Chiral tertiary amine/L-proline cocatalyzed enantioselective Morita-Baylis-Hillman (MBH) reaction

Article abstract of DOI:10.1002/ejoc.200700794

Four types of chiral amines have been synthesized starting from readily available chiral sources. These chiral amines in combination with L-proline have been found to be efficient cocatalysts for the asymmetric Morita-Baylis-Hillman (MBH) reaction between methyl vinyl ketone (MVK) and aromatic aldehydes. The corresponding adducts were formed in reasonable chemical yields and with good enantioselectivities (up to 83 % ee). Moreover, parallel cocatalytic reactions with the two enantiomers of chiral amine 4 and L-proline revealed that it is the proline stereochemistry that determines the configuration of the newly formed chiral center. In addition, the existence of the free hydroxy group in amine 4a enhanced the enantioselectivity of the reaction. Based on these findings, a plausible mechanism for this cocatalytic MBH reaction has been proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700794

FULL PAPER
DOI: 10.1002/ejoc.200700794
Chiral Tertiary Amine/
L
-Proline Cocatalyzed Enantioselective
Morita–Baylis–Hillman (MBH) Reaction
Hongying Tang,[a] Guofeng Zhao,[a] Zhenghong Zhou,*[a] Peng Gao,[a] Liangnian He,*[a]
and Chuchi Tang[a]
Keywords: Chirality / Amines / Organocatalysis / Asymmetric catalysis / Morita–Baylis–Hillman reactions / Enantio-
selectivity
Four types of chiral amines have been synthesized starting
from readily available chiral sources. These chiral amines in
combination with L-proline have been found to be efficient
cocatalysts for the asymmetric Morita–Baylis–Hillman (MBH)
reaction between methyl vinyl ketone (MVK) and aromatic
aldehydes. The corresponding adducts were formed in rea-
sonable chemical yields and with good enantioselectivities
(up to 83% ee). Moreover, parallel cocatalytic reactions with
that it is the proline stereochemistry that determines the con-
figuration of the newly formed chiral center. In addition, the
existence of the free hydroxy group in amine 4a enhanced
the enantioselectivity of the reaction. Based on these find-
ings, a plausible mechanism for this cocatalytic MBH reac-
tion has been proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
the two enantiomers of chiral amine 4 and L-proline revealed
Hatakeyama and coworkers, employing a quinidine deriva-
tive as the catalyst, attained an enantioselectivity of up to
91% ee. However, the activated alkene was limited to
1,1,1,3,3,3-hexafluoro-2-propyl acrylate.[3f–3j] By employing
the same catalyst Hatakeyama and coworkers also devel-
oped a highly diastereoselective racemization-free MBH re-
action of chiral N-Boc-α-amino aldehydes for the prepara-
tion of highly enantiomerically pure α-methylene-β-hy-
droxy-γ-amino acid derivatives.[3k] Shi and Jiang rein-
vestigated Hatakeyama’s catalyst. Enantioselectivities of 92
and 49% ee were obtained when α-naphthyl acrylate and
MVK were used as the substrate, respectively.[3l] Krishna et
al. reported -prolinol-catalyzed MBH reaction of MVK
with aryl aldehydes in which up to 78% ee was obtained.[3m]
Recently, some examples of the third type of catalysts were
reported. Barrett et al. reported the chiral pyrrolizidine-cat-
alyzed reaction of ethyl vinyl ketone and aromatic alde-
hydes. The best enantioselectivity of 72% ee was observed
in the presence of NaBF4.[4a] Miller and coworkers devel-
oped an efficient cocatalytic system of -proline and pep-
tides for the asymmetric MBH reaction of MVK and aro-
matic aldehydes. The corresponding adducts were formed
with up to 81% ee.[4b,4c] Only a few catalytic systems of the
fourth category have been reported. The achiral weak base
imidazole and -proline cocatalyzed MBH reaction between
MVK and aryl aldehydes was examined by Shi et al. Al-
though a rate acceleration of the reaction was clearly ob-
served, the enantioselectivities of the reaction were quite
low (5–10% ee).[5a] The combination of 1,4-diazabicyclo-
[2.2.2]octane (DABCO) and a chiral Lewis acid, formed by
treatment of a -camphor-derived diimino ligand and La-
Introduction
Recently, the tertiary-amine-catalyzed asymmetric
Morita–Baylis–Hillman (MBH) reaction has attracted
much attention and significant progress has been witnessed
in this area.[1] The tertiary amines that have been employed
as the catalyst in this reaction can be classified into the
following four categories. (1) Chiral tertiary amines without
a free hydroxy group that functions as a nucleophile to pro-
mote the Michael addition onto activated alkenes.[2] (2)
Chiral tertiary amines containing a free hydroxy group. The
existence of a suitably positioned hydroxy group can stabi-
lize the enolate intermediate through a hydrogen-bonding
interaction between the hydroxy group and the enolate
formed in the reaction.[3] (3) Chiral tertiary amines in com-
bination with a Lewis acid or Brønsted acid which acts as
cocatalyst in the MBH reaction.[4] (4) Achiral tertiary
amines with a chiral Lewis acid or Brønsted acid as a cocat-
alyst.[5] Only a few examples of tertiary amines without free
hydroxy groups have been documented because of their
poor enantioselectivities. The best result (75% ee) in the
coupling of methyl vinyl ketone (MVK) with an aromatic
aldehyde was obtained by Hayashi et al.[2d] The second type
of tertiary amine catalysts seems more important and ef-
ficient. Among them, the alkaloids quinine or quinidine
and their derivatives demonstrated good catalytic activity.
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P.R. China
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
126
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Eur. J. Org. Chem. 2008, 126–135

Chiral Amine/-Proline Cocatalyzed Reaction
(OTf)3, provided high enantioselectivity (up to 95% ee) in
an acrylate-based MBH reaction.[5b] Most recently, by using
a cocatalyst system involving N-methylimidazole and pipec-
olinic acid, Miller and coworkers realized a catalytic asym-
metric intermolecular MBH reaction in which an ee of 84%
was achieved.[5c] Although only a few examples have been
documented for the third type of catalyst, which is sup-
posed to mediate the reaction by dual activation of the elec-
trophile and the nucleophile,[6] it is attracting more and
more attention from organic chemists because of its efficacy
in rate acceleration and enantioselectivity improvement in
asymmetric MBH reactions. Our group has developed some
chiral tertiary amine/-proline cocatalytic systems for the
MBH reaction in which enantioselectivities of up to 83%
have been observed. This was the best result to be obtained
in MVK-based MBH reactions prior to this work. The pre-
liminary results of this work have already been communi-
cated.[7] Herein, the full details of the scope and limitations
and the mechanistic insights of this catalytic, asymmetric
MBH reaction are described.
Scheme 2. Reagents and conditions: i. Et3N/CH2Cl2, 0 °C; ii. Fe/
AcOH, 110 °C; iii. LiAlH4/THF, –10 °CǞreflux temp., N2.
In accord with Juaristic and coworkers’ procedure,[11] the
ring-opening of cyclohexene oxide readily took place in the
presence of anhydrous lithium perchlorate. The correspond-
ing diastereomeric 2-aminocyclohexanols 6a (minor, 24%)
and 6b (major, 57%) were separated by column chromatog-
raphy on silica gel. Further, N-methylation of 6a and 6b
with formaldehyde and formic acid afforded 3a and 3b,
respectively (Scheme 3).
Results and Discussion
Synthesis of Catalysts
Following Breitmaier and Zadel’s procedure,[8] dimeriza-
tion of -proline methyl ester and then reduction of the cor-
responding cyclic dipeptide gave (5aS,10aS)-(+)-octahydro-
1H,5H-dipyrrolo[1,2-a:1Ј,2Ј-d]pyrazine (1) (Scheme 1).
Scheme 3. Reagents and conditions: i. LiClO4/MeCN, reflux, 18 h;
ii. separation of diastereomers by column chromatography; iii.
HCO2H/HCHO, reflux, 4 h.
Scheme 1. Reagents and conditions: i. 50% K2CO3, 0 °C; ii. 105 °C;
iii. LiAlH4/THF, room temp.Ǟreflux temp., N2.
As the precursor of the antibiotic chloramphenicol,
(1R,2R)-(–)- and (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-
1,3-propanediol (7) are readily available from industrial
products. Chiral tertiary amine 4 was most conveniently ob-
tained by N,N-dimethylation of 7 (Scheme 4).[12]
Chiral tricyclic benzodiazepine 5 was synthesized start-
ing from o-nitrobenzoic acid and -proline methyl ester hy-
drochloride (Scheme 2). Many procedures for the synthesis
of 5 have been reported in which the common starting ma-
terial is 2-azidobenzoic acid[9] or anthranilic acid (2-amino-
benzoic acid).[10] The use of o-nitrobenzoic acid as the start-
ing material shortens the access to 5. Most importantly, 5
was obtained in good chemical yield in the key reduction
ring-closing step by utilizing cheap and readily available
iron filings as the reductant. Further reduction of 5 pro-
vided 2. This convenient and practical method may be use-
ful for the synthesis of chiral benzodiazepine pharmaceuti-
cals.
Scheme 4. Reagents and conditions: HCO2H/HCHO, reflux, 4 h.
Eur. J. Org. Chem. 2008, 126–135
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127

H. Tang, G. Zhao, Z. Zhou, P. Gao, L. He, C. Tang
FULL PAPER
Catalyst Evaluation
water dramatically promoting the MBH reaction. However,
With these chiral tertiary amines in hand, we then car- the addition of water had a detrimental effect on the reac-
ried out the asymmetric MBH reaction, employing the tion with the cocatalytic system. For example, the adduct
amines as the catalysts. The reaction of o-nitrobenzaldehyde from the 2/-proline-catalyzed MBH reaction was obtained
and MVK was selected as a model reaction. Almost no re- in 50% yield with 35% ee (Table 2, entry 4). With the ad-
action was observed after stirring for several days at 20 °C dition of water, a clear decrease both in yield and selectivity
when each of the prepared tertiary amines was employed was observed (19% yield, 3% ee).
alone as the catalyst. However, the reactions readily took
place with good results on addition of -proline as an addi- peratures (0, 20 and 40 °C, respectively, see Table 2, en-
tive (Tables 1, 2, 3, and 4). tries 6, 11 and 12, Table 3, entries 3, 8 and 9, Table 4, en-
Comparison of the reactions carried out at different tem-
Evaluation of results revealed that the solvent has a sig- tries 7, 14 and 15) shows that 20 °C (room temperature) is
nificant influence on the enantioselectivity of the reaction; the optimum reaction temperature for the reaction. Lower-
for all the reactions, the best enantioselectivities were ob- ing of the temperature results in a decrease both in chemical
tained in a mixture of CHCl3/THF (4:1, v/v) no matter yield and stereoselectivity. Raising the temperature acceler-
what combination of cocatalyst was employed (Table 1, en- ates the reaction and leads to an increase in yield but a
try 1, 66% ee; Table 2, entry 6, 83% ee; Table 3, entry 3, dramatic decrease in the enantiomeric excesses.
81% ee; Table 4, entry 7, 82% ee). In our previous work,
It was proved that the catalyst loading and molar ratio
polar solvents such as water were found to stabilize the of the tertiary amine to -proline was also an important
widely accepted charged transition states and intermediates factor in the reaction. The optimum catalyst loading and
through intermolecular charge–dipole interactions as well molar ratio of catalyst to -Pro varied depending on the
as by hydrogen-bonding interactions.[13] These stabilizing catalyst employed. For example, the best result was ob-
interactions, in part, contributed to the observed effect of tained with 5 mol-% of 1 and 1:1 of 1 to -Pro (Table 1,
Table 1. Chiral amine 1/-proline cocatalyzed MBH reaction between MVK and o-nitrobenzaldehyde.[a]
Entry
1 [mol-%]
1/-Pro
Time [d]
% Yield[b]
% ee[c]
Configuration[d,e]
1
2
3
4
5
5
10
3
5
5
1:1
1:1
1:1
2:1
1:2
5
2
7
6
4
79
97
60
61
80
66
17
35
47
51
R
R
R
R
R
[a] All the reactions were conducted at 20 °C. [b] Isolated yield. [c] Determined by HPLC analysis on a chiralcel AD-H column, hexane/
2-propanol = 90:10, flow rate 0.7 mL/min, Rt = 32.8 and 36.6 min. [d] Assigned based on the literature optical rotation value.[4b] [e] The
previously reported absolute configuration of the MBH adduct in ref.[7a] is wrong.
Table 2. Chiral amine 2/-proline cocatalyzed MBH reaction between MVK and o-nitrobenzaldehyde.
Entry
2 [mol-%]
2/-Pro
Solvent[a]
Temp. [°C]
Time [d]
% Yield[b]
% ee[c]
Configuration[d]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
10
3
2:1
2:1
2:1
2:1
2:1
2:1
3:1
1:1
2:1
2:1
2:1
2:1
DMF
CH3CN
THF
CH3OH
THF/CHCl3
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
20
20
20
20
3
3
5
8
5
5
45
7
3
7
34
53
80
50
82
68
45
55
78
71
50
77
52
75
63
35
58
83
27
26
63
45
76
27
S
R
R
R
R
R
R
R
R
R
R
R
20
20
20
20
20
0
9
10
11
12
5
5
8
3
40
[a] All the mixed solvents were used in a ratio of 4:1 (v/v). [b] Isolated yield. [c] Determined by HPLC analysis on a chiralcel AD-H
column, hexane/2-propanol = 90:10, flow rate 0.7 mL/min, Rt = 32.8 and 36.6 min. [d] Assigned based on the literature optical rotation
value.[4b]
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Chiral Amine/-Proline Cocatalyzed Reaction
Table 3. Chiral amine 3/-proline cocatalyzed MBH reaction between MVK and o-nitrobenzaldehyde.
Entry
3 [mol-%]
2/-Pro
Solvent[a]
Temp. [°C]
Time [d]
% Yield[b]
% ee[c]
Configuration[d]
1
2
3
4
5
6
7
8
9
10
3a, 30
3a, 30
3a, 30
3a, 30
3a, 30
3a, 40
3a, 20
3a, 30
3a, 30
3b, 30
1:1
1:1
1:1
1:2
2:1
1:1
1:1
1:1
1:1
1:1
CH3CN
THF
20
20
20
20
20
20
20
0
5
5
6
3
7
4
7
6
3
7
88
83
66
77
35
84
56
56
70
61
17
12
81
35
54
74
61
29
26
51
R
R
R
R
R
R
R
R
R
R
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
40
20
[a] All the mixed solvents were used in a ratio of 4:1 (v/v). [b] Isolated yield. [c] Determined by HPLC analysis on a chiralcel AD-H
column, hexane/2-propanol = 90:10, flow rate 0.7 mL/min, Rt = 32.8 and 36.6 min. [d] Assigned based on the literature optical rotation
value.[4b]
Table 4. Chiral amine 4a/-proline cocatalyzed MBH reaction between MVK and o-nitrobenzaldehyde.
[a]
Entry 4a [mol-%] -Proline [mol-%]
Solvent
Temp. [°C]
Time [d]
% Yield[b]
% ee[c]
Configuration[d]
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
5
20
10
10
10
10
10
10
30
30
30
30
30
30
30
15
60
10
5
MeCN
THF
20
20
20
20
20
20
20
20
20
20
20
20
20
0
5
5
5
5
5
5
5
7
3.5
5
73
76
37
60
27
54
64
52
52
49
53
45
74
44
76
45
77
52
68
63
67
82
44
45
66
82
59
74
72
19
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
F2CHCF2CH2OH
CHCl3/MeCN
THF/MeCN
CH3CN/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
CHCl3/THF
9
10
11
12
13
14
15
6
40
20
30
30
14
5.5
6
40
2
[a] All the mixed solvents were used in a ratio of 4:1 (v/v). [b] Isolated yield. [c] Determined by HPLC analysis on a chiralcel AD-H
column, hexane/2-propanol = 90:10, flow rate 0.7 mL/min, Rt = 32.8 and 36.6 min. [d] Assigned based on the literature optical rotation
value.[4b]
entry 1, 66% ee). For the catalyst 2, the highest ee value and 4a, respectively. The experimental results are listed in
(83%) was also observed with a catalyst loading of 5 mol- Tables 5, 6, and 7.
%, but with a 2:1 molar ratio of 2 to -Pro (Table 2, en-
As shown in Tables 5, 6, and 7, these cocatalytic systems
try 6). The optimum catalyst system involving 3 consists of demonstrate a moderate substrate generality. The electron-
30 mol-% of chiral amine 3a and 30 mol-% of -proline, af- deficient aromatic aldehydes were converted into the corre-
fording an enantioselectivity of 81% ee (Table 3, entry 3). sponding MBH adducts in fair-to-good yields with accept-
For the catalytic system of amine 4a and -proline, 10 mol- able reaction times. Moreover, good enantioselectivities
% of 4a and a 1:3 molar ratio of 4a to -Pro was the opti- were observed for those aldehydes bearing a nitro group
mum choice (Table 4, entry 7, 82% ee).
on the benzene ring. Moderate enantiomeric excesses were
obtained for other aromatic aldehydes substituted with elec-
tron-withdrawing groups. As for the activated alkenes,
MVK proved to be the most suitable. Others, such as 2-
Substrate Scope
Based on these results, a set of aromatic aldehydes was cyclohexenone and acetonitrile, exhibit poor reactivity in
employed in reactions with different activated alkenes under this reaction. Although almost the same highest ee value
the optimized reaction conditions for chiral amines 2, 3a, was observed for the catalysts 2, 3a and 4a (83, 81 and
Eur. J. Org. Chem. 2008, 126–135
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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129

H. Tang, G. Zhao, Z. Zhou, P. Gao, L. He, C. Tang
FULL PAPER
Table 5. Chiral amine 2/-proline cocatalyzed MBH reaction.
Entry
R
Activated alkene
Time [d]
% Yield[a]
% ee[b]
1
2
3
4
5
6
7
2-nitrophenyl
3-nitrophenyl
3-methoxy-2-nitrophenyl
4-chloro-2-fluorophenyl
5-chloro-2-nitrophenyl
1-nitro-2-naphthyl
2-nitrophenyl
MVK
MVK
MVK
MVK
MVK
5
4
10
5
5
5
68
76
66
66
54
70
44
83
59
52
31
32
46
37
MVK
2-cyclohexenone
8
[a] Isolated yield. [b] Determined by HPLC analysis with a chiral column.
Table 6. Chiral amine 3a/-proline cocatalyzed MBH reaction.
lyst system displayed a clear match/mismatch effect between
the chiralities of the chiral amine 4 and -proline. The com-
bination of -proline and (1R,2R)-(–)-4a afforded the best
results (82% ee). Replacement of the R,R amine by the S,S
amine resulted in a decrease in the enantioselectivity (69%
ee). However, both cocatalysts (–)-4a/-proline and (+)-4b/
-proline produced the R adduct, indicating that the con-
figuration of the newly formed chiral center was determined
by the chirality of the proline. The same phenomenon was
also observed for the chiral amine 3. Under the same condi-
tions, diastereomeric 3b gave much lower selectivity
(Table 3, entries 3 and 10, 81 vs. 51% ee). This result implies
Entry
R
Time [d] % Yield[a] % ee[b]
1
2
3
4
5
6
2-nitrophenyl
3-nitrophenyl
3-methoxy-2-nitrophenyl
4-chloro-2-fluorophenyl
3-fluorophenyl
6
5
8
7
10
5
66
56
60
71
66
73
81
63
59
49
46
61
1-nitro-2-naphthyl
[a] Isolated yield. [b] Determined by HPLC analysis with a chiral that 3b and -proline constitute a mismatched cocatalyst.
column.
82%, respectively), we recommend 4a/-proline as the most
suitable reaction system in terms of both the availability of
the catalyst and substrate generality.
Preliminary Mechanistic Survey
We have chosen (1R,2R)-2-dimethylamino-1-(4-ni-
trophenyl)-1,3-propanediol (4a) as the example to investi-
gate whether the free hydroxy group in the chiral amine
Match/Mismatch Effect Between the Chiralities of Chiral
Amines and L-Proline
The performance of parallel cocatalytic reactions with plays a major role in chirality induction in the MBH reac-
chiral amine 4a (or 4b) and -proline revealed this cocata- tion. Thus, the following compounds were synthesized
Table 7. Chiral amine 4a/-proline cocatalyzed MBH reaction.
Entry
R
Activated alkene
Time [d]
% Yield[a]
% ee[b]
1
2
3
4
5
6
7
8
9
10
2-nitrophenyl
3-nitrophenyl
3-methoxy-2-nitrophenyl
4-chloro-2-fluorophenyl
1-naphthyl
1-nitro-2-naphthyl
2-pyridinyl
2-nitrophenyl
2-nitrophenyl
2-nitrophenyl
MVK
MVK
MVK
MVK
MVK
MVK
MVK
5
5
8
6
10
5
6
7
7
10
64
92
70
79
46
91
71
46
50
36
82
72
52
37
39
54
30
55
41
13
methyl acrylate
2-cyclohexenone
acetonitrile
[a] Isolated yield. [b] Determined by HPLC analysis with a chiral column.
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Chiral Amine/-Proline Cocatalyzed Reaction
(Scheme 5) and employed as the catalyst in combination obtained for catalyst 8 with a protected hydroxy group at
with -proline in the coupling of o-nitrobenzaldehyde and the 1-position was higher than that of compound 10 with a
MVK: Compound 4a with the terminal hydroxy group terminal hydroxy group, which implies that the hydroxy
masked as a silyl ether (8), with both hydroxy groups pro- group at the 1-position has a more important influence on
tected (9), and with the secondary alcohol selectively acety- the reaction and may participate in the formation of the
lated 10. The results are listed in Table 8.
transition state.
Currently the exact mechanism is still unclear for the chi-
ral tertiary amine/-proline cocatalyzed asymmetric MBH
reaction. List and coworkers have thoroughly investigated
-proline-catalyzed direct asymmetric aldol reactions and
assumed this reaction occurred via an enamine intermediate
derived from -proline.[14] This type of enamine intermedi-
ate also fits the chiral tertiary amine/-proline cocatalyzed
asymmetric MBH reaction.[4b,5a] Based on the enamine
concept and the accepted traditional MBH reaction mecha-
nism combined with the aforementioned findings, we have
proposed a transition state for this reaction which is pre-
sented as a Newman projection along with the forming C–
C bond in Figure 1.
Scheme 5. Reagents and conditions: i. tBuMe2SiCl, Et3N, DMAP/
CH2Cl2, 25 °C, 18 h; ii. AcCl, Et3N, DMAP/CH2Cl2, 0–25 °C, 5 h;
iii. nBu4NF/THF, 25 °C, 40 min.
First, nucleophilic attack of the amino group of proline
and subsequent dehydration of the carbinol amine interme-
diate lead to the formation an iminium species. Michael ad-
dition of amine 4a to the iminium then provides an enamine
ion-pair. There may exist a favorable hydrogen-bonding in-
teraction between the hydroxy group at the 1-position and
the carboxylate. Then the enamine attacks the re face of the
aromatic aldehyde carbonyl sp2 carbon center leading to the
Table 8. Catalytic activities of 4a and its hydroxy-protected deriva-
tives.[a]
Entry
Cocatalyst system % Yield[b]
% ee[c]
Config.[d]
1
2
3
4
4a/-proline
8/-proline
9/-proline
10/-proline
64
49
57
57
82
25
13
15
R
R
R
R
[a] The coupling of o-nitrobenzaldehyde and MVK was carried out desired (R)-hydroxy configuration.
in CHCl3/THF (4:1, v/v) at 20 °C for 5 days with 10 mol-% of cata-
lyst in a 1:3 molar ratio of chiral amine 4a to proline. [b] Isolated
yield. [c] Determined by HPLC analysis on a chiralcel AD-H col-
umn, hexane/2-propanol = 90:10, flow rate 0.7 mL/min, Rt = 32.8
Conclusion
and 36.6 min. [d] Assigned based on the literature optical rotation
In conclusion, some chiral tertiary amines have been syn-
thesized starting from readily available chiral sources such
value.[4b]
As shown in Table 8, a dramatic decrease in enantio- as -proline, (S)-α-phenylethylamine, and the precursor of
selectivity as well as a small decrease in yield was observed the antibiotic chloramphenicol. These chiral amines have
with partial or total masking of the hydroxy group (Table 8, been successfully applied in combination with -proline as
entries 2–4). Moreover, it is worth noting that the ee value efficient cocatalysts for the asymmetric MBH reaction be-
Figure 1. Transition state for the (–)-4a/-proline-catalyzed MBH reaction between aromatic aldehyde and MVK.
Eur. J. Org. Chem. 2008, 126–135
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131

H. Tang, G. Zhao, Z. Zhou, P. Gao, L. He, C. Tang
FULL PAPER
(S)-(–)-Benzodiazepine (2): A suspension of lithium aluminium hy-
dride (1.60 g, 142 mmol) in dry THF (42 mL) was added to a solu-
tion of compound 5 (3.02 g, 14 mmol) in dry THF (105 mL) at
–10 °C under nitrogen. After the addition, the resulting mixture
was warmed gradually to room temperature and then heated at
reflux until total consumption of the starting material (monitored
by TLC, 4–6 h). The reaction was cooled to 0 °C, quenched with
careful addition of chilling water, and extracted with ethyl acetate
(3ϫ75 mL). The combined organic phase was washed with satu-
rated brine and dried with anhydrous sodium sulfate. Removal of
tween aromatic aldehydes and MVK. The corresponding
adducts were obtained in fair-to-good yields and with good
enantioselectivity (up to 83% ee). Moreover, it was found
that it is the proline stereochemistry that determines the
configuration of the newly formed chiral center. In ad-
dition, the hydroxy groups at the 1,3-positions of amine 4a
play an important role in determining the enantioselectivity
of the reaction. Based on the enamine concept and the
traditional MBH reaction mechanism combined with the
experimental results, a transition state for this reaction has the solvent afforded the target compound with satisfactory purity
(2.10 g, 80.0%). M.p. 102–104 °C, [α]2D0 = –177.7 (c = 1.0, CHCl3).
been proposed.
1H NMR (CHCl3, 300 MHz): δ = 1.41–1.54 (m, 1 H), 1.75–1.99
(m, 3 H), 2.44–2.63 (m, 2 H), 2.75 (dd, J = 12.6, 9.6 Hz, 1 H, one
proton of NCH2), 3.16 (dt, J = 8.4, 2.7 Hz, 1 H, CH), 3.33 (dd, J
Experimental Section
= 12.6, 1.5 Hz, 1 H, one proton of NCH2), 3.52 (d, J = 13.5 Hz, 1
1
General: H NMR spectra were recorded in CDCl3 with a Bruker
H, one proton of PhCH2), 3.83 (d, J = 13.5 Hz, 1 H, one proton
AMX-300 or Varian 400 MHz instrument using TMS as an in-
ternal standard. Specific rotations were measured with a Perkin-
of PhCH2), 3.86 (br., 1 H, NH), 6.72 (dd, J = 7.8, 0.6 Hz, 1 Har),
6.83 (dt, J = 7.5, 1.2 Hz, 1 Har), 7.04–7.13 (m, 2 Har) ppm.
Elmer 341MC polarimeter. Enantiomeric excesses were determined
C12H16N2 (188.26): calcd. C 76.55, H 8.57, N 14.88; found C 76.57,
with an HP-1100 instrument (chiral column; mobile phase: hexane/
H 8.50, N 14.71.
iPrOH). Elemental analyses were conducted with a Yanaco CHN
Corder MT-3 automatic analyzer. Melting points were determined
with a T-4 melting point apparatus and are uncorrected.
2-(α-Phenylethylamino)cyclohexanol (6): Anhydrous lithium per-
chlorate (5.32 g, 50 mmol) was added to a solution of cyclohexene
oxide (4.91 g, 50 mmol) in acetonitrile (10 mL). The resulting mix-
(5aS,10aS)-(+)-Octahydro-1H,5H-dipyrrolo[1,2-a:1Ј,2Ј-d]pyrazine
ture was then stirred until complete solution of the salt. (S)-α-Phen-
(1): Compound 1 was prepared according to the literature pro-
ylethylamine (6.06 g, 50 mmol) was added dropwise to the stirred
clear solution at room temperature. Then the reaction mixture was
cedure.[8] Pale yellow solid, 72% yield, m.p. 44–48 °C, [α]2D0 = +7.2
1
(c = 2.3, CHCl3). H NMR (CDCl3, 300 MHz): δ = 1.56–1.84 (m,
refluxed for 18 h, diluted with water (20 mL), and extracted with
8 H), 2.37–2.48 (m, 4 H), 2.55–2.57 (m, 4 H), 2.76–2.83 (m, 2
diethyl ether (3 ϫ 40 mL). The combined ethereal solution was
H) ppm. C10H18N2 (166.26): calcd. C 72.24, H 10.91, N 16.85;
found C 72.17, H 10.77, N 16.71.
dried with anhydrous sodium sulfate and evaporated under reduced
pressure. The oily residue was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate/triethylamine = 10:1:0.1)
to afford 2-aminocyclohexanol 6 as a pair of diastereoisomers.
(S)-(+)-Benzodiazepinedione (5): Triethylamine (14.40 g, 141 mmol)
was added to a stirred solution of -proline methyl ester hydrochlo-
ride (10.60 g, 64 mmol) in dichloromethane (200 mL). Then a solu-
tion of o-nitrobenzoyl chloride (14.30 g, 77 mmol) in dichlorometh-
ane (50 mL) was added dropwise at 0 °C to the resulting mixture.
After the addition was complete the reaction mixture was warmed
gradually to room temperature and stirred for 18 h. The reaction
mixture was diluted with dichloromethane, washed with water, and
dried with anhydrous sodium sulfate. After removal of the solvent,
the crude product was purified by column chromatography on silica
gel (200–300 mesh, eluted with 2:1 petroleum ether/ethyl acetate)
to afford N-(2-nitrobenzoyl)--proline methyl ester (12.89 g,
73.0 %). 1H NMR (CHCl3, 300 MHz): δ = 1.89–2.10 (m, 3 H),
2.21–2.39 (m, 1 H), 3.17–3.25 (m, 1 H), 3.30–3.38 (m, 1 H), 3.81
(s, 3 H, CH3), 4.74 (dd, J = 8.1, 4.2 Hz, 1 H, NCH), 7.31–7.74 (m,
3 Har), 8.20 (d, J = 8.4 Hz, 1 Har) ppm.
20
6b: Pale yellow oil (first fractions, 6.21 g, 56.9%), [α] +0.82 (c =
546
1.1, MeOH). 1H NMR (CHCl3, 300 MHz): δ = 0.98–1.16 (m, 4 H),
1.40 (d, J = 6.9 Hz, 3 H), 1.57–1.68 (m, 3 H), 2.00–2.05 (m, 1 H),
2.25 (s, 3 H), 2.20–2.29 (m, 1 H), 3.34 (dt, J = 5.2, 9.9 Hz, 1 H),
3.72 (q, J = 6.9 Hz, 1 H), 3.89 (br., 1 H), 7.21–7.34 (m, 5 Har) ppm.
6a: Colorless crystal (later fractions, 2.65 g, 24.3%), m.p. 45–47 °C,
20
1
[α] –109.6 (c = 1.2, MeOH). H NMR (CHCl3, 300 MHz): δ =
546
1.17–1.27 (m, 4 H), 1.36 (d, J = 6.9 Hz, 3 H), 1.57–1.72 (m, 3 H),
2.05 (s, 3 H), 2.13–2.16 (m, 1 H), 2.62–2.70 (m, 1 H), 3.41 (dt, J =
5.2, 9.9 Hz, 1 H), 3.69 (q, J = 6.9 Hz, 1 H), 3.95 (br., 1 H), 7.24–
7.34 (m, 5 Har) ppm.
(–)-(1R,2R,1ЈS)- (3a) and (+)-(1S,2S,1ЈS)-2-[Methyl(α-phenylethyl)-
amino]cyclohexanol (3b): 2-Aminocyclohexanol 6 (2.19 g,
10 mmol), 37% aqueous formaldehyde solution (1.14 g, 14 mmol),
and 85% formic acid (1.29 g, 28 mmol) were placed in a 25 mL
round-bottomed flask. The resulting mixture was refluxed until the
release of carbon dioxide had ceased (ca. 4 h). The excess formalde-
hyde and formic acid were removed under reduced pressure, then
an aqueous ammonia solution (25%, 1.36 g) was added, and the
resulting mixture was stirred at 80 °C for 20 min. After cooling to
room temperature the reaction mixture was extracted with dichlo-
romethane (3ϫ30 mL). Evaporation of the dried (anhydrous so-
dium sulfate) solution gave the crude product 3 which was further
purified by column chromatography on silica gel (200–300 mesh,
gradient elution with petroleum ether and ethyl acetate).
Iron filings (25.20 g, 450 mmol) were added to a solution of N-(2-
nitrobenzoyl)--proline methyl ester (12.51 g, 45 mmol) in glacial
acetic acid (200 mL) at room temperature. The reaction mixture
was heated at 110 °C until total consumption of the starting mate-
rial (monitored by TLC, 4–6 h). After filtration the filtrate was ex-
tracted with chloroform (3ϫ75 mL). The combined organic phase
was washed with saturated aqueous sodium hydrogen carbonate
until free of acid and dried with anhydrous sodium sulfate. After
removal of solvent, the residue was recrystallized from water to
afford the title compound as a pale yellow solid (6.51 g, 68.0%).
1
M.p. 219–221 °C. H NMR (CHCl3, 300 MHz): δ = 2.00–2.04 (m,
3 H), 2.74–2.80 (m, 1 H), 3.56–3.65 (m, 1 H), 3.77–3.84 (m, 1 H),
4.10 (d, J = 6.0 Hz, 1 H), 7.01 (d, J = 5.1 Hz, 1 Har), 7.25 (dt, J = 3b: Colorless crystal (1.77 g, 76%), m.p. 72–74 °C, [α]2D0 = +45.2 (c
1
5.1, 1.2 Hz, 1 Har), 7.47 (dt, J = 7.8, 1.8 Hz, 1 Har), 8.00 (dt, J = = 1.0, MeOH). H NMR (CHCl3, 300 MHz): δ = 0.98–1.16 (m, 4
7.8, 1.5 Hz, 1 Har), 8.47 (s, 1 H, NH) ppm. C12H12N2O2 (216.23):
calcd. C 66.65, H 5.59, N 12.96; found C 66.67, H 5.61, N 12.94.
H), 1.40 (d, J = 6.9 Hz, 3 H), 1.57–1.68 (m, 3 H), 2.00–2.05 (m, 1
H), 2.25 (s, 3 H), 2.20–2.29 (m, 1 H), 3.34 (dt, J = 5.2, 9.9 Hz, 1
132
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 126–135

Chiral Amine/-Proline Cocatalyzed Reaction
H), 3.72 (q, J = 6.9 Hz, 1 H), 3.89 (br., 1 H), 7.21–7.34 (m, 5 2.80 (m, 1 H), 4.02–4.05 (m, 3 H) 4.48 (d, J = 9.6 Hz, 1 H), 7.55
Har) ppm. C15H23NO (233.34): calcd. C 77.20, H 9.94, N 6.00;
found C 77.45, H 9.84, N 6.07.
(d, J = 8.4 Hz, 2 Har), 8.20 (d, J = 8.4 Hz, 2 Har) ppm. C13H18N2O5
(282.29): calcd. C 55.31, H 6.43, N 9.92; found C 55.42, H 6.54, N
10.01.
1
3a: Pale yellow oil (2.31, 99%), [α]2D0 = –68.2 (c = 1.0, MeOH). H
NMR (CHCl3, 300 MHz): δ = 1.17–1.27 (m, 4 H), 1.36 (d, J =
6.9 Hz, 3 H), 1.57–1.72 (m, 3 H), 2.05 (s, 3 H), 2.13–2.16 (m, 1 H),
2.62–2.70 (m, 1 H), 3.41 (dt, J = 5.2, 9.9 Hz, 1 H), 3.69 (q, J =
6.9 Hz, 1 H), 3.95 (br., 1 H), 7.24–7.34 (m, 5 Har) ppm. C15H23NO
(233.34): calcd. C 77.20, H 9.94, N 6.00; found C 77.20, H 9.90, N
6.16.
General Procedure for the Chiral Tertiary Amine/L-Proline Cocata-
lyzed MBH Reaction: Activated alkene (6 mmol) was added to a
solution of aldehyde (2 mmol), chiral amine (as depicted in the
text), and -proline (as depicted in the text) in solvent (2.5 mL).
The resulting mixture was stirred at 20 °C until completion of the
reaction (monitored by TLC). After removal of the solvent, the
residue was purified by column chromatography on silica gel (200–
300 mesh, gradient elution with petroleum ether/ethyl acetate) to
afford the product.
(1R,2R)- (4a) and (1S,2S)-2-(Dimethylamino)-1-(4-nitrophenyl)-1,3-
propanediol (4b): Chiral tertiary amine 4 was prepared according
to the literature procedure.[12]
4a: M.p. 97.5–99 °C, [α]2D0 –26.2 (c = 1, EtOH).
4b: M.p. 97–97.5 °C, [α]2D0 = +26.5 (c = 1, EtOH).
3-[Hydroxy(2-nitrophenyl)methyl]but-3-en-2-one:[4c] Yellow-brown
1
solid, m.p. 80–82 °C. H NMR (CHCl3, 400 MHz): δ = 2.38 (s, 3
H, CH3), 3.47 (br., 1 H, OH), 5.80 (s, 1 H, CH), 6.18 (s, 1 H, =CH),
6.22 (s, 1 H, =CH), 7.47 (t, J = 8.0 Hz, 1 Har), 7.66 (t, J = 8.0 Hz,
1 Har), 7.78 (d, J = 8.0 Hz, 1 Har), 7.98 (d, J = 8.0 Hz, 1 Har) ppm.
HPLC conditions: AD-H column, hexane/2-propanol = 90:10, flow
rate 0.7 mL/min, Rt = 32.8 (minor) and 36.6 min (major).
(1R,2R)-3-(tert-Butyldimethylsiloxy)-2-(dimethylamino)-1-(4-nitro-
phenyl)-1-propanol (8):[15] Compound 4a (1.20 g, 5 mmol), tert-bu-
tylchlorodimethylsilane (0.83 g, 5.5 mmol), triethylamine (0.56 g,
5.5 mmol), DMAP (0.05 g, 0.2 mmol), and dichloromethane
(25 mL) were placed in a 50 mL flask. The resulting mixture was
stirred at room temperature for 18 h (monitored by TLC), then
washed with water, and the aqueous layer was extracted with
dichloromethane. The combined organic phase was washed with
brine and dried with anhydrous sodium sulfate. After removal of
the solvent the crude product was purified by column chromatog-
raphy on silica gel (200–300 mesh, gradient elution with petroleum
ether and ethyl acetate) to afford compound 8 as a colorless oil
(1.16 g, 73%). [α]2D0 = +16.2 (c = 1, CHCl3). 1H NMR (CHCl3,
400 MHz): δ = –0.04 (s, 3 H), –0.03 (s, 3 H), 0.87 (s, 9 H), 2.46–
2.50 (m, 8 H), 3.46 (dd, J = 6.0, 11.2 Hz, 1 H), 3.64 (dd, J = 2.8,
11.2 Hz, 1 H), 4.62 (d, J = 9.6 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 2
Har), 8.20 (d, J = 8.8 Hz, 2 Har) ppm.
3-[Hydroxy(3-nitrophenyl)methyl]but-3-en-2-one:[5a] Viscous oil. 1H
NMR (CHCl3, 400 MHz): δ = 2.33 (s, 3 H, CH3), 3.55 (s, 1 H,
OH), 5.64 (s, 1 H, CH), 6.09 (s, 1 H, =CH), 6.27 (s, 1 H, =CH),
7.47 (t, J = 8.0 Hz, 1 Har), 7.69 (d, J = 8.0 Hz, 1 Har), 8.08 (d, J =
8.0 Hz, 1 Har), 8.18 (s, 1 Har) ppm. HPLC conditions: AD-H col-
umn, hexane/2-propanol = 95:5, flow rate 0.8 mL/min, Rt = 63.9
(minor) and 73.4 min (major).
3-[Hydroxy(3-methoxy-2-nitrophenyl)methyl]but-3-en-2-one:[4c] Vis-
cous oil. 1H NMR (CHCl3, 400 MHz): δ = 2.34 (s, 3 H, CH3), 3.47
(br., 1 H, OH), 3.89 (s, 3 H, OCH3), 5.65 (s, 1 H, CH), 5.96 (s, 1
H, =CH), 6.23 (s, 1 H, =CH), 6.99 (d, J = 8.4 Hz, 1 Har), 7.13 (d,
J = 8.4 Hz, 1 Har), 7.43 (t, J = 8.4 Hz, 1 Har) ppm. HPLC condi-
tions: AD-H column, hexane/2-propanol = 90:10, flow rate 1.0 mL/
min, Rt = 36.8 (minor) and 42.4 min (major).
(1R,2R)-1-Acetoxy-3-(tert-butyldimethylsiloxy)-2-(dimethylamino)-
1-(4-nitrophenyl)propane (9): A solution of acetyl chloride (1 mL)
in dichloromethane (5 mL) was added dropwise to a stirred solu-
tion of 8 (0.71 g, 2 mmol), DMAP (0.05 g, 0.2 mmol), and triethyl-
amine (1 mL) in dichloromethane (5 mL) at 0 °C. The resulting
mixture was warmed to room temperature and stirred for 5 h (mon-
itored by TLC). The reaction mixture was successively washed with
water and brine and then dried with anhydrous sodium sulfate.
After removal of the solvent the residue was purified by column
chromatography on silica gel (200–300 mesh, gradient elution with
petroleum ether and ethyl acetate) to provide compound 9 as a
colorless oil (0.60 g, 76%). [α]2D0 –56.5 (c = 1, CHCl3). 1H NMR
(CHCl3, 400 MHz): δ = –0.05 (s, 3 H), –0.02 (s, 3 H), 0.88 (s, 9 H),
2.11 (s, 3 H), 2.45 (s, 6 H), 2.87–2.91 (m, 1 H), 3.40 (dd, J = 4.8,
10.8 Hz, 1 H), 3.72 (dd, J = 4.4, 10.4 Hz, 1 H), 6.08 (d, J = 7.6 Hz,
1 H), 7.56 (d, J = 8.4 Hz, 2 Har), 8.19 (d, J = 8.4 Hz, 2 Har) ppm.
C19H32N2O5Si (396.55): calcd. C 57.54, H 8.13, N 7.06; found C
57.45, H 8.64, N 6.91.
3-[(4-Chloro-2-fluorophenyl)hydroxymethyl]but-3-en-2-one: Viscous
oil. 1H NMR (CHCl3, 400 MHz): δ = 2.34 (s, 3 H, CH3), 3.64 (br.,
1 H, OH), 5.78 (s, 1 H, CH), 5.88 (s, 1 H, =CH), 6.18 (s, 1 H,
=CH), 7.18 (dd, J = 9.6, 1.6 Hz, 1 Har), 7.28 (dd, J = 8.0, 1.6 Hz,
1 Har), 7.34 (t, J = 8.0 Hz, 1 Har) ppm. C11H10ClFO2 (228.64):
calcd. C 57.78, H 4.41; found C 57.64, H 4.25. HPLC conditions:
AD-H column, hexane/2-propanol = 95:5, flow rate 1.0 mL/min,
Rt = 32.7 (minor) and 34.6 min (major).
3-[(5-Chloro-2-nitrophenyl)hydroxymethyl]but-3-en-2-one:[16] Color-
less crystal, m.p. 85–85.5 °C. 1H NMR (CHCl3, 400 MHz): δ = 2.39
(s, 3 H, CH3), 3.54 (br., 1 H, OH), 5.75 (s, 1 H, CH), 6.17 (s, 1 H,
=CH), 6.24 (s, 1 H, =CH), 7.42 (dd, J = 8.8, 2.0 Hz, 1 Har), 7.78
(d, J = 2.0 Hz, 1 Har), 7.96 (d, J = 8.8 Hz, 1 Har) ppm. HPLC
conditions: AD-H column, hexane/2-propanol = 95:5, flow rate
0.8 mL/min, Rt = 20.3 (major) and 26.6 min (minor).
3-[Hydroxy(1-nitro-2-naphthyl)methyl]but-3-en-2-one:[4c]
Viscous
(1R,2R)-3-Acetoxy-2-(dimethylamino)-3-(4-nitrophenyl)-1-propanol
(10): A mixture of 9 (0.77 g, 2 mmol) and tetrabutylammonium
fluoride (1.57 g, 6 mmol) in THF (10 mL) was stirred at room tem-
perature for 40 min. The reaction mixture was diluted with water
(10 mL) and then extracted with dichloromethane (3ϫ10 mL). The
combined organic phase was dried with anhydrous sodium sulfate.
After removal of the solvent the crude product was purified by
column chromatography on silica gel (200–300 mesh, gradient elu-
tion with petroleum ether and ethyl acetate) to give compound 10
as a colorless oil (0.31 g, 54% yield). [α]2D0 = +27.8 (c = 1, CHCl3).
1H NMR (CHCl3, 400 MHz): δ = 1.92 (s, 3 H), 2.49 (s, 6 H), 2.75–
oil. 1H NMR (CHCl3, 400 MHz): δ = 2.36 (s, 3 H, CH3), 3.57 (br.,
1 H, OH), 5.89 (s, 1 H, CH), 6.01 (s, 1 H, =CH), 6.29 (s, 1 H,
=CH), 7.58–7.78 (m, 4 Har), 7.90 (d, J = 8.0 Hz, 1 Har), 7.99 (d, J
= 8.0 Hz, 1 Har) ppm. HPLC conditions: AD-H column, hexane/
2-propanol = 93:7, flow rate 0.75 mL/min, Rt = 52.5 (minor) and
59.5 min (major).
3-[(3-Fluorophenyl)methyl]hydroxybut-3-en-2-one:[17] Viscous oil. 1H
NMR (CHCl3, 400 MHz): δ = 2.35 (s, 3 H, CH3), 3.27 (br., 1 H,
OH), 5.58 (d, J = 3.6 Hz, 1 H, CH), 5.99 (s, 1 H, =CH), 6.22 (s, 1
H, =CH), 6.95 (dt, J = 8.0, 2.4 Hz, 1 Har), 7.08 (dd, J = 10.0,
Eur. J. Org. Chem. 2008, 126–135
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133

H. Tang, G. Zhao, Z. Zhou, P. Gao, L. He, C. Tang
FULL PAPER
972; d) I. E. Marko, P. R. Giles, N. J. Hindley, Tetrahedron
1997, 53, 1015–1024; e) L. J. Brzezinski, S. Rafel, J. W. Leahy,
Tetrahedron 1997, 53, 16423–16434; f) Y. Iwabuchi, M. Nakat-
ani, N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc. 1999,
121, 10219–10220; g) Y. Iwabuchi, T. Sugihara, T. Esumi, S.
Hatakeyama, Tetrahedron Lett. 2001, 42, 7867–7871; h) Y. Iwa-
buchi, M. Furukawa, T. Esumi, S. Hatakeyama, Chem. Com-
mun. 2001, 2030–2031; i) Y. Iwabuchi, S. Hatakeyama, Synth.
Org. Chem. Jpn. 2002, 60, 1–14; j) A. Nakano, S. Kawahara,
S. Akamatsu, K. Morokuma, M. Nakatani, Y. Iwabuchi, K.
Takahashi, J. Ishihara, S. Hatakeyama, Tetrahedron 2006, 62,
381–389; k) A. Nakano, S. Kawahara, S. Akamatsu, K. Moro-
kuma, M. Nakatani, Y. Iwabuchi, K. Takahashi, J. Ishihara, S.
Hatakeyama, Org. Lett. 2006, 8, 5357–5360; l) M. Shi, J. K.
Jiang, Tetrahedron: Asymmetry 2002, 13, 1941–1947; m) P. R.
Krishna, V. Kannan, P. V. N. Reddy, Adv. Synth. Catal. 2004,
346, 603–606.
a) A. G. M. Barrett, A. S. Cook, A. Kamimura, Chem. Com-
mun. 1998, 2533–2534; b) J. E. Imbriglio, M. M. Vasbinder, S. J.
Miller, Org. Lett. 2003, 5, 3741–3743; c) M. M. Vasbinder, J. E.
Imbriglio, S. J. Miller, Tetrahedron 2006, 62, 11450–11459.
a) M. Shi, J. K. Jiang, C. Q. Li, Tetrahedron Lett. 2002, 43,
127–130; b) K. S. Yang, W. D. Lee, J. F. Pan, K. M. Chen, J.
Org. Chem. 2003, 68, 915–919; c) C. E. Aroyan, M. M. Vas-
binder, S. J. Miller, Org. Lett. 2005, 7, 3849–3851.
2.0 Hz, 1 Har), 7.12 (d, J = 8.0 Hz, 1 Har), 7.27–7.32 (m, 1
Har) ppm. HPLC conditions: OD-H column, hexane/2-propanol =
90:10, flow rate 1.0 mL/min, Rt = 18.1 (minor) and 19.4 min
(major).
3-[Hydroxy(1-naphthyl)methyl]but-3-en-2-one:[18] Viscous oil. 1H
NMR (CHCl3, 400 MHz): δ = 2.35 (s, 3 H, CH3), 3.24 (br., 1 H,
OH), 5.66 (s, 1 H, CH), 6.19 (s, 1 H, =CH), 6.45 (s, 1 H, =CH),
7.47–7.52 (m, 3 Har), 7.67 (d, J = 7.2 Hz, 1 Har), 7.82 (d, J =
8.0 Hz, 1 Har), 7.86–7.89 (m, 2 Har) ppm. HPLC conditions: AD-
H column, hexane/2-propanol = 95:5, flow rate 1.0 mL/min, Rt =
37.7 (minor) and 45.4 min (major).
3-[Hydroxy(2-pyridyl)methyl]but-3-en-2-one:[5a] Viscous oil. 1H
NMR (CHCl3, 400 MHz): δ = 2.33 (s, 3 H, CH3), 4.81 (br., 1 H,
OH), 5.69 (s, 1 H, CH), 6.15 (s, 1 H, =CH), 6.21 (s, 1 H, =CH),
7.15–7.18 (m, 1 Har), 7.41 (d, J = 8.0 Hz, 1 Har), 7.61–7.66 (m, 1
Har), 8.49 (d, J = 8.0 Hz, 1 Har) ppm. HPLC conditions: AD-H
column, hexane/2-propanol = 95:5, flow rate 0.8 mL/min, Rt = 21.8
(minor) and 23.2 min (major).
[4]
[5]
2-[Hydroxy(2-nitrophenyl)methyl]cyclohex-2-enone:[19] Yellow solid,
1
m.p. 124–125 °C. H NMR (CHCl3, 300 MHz): δ = 1.98 (quint, J
= 6.4 Hz, 2 H, CH2), 2.34–2.38 (m, 2 H, CH2), 2.44–2.48 (m, 2 H,
CH2), 3.70 (br., 1 H, OH), 6.17 (s, 1 H, =CH), 6.62 (t, J = 4.0 Hz,
1 H, =CH), 7.44 (t, J = 8.0 Hz, 1 Har), 7.64 (t, J = 8.0 Hz, 1 Har),
7.81 (d, J = 8.0 Hz, 1 Har), 7.92 (d, J = 8.0 Hz, 1 Har) ppm. HPLC
conditions: AD-H column, hexane/2-propanol = 95:5, flow rate
0.8 mL/min, Rt = 53.3 (major) and 58.5 min (minor).
[6]
[7]
J. A. Ma, D. Cahard, Angew. Chem. Int. Ed. 2004, 43, 4566–
4583.
a) H. Y. Tang, G. F. Zhao, Z. H. Zhou, Q. L. Zhou, C. C. Tang,
Tetrahedron Lett. 2006, 47, 5717–5721; b) H. Y. Tang, P. Gao,
G. F. Zhao, Z. H. Zhou, L. N. He, C. C. Tang, Catal. Commun.
2007, 8, 1811–1814.
Methyl 2-[Hydroxy(2-nitrophenyl)methyl]acrylate: Straw colored
oil.[20] 1H NMR (CHCl3, 300 MHz): δ = 2.03 (br., 1 H, OH), 3.73
(s, 3 H, CH3), 5.73 (s, 1 H, CH), 6.20 (s, 1 H, =CH), 6.37 (s, 1 H,
=CH), 7.47 (t, J = 8.1 Hz, 1 Har), 7.65 (t, J = 8.1 Hz, 1 Har), 7.75
(d, J = 8.1 Hz, 1 Har), 7.95 (d, J = 8.1 Hz, 1 Har) ppm. HPLC
conditions: OD-H column, hexane/2-propanol = 90:10, flow rate
1.0 mL/min, Rt = 16.2 (major) and 19.6 min (major).
2-[Hydroxy(2-nitrophenyl)methyl]acrylonitrile:[16] Viscous oil. 1H
NMR (CHCl3, 400 MHz): δ = 3.07 (br., 1 H, OH), 6.01 (s, 1 H,
CH), 6.15 (s, 1 H, =CH), 6.19 (s, 1 H, =CH), 7.56 (t, J = 8.0 Hz,
1 Har), 7.75 (t, J = 8.0 Hz, 1 Har), 7.85 (d, J = 8.0 Hz, 1 Har),
8.05 (d, J = 8.0 Hz, 1 Har) ppm. HPLC conditions: AD-H column,
hexane/2-propanol = 95:5, flow rate 0.8 mL/min, Rt = 37.0 (major)
and 39.9 min (major).
[8]
[9]
G. Zadel, E. Breitmaier, Chem. Ber. 1994, 127, 1323–1326.
a) P. Molina, I. Diaz, A. Tarraga, Tetrahedron 1995, 51, 5617–
5630; b) A. Kamal, B. S. P. Reddy, B. S. N. Reddy, Tetrahedron
Lett. 1996, 37, 6803–6806; c) M. H. J. Ohlmeyer, WO 9701560,
1997 [Chem. Abstr. 1997, 126, 171624]; d) A. Kamal, Y. Da-
mayanthi, B. S. N. Reddy, B. Lakminarayana, B. S. P. Reddy,
Chem. Commun. 1997, 1015–1016; e) A. Kamal, E. Laxman,
N. Laxman, R. N. Venugopal, Bioorg. Med. Chem. Lett. 2000,
10, 2311–2313; f) A. Kamal, E. Laxman, M. Arifuddin, Tetra-
hedron Lett. 2000, 41, 7743–7746; g) A. Kamal, K. S. Reddy,
B. R. Prasad, A. H. Babu, A. V. Ramana, Tetrahedron Lett.
2004, 45, 6517–6521; h) A. Kamal, A. V. Ramana, K. S. Reddy,
K. V. Ramana, A. Haribabu, B. R. Prasad, Tetrahedron Lett.
2004, 45, 8187–8190; i) A. Kamal, K. L. Reddy, V. Devaiah, N.
Shankaraiah, Synlett 2004, 2533–2536.
a) A. G. Schultz, P. J. McCloskey, P. Sundararaman, J. P.
Springer, Tetrahedron Lett. 1985, 26, 1619–1622; b) T. Naga-
saka, Y. Koseki, F. Hamaguchi, Tetrahedron Lett. 1989, 30,
1871–1872; c) M. Feigel, G. Lugert, J. Manero, M. Bremer, Z.
Naturforsch., B: Chem. Sci. 1990, 45, 258–266; d) A. Kamal, J.
Org. Chem. 1991, 56, 2237–2240; e) M. Akssira, M.
Boumzebra, H. Kasmi, A. Dahdouh, M. L. Roumestant, P. Vi-
allefont, Synth. Commun. 1993, 23, 2265–2272.
C. Anaya de Parrodi, G. E. Moreno, L. Quintero, E. Juaristic,
Tetrahedron: Asymmetry 1998, 9, 2093–2099.
C. C. Tang, G. P. Wu, Huaxue Shiji 1988, 10, 104–105 [Chem.
Abstr. 1989, 110, 57206].
J. X. Cai, Z. H. Zhou, G. F. Zhao, C. C. Tang, Org. Lett. 2002,
4, 4723–4725.
a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc.
2000, 122, 2395–2396; b) L. Hoang, S. Bahmanyar, K. N.
Houk, B. List, J. Am. Chem. Soc. 2003, 125, 16–17; c) S. Bah-
manyar, K. N. Houk, H. J. Martin, B. List, J. Am. Chem. Soc.
2003, 125, 2475–2479.
a) B. Jiang, Z. Chen, W. Xiong, Chem. Commun. 2002, 1524–
1525; b) D. Pini, A. Matantuono, P. Salvadori, Tetrahedron:
Asymmetry 1994, 5, 1875–1876.
[10]
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20472033 and 20772058) and the Key Science and
Technology Project of the Ministry of Education of China for gen-
erous financial support for our programs.
[11]
[12]
[13]
[14]
[1] a) D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003,
103, 811–892; b) J. X. Cai, Z. H. Zhou, C. C. Tang, Huaxue
Yanjiu 2001, 12, 54–64; c) P. Langer, Angew. Chem. Int. Ed.
2000, 39, 3049–3052.
[2] a) T. Oishi, M. Hirama, Tetrahedron Lett. 1992, 33, 639–642;
b) T. Oishi, H. Oguri, M. Hirama, Tetrahedron: Asymmetry
1995, 6, 1241–1244; c) A. G. M. Barrett, P. Dozzo, A. J. P.
White, D. J. Williams, Tetrahedron 2002, 58, 7303–7313; d) Y.
Hayashi, T. Tamura, M. Shoji, Adv. Synth. Catal. 2004, 346,
1106–1110.
[3] a) S. E. Drewes, G. H. P. Roos, Tetrahedron 1988, 44, 4653–
4670; b) M. Bailey, I. E. Marko, W. D. Olis, P. R. Rassmussen,
Tetrahedron Lett. 1990, 31, 4509–4512; c) A. Gilbert, T. W.
Heritage, N. S. Isaacs, Tetrahedron: Asymmetry 1991, 2, 969–
[15]
[16]
K. Y. Lee, J. M. Kim, J. N. Kim, Tetrahedron 2003, 59, 385–
390.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 126–135

Chiral Amine/-Proline Cocatalyzed Reaction
[17] J. W. Huang, M. Shi, Adv. Synth. Catal. 2003, 345, 953–958.
[18] Y. S. Lin, C. W. Liu, T. Y. R. Tsai, Tetrahedron Lett. 2005, 46,
1859–1861.
[19] M. Shi, Y. M. Xu, G. L. Zhao, X. F. Wu, Eur. J. Org. Chem.
2002, 3666–3679.
[20] D. K. O’Dell, K. M. Nicholas, J. Org. Chem. 2003, 68, 6427–
6430.
Received: August 28, 2007
Published Online: November 12, 2007
Eur. J. Org. Chem. 2008, 126–135
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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