ppm; HRMS (ESI): m/z calcd for C14H16O5: 287.0895 [M+Na]+;
found: 287.0899; IR (KBr): n˜ =3488, 2987, 2926, 1791, 1739, 1410, 1373,
1342, 1298, 1252, 1207, 1135, 1096, 980, 748, 696 nm; HPLC (Daicel Chir-
alpak OJ-H; n-hexane/isopropanol/TFA, 85:15:1; flow rate: 1.0 mLminÀ1
l=254 nm): tRA(major)=7.9 min, tRA(minor)=10.3 min.
AHCTUNGTERG(NNUN 2S,3S,4S)-Ethyl-4-hydroxy-3-iodo-6-oxo-2-phenyltetrahydro-2H-pyran-4-
;
C
CHTUNGTRENNUNG
Scheme 3. Utility of the enantioselective cross-aldol reaction and
ORTEP drawing of compound (2S,3S,4S)-8; thermal ellipsoids are set at
40% probability.
carboxylate (8): To a solution of compound 7 (39.6 mg, 0.15 mmol) in dry
MeCN (1.5 mL) was added NaHCO3 (37.9 mg, 0.45 mmol) at 08C and
the resulting suspension was stirred for 15 min at 08C. Then, iodine
(113.8 mg, 0.45 mmol) was added and the mixture was stirred at 08C for
2.5 days in the darkness until the reaction had been completed (moni-
tored by TLC). The reaction mixture was quenched with water (1.5 mL)
and extracted with CHCl3 (4ꢂ10 mL). The organic layer was washed
with a saturated aqueous solution of sodium thiosulfate to remove any
excess iodine. The organic layer was dried over anhydrous sodium sulfate
prior to concentration. Purification by column chromatography on silica
gel (petroleum ether/EtOAc, 4:1) afforded iodolactone 8 (20:1 d.r., 75%
yield, 91% ee). Recrystallization from n-hexane and Et2O afforded enan-
tiomerically pure iodolactone 8 (99.9% ee). Rf =0.61 (petroleum ether/
ethyl acetate 2:1); M.p. 139–1418C; [a]2D5 =+40.5 (c=0.4, CH2Cl2; 99.9%
Experimental Section
General procedure for the enantioselective cross-aldol reaction between
acetaldehyde and ketones: To a solution of ketone 1a (0.1 mmol) and
catalyst VA (10 mol%) in HMPA (20 mL) in a test tube was added TfOH
(4.5 mg, 2.7 mL, 30 mol%) at 08C and the mixture was stirred for 15 min,
followed by the addition of acetaldehyde (56 mL, 1 mmol). Then, the mix-
ture was stirred at 08C for 24–72 h until the reaction had been completed
(by TLC). Excess acetaldehyde was removed under reduced pressure.
The crude mixture was dissolved in MeOH (1.5 mL) at 08C, reduced
with NaBH4 (114 mg, 3 mmol) for 1 h, and quenched with water (3 mL).
The mixture was extracted with EtOAc (5ꢂ10 mL) and the combined or-
ganic extract was dried with anhydrous Na2SO4, filtered, concentrated
under vacuum, and purified by flash chromatography on silica gel to
afford the corresponding product (3a) as a white solid (81% yield). Rf =
0.22 (petroleum ether/EtOAc, 1:2); M.p. 85–878C; [a]2D5 =+19.1 (c=0.3,
MeOH; 92% ee); 1H NMR (400 MHz, [D6]acetone): d=7.48–7.23 (m,
5H; Ar-H), 6.79 (d, J=16.0 Hz, 1H; CH=CH), 6.46 (d, J=16.0 Hz, 1H;
CH=CH), 4.34 (s, 1H), 4.11–4.07 (m, 2H), 3.89–3.77 (m, 2H), 3.60–3.52
(m, 2H), 2.07–2.02 (m, 1H), 1.90–1.84 ppm (m, 1H); 13C NMR
(100 MHz, [D6]acetone): d=137.5, 134.0, 128.6, 128.5, 127.1, 126.3, 75.7,
69.2, 58.5, 39.0 ppm; HRMS (ESI): m/z calcd for C12H16O3: 231.0997
[M+Na]+; found: 231.1003; IR (KBr): n˜ =3379, 3310,3028, 2930, 2859,
1445, 1135, 1047, 978, 748, 694 cmÀ1; HPLC (Daicel Chiralpak OD-H;
ee); 1H NMR (400 MHz, CDCl3): d=7.42
ACTHNUTRGNE(UNG s, 5H), 5.71 (d, J=11.3 Hz),
4.64 (d, J=11.3 Hz), 4.46–4.32 (m, 2H), 3.23 (d, J=16.6 Hz, 1H), 3.31 (d,
J=17.4 Hz, 1H), 3.06 (d, J=17.4 Hz), 1.40 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=171.3, 166.4, 136.7, 129.7, 128.6, 128.0,
83.0, 75.2, 64.0, 39.7, 34.2, 14.2 ppm; HRMS (ESI): m/z calcd for
C14H15IO5: 412.9862 [M+Na]+; found: 412.9865; IR (KBr): n˜ =3396,
2960, 2921, 1763, 1726, 1456,1433, 1396, 1353, 1244, 1201, 1115, 1093, 991,
733 nm; HPLC (Daicel Chiralpak OJ-H; n-hexane/isopropanol, 85:15,
flow rate: 1.0 mLminÀ1; l=210 nm): t
RACTHNUGTNER(NUNG minor)=16.2 min, tRACHTUNGTRENNUNG
(major)=
17.6 min.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
was equipped with a stirrer bar under a nitrogen atmosphere. Iodolac-
tone 8 (20 mg, 0.05 mmol) was suspended in dry THF (1 mL) and treated
with tri-n-butyltin hydride (15.3 mL, 0.06 mmol) in the presence of a cata-
lytic amount of AIBN (1.2 mg, 10 mol%) as a free-radical initiator. The
reaction was heated at reflux for 4 h. The reaction was cooled to ambient
temperature and THF was removed under vacuum. The crude mixture
was purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 4:1) to afford d-lactone 9 (12.6 mg, 95% yield, 99.8% ee).
Rf =0.57 (petroleum ether/EtOAc, 2:1); M.p. 100–1028C; [a]2D5 =À4.8
(c=0.2, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.42–7.36 (m, 5H),
5.74 (dd, J=3 Hz, J=11.9 Hz, 1H), 4.35–4.30 (m, 2H), 3.62 (s, 1H), 3.07
n-hexane/isopropanol, 90:10; flow rate: 1.0 mLminÀ1
RA(major)=24.6 min, tRA(minor)=32.8 min.
(R,E)-Ethyl-2-hydroxy-2-(2-oxoethyl)-4-phenylbut-3-enoate (2r): To a
; l=254 nm):
t
C
CHTUNGTRENNUNG
T
solution of compound 1r (72 mL, 0.4 mmol) and catalyst VA (16.8 mg,
10 mol%) in HMPA (20 mL) in a test tube was added TfOH (10.8 mL,
30 mol%) at 08C and the mixture was stirred for 15 min, followed by the
addition of acetaldehyde (56 mL, 1 mmol). Then, the mixture was stirred
at 08C for 37 h. The mixture was purified by flash column chromatogra-
7148
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Chem. Eur. J. 2013, 19, 7143 – 7150

Enantioselective Aldol Reactions Catalyzed by Primary Amines
FULL PAPER
(d, J=17.5 Hz, 1H), 2.84 (dd, J=1.6 Hz, J=17.5 Hz, 1H), 2.31 (q, J=
12.0 Hz, 1H), 2.20–2.16 (m, 1H), 1.34 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=173.8, 168.3, 138.6, 128.7, 128.7, 125.9, 77.6, 71.5,
63.2, 40.8, 40.0, 14.1 ppm; 13C DEPT-135 NMR (100 MHz, [D6]acetone):
d=+128.8, +128.7, +125.9, +77.6, À63.2, À40.8, À40.0, +14.1 ppm;
HRMS (ESI): m/z calcd for C14H16O5: 287.0895 [M+Na]+; found:
287.0892; IR (KBr): n˜ =3508, 3280, 3030, 2984, 2944, 1737, 1603, 1499,
1405, 1298, 1265, 1220, 1128, 1094, 1009, 904, 724, 644, 604 nm; HPLC
(Daicel Chiralpak AD-H; n-hexane/isopropanol, 92:8; flow rate:
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1.0 mLminÀ1; l=210 nm): t
RACHTNUGTRENNUG(major)=22.9 min, tRACHTUNGTREN(NGUN minor)=25.0 min.
CCDC-930397 ((R)-3g) and CCDC-930398 (8) contain the supplementa-
ry crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
Acknowledgements
This work was financially supported by the NSFC (20772097, 21102116)
and by Sichuan Province. We thank the Supercomputing Center of the
USTC for the use of their computing resources.
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Received: February 6, 2013
Published online: April 4, 2013
7150
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Chem. Eur. J. 2013, 19, 7143 – 7150