A domino reaction of a β-ketoester, phenylethylamine and ethyl glyoxylate: leading to chiral tricarboxylate containing multiple stereocenters

Article abstract of DOI:10.1016/j.tetasy.2008.10.028

A new type of chiral tricarboxylate containing multiple stereocenters was synthesized via the one-pot reaction of a β-ketoester, (S)-phenylethylamine, and ethyl glyoxylate. High yields and diastereoselectivities (up to 96:4 dr) were obtained under optimal conditions. The reaction of the chiral tricarboxylate with Zn(BH₄)₂ gave chiral γ-lactones in good yields with up to 92:8 dr. The structures and configurations of the new chiral tricarboxylates were characterized by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tetasy.2008.10.028

Tetrahedron: Asymmetry 19 (2008) 2529–2535
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Tetrahedron: Asymmetry
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A domino reaction of a b-ketoester, phenylethylamine and ethyl glyoxylate:
leading to chiral tricarboxylate containing multiple stereocenters
*
Xiaoguang Huang, Xueming Chen, Yunyun Chen, Aiqin Zhang, Xingshu Li
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new type of chiral tricarboxylate containing multiple stereocenters was synthesized via the one-pot
reaction of a b-ketoester, (S)-phenylethylamine, and ethyl glyoxylate. High yields and diastereoselectiv-
ities (up to 96:4 dr) were obtained under optimal conditions. The reaction of the chiral tricarboxylate
Received 9 October 2008
Accepted 20 October 2008
Available online 27 November 2008
with Zn(BH4)2 gave chiral
of the new chiral tricarboxylates were characterized by X-ray diffraction analysis.
Ó 2008 Elsevier Ltd. All rights reserved.
c-lactones in good yields with up to 92:8 dr. The structures and configurations
1. Introduction
tons in organic synthesis.8 A great deal of chiral catalysts and
methods have been developed in recent decades.9 Among them,
Koga and co-workers developed an asymmetric Michael reaction
The development of efficient methods to access complex mole-
cules with multiple stereocenters continues to be a substantial
challenge in both academic research and industrial applications.1
Many methods have been developed for the synthesis of chiral
complex molecules over the past decades. In recent years much
attention is being paid to the Mannich reaction, which is one of
the classical methods for the preparation of b-amino carbonyl
compounds. This is mainly because nitrogen atoms exist in many
drugs and natural products, as well as due to the potential of this
multi-component reaction to generate molecular diversity in
medicinal chemistry and evolutionary chemistry.2 Furthermore,
the asymmetric Mannich reaction of b-ketoesters with imines is
one of the most efficient methods for constructing vicinal quater-
via chiral
using a chiral amine as the ligand and a ketone as the Michael do-
nor.10b,c They also reported the Michael reaction of
-valine-based
a
,b-unsaturated aldimines,10a and studied the reaction
L
chiral lithioenamine of ethyl acetoacetate and alkylidene malo-
nates.10d–g Christoffers et al. made extensive investigations on chi-
ral auxiliaries and active metals for the Michael addition of 1,3-
dicarbonyl compounds with vinyl ketones, especially, with valine
diethylamide as the chiral auxiliary, with up to 99% ee being ob-
tained at ambient temperature.11 Herein, we report a domino reac-
tion of a b-ketoester, phenylethylamine, and ethyl glyoxylate to
produce a chiral tricarboxylate containing multi-functional groups
and stereocenters under catalyst-free conditions.
nary carbon stereocenters.3 In 2003, Jørgensen et al. reported
4
the first asymmetric Mannich-type addition of unmodified b-keto-
sters to activated N-tosyl-a-imino esters catalyzed by chiral
2. Results and discussion
Cu(OTf)2/BOX complexes to give excellent enantio- and diastere-
oselectivities. Subsequently, Sodeoka5 reported the direct Man-
nich-type reaction of b-ketoesters with various imines catalyzed
with chiral Palladium complex. Schaus et al.6 developed cinchona
alkaloid catalysts for indirect Mannich reactions of b-ketoesters
with acyl imines. In addition, Deng et al. reported the indirect Man-
nich-type reaction of b-ketoesters and Boc-protected imines with
bifunctional cinchona alkaloids as a catalyst,7a as well as the reac-
tion with the in situ generation of carbamate-protected imines,
catalyzed by a bifunctional thiourea cinchona alkaloid.7b On the
other hand, the asymmetric Michael reaction is one of the most
important strategies for constructing chiral 1,5-dicarbonyl skele-
Usually, there are two general approaches to prepare chiral
molecules, one is catalytic enantioselective reactions while the
other is asymmetric inducement with a chiral auxiliary. Although
asymmetric catalytic reactions have emerged as powerful tools
for the preparation of enantiopure compounds in recent years, it
is also necessary to use an inexpensive chiral auxiliary for the syn-
thesis of complex molecules as an alternative method, especially
for those with multiple stereogenic centers. Among the various
chiral auxiliaries,
a-phenylethylamine (
a-PEA) is well known as a
simple and powerful chiral adjuvant. Both enantiomers of
a
-PEA
are readily available. Therefore, their recovery may not be critical
even when used on a large scale. With this in mind, we began
our investigation with methyl acetoacetate and the imine derived
from ethyl glyoxylate and (S)-phenylethylamine, to obtain a mul-
ti-functional compound 1. In addition to the anticipated Mannich
addition product 1 (38% yield), a double b-ketoesters addition
* Corresponding author. Tel.: +86 20 35693517; fax: +86 20 39332673.
E-mail address: xsli219@yahoo.com (X. Li).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.028

2530
X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
Ph
O
O
CH3
OR
Ph
NH
O
O
O
O
OR
O
O
O
H
O
N
H3C
OR
+
H
H
EtO
HN
RO
OEt
O
Ph
1
2
Scheme 1. The reaction of an imine with b-ketoesters.
product 2 (26%) was also obtained. Compound 2 was very stable in
the work-up process. The other way round, compound 1 was partly
converted to its diastereoisomer when purified with silica gel (see
Scheme 1).
We then carried out a one-pot reaction using ethyl glyoxylate,
(S)-phenylethylamine, and ethyl acetoacetate as the starting mate-
rials. Higher yields of compound 2 were obtained than those with
imines as substrates. The results indicated that free amine and car-
bonyl compounds were favorable to form compound 2. When the
molecular ratio of b-ketoesters, ethyl glyoxylate, and (S)-phenyl-
ethylamine was changed to 2:1:1, we obtained compound 2 as
the only product.
The single crystal of compound 2 was obtained, and the struc-
ture was characterized by X-ray diffraction analysis (Fig. 1). The
(S)-configuration of C1 hails from (S)-phenylethylamine which in-
duces another two new stereocenters at C14 (R) and C17 (S).
A possible mechanism of the reaction is shown in Scheme 2.
Firstly, ethyl glyoxylate and (S)-phenylethylamine react with
methyl acetoacetate to give the Knoevenagel product 5 and the
enamine 4. The Michael addition of 5 and 4 forms the chiral tri-
carboxylate derivative 2.
On the other hand, the Mannich reaction product 1 also under-
goes elimination to form compound 5 and phenylethylamine,
which resulted in a mixture of products 1 and 2 when the imine
and methyl acetoacetate were used as the starting materials (see
Scheme 3).
solvent for the reaction at room temperature (96% yields). Mixed
solvents were found to be unfavorable to the reaction. For example,
the yields slightly decreased when the mixture of the two solvents
was used (Table 1, entry 3, Tol/DCM = 1:2, 65% yield; entry 4, Tol/
DCM = 9:1, 67% yield). We studied this reaction further by using
different b-ketoesters, such as methyl acetoacetate, ethyl acetoac-
etate, and t-butyl acetoacetate; among them methyl acetoacetate
had shown a greater effect in the yields as well as in diastereose-
lectivity (Table 1, entries 9–11).
Other amines, such as (S)-1-naphthylethylamine, (S)-2-naph-
thylethylamine, and the ester of amino acids, were also tested for
the reaction with b-ketoester and ethyl glyoxylate, and the results
are listed in Table 2. The use of naphthylethylamine gave the nor-
mal domino reactions similar to that of phenylethylamine (Table 2,
entries 1 and 2: 77% yields with 80:20 dr for (S)-1-naphthylethyl-
amine, and 85% yields with 82:18 dr for (S)-2-naphthylethylamine
were obtained, respectively). On the other hand, the reaction of the
b-ketoester, ethyl glyoxylate, and the esters of amino acids
gave only the enamine under the same reaction conditions (Table
2, entries 3–5). The stereo effect of the b-ketoester was very
important for the reaction. For example, the reaction of methyl
acetoacetate with ethyl glyoxylate and amines gave good to excel-
lent chemical yields (Table 1, entry 9, 96% yield for phenylethyl-
amine; Table 2, entries 1 and 2, 77% and 85% yields for 1- and 2-
naphthylethylamine); however, under the same reaction condi-
tions, the reaction of methyl 3-oxopentanoate provided lower
yields (Table 2, entries 6–8, 73% yield for phenylethylamine, 61%
and 65% for 1- and 2-naphthylethylamine, respectively). Methyl
4-methyl-3-oxopentanoate and ethyl 3-oxo-3-phenylpropanoate,
which bear more hindered groups, only gave aldol reaction (Table
2, entries 9 and 10).
The yields of the domino reaction of the b-ketoester, (S)-phen-
ylethylamine, and ethyl glyoxylate were found to be sensitive to
the choice of solvents. The use of dichloromethane, toluene, tetra-
hydrofuran, and acetonitrile gave yields ranging from 69% to 96%
(Table 1, entries 1, 2 and 8, 9). Acetonitrile was found to be the best
Figure 1. ORTEP of the molecule of chiral tricarboxylate bearing multi-functional groups and stereocenters at 50% probability (CCDC 696159).

X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
2531
O
H
O
O
O
O
O
O
Knoevenagel reaction
OR
OEt
+
H
OR
O
5
O
O
Ph
NH
Ph
NH
O
O
O
O
5
Ph
NH2
OR
OR
O
O
Michael addition
4
O
O
2
Scheme 2. The possible reaction mechanism.
O
O
OH
O
O
O
O
O
O
Ph
N
elimination
OR
Ph
N
H
OR
+
Ph
NH2
OEt
H
O
H
OR
H
O
1
3
5
Scheme 3. The other route to intermediate 5.
Table 1
Optimization of the double b-ketoester addition conditionsa
O
O
OR
Ph
NH
O
O
O
O
O
OEt
+
+
H
Ph
NH2
OR
H
RO
O
H
O
2a-c(R = Me, Et, t-Bu)
Yields of 2c (%)
Entry
R
Solvent
Time (h)
drd (major:others)
1(D)b
2(D)
3(D)
4(D)
5(I)b
6(I)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Toluene
DCM
Tol/DCM = 1:2
Tol/DCM = 9:1
Toluene
DCM
Tol/DCM = 5:1
THF
48
48
48
72
48
60
48
48
40
40
40
76
69
65
67
72
62
74
85
96
90
87
95:5
90:10
96:4
95:5
93:7
84:16
95:5
94:6
96:4
70:30
65:35
7(I)
8(D)
9(D)
10(D)
11(D)
CH3CN
CH3CN
CH3CN
t-Bu
a
All reactions were performed on a 0.8 mmol scale and the ratio of substrates was 1:1:2 (phenylethylamine–ethyl glyoxylate–b-ketoester).
D: direct reaction (one-pot reaction of amine, ethyl glyoxylate, and b-ketoester); I: indirect reaction (the reaction of imine with b-ketoester).
Isolated yield.
b
c
d
Determined by 1H NMR analysis of the flash chromatography purified product.
We also screened a simple aldehyde, such as benzaldehyde or
the corresponding c-lactone in high yield and stereoselectivity (up
propionaldehyde, and reacted it with an amine and b-ketoesters
(Scheme 4). The results indicate that these simple aldehydes also
gave aldol reactions under the same reaction conditions.
The chiral tricarboxylate derivative could be converted to other
useful chiral compounds. For example, on reacting with zinc boro-
hydride,12 the chiral tricarboxylate derivative 2 was converted into
to 92:8 dr) (see Scheme 5).
In conclusion, we have found an unexpected domino reaction of
b-ketoesters, amines, and ethyl glyoxylates, which gave a chiral tri-
carboxylate containing multi-functional groups and multi-stereo-
centers. The reaction could be carried out under very mild
conditions without any catalyst or additives with high yields and

2532
X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
Table 2
The reaction of different amines, b-ketoesters, and ethyl glyoxylatesa
O
R1
O
R3
O
O
O
NH
R2
O
R2
OR3
OEt
or enamines or Aldol products
Amines
O
+
H
R3
O
H
CH3CN, RT
O
7
8
H
O
R2
O
2
Entry
1
Amines
R2
R3
Products
Times (h)
40
Yieldsb (%)
77
drc (major:others)
80:20
Me
Me
2d
H2N
2
3
4
Me
Me
Me
Me
Me
Me
2e
7a
7b
40
40
40
85
83
86
82:18
—
H2N
Ph
H2N
Ph
CO2Me
CO2Me
—
H2N
5
6
Me
Et
Me
Me
7c
2f
40
40
81
73
—
H2N
H2N
CO2Me
50:50
7
Et
Me
Me
Me
Et
2g
2h
8a
8b
40
40
65
90
61
65
82
87
61:39
71:29
—
H2N
H2N
8
Et
9d
i-Prop
Ph
H2N
H2N
10
—
a
All reactions were performed on a 0.8 mmol scale and the ratio of substrates was 1:1:2 (amine–ethyl glyoxylate–b-ketoester).
Isolated yield.
b
c
Determined by 1H NMR analysis of the flash chromatography purified product.
Reactions of entries 9 and 10 were carried out at 40 oC.
d
diasteroselectivities. Further studies on the scope and application
3.1. The preparation of (Z)-4-ethyl 3,5-dimethyl 6-oxo-2-((S)-1-
of this reaction are currently underway.
phenylethylamino)hept-2-ene-3,4,5-tricarboxylate 2a
To a dried flask containing (S)-phenylethylamine (0.100 g,
0.825 mmol) in 1 ml CH3CN was added ethyl glyoxylate (0.169 g,
0.825 mmol, 50% solution in toluene) and stirred for 10 min at
0 oC, methyl acetoacetate (0.192 g, 1.650 mmol) in 0.8 ml CH3CN
was added in one portion. The reaction mixture was stirred at
0 oC for 2 h and then at room temperature for 38 h. The solvent
was removed under reduced pressure and the residue was purified
3. Experimental
All reagents were purchased from either Acros or Aldrich Com-
pany and were used without further purification. The 1H NMR and
13C NMR spectra were recorded on a Varian Mercury-Plus 300
spectrometer. HRMS spectra were obtained on a VG-ZAB-HS mass
spectrometer with EI resource.

X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
2533
NH2
CH3
OH CH3
O
O
O
O
H
+
H3C
OCH3
CH3CN, RT
40h
O
OCH3
8c(81%)
NH2
CH3
OH CH3
O
O
O
O
+
H3C
OCH3
H
CH3CN, RT
40h
O
OCH3
8d(35%)
Scheme 4. The reaction of a simple aldehyde with an amine and b-ketoester.
O
O
O
H
O
NH
(S)
NH
(S)
O
O
Zn(BH4)2
THF, 0oC
(R)
(S)
O
(R)
H
2
J2,3=10.5Hz
J3,4=9.9Hz
H
O
O
3
O
H
O
(R)
O
4
(S)
O
H
8 (92:8 dr)
Scheme 5. The reduction of chiral tricarboxylate derivative 2 with zinc borohydride.
by column chromatography to give the desired product (0.332 g,
0.792 mmol, 96% yield) as a colorless solid. 1H NMR (300 MHz,
CDCl3) d 10.02–10.00 (d, J = 6.0 Hz, 1H), 7.31–7.29 (t, J = 6.6 Hz,
2H), 7.21–7.16 (t, J = 8.1 Hz, 3H), 4.67 (dq, J = 6.6 Hz, J0 = 6.9 Hz,
1H), 4.47 (d, J = 10.5 Hz, 1H), 4.26 (d, J = 10.5 Hz, 1H), 4.16–4.06
(m, 2H), 3.66 (s, 3H), 3.30 (s, 3H), 2.30 (s, 3H), 1.95 (s, 3H), 1.64
(d, J = 6.9 Hz, 3H), 1.19 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 201.4, 173.5, 170.2, 167.9, 162.7, 145.2, 129.0, 127.3,
125.6, 89.5, 61.2, 61.1, 53.8, 52.3, 50.6, 43.9, 30.5, 25.3, 16.3, and
14.6; HRMS (EI): m/z [M]+ calcd for C22H29NO7: 419.1944; found:
419.1939.
4.30 (m, 1H), 4.17 (d, J = 10.5 Hz, 1H), 4.09–4.02 (m, 2H), 2.29 (s,
3H), 2.00 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H), 1.51 (d, J = 5.1 Hz, 3H),
1.49 (s, 9H), 1.40 (t, J = 6.6 Hz, 3H), 1.27 (s, 9H); 13C NMR(75 MHz,
CDCl3) d 201.7, 173.9, 169.5, 169.4, 167.0, 161.9, 152.5, 145.4,
128.8, 127.2, 127.0, 125.9, 110.0, 90.2, 81.7, 79.4, 69.9, 62.2, 62.1,
61.1, 53.9, 44.3, 35.8, 35.7, 33.3, 30.4, 30.3, 28.9, 28.2, 27.1, 25.5,
24.1, 23.3, 23.2, 20.5, 20.3, 20.1, 16.5, 16.4, 14.6, and 14.5; HRMS
(EI): m/z [M]+ calcd for C28H41NO7: 503.2883; found: 503.2878.
3.4. The preparation of (Z)-4-ethyl 3,5-dimethyl 6-oxo-2-((S)-1-
(1-naphthalen)-ethylamino)hept-2-ene-3,4,5-tricarboxylate 2d
3.2. (Z)-Triethyl 6-oxo-2-((S)-1-phenylethylamino)hept-2-ene-
3,4,5-tricarboxylate 2b
The preparation of 2d was carried out in the same way as de-
scribed for 2a. Colorless solid, 77% yield. 1H NMR (400 MHz, CDCl3)
d 10.21 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 7.75
(d, J = 7.2 Hz, 1H), 7.51 (d, J = 8.4, 2H), 7.41 (t, J = 5.6 Hz, J0 = 7.2 Hz,
1H), 7.34 (d, J = 6.0 Hz, 1H), 5.49 (dq, J = 6.6 Hz, J0 = 6.9 Hz, 1H), 4.51
(d, J = 11.2, 1H), 4.27 (d, J = 10.4, 1H), 4.14–4.04 (m, 2H), 3.71 (s,
3H), 3.34 (s, 3H), 2.31 (s, 3H), 1.89 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H),
1.19 (t, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 201.3, 173.4,
170.2, 167.8, 162.6, 140.7, 133.9, 129.8, 129.2, 127.8, 126.5,
125.8, 125.7, 122.4, 122.0, 89.5, 61.0, 60.8, 52.1, 50.3, 49.7, 43.6,
30.2, 23.8, 15.9 and 14.2; HRMS(EI): m/z [M]+ calcd for
C26H31NO7: 469.2101; found: 469.2097.
The preparation of 2b was carried out in the same way as
described for 2a. Colorless solid, 90% yield. 1H NMR (300 MHz,
CDCl3) d 10.01 (d, J = 6.9 Hz, 1H), 7.32 (t, J = 4.5 Hz, 1H), 7.29 (s,
1H), 7.27 (s, 1H), 7.20 (t, J = 7.5 Hz, 2H), 4.67 (dq, J = 6.6 Hz,
J0 = 6.9 Hz, 1H), 4.50 (d, J = 10.2 Hz, 1H), 4.25 (d, J = 10.2 Hz, 1H),
4.18–4.00 (m, 6H), 2.30 (s, 3H), 1.98 (s, 3H), 1.52 (d, J = 6.6 Hz,
3H), 1.28 (t, J = 6.9 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H), 0.97 (t,
J = 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 201.5, 173.6, 169.8,
167.7, 162.5, 145.3, 128.9, 127.3, 125.7, 89.5, 61.5, 61.2, 59.2,
53.8, 43.9, 30.4, 25.4, 16.4, 14.8, 14.5, and 14.3; HRMS (EI): m/z
[M]+ calcd for C24H33NO7: 447.2257; found: 447.2252.
3.5. The preparation of (Z)-4-ethyl-3,5-dimethyl 6-oxo-2-((S)-1-
(2-naphthalen)-ethylamino)hept-2-ene-3,4,5-tricarboxylate 2e
3.3. (Z)-3,5-Di-tert-butyl 4-ethyl 6-oxo-2-((S)-1-
phenylethylamino)hept-2-ene-3,4,5-tricarboxylate 2c
The preparation of 2e was carried out in the same way as de-
scribed for 2a. Colorless solid, 85% yield. 1H NMR (400 MHz, CDCl3)
d 10.14 (d, J = 5.6 Hz, 1H), 7.80 (s, 4H), 7.45 (s, 2H), 7.34 (d,
J = 8.8 Hz, 1H), 4.85 (dq, J = 6.4 Hz, J0 = 6.6 Hz, 1H), 4.49 (d,
J = 10.4 Hz, 1H), 4.27 (d, J = 10.4 Hz, 1H), 4.18–4.01 (m, 2H), 3.70
(s, 3H), 3.22 (s, 3H), 2.30 (s, 3H), 1.99 (s, 3H), 1.61 (d, J = 6.4 Hz,
The preparation of 2c was carried out in the same way as
described for 2a. Colorless solid, 87% yield (both diastereomers).
1H NMR (300 MHz, CDCl3) d 9.97–9.87 (m, 1H), 7.33 (d, J = 4.5 Hz,
2H), 7.27–7.21 (m, 3H), 4.63 (dq, J = 6.3 Hz, J0 = 6.6 Hz, 1H), 4.45–

2534
X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
3H), 1.18 (t, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 201.4,
173.4, 170.2, 167.8, 162.7, 152.6, 142.5, 133.5, 132.7, 128.8,
127.7, 127.6, 126.4, 125.9, 123.9, 123.8, 89.3, 61.0, 53.7, 52.0,
50.3, 43.6, 30.2, 24.9, 16.0 and 14.2; HRMS(EI): m/z [M]+ calcd for
C26H31NO7: 469.2101; found: 469.2097.
141.3, 140.9, 138.3, 134.0, 133.9, 130.6, 129.8, 129.2, 129.0,
128.1, 127.7, 126.5, 126.3, 125.8, 125.7, 125.6, 124.4, 123.1,
122.3, 121.9, 88.8, 87.6, 70.0, 69.4, 64.3, 62.2, 61.8, 61.0, 60.8,
60.1, 58.3, 52.4, 52.0, 50.4, 49.1, 43.4, 43.3, 38.7, 36.4, 36.2, 29.7,
24.0, 23.0, 22.1, 14.2, 14.1, 14.0, 12.7, 12.5, 7.6, 7.4 and 7.2;
HRMS(EI): m/z [M]+ calcd for C28H35NO7: 497.2414; found:
497.2410.
3.6. Enamine 7a (Table 2, entry 3)
Colorless oil, 83% yield. 1H NMR (400 MHz, CDCl3) d 9.54 (d,
J = 7.2 Hz, 1H), 7.41–7.32 (m, 5H), 5.20 (d, J = 8.0 Hz, 1H), 4.58 (s,
1H), 3.74 (s, 3H), 3.68 (s, 3H), 1.79 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 170.7, 170.6, 159.5, 137.4, 129.1, 128.5, 126.8, 85.0,
60.0, 53.0, 50.2, 29.7 and 19.6; HRMS(EI): m/z [M]+ calcd for
C14H17NO4: 263.1158; found: 263.1155.
3.11. (Z)-5-Ethyl 4,6-dimethyl 7-oxo-3-((S)-1-(2-naphthalen)-
ethylamino)non-3-ene-4,5,6-tricarboxylate 2h
The preparation of 2h was carried out in the same way as de-
scribed for 2a. Colorless solid, 65% yield (both diastereomers). 1H
NMR (400 MHz, CDCl3) d 10.17–10.03 (m, 1H), 7.79 (s, 4H), 7.60
(d, J = 11.6 Hz, 1H), 7.45 (s, 2H), 4.78 (q, J = 6.6 Hz, 1H), 4.50 (d,
J = 12.0 Hz, 1H), 4.27 (d, J = 10.4 Hz, 1H), 4.13–4.02 (m, 2H), 3.71
(s, 3H), 3.16 (s, 3H), 2.73–2.15 (m, 4H), 1.61 (d, J = 6.0 Hz, 3H),
1.26–1.18 (m, 6H), 1.08 (t, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 205.3, 204.7, 204.1, 203.8, 173.6, 170.6, 168.0, 167.5,
163.2, 152.6, 142.9, 140.1, 133.4, 132.8, 132.7, 132.6, 128.7,
128.4, 127.9, 127.8, 127.7, 127.6, 126.3, 126.2, 125.9, 125.8,
125.5, 125.0, 123.7, 123.5, 88.6, 87.3, 70.0, 69.7, 69.4, 62.2, 61.8,
61.2, 61.0, 60.8, 60.1, 58.3, 53.0, 51.9, 50.3, 43.3, 38.6, 36.4, 36.2,
29.7, 25.0, 23.7, 22.0, 14.2, 14.0, 12.6, 12.4, 12.0, 11.8, 7.6, 7.4
and 7.3; HRMS(EI): m/z [M]+ calcd for C28H35NO7: 497.2414; found:
497.2410.
3.7. Enamine 7b (Table 2, entry 4)
Colorless oil, 86% yield. 1H NMR (400 MHz, CDCl3) d 8.90 (d,
J = 9.2 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H),
7.20 (d, J = 6.8 Hz, 2H), 4.45 (s, 1H), 4.32–4.26 (m, 1H), 3.73 (s,
3H), 3.64 (s, 3H), 3.16 (dd, J = 5.2 Hz, J0 = 13.6 Hz, 1H), 2.98 (dd,
J = 8.8 Hz, J0 = 13.6 Hz), 1.62 (s, 3H); 13C NMR (100 MHz, CDCl3) d
170.1, 168.7, 158.1, 134.4, 127.5, 126.8, 125.3, 82.5, 56.1, 50.6,
48.3, 38.5 and 17.4; HRMS(EI): m/z [M]+ calcd for C15H19NO4:
277.1314; found: 277.1311.
3.8. Enamine 7c (Table 2, entry 5)
3.12. Aldol product 8a (Table 2, entry 9)
Colorless oil, 81% yield. 1H NMR (400 MHz, CDCl3) d 8.90 (d,
J = 8.8 Hz, 1H), 4.54 (s, 1H), 3.91 (dd, J = 6.0 Hz, J0 = 10.0 Hz, 1H),
3.75 (s, 3H), 3.65 (s, 3H), 2.23–2.15 (m, J = 6.4 Hz, 1H), 1.87 (s,
3H), 1.02 (d, J = 5.2 Hz, 3H), 1.00 (d, J = 5.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.4, 168.9, 158.7, 82.3, 59.9, 50.3, 48.3,
30.0, 17.7, 17.4 and 16.1; HRMS(EI): m/z [M]+ calcd for
C11H19NO4: 229.1314; found: 229.1311.
Colorless oil, 82% yield (both diastereomers). 1H NMR
(400 MHz, CDCl3) d 6.84 (s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 3.83 (s,
3H), 2.89 (m, 1H), 2.03 (d, J = 12.8 Hz, 1H), 1.31–1.26 (m, 4H),
1.20 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 206.0, 200.1,
164.1, 163.5, 146.5, 144.0, 129.5, 128.2, 61.8, 61.7, 53.0, 52.8,
41.1, 37.0, 29.7, 18.5, 17.7 and 14.0; HRMS(EI): m/z [M]+ calcd for
C11H18O6: 246.1103; found: 246.1100.
3.9. (Z)-5-Ethyl 4,6-dimethyl 7-oxo-3-((S)-1-
phenylethylamino)non-3-ene-4,5,6-tricarboxylate 2f
3.13. Aldol product 8b (Table 2, entry 10)
The preparation of 2f was carried out in the same way as de-
scribed for 2a. Colorless solid, 73% yield (both diastereomers). 1H
NMR (400 MHz, CDCl3) d 10.08–9.92 (m, 1H), 7.29 (t, J = 7.2 Hz,
3H), 7.19 (d, J = 7.2 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 4.64 (dq,
J = 6.0 Hz, J0 = 6.6 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 4.26 (d,
J = 10.4 Hz, 1H), 4.12–4.05 (m, 2H), 3.67 (s, 3H), 3.26 (s, 3H),
2.75–2.22 (m, 3H), 2.15–2.06 (m, 1H), 1.53 (d, J = 6.4 Hz, 3H),
1.19 (t, J = 7.2 Hz, 6H), 1.07 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 203.6, 202.4, 171.8, 168.7, 168.6, 167.6, 166.4, 166.2,
165.7, 143.8, 143.3, 127.1, 127.0, 125.4, 123.9, 123.6, 123.4, 86.7,
85.4, 59.2, 58.4, 56.5, 51.2, 51.1, 50.6, 50.1, 48.5, 41.6, 41.5, 37.0,
34.7, 23.3, 20.4, 20.2, 12.4, 10.8, 10.6, 5.9 and 5.4; HRMS(EI): m/z
[M]+ calcd for C24H33NO7: 447.2257; found: 447.2253.
Colorless oil, 87% yield. 1H NMR (400 MHz, CDCl3) d 7.89 (d,
J = 7.2 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 6.8 Hz, 2H), 7.07
(s, 1H), 4.25 (q, J = 6.0 Hz, 2H), 4.06 (q, J = 5.6 Hz, 2H), 1.60 (s,
1H), 1.26 (s, 1H), 1.21 (t, J = 6.8 Hz, 3H), 1.07 (t, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 192.3, 163.8, 163.2, 145.2, 135.8,
133.8, 130.7, 128.8, 128.7, 62.5, 61.7, 29.7, 13.9 and 13.6;
HRMS(EI): m/z [M]+ calcd for C15H18O6: 294.1103; found:
294.1100.
3.14. Aldol product 8c
Colorless oil, 81% yield. 1H NMR (400 MHz, CDCl3) d 7.51 (s, 1H),
7.35 (t, J = 2.8 Hz, 2H), 7.34 (t, J = 1.6 Hz, 2H), 7.32 (d, J = 3.2 Hz,
1H), 7.19 (s, 1H), 3.78 (s, 3H), 2.36 (s, 3H), 1.93 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 192.7, 166.4, 139.8, 132.5, 131.0, 129.0,
127.6, 127.1, 50.7, 27.8 and 24.7; HRMS(EI): m/z [M]+ calcd for
C12H14O4: 222.0892; found: 222.0889.
3.10. (Z)-5-Ethyl 4,6-dimethyl 7-oxo-3-((S)-1-(1-naphthalen)-
ethylamino)non-3-ene-4,5,6-tricarboxylate 2g
The preparation of 2g was carried out in the same way as de-
scribed for 2a. Colorless solid, 61% yield (both diastereomers). 1H
NMR (400 MHz, CDCl3) d 10.29–10.11 (m, 1H), 8.03 (t, J = 6.0 Hz,
1H), 7.87 (s, 1H), 7.73 (t, J = 6.4 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H),
7.48 (d, J = 9.6 Hz, 1H), 7.40 (d, J = 6.8 Hz, 1H), 5.47 (q, J = 6.6 Hz,
1H), 4.52 (d, J = 11.2 Hz, 1H), 4.32 (d, J = 7.2 Hz, 1H), 4.26 (d,
J = 10.8 Hz, 1H), 4.14–4.03 (m, 2H), 3.72 (s, 3H), 3.26 (s, 3H),
2.76–2.29 (m, 4H), 1.66 (d, J = 5.2 Hz, 3H), 1.26–1.19 (m, 6H),
1.07 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 205.2, 204.7,
204.1, 203.8, 173.6, 170.6, 168.2, 167.9, 167.4, 163.3, 152.7,
3.15. Aldol product 8d
Colorless oil, 35% yield (both diastereomers). 1H NMR
(400 MHz, CDCl3) d 7.20 (s, 1H), 5.89 (dq, J = 1.6 Hz, J0 = 1.2 Hz,
1H), 3.70 (s, 3H), 3.08 (d, J = 6.8 Hz, 1H), 2.54 (d, J = 4.4 Hz, 1H),
2.10 (d, J = 8.4 Hz, 1H), 1.91–1.88 (m, 3H), 1.46–1.36 (m, 2H),
1.35–1.25 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 199.2, 198.0, 172.5, 170.7, 156.4, 155.5, 128.6, 128.2,
52.3, 52.1, 50.7, 39.9, 39.2, 39.1, 38.8, 29.7, 29.3, 26.6, 26.3, 23.3,

X. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 2529–2535
2535
22.9, 11.4 and 11.0; HRMS(EI): m/z [M]+ calcd for C8H14O4:
174.0892; found: 174.0889.
2. (a) Weber, L. Drug Discovery Today 2002, 7, 143–147; (b) Guillena, G.; Ramón, D.
J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693–700; (c) Dondoni, A.; Massi, A.
Acc. Chem. Res. 2006, 39, 451–463; (d) Chi, Y.; Scroggins, S. T.; Fréchet, J. M. J. J.
Am. Chem. Soc. 2008, 130, 6322–6323.
3. (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401; (b)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–4597.
4. Marigo, M.; KjOrsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur.
J. 2003, 9, 2359–2367.
5. Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka,
M. Angew. Chem., Int. Ed. 2005, 44, 1525–1529.
3.16. Procedure for the reduction of 2a by zinc borohydride
leading to: (2R,3S,4R)-methyl-4-((Z)-1-methoxy-1-oxo-3-((S)-1-
phenylethylamino)but-2-en-2-yl)-2-methyl-5-oxo-
tetrahydrofuran-3-carboxylate
6. (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127,
11256–11257; (b) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003–2006.
7. (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048–6049; (b) Song,
J.; Shih, H.; Deng, L. Org. Lett. 2007, 9, 603–606.
8. (a) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Sakuraba, S.; Ohshima, T.;
Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 4635–4637; (b) Ohshima, T.; Xu,
Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124,
14546–14547; (c) Xu, Y.; Ohori, K.; Ohshima, T.; Shibasaki, M. Tetrahedron
2002, 58, 2585–2588; (d) Mahboobi, S.; Popp, A.; Burgemeister, T.;
Schollmeyer, D. Tetrahedron: Asymmetry 1998, 9, 2369–2376.
9. (a) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008,
47, 4722–4724; (b) Yamamoto, Y.; Suzuki, H.; Yasuda, Y.; Iida, A.; Tomioka, K.
Tetrahedron Lett. 2008, 49, 4582–4584; (c) Shibasaki, M.; Matsunaga, S.;
Kumagai, N. Catalysts for Fine Chemical Synthesis 2004, 3, 210–216; (d) Ryoda,
A.; Yajima, N.; Haga, T.; Kumamoto, T.; Nakanishi, W.; Kawahata, M.;
Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73, 133–141; (e) Delarue-
Cochin, S.; Pan, J.-J.; Dauteloup, A.; Hendra, F.; Angoh, R. G.; Joseph, D.;
Stephens, P. J.; Cavé, C. Tetrahedron: Asymmetry 2007, 18, 685–691; (f)
Krawczyk, H.; Sliwinski, M.; Kedzia, J.; Wojciechowski, J.; Wolf, W. M.
Tetrahedron: Asymmetry 2006, 17, 908–915; (g) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215; (h) Ikariya,
T. Organomet. News 2005, 12–16.
10. (a) Hashimoto, S.; Komeshima, N.; Yamada, S.; Koga, K. Tetrahedron Lett. 1977,
18, 2907–2908; (b) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37,
6343–6346; (c) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38,
3531–3534; (d) Tomioka, K.; Ando, K.; Yasuda, K.; Koga, K. Tetrahedron Lett.
1986, 27, 715–716; (e) Tomioka, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986,
27, 4611–4614; (f) Tomioka, K.; Seo, W.; Ando, K.; Koga, K. Tetrahedron Lett.
1987, 28, 6637–6640; (g) Ando, K.; Seo, W.; Tomioka, K.; Koga, K. Tetrahedron
1994, 50, 13081–13088.
11. (a) Christoffers, J.; Scharl, H.; Frey, W.; Baro, A. Org. Lett. 2004, 6, 1171–1173;
(b) Christoffers, J.; Oertling, H.; Önal, N. J. Prakt. Chem. 2000, 342, 546–553; (c)
Kreidler, B.; Baro, A.; Frey, W.; Christoffers, J. Chem. Eur. J. 2005, 11, 2660–2667;
(d) Christoffers, J.; Schuster, K. Chirality 2003, 15, 777–782; (e) Christoffers, J.;
Kreidler, B.; Unger, S.; Frey, W. Eur. J. Org. Chem. 2003, 2845–2853; (f)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–1690; (g)
Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505–1508; (h) Christoffers, J.;
Mann, A. Chem. Eur. J. 2001, 7, 1014–1027; (i) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2000, 39, 2752–2754; (j) Christoffers, J.; Oertling, H.; Frey, W.
Eur. J. Org. Chem. 2003, 1665–1671; (k) Christoffers, J.; Mann, A. Eur. J. Org.
Chem. 1999, 2511–2514; (l) Christoffers, J.; Mann, A. Eur. J. Org. Chem. 1999,
1475–1479; (m) Koripelly, G.; Saak, W.; Christoffers, J. Eur. J. Org. Chem. 2007,
5840–5846; (n) Kreidler, B.; Baro, A.; Christoffers, J. Eur. J. Org. Chem. 2005,
5339–5348; (o) Christoffers, J. Chem. Eur. J. 2003, 9, 4862–4867.
To a dried flask containing NaBH4 (0.235 g, 6.220 mmol) and
freshly fused ZnCl2 (0.424 g, 3.110 mmol) was added 5 ml of dry
tetrahydrofuran at 0 oC. The mixture was stirred at room tempera-
ture for 24 h under an Ar atmosphere and then filtered by suction.
The filtrate was cooled to 0 oC, after which compound 2a (0.100 g,
0.238 mmol) in 1 ml of THF was added. After it was stirred at the
same temperature for 24 h, the mixture was cooled with ice water
and ethyl acetate (20 ml), and saturated NH4Cl solution (20 ml)
was added carefully for quenching the reaction. The organic layers
were separated and the aqueous phase was extracted with ethyl
acetate (20 ml ꢀ 2). The combined organic phase was washed
(brine) and dried (magnesium sulfate). The removal of the solvent
under reduced pressure gave the crude product which was purified
by chromatography to give the reduced product 6 as a colorless oil
(0.085 g, 0.226 mmol, 95% yield). 1H NMR (300 MHz, CDCl3) d 10.04
(s, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.23 (t, J = 6.3 Hz, 3H), 4.67 (dq,
J = 6.3 Hz, J0 = 6.6 Hz, 1H), 4.49 (dq, J = 6.0 Hz, J0 = 6.6 Hz, 1H), 3.90
(d, J = 10.5 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 3H), 3.18 (t, J = 9.9 Hz,
1H), 1.90 (s, 3H), 1.53 (s, 3H), 1.52 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 176.6, 172.5, 169.2, 162.6, 144.9, 129.0, 127.4, 125.6,
88.4, 75.7, 54.7, 53.9, 52.6, 50.7, 45.6, 25.4, 21.2, and 16.1;
HRMS(EI): m/z [M]+ calcd for C20H25NO6: 375.1682; found:
375.1678.
Acknowledgments
We thank Science and Technology Foundation of Guangzhou
(07A8206031) and National Science Foundation of China
(20472116) for the financial support.
References
1. (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134–7186; (b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551–564.
12. (a) Gensler, W. J.; Johnson, F.; Sloan, A. D. B. J. Am. Chem. Soc. 1960, 82, 6074–
6081; (b) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338–344.