Component match in rhodium catalyzed three-component reactions of ethyl diazoacetate, H2O and aryl imines: A highly diastereoselective one-step synthesis of β-aryl isoserine derivatives

Article abstract of DOI:10.1039/b915013g

Water and ethyl diazoacetate were found to be matched components for generating highly reactive nucleophilic oxonium ylide in the presence of a dirhodium acetate catalyst. Simultaneous trapping of the oxonium ylide intermediate with aryl imines gave β-ary

Full text of DOI:10.1039/b915013g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Component match in rhodium catalyzed three-component reactions of ethyl
diazoacetate, H2O and aryl imines: a highly diastereoselective one-step
synthesis of b-aryl isoserine derivatives†
Zhenqiu Guo, Taoda Shi, Jun Jiang, Liping Yang and Wenhao Hu*
Received 24th July 2009, Accepted 9th September 2009
First published as an Advance Article on the web 12th October 2009
DOI: 10.1039/b915013g
Water and ethyl diazoacetate were found to be matched components for generating highly reactive
nucleophilic oxonium ylide in the presence of a dirhodium acetate catalyst. Simultaneous trapping of
the oxonium ylide intermediate with aryl imines gave b-aryl isoserine derivatives with high
diastereoselectivity.
developing synthetic methods5 as well as investigating the structure
Introduction
activity relationship for the C-13 side chain analogs of taxoids.6 In
New synthetic strategies for enhancing synthetic efficiency for
addition, the b-amino-a-hydroxyl ester or amide moiety is found
in some efficient enzyme-inhibitors.7
rapid construction of organic molecules remain a challenge in
the chemical transformations. Compared to stepwise syntheses,
multicomponent reactions (MCRs) represent an attractive strat-
egy for building molecular complexity,1 because it makes the
formation of multiple bonds and stereogenic centers in a single
synthetic operation possible. Although various metal-catalytic
multicomponent reactions have been developed and applied in
modern organic synthesis,2 these reactions generally must be
carried out under strictly anhydrous conditions. In addition,
recovery and reuse of the expensive metal catalysts are formidable
tasks, which have restricted the use of metal catalysts. To date,
only few water-compatible and metal-catalytic reactions have
been developed.3 We herein report a Rh(II)-catalyzed and water-
compatible approach to b-phenyl isoserine from diazo acetate,
water, and aryl imines. It can proceed well in a biphasetic system
in which an excess of water was used, facilitating the recycling
of the Rh2(OAc)4. b-Phenyl isoserine plays an important role as
the C-13 side chain in taxoids including paclitaxel and docetaxel4
(Fig. 1), as it is crucial for the strong antitumor activity of these
diterpenes. So far, various research groups have been involved in
Our group recently reported Rh(II)-catalyzed three-component
reactions of aryldiazoacetates, alcohols and imines, in which an
alcoholic oxonium ylide in situ generated from alcohol and aryl-
diazoacetate was efficiently trapped by imines via a nucleophilic
addition affording b-amino-a-aryl-a-alkyloxy esters in a single
step8,9 (Scheme 1).
Scheme 1 The three-component reaction of aryl diazo acetates, alcohols
and imines.
However, the efficient synthetic method was mostly limited to
aryldiazoacetates, and therefore, the synthetic utility was quite
limiting. In our continuing efforts to extend the substrate scope of
the reaction, we demonstrate here a highly diastereoselective one-
step synthesis of b-aryl isoserine esters by successfully employing
ethyl diazoacetate and 2-alkyl-1-diazoacetates in the reaction. Key
to the success was the discovery of component match in specific
oxonium ylide intermediates and the electrophilic aryl imines.
We found that the oxonium ylide derived from water and ethyl
diazoacetate in the presence of rhodium acetate reacted smoothly
with aryl imines to afford racemic b-aryl isoserine esters in good
yield with high diastereoselectivity (Scheme 2).
Fig. 1 Anticancer taxoids.
Department of Chemistry, East China Normal University, Shanghai 200062,
P. R. China. E-mail: whu@chem.ecnu.edu.cn; Fax: +86-021-62233176
† Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra. CCDC reference number 725598. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b915013g
Scheme 2 Three-component reactions of EDA, water and aryl imines.
5028 | Org. Biomol. Chem., 2009, 7, 5028–5033
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Table 1 Reaction of diazoacetate 1, water, and aryl imines 2 catalyzed by dirhodium acetatea
Entry
R
Ar1/Ar2 (3)
4
Yield (%)b
Dr (threo: erythro)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
20d
21d
22d,e
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
CH3 (1b)
CH3 (1b)
Bn (1c)
CH3 (1b)
Ph/Ph (3a)
Ph/p-CH3O-C6H5 (3b)
Ph/m-Cl-C6H5 (3c)
p-CH3O-C6H5/Ph (3d)
p-CH3O-C6H5/m-Cl-C6H5 (3e)
m-Cl-C6H5/Ph (3f)
p-Cl-C6H5/Ph (3g)
m,p-Cl,Cl-C6H5/Ph (3h)
p-Br-C6H5/Ph (3i)
p-Br-C6H5/p-Br-C6H5 (3j)
p-Br-C6H5/p-Cl-C6H5 (3k)
p-NO2-C6H5/Ph (3l)
p-NO2-C6H5/p-CH3O-C6H5 (3m)
p-NO2-C6H5/o-CH3O-C6H5 (3n)
p-NO2-C6H5/p-CH3-C6H5 (3o)
p-NO2-C6H5/p-Br-C6H5 (3p)
p-NO2-C6H5/m-Cl-C6H5 (3q)
o-NO2-C6H5/Ph (3r)
Ph/Ph (3a)
4a
4b
4c
4d
4e
4f
4g
4h
4i
62 (82)
48
71
43
60
51
84
68
66
59
63
71(86)
67
56
60
80
63
65
66 : 34 (54 : 46)
63 : 37
93 : 7
56 : 44
90 : 10
95 : 5
91 : 9
93 : 7
96 : 4
88 : 12
90 : 10
96 : 4 (50 : 50)
98 : 2
98 : 2
98 : 2
97 : 3
97 : 3
80 : 20
80 : 20
86 : 14
58 : 42
—
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
75
51
82
0
p-NO2-C6H5/p-Cl-C6H5 (3s)
Ph/Ph (3a)
Ph/Ph (3a)
4u
—
a Unless otherwise noted, reaction conditions: 1 mol% Rh2(OAc)4, EDA 1a (3 equiv), H2O 2 (3 equiv), Aryl imines 3 (1 equiv), CH2Cl2 12 mL, rt, 1h. The
results in parentheses were obtained with 1 mol% Rh2(OAc)4 and 20 mol% p-TsOH. 1a:2:3= 3:3:1. b Isolated yield based on aryl imines 3. c Determined
by 1H NMR analysis of crude product. d Reaction was run with 1:2:3= 1:1:1. e Using BnOH instead of H2O 2 in the presence of 4 A MS (100 mg), no
˚
three-component product was obtained.
the similar d.r. of 66 : 34. It was found that a Lewis acid or
Brønsted acid co-catalyst can further increase the product yield at
Results and discussion
the expense of lowering diastereoselectivity. For example, by using
20 mol% p-toluenesufonic acid as a co-catalyst, the yield of 4a was
increased to 82% with d.r. dropped to 54 : 46.
To extend the substrate scope to ethyl diazoacete (EDA) instead of
aryldiazoacetates, we began the Rh(II) catalyzed three-component
reaction with previously demonstrated reaction conditions by
using one equivalent each of EDA 1a, benzyl alcohol, and N-
phenylbenzaldimine 3a as starting materials. Interestingly, what we
detected is not the desired product ethyl 2-benzyloxy-3-phenyl-3-
(phenylamino) propanoate but another three-component product
4a derived from EDA, imine 3a and water, indicating that trace
amount of water in the system participated in the reaction.
Therefore, water was used to replace the benzyl alcohol as
a component in the three-componet reaction under the same
reaction conditions. Not surprisingly, the reaction went smoothly
to afford the desired three-component product 4a (4: Ar1 = Ar2 =
Ph) in44% isolatedyieldwith67:34d.r. favouringthe threoisomer.
To directly compare the reactivity between benzyl alcohol and
water, a competing reaction was conducted by using one equivalent
each of EDA, imine 3a and both benzyl alcohol and water. Again,
43% yield of product 4a derived from water was isolated together
with trace amount of the O-H insertion from benzyl alcohol
as a side product. Although we previously observed that water
can participate in the three-component reactions employing a
phenyldiazoacetate as a substrate,9b,10 the striking difference in
reactivity of corresponding ylide between water and alcohol is
just realized in the current system with ethyl diazoacetate. To
improve the product yield, three equivalents of EDA and water
were employed. Yield of 4a increased to 62% while maintaining
A number of aryl imines 3 were then employed in the reaction
with EDA and H2O in the presence of dirhodium acetate, and the
results were summarized in the Table 1. The diastereoselectivity
of the reaction was found to be dependent on the imine substrates
used. The d.r. of the product was found to be manageable
by adjusting Ar2 group in 3. For example, the d.r. increased
significantly from 66 : 34 to 93 : 7 by replacing Ar2 from phenyl
to m-Cl-phenyl group (Table 1, entry 1 vs. 3). Similarly, the d.r.
from the reaction with electron-rich imine 4d increased from 56 :
44 to 90 : 10 while replacing Ar2 to m-Cl-phenyl group (Table 1,
entry 4 vs. 5). Consistently high d.r. of 4 was obtained by using
halogen susbtituted or electron-deficient aryl imines, regardless of
the Ar1 functionality in 3 (Table 1, entries 6–18). Again, adding
of the Brønsted acid co-catalyst was beneficial to the product
yield, but dramatically decreased the d.r. (Table 1, entry 12). The
structure and relative configuration of isomer 4k was confirmed
by single-crystal X-ray analysis11 (Fig. 2) to be threo in accordance
with the relative stereochemistry in C-13 side chain in taxoids, and
the relative stereochemistry of other products 4 were tentatively
assigned by analogy.
The scope of the reaction was further extended to ethyl
diazopropionate 1b and ethyl diazophenylpropionate 1c. The
reaction afforded desired three-component products 4s and 4u
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General Procedure for three-component reaction of aryl imines 3,
EDA 1a, and water catalyzed by dirhodium acetate and
p-toluenesufonic acid
To a mixtrue of Rh2(OAc)4 (0.003 mmol), p-toluenesufonic acid
(0.06 mmol), aryl imines 3 (0.30 mmol), CH2Cl2 (8 mL) and water
2b (0.9 mmol), was added EDA 1a (0.9 mmol) in 4 mL of CH2Cl2
via a syringe pump over 1 h at rt. 0.1 ml saturated NaHCO3
was added to quench the reaction. Solvent was removed, and a
portion of crude product was subjected to 1H NMR analysis for
determination of the product ratio. The crude product was purified
by flash chromatography on silica gel to provide the corresponding
product 4 as a mixture of diastereoisomers.
Fig. 2 ORTEP representation of the crystal structure of threo-4k
confirming stereochemistry of the product, the percentage probability
chosen for the ellipsoids is 30%.
General Procedure for three-component reaction of aryl imines 3,
2-alkyl-1-diazoacetates 1b or 1c, and water catalyzed by dirhodium
acetate
in 75% and 82% yield with 80 : 20 and 58 : 42 d.r., respectively
(Table 1, entries 19 and 21). Note that the three-component
reaction did not occur with the use of benzyl alcohol substrate
(Table 1, entry 22), demonstrating that the compound match of
water applied to 2-alkyl-1-diazoacetates. This is the first report
that the 2-alkyl-1-diazoacetates have been successfully employed
in the current three-component reactions.
To a mixtrue of Rh2(OAc)4 (0.003 mmol), aryl imines 3
(0.30 mmol) CH2Cl2 (8 mL) and water 2b (0.3 mmol), was added
alkyl diazoacetates 1b or 1c (0.3 mmol) in 4 mL of CH2Cl2 via
a syringe pump over 1 h at rt. Solvent was removed, and a
portion of crude product was subjected to1H NMR analysis for
determination of the product ratio. The crude product was purified
by flash chromatography on silica gel to provide the corresponding
product 4 as a mixture of diastereoisomers.
Conclusion
All diastereoisomers were characterized as a mixture.
In summary, we have described a highly diastereoselective one-
step synthesis of threo b-aryl isoserine derivatives in racemic
form. An important component match of water with diazoacetates
was examined to achieve high chemo- and diastereoselectivity
in the reactions. 2-Alkyl-1-diazoacetates were first successfully
employed in the reactions. The reaction provides a facile and
efficient synthetic strategy to the C-13 side chain analogs of taxol
in racemic form. Further investigations to apply chiral catalysts
for the enantioselective three-component reaction is currently in
progress in our laboratory.
(2S*,3R*)-ethyl 2-hydroxy-3-phenyl-3-(phenylamino) propano-
ate and (2S*,3S*)-ethyl 2-hydroxy-3-phenyl-3-(phenylamino)-
propanoate (threo-4a:erythro-4a = 66 : 34). (mixture of diastere-
omers) 1H NMR (CDCl3, 500 MHz): d (threo) 7.39-7.24 (m, 5 H),
7.11-7.07 (m, 2 H), 6.67-6.56 (m, 3 H), 4.93 (d, J = 2.5 Hz, 1 H),
4.50 (d, J = 2.5 Hz, 1 H), 4.26-4.21 (m, 2 H), 1.31-1.22 (m, 3 H);
(erythro) 7.39-7.24 (m, 5 H), 7.11-7.07 (m, 2 H), 6.67-6.56 (m,
3 H), 4.85 (d, J = 2.5 Hz, 1 H), 4.66 (d, J = 2.5 Hz, 1 H), 4.16
(m, 1 H), 1.31-1.22 (m, 3 H); 13C NMR(CDCl3, 125 MHz): 172.9,
172.1, 146.5, 146.3, 139.4, 137.2, 129.2, 129.1, 128.6, 128.5, 128.0,
127.6, 127.5, 127.0, 118.0, 117.9, 113.9, 74.6, 73.6, 62.4, 62.0, 59.6,
59.0, 14.1; HRMS: calcd for C17H19NO3 [M+], 285.1365; found
285.1368.
Experimental section
General
(2S*,3R*)-ethyl 3-(4-methoxyphenylamino)-2-hydroxy-3-phenyl-
propanoate and (2S*,3S*)- ethyl 3-(4-methoxyphenylamino)-2-
hydroxy-3-phenylpropanoate (threo-4b:erythro-4b = 63 : 37).
(mixture of diastereomers) 1H NMR (CDCl3, 500 MHz): d (threo)
7.37-7.22 (m, 5 H), 6..70-6.68 (m, 2 H), 6.58-6.51 (m, 2 H), 4.83 (d,
J = 2.5 Hz, 1 H), 4.46 (d, J = 2.5 Hz, 1 H), 4.23-4.19 (m, 2 H), 3.68
(s, 3 H), 1.25-1.20 (m, 3 H); (erythro) 7.37-7.22 (m, 5 H), 6..70-
6.68 (m, 2 H), 6.58-6.51 (m, 2 H), 4.77 (d, J = 3.5 Hz, 1 H), 4.63
(d, J = 3.5 Hz, 1 H), 4.15-4.12 (m, 2 H), 3.67 (s, 3 H), 1.25-1.20
(m, 3 H); 13C NMR(CDCl3, 125 MHz):172.9, 172.1, 152.4, 152.3,
140.4, 140.1, 139.4, 137.2, 128.5, 128.3, 127.9, 127.5, 127.0, 115.4,
115.3, 114.7, 74.6, 73.4, 62.2, 61.8, 60.5, 60.0, 55.6, 14.0; HRMS:
calcd for C18H21NO4 [M+], 315.1471; found 315.1476.
All reactions were performed under an air atmosphere in a well-
dried reaction flask. Melting points are uncorrected. 1H and
13C NMR spectra were recorded at 500 MHz and 125 MHz with
Brucker-500 MHz spectrometer. HRMS (ESI) Mass spectra were
recorded on BRUKER FT-MS. Dichloromethane was distilled
over calcium hydride.
General Procedure for three-component reaction of aryl imines 3,
EDA 1a, and water catalyzed by dirhodium acetate
To a mixtrue of Rh2(OAc)4 (0.003 mmol), aryl imines 3
(0.30 mmol), CH2Cl2 (8 mL) and water 2b (0.9 mmol), was added
EDA 1a (0.9 mmol) in 4 mL of CH2Cl2 via a syringe pump over
1 h at rt. Solvent was removed, and a portion of crude product was
(2S*,3R*)-ethyl 3-(3-chlorophenylamino)-2-hydroxy-3-phenyl-
propanoate (threo-4c:erythro-4c= 93 : 7). 1H NMR (CDCl3,
500 MHz): d 7.37-7.26 (m, 5 H), 6.99 (t, J = 8.0 Hz, 1 H), 6.62 (d,
J = 7.0 Hz, 1 H), 6.55 (s, 1 H), 6.43 (d, J = 7.0 Hz, 1 H), 4.90 (d,
J = 7.5 Hz, 1 H), 4.80 (d, J = 9.0 Hz, 1 H), 4.50 (t, J = 2.5 Hz, 1 H),
1
subjected to H NMR analysis for determination of the product
ratio. The crude product was purified by flash chromatography on
silica gel to provide the corresponding product 4 as a mixture of
diastereoisomers.
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4.27-4.23 (m, 2 H), 3.08 (d, J = 3.5 Hz, 1 H), 1.25-1.20 (m, 3 H); 13C
NMR(CDCl3, 125 MHz):172.1, 146.8, 146.6, 135.1, 130.3, 127.9,
123.9, 118.5, 113.5, 112.0, 73.1, 63.0, 58.3, 14.1; HRMS: calcd for
C17H18NO3Cl [M+], 319.0975; found 319.0960.
7.0 Hz, 1 H), 6.53 (d, J = 10 Hz, 2 H), 4.87 (d, J = 8.0 Hz, 1 H),
4.67 (d, J = 8.0 Hz, 1 H), 4.43 (d, J = 4.0 Hz, 1 H), 4.25-4.20 (m,
2 H), 3.02 (d, J = 4.0 Hz, 1 H), 1.22 (t, J = 7.0 Hz, 3 H); 13C
NMR(CDCl3, 125 MHz) :172.5, 145.8, 140.0, 132.7, 131.6, 130.5,
129.2, 129.1, 126.4, 118.4, 113.8, 74.1, 62.7, 58.1, 14.1; HRMS:
calcd for C17H17NO3Cl2 [M+], 353.0585; found 353.0587.
(2S*,3R*)-ethyl 2-hydroxy-3-(4-methoxyphenyl)-3-(phenylamino)-
propanoate and (2S*,3S*)-ethyl 2-hydroxy-3-(4-methoxyphenyl)-
3-(phenylamino)propanoate (threo-4d: erythro-4d = 56 : 44)
(2S*,3R*)-ethyl 2-hydroxy-3-(4-bromophenyl)-3-(phenyl amino)-
propanoate (threo-4i:erythro-4i>96 : 4). 1H NMR (CDCl3,
500 MHz): d 7.44 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz,
2 H), 7.08 (t, J = 7.5 Hz, 2 H), 6.67 (t, J = 7.0 Hz, 1 H), 6.53 (d,
J = 7.5 Hz, 2 H), 4.88 (d, J = 2.0 Hz, 1 H), 4.45 (d, J = 2.0 Hz, 1 H),
4.26-4.20 (m, 2 H), 1.24 (t, J = 7.0 Hz, 3 H); 13C NMR(CDCl3,
125 MHz) :172.6, 146.0, 138.5, 131.7, 129.2, 128.7, 121.5, 118.1,
113.8, 74.2, 62.5, 58.4, 14.0; HRMS: calcd for C17H18NO3Br [M+],
363.0470; found 363.0479.
(Mixture of diastereomers) 1H NMR (CDCl3, 500 MHz): d (threo)
7.29 (d, J = 8.5 Hz, 2 H), 7.09-7.08 (m, 2 H), 6.85 (d, J = 8.5 Hz,
2 H), 6.60-6.55 (m, 3 H), 4.88 (d, J = 2 Hz, 1 H), 4.45 (d, J =
2 Hz, 1 H), 4.23-4.15 (m, 2 H), 3.75 (s, 3 H), 1.28-1.21 (m, 3 H);
(erythro) 7.20 (d, J = 8.5 Hz, 2 H), 7.09-7.08 (m, 2 H), 6.80 (d,
J = 8.5 Hz, 2 H), 6.60-6.55 (m, 3 H), 4.80 (d, J = 2 Hz, 1 H), 4.70
(d, J = 2 Hz, 1 H), 4.23-4.15 (m, 2 H), 3.74 (s, 3 H), 1.28-1.21
(m, 3 H); 13C NMR(CDCl3, 125 MHz) :172.9, 172.2, 159.3, 159.0,
146.5, 146.3, 131.2, 129.1, 128.6, 128.0, 117.9, 117.8, 114.0, 113.9,
113.8, 74.6, 73.6, 62.3, 61.9, 58.9, 58.5, 55.2, 55.1, 14.1; HRMS:
calcd for C18H21NO4 [M+], 315.1471; found 315.1478.
(2S*,3R*)-ethyl 3-(4-bromophenylamino)-3-(4-bromo phenyl)-2-
hydroxypropanoate (threo-4j:erythro-4j= 88 : 12). 1H NMR
(CDCl3, 500 MHz): d 7.43 (d, J = 8.0 Hz, 2 H), 7.21 (d, J =
8.0 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.39 (d, J = 8.5 Hz, 2 H),
4.80 (d, J = 7.5 Hz, 1 H), 4.71 (d, J = 9.0 Hz, 1 H), 4.42 (d, J =
2.5 Hz, 1 H), 4.23 (q, J = 7.0 Hz, 2 H), 3.17 (d, J = 3.5 Hz, 1 H),
1.22 (t, J = 7.0 Hz, 3 H); 13C NMR(CDCl3, 125 MHz) :172.4,
145.0, 137.9, 131.9, 131.6, 128.6, 121.7, 115.3, 109.8, 74.1, 62.6,
58.4, 14.1; HRMS: calcd for C17H17NO3Br2 [M+], 442.9555; found
442.9568.
(2S*,3R*)-ethyl 2-hydroxy-3-(4-methoxyphenyl)-3-(phenylamino)-
propanoate and (2S*,3S*)-ethyl 2-hydroxy-3-(4-methoxyphenyl)-
3-(phenylamino)propanoate (threo-4e: erythro-4e = 90 : 10)
(mixture of diastereomers) 1H NMR (CDCl3, 500 MHz): d (threo)
7.27 (d, J = 9.0 Hz, 2 H), 6.98 (t, J = 8.0 Hz, 1 H), 6.86 (d, J =
9.0 Hz, 2 H), 6.60 (d, J = 7.5 Hz, 1 H), 6.54 (s, 1 H), 6.40 (d,
J = 7.5 Hz, 1 H), 4.82-4.81 (m, 2 H), 4.25-4.21 (m, 2 H), 3.76
(s, 3 H), 1.28-1.21 (m, 3 H); (erythro) 7.20 (d, J = 9.0 Hz, 2 H),
6.98 (t, J = 8.0 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 2 H), 6.60 (d, J =
7.5 Hz, 1 H), 6.54 (s, 1 H), 6.40 (d, J = 7.5 Hz, 1 H), 4.84-4.80
(2S*,3R*)-ethyl 3-(4-chlorophenylamino)-3-(4-bromophenyl)-2-
hydroxypropanoate (threo-4k:erythro-4k= 90 : 10). 1H NMR
(CDCl3, 500 MHz): d 7.43 (d, J = 8.5 Hz, 2 H), 7.22 (d, J = 8.0 Hz,
2 H), 7.01 (d, J = 9.0 Hz, 2 H), 6.43 (d, J = 9.0 Hz, 2 H), 4.81-4.79
(m, 1 H), 4.74-4.71 (m, 1 H), 4.42 (d, J = 2.5 Hz, 1 H), 4.23 (q, J =
7.0 Hz, 2 H), 3.18 (d, J = 2.5 Hz, 1 H), 1.24 (t, J = 7.0 Hz, 3 H);
13C NMR(CDCl3, 125 MHz) :172.4, 144.6, 137.9, 131.7, 129.2,
128.7, 122.7, 121.6, 114.9, 74.1, 62.6, 58.5, 14.0; HRMS: calcd for
C17H17NO3ClBr [M+], 397.0080; found 397.0072.
(m, 2 H), 4.19-4.16 (m, 2 H), 3.75 (s, 3 H), 1.28-1.21 (m, 3 H); 13
C
NMR (CDCl3, 125 MHz) :172.9, 172.2, 159.2, 159.1, 147.2, 147.1,
134.8, 130.6, 130.0, 128.5, 127.9, 117.7, 114.1, 113.9, 113.5, 113.4,
112.0, 111.9, 74.4, 62.4, 58.2, 55.2, 55.1, 14.1, 14.0; HRMS: calcd
for C18H20NO4Cl [M+], 349.1081; found 349.1080.
(2S*,3R*)-ethyl 2-hydroxy-3-(4-nitrophenyl)-3-(phenylamino)
propanoate (threo-4l:erythro-4l>96 : 4). 1H NMR (CDCl3,
500 MHz): d 8.18 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H),
7.09 (t, J = 8.0 Hz, 2 H), 6.69 (t, J = 7.5 Hz, 1 H), 6.53 (d, J =
8.0 Hz, 2 H), 5.03 (d, J = 9.0 Hz, 1 H), 4.74 (d, J = 9.0 Hz, 1 H),
4.50 (d, J = 2.5 Hz, 1 H), 4.30-4.23 (m, 2 H), 1.24 (t, J = 7.0 Hz,
3 H);13C NMR(CDCl3, 125 MHz) :172.3, 147.4, 147.2, 145.6,
129.2, 128.0, 123.7, 118.5, 113.8, 113.7, 73.9, 62.7, 58.5, 14.0;
HRMS: calcd for C17H18N2O5 [M+], 330.1216; found 330.1228.
(2S*,3R*)-ethyl 2-hydroxy-3-(3-chlorophenyl)-3-(phenyl amino)
propanoate (threo-4f:erythro-4f >95 : 5). 1H NMR (CDCl3,
500 MHz): d 7.39 (s, 1 H), 7.27-7.23 (m, 3 H), 7.10 (t, J = 10 Hz,
2 H), 6.68 (t, J = 10 Hz, 1 H), 6.55 (d, J = 10 Hz, 2 H), 4.90 (d,
J = 2 Hz, 1 H), 4.65 (br, 1 H), 4.47 (d, J = 2 Hz, 1 H), 4.26-4.20
(m, 2 H), 1.25 (t, J = 7.5 Hz, 3 H); 13C NMR(CDCl3, 125 MHz)
:172.7, 146.2, 141.9, 134.7, 130.0, 129.3, 128.0, 127.4, 125.3, 118.3,
114.0, 74.4, 62.7, 58.7, 14.2; HRMS: calcd for C17H18NO3Cl [M+],
319.0975; found 319.0967.
(2S*,3R*)-ethyl
nitrophenyl)propanoate (threo-4m:erythro-4m >98
3-(4-methoxyphenylamino)-2-hydroxy-3-(4-
2). 1H
(2S*,3R*)-ethyl 2-hydroxy-3-(4-chlorophenyl)-3-(phenyl amino)
propanoate (threo-4g:erythro-4g = 90 : 10). 1H NMR (CDCl3,
500 MHz): d 7.35-7.26 (m, 4 H), 7.10 (t, J = 8.0 Hz, 2 H), 6.68 (t,
J = 7.5 Hz, 1 H), 6.55 (d, J = 11 Hz, 2 H), 4.92 (d, J = 2.5 Hz, 1 H),
4.47 (d, J = 2.5 Hz, 1 H), 4.28-4.22 (m, 2 H), 1.25 (t, J = 7.0 Hz,
3 H); 13C NMR(CDCl3, 125 MHz) :172.6, 146.1, 137.9, 133.3,
129.1, 128.7, 128.4, 118.1, 113.8, 74.3, 62.5, 58.4, 14.0; HRMS:
calcd for C17H18NO3Cl [M+], 319.0975; found 319.0988.
:
NMR (CDCl3, 500 MHz): d 8.16 (d, J = 8.5 Hz, 2 H), 7.55 (d,
J = 8.5 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 6.48 (d, J = 9.0 Hz,
2 H), 4.94 (s, 1 H), 4.47 (s, 1 H), 4.25 (q, J = 7.0 Hz, 2 H), 3.67 (s,
3 H), 3.29 (s, 1 H), 1.24 (t, J = 7.0 Hz, 3 H); 13C NMR(CDCl3,
125 MHz) :172.4, 152.7, 147.5, 147.4, 139.6, 128.1, 123.7, 115.3,
114.8, 73.9, 62.7, 59.5, 55.6, 14.0; HRMS: calcd for C18H20N2O6
[M+], 360.1321; found 360.1328.
(2S*,3R*)-ethyl
2-hydroxy-3-(3,4-dichlorophenyl)-3-(phenyl
(2S*,3R*)-ethyl
3-(2-methoxyphenylamino)-2-hydroxy-3-(4-
amino) propanoate (threo-4h:erythro-4h= 93 : 7). 1H NMR
(CDCl3, 500 MHz): d 7.50 (s, 1 H), 7.39 (d, J = 10 Hz, 1 H),
7.22 (d, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 2 H), 6.68 (t, J =
nitro phenyl)propanoate (threo-4n:erythro-4n>98 : 2) 1H NMR
(CDCl3, 500 MHz). d 8.16 (d, J = 8.5 Hz, 2 H), 7.54 (d, J =
8.5 Hz, 2 H), 6.78-6.76 (m, 1 H), 6.70-6.64 (m, 2 H), 6.35 (d,
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J = 7.5 Hz, 2 H), 5.33 (d, J = 9.5 Hz, 1 H), 5.04 (d, J = 8.0 Hz,
1 H), 4.53 (t, J = 3.0 Hz, 1 H), 4.28-4.24 (m, 2 H), 3.89 (s,
3 H), 3.27 (d, J = 3.5 Hz, 1 H), 1.28 (t, J = 7.0 Hz, 3 H); 13C
NMR(CDCl3, 125 MHz) :172.3, 147.5, 147.3, 147.2, 135.6, 128.0,
123.7, 121.0, 117.9, 111.5, 109.9, 74.0, 62.7, 58.7, 55.6, 14.0;
HRMS: calcd for C18H20N2O6 [M+], 360.1321; found 360.1329.
62.5, 62.4, 24.2, 14.1; HRMS: calcd for C18H21NO3 [M+], 299.1521;
found 299.1533.
(2S*,3R*)-ethyl 3-(4-chlorophenylamino)-2-hydroxy-2-methyl-
3-(4-nitrophenyl)propanoate and (2S*,3S*)-ethyl 3-(4-chloro-
phenylamino)-2-hydroxy-2-methyl-3-(4-nitrophenyl)
propanoate
(threo-4t: erythro-4t= 86 : 14). 1H NMR (CDCl3, 500 MHz): d
(threo) 8.17 (d, J = 10 Hz, 2 H), 7.57 (d, J = 10 Hz, 2 H), 7.01
(d, J = 10 Hz, 2 H), 6.45 (d, J = 10 Hz, 2 H), 4.82 (d, J = 10 Hz,
1 H), 4.76 (d, J = 10 Hz, 1 H), 4.30-4.24 (m, 2 H), 1.27-1.24 (m,
6 H); (erythro) 8.14 (d, J = 10 Hz, 2 H), 7.47 (d, J = 8.5 Hz,
2 H), 7.01 (d, J = 10 Hz, 2 H), 6.45 (d, J = 10 Hz, 2 H), 4.88
(d, J = 10 Hz, 1 H), 4.72 (d, J = 10 Hz, 1 H), 4.21 (m, 1 H),
4.07 (m, 1 H), 1.51 (s, 3 H), 1.27-1.24 (m, 3 H); 13C NMR(CDCl3,
125 MHz) :175.7, 174.4, 147.8, 145.5, 144.3, 129.8, 129.3, 129.2,
129.0, 123.5, 123.3, 115.2, 114.7, 76.5, 63.1, 62.8, 62.3, 62.2, 24.4,
24.3, 14.2, 14.1; HRMS: calcd for C18H19N2O5Cl [M+], 378.0982;
found 378.0983.
(2S*,3R*)-ethyl 3-(p-tolylamino)-2-hydroxy-3-(4-nitro phenyl)-
propanoate (threo-4o:erythro-4o>98 : 2). 1H NMR (CDCl3,
500 MHz): d 8.17 (d, J = 9.0 Hz, 2 H), 7.56 (d, J = 9.0 Hz,
2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.45 (d, J = 8.5 Hz, 2 H), 4.99 (d,
J = 7.5 Hz, 1 H), 4.59 (d, J = 9.5 Hz, 1 H), 4.48 (s, 1 H),4.28-4.23
(m, 2 H), 3.24 (s, 1 H), 2.17 (s, 3 H), 1.24 (t, J = 7.0 Hz, 3 H);
13C NMR (CDCl3, 125 MHz) :172.4, 147.4, 143.2, 129.8, 128.0,
127.8, 123.7, 113.9, 73.9, 62.7, 58.8, 20.3, 14.1; HRMS: calcd for
C18H20N2O5 [M+], 344.1372; found 344.1375.
(2S*,3R*)-ethyl 3-(4-bromophenylamino)-2-hydroxy-3-(4-nitro-
phenyl) propanoate (threo-4p:erythro-4p>97 : 3). 1H NMR
(CDCl3, 500 MHz): d 8.20 (d, J = 8.5 Hz, 2 H), 7.55 (d, J =
8.5 Hz, 2 H), 7.18 (d, J = 9.0 Hz, 2 H), 6.41 (d, J = 9.0 Hz, 2 H),
4.97 (s, 1 H), 4.78 (br, 1 H), 4.49 (s, 1 H), 4.26 (q, J = 7.0 Hz, 2 H),
3.25 (s, 1 H), 1.26 (t, J = 7.0 Hz, 3 H); 13C NMR(CDCl3, 125 MHz)
:172.2, 147.6, 146.6, 144.7, 132.1, 128.0, 123.9, 115.3, 110.3, 73.8,
62.9, 58.5, 14.1; HRMS: calcd for C17H17N2O5Br [M+], 408.0321;
found 408.0336.
(2S*,3R*)-ethyl 2-benzyl-2-hydroxy-3-phenyl-3-(phenyl amino)-
propanoate and (2S*, 3S*) -ethyl 2-benzyl-2-hydroxy-3-phenyl-3-
(phenylamino)propanoate (threo-4u: erythro-4u = 58 : 42). 1H
NMR (CDCl3, 500 MHz): d (threo) 7.50-7.08 (m, 12 H), 6.68-
6.60 (m, 3 H), 5.09-4.88 (m, 2 H), 4.17-4.12 (m, 2 H), 3.05 (d, J =
14 Hz, 1 H), 2.58 (d, J = 14 Hz, 1 H), 1.22-1.19 (m, 3 H); (erythro)
7.50-7.08 (m, 12 H), 6.68-6.60 (m, 3 H), 5.09-4.88 (m, 2 H), 3.99-
3.93 (m, 2 H), 3.59 (d, J = 14 Hz, 1 H), 3.23 (d, J = 14 Hz, 1 H),
1.22-1.19 (m, 3 H); 13C NMR(CDCl3, 125 MHz) :174.5, 173.2,
146.8, 146.4, 138.7, 138.2, 136.1, 135.4, 130.3, 130.1, 129.5, 129.3,
129.1, 129.0, 128.3, 128.2, 128.1, 127.9, 127.1, 126.9, 117.9, 117.6,
114.2, 113.7, 81.4, 80.8, 62.6, 62.5, 62.4, 62.1, 43.4, 43.1, 14.2, 14.1;
HRMS: calcd for C24H25NO3 [M+], 375.1834; found 375.1845.
(2S*,3R*)-ethyl 3-(3-chlorophenylamino)-2-hydroxy-3-(4-nitro-
phenyl)propanoate (threo-4q:erythro-4q>95
:
5). 1H NMR
(CDCl3, 500 MHz): d 8.20 (d, J = 9.0 Hz, 2 H), 7.56 (d, J =
9.0 Hz, 2 H), 7.00 (t, J = 8.0 Hz, 1 H), 6.66 (d, J = 8.0 Hz, 1 H),
6.52 (s, 1 H), 6.40 (d, J = 8.0 Hz, 1 H), 5.00 (d, J = 9.0 Hz, 1 H),
4.86 (d, J = 9.0 Hz, 1 H), 4.50 (s, 1 H), 4.27 (q, J = 7.0 Hz, 2 H), 3.33
(br, 1 H), 1.25 (t, J = 7.0 Hz, 3 H); 13C NMR(CDCl3, 125 MHz)
:172.1, 147.6, 146.9, 146.6, 135.1, 130.3, 128.0, 123.9, 118.5, 113.5,
111.9, 73.8, 62.9, 58.3, 14.1; HRMS: calcd for C17H17N2O5Cl [M+],
364.0826; found 364.0818.
Acknowledgements
We thank financial support from National Science Foundation
of China (Grant No. 20872036), Shanghai Municipal Education
Commission (09ZZ45) and Science and Technology Commission
of Shanghai Municipality (09JC1404900).
(2S*,3R*)-ethyl 2-hydroxy-3-(2-nitrophenyl)-3-(phenylamino)-
propanoate (threo-4r:erythro-4r= 80 : 20). 1H NMR (CDCl3,
500 MHz): d 7.89 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 8.5 Hz,
2 H), 7.53 (t, J = 6.0 Hz, 1 H), 7.41 (t, J = 6.0 Hz, 1 H), 7.12
(t, J = 8.5 Hz, 2 H), 6.72-6.69 (m, 3 H), 5.77 (br, 1 H), 5.03 (d,
J = 9.0 Hz, 1 H), 4.83-4.80 (m, 1 H), 4.62-4.60 (m, 1 H), 4.25-
4.23 (m, 1 H), 4.05-4.03 (m, 1 H), 1.24 (t, J = 7.0 Hz, 3 H); 13C
NMR(CDCl3, 125 MHz) :172.0, 149.8, 145.5, 133.0, 129.5, 129.3,
128.7, 125.0, 118.6, 113.9, 72.8, 62.7, 54.1, 13.8; HRMS: calcd for
C17H18N2O5 [M+], 330.1216; found 330.1227.
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propanoate and (2S*,3S*)-ethyl 2-hydroxy-2-methyl-3-phenyl-3-
(phenylamino)propanoate (threo-4s: erythro-4s = 80 : 20). 1H
NMR (CDCl3, 500 MHz): d (threo) 7.38 (d, J = 7.5 Hz, 2 H),
7.31-7.24 (m, 4 H), 7.07-7.03 (m, 2 H), 6.62-6.55 (m, 2 H), 4.80-
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11 Crystal data for 4k (threo):Formula: C17H17Br1Cl1N1O3. Unit cell
parameters: a 8.8875 (3) b 9.6663 (3) c 11.1750 (3) a 84.7920 (10)
b 76.1370 (10) g 67.1100 (10) space group P-1. The crystal structure
has been deposited at the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 725598.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5028–5033 | 5033
©