Rh2(OAc)4 and InCl3 co-catalyzed diastereoselective trapping of carbamate ammonium ylides with aldehydes for the synthesis of β-hydroxyl-α-amino acid derivatives

Article abstract of DOI:10.1016/j.tet.2015.11.027

A Rh₂(OAc)₄ and InCl₃ co-catalyzed three component reaction of diazo compounds, carbamates and aldehydes has been developed to synthesize β-hydroxyl-α-amino acid derivatives in good yields with excellent diastereoselectivity. The reaction is proceeded via trapping of active carbamate ammonium ylide intermediates by aromatic aldehydes.

Full text of DOI:10.1016/j.tet.2015.11.027

Accepted Manuscript
Rh (OAc) and InCl co-catalyzed diastereoselective trapping of carbamate
2
4
3
ammonium ylides with aldehydes for the synthesis of β-hydroxyl-α-amino acid
derivatives
Jian-Bei Xi, Ming-Liang Ma, Wenhao Hu
PII:
S0040-4020(15)30212-X
10.1016/j.tet.2015.11.027
TET 27284
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 September 2015
Revised Date: 10 November 2015
Accepted Date: 16 November 2015
Please cite this article as: Xi J-B, Ma M-L, Hu W, Rh (OAc) and InCl co-catalyzed diastereoselective
2
4
3
trapping of carbamate ammonium ylides with aldehydes for the synthesis of β-hydroxyl-α-amino acid
derivatives, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.027.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Rh2(OAc)4 and InCl3 co-catalyzed diastereoselective
trapping of carbamate ammonium ylides with
aldehydes for the synthesis of β-hydroxyl-α-amino
acid derivatives
Leave this area blank for abstract info.
Jian-Bei Xi, Ming-Liang Ma, and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062,China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Rh2(OAc)4 and InCl3 co-catalyzed diastereoselective trapping of carbamate
ammonium ylides with aldehydes for the synthesis of β-hydroxyl-α-amino acid
derivatives
Jian-Bei Xi, Ming-Liang Ma, and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, China
ARTICLE INFO
ABSTRACT
A Rh2(OAc)4 and InCl3 co-catalyzed three component reaction of diazo compounds, carbamates
and aldehydes has been developed to synthesize β-hydroxyl-α-amino acid derivatives in good
yields with excellent diastereoselectivity. The reaction is proceeded via trapping of active
carbamate ammonium ylide intermediates by aromatic aldehydes.
.
Article history:
Received
Received in revised form
Accepted
Available online
2015 Elsevier Ltd. All rights reserved
.
Keywords:
Carbamate ammonium ylide
Cooperative catalysis
Diazo decomposition
Multicomponent reaction
Amino acid
to afford β-hydroxyl-α-amino acid scaffolds (Scheme 1A).3 Che
and collaborators developed an asymmetric approach to chiral β-
hydroxyl-α-aminophosphonates with chiral dirhodium (II)
carboxamidates (Scheme 1B).4 Gong and co-workers have
reported the enantioselective Brønsted acid/rhodium(II)
cooperatively catalyzed three-component aldol-type reaction of
trapping ammonium ylides with glyoxylates (Scheme 1C).5
However, only arylamines were effective in forming active
ylides, and the N-aryl group can not be easily removed from the
products, thus limiting their synthetic application. Recently, our
group discovered a three-component Mannich-type reaction by
trapping carbamate ammonium ylides with imines.6 As part of
our continuing interest in developing practical methods for the
synthesis of β-hydroxyl-α-amino acid derivatives, we decided to
extend substrates of the carbamate ammonium ylide trapping
process to aldehydes. Herein, we report the reaction through
trapping of carbamate ammonium ylides with aldehydes, which
gives β-hydroxyl-α-amino acid derivatives in good yields with
excellent diastereoselectivity (Scheme 1D).
1. Introduction
β-hydroxyl-α-amino acid derivatives are important structural
motifs present in many drugs, including Chloramphenicol,
Thiamphenicol, and Droxidopa (Fig. 1).1 As such, the
development of efficient approaches for the construction of β-
hydroxyl-α-amino acid structures with high stereoselectivity is
much desirable in organic synthesis. As one of the most powerful
strategies, multicomponent reactions (MCRs) can construct
polyfunctional molecules that contain multiple stereogenic
centers from simple substrates in
a
convergent and
atomeconomical manner within one synthetic operation.2
Fig. 1. Representative drugs containing a β-hydroxyl-α-amino acid fragment.
Previously, we reported a novel Rh2(OAc)4 catalyzed three-
component reaction through trapping of ammonium ylides
generated in situ from α-diazo esters and amines with aldehydes

2
Tetrahedron
4
Zn(OTf)2
50
24
>20:1
>20:1
>20:1
>20:1
-
ACCEPTED MANUSCRIPT
5
Yb(OTf)2
6
In(OTf)2
InCl3
50
7
8d
55
InCl3
trace
a
Unless otherwise noted, all reactions were carried out with 0.15 mmol scale,
b
1 mol % Rh2(OAc)4 and 15 mol % Lewis acids, and 1:2:3=1.3:1.0:1.2.
c
Isolated yields were obtained after column chromatography purification.
The diastereomeric ratio was detected by 1H NMR(400 MHz) spectroscopy. d
In the absence of Rh2(OAc)4.
Then, various solvents were tested and CH2Cl2 was found to be
the most efficient (Table 2, entry 1). The reaction temperature
was also investigated and it has negligible effect on the reaction
(Table 2, entries 4-6). The isolated product yield was slightly
improved to 65% when the amount of methyl phenyldiazoacetate
was increased from 1.3 to 1.9 equiv (Table 2, entry 8). It is worth
mentioning that diazo compounds can be added in portions,
avoiding gradual addition of diazo compounds. This change
makes the synthetic protocol more practical and convenient.
Table 2
Optimization of reaction conditionsa
Scheme 1. Synthesize β-Hydroxyl-α-Amino acid derivatives
2. Results and discussion
In recent years, cooperative catalysis, including dual-metal and
metal-organo catalysis, has proved to be an effective strategy to
enhance selectivity and reactivity.7 We have applied such a
strategy
to
effectively
control
stereoselectivity
in
multicomponent reactions based on oxonium,8 ammonium,9
carbamate ammonium ylides,6 and zwitterionic intermediates
trapping process.10 Initially, we began to investigate the reaction
of methyl phenyldiazoacetate (1), benzyl carbamate (2) and 4-
nitrobenzaldehyde (3) in the presence of Rh2(OAc)4 catalyst
alone. The desired three-component product 4 was obtained in
very low yield due to insufficient reactivity of 4-nitrobenzalde.
Significant amount of N-H insertion product 5 (from benzyl
carbamate) was isolated as a major side product (Table 1, entry
1). We envisioned that an appropriate Lewis acid co-catalyst
would activate the aldehydes. To validate this hypothesis, we
screened a number of Lewis acids as co-catalysts. Although
Cu(OTf)2 was ineffective in the reaction, we obtained the desired
three-component product when we used Mg(OTf)2,
Zn(OTf)2,Yb(OTf)3, In(OTf)2 and InCl3 as a co-catalyst (Table 1,
entries 2–7). Among the effective co-catalysts, InCl3 gave the
best result, with the formation of product in 55% yield with
excellent diastereoselectivity in favor of the anti isomer (Table 1,
entry 7). Control experiment revealed that Rh2(OAc)4 was
indispensable for this reaction (Table 1, entry 8).
Entry
Solvent
DCM
CHCl3
toluene
DCM
DCM
DCM
DCM
DCM
T (oC)
Yield (% )b
drc
1
2
rt
rt
55
39
31
52
51
48
57
65
>20:1
>20:1-
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
3
rt
4
rt
5
0
6
-20
rt
7d
8e
rt
a Unless otherwise noted, all reactions were carried out with 0.15 mmol scale,
1 mol% Rh2(OAc)4 and 15 mol% InCl3, and 1:2:3=1.3:1.0:1.2. Isolated
b
c
yields were obtained after column chromatography purification. The
diastereomeric ratio was detected by H NMR(400 MHz) spectroscopy. d 1.6
1
equiv of 1 was used. e 1.9 equiv of 1 was used.
With the optimized reaction conditions in hand, we turned to
evaluate the generality of this protocol. A variety of substituted
aldehydes were first examined. Benzaldehyde that bears no
electron withdrawing group delivered the product in 60% yield
with excellent diastereoselectivity (Table 3, entry 1). To our
delight, even electron-donating 4-methoxybenzaldehyde afforded
the corresponding product 4b in 39% yield (Table 3, entry 2).
Aromatic aldehydes bearing an electron withdrawing group,
Table 1
Screening of co-catalystsa
Table 3
The generality of the reaction with different aldehydesa
4, Yield (%)b
Entry
Cocat. ( 15 % mol )
drc
1
2
3
-
<5
<5
10
-
-
Entry
R
Ph
4, Yield (% )b
4a, 60
drc
Cu(OTf)2
Mg(OTf)2
1
2
>20:1
>20:1
>20:1
p-MeOPh
4b, 39

3
3
4
p-SO2Ph
p-BrPh
4c, 76
4d, 85
4e, 75
4f, 67
4g, 65
4h, 69
4i, 64
4j, 62
>20:1
Fig. 2. X-Ray crystal structure of anti-4p.
ACCEPTED MANUSCRIPT
>20:1
5
o-NO2Ph
m-NO2Ph
P-NO2Ph
2-furyl
>20:1
>20:1
>20:1
>20:1
>20:1
6
7
8
9
2-thienyl
Scheme 2. Deprotection of the product anti-4k.
10
cinnamonyl
60:40
a Unless otherwise noted, all reactions were carried out with 0.2 mmol scale,
1 mol % Rh2(OAc)4 and 15 mol % InCl3, and 1a:2a:3a=1.9:1.0:1.2. b Isolated
yields were obtained after column chromatography purification. c The
diastereomeric ratio was detected by 1H NMR(400 MHz) spectroscopy.
regardless of the arene substitution (o-, m-, p-), generally gave
much higher yields (Table 3, entries 3-7). When using
heteroaromatic aldehydes, such as 2-furaldehyde and 2-
thiophenyl aldehyde, the reactions led to products in 69% and
64% yields, respectively (Table 3, entries 8 and 9). Gratifyingly,
even conjugated aldehyde, (E)-cinnamaldehyde reacted with
methyl phenyldiazoacetate and benzyl carbamate to afford γ,δ-
unsaturated β-hydroxyl-α-amino acidin 62% yield, though with
decreased diastereoselectivity (Table 3, entry 10).
The relative stereochemistry of the products was assigned as
anti in analogy with anti-4p as determined by single-crystal X-
ray diffraction (Fig. 2). Deprotection of the product was easily
carried out by using TFA at room temperature in CH2Cl2 to give
free amine in 80% yield (Scheme 2).11
A plausible reaction pathway for this Rh2(OAc)4 and InCl3 co-
catalyzd three component reaction is shown in Scheme 3.
Rh2(OAc)4 decomposes diazo compounds to form the
corresponding rhodium carbene species I, which further reacts
with carbamates to give the active carbamate ammonium ylides
IIa or IIb. In the presence of aromatic aldehydes that was
activated by InCl3, the active ylide species undergo aldol-type
addition to afford the desired three component product. To have
an insight into the reaction process, we carried out control
experiments to exclude the possibility that the product 4g is
produced from N–H insertion product 5. As a result, when treated
the N–H insertion product 5 with aldehyde under the identical
conditions, no three component product was detected. The
observed stereoselective control can be explained by comparing
the transition states IIIa and IIIb, as shown in Scheme 3. The
anti-4 is obtained from the favored transition state IIIb with less
steric hindrance compared with the disfavored TS IIIa.
We next carried out screening of a series of carbamates and
diazo compounds. FmocNH2 and BocNH2 are equally good
substrates, which gave products with similar yields and
stereoselectivity (Table 4, entries 2 and 3). In general, the
reaction was tolerated to various substituted electron-rich and -
deficient aryldiazo compounds, giving rise to the products with
moderate to good yields and high diastereoselectivity (Table 4,
entries 4-9).
Table 4
The generality of the reaction towards carbamates and diazo compoundsa
Entry
Ar1
Ph
R1
Cbz
Boc
Fmoc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
4, Yield (%)b
4g, 65
drc
1
2
3
4
5
6
7
8
9
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Ph
4k, 58
Ph
4l, 60
p-MePh
p-MeOPh
p-FPh
o-BrPh
m-BrPh
P-BrPh
4m, 70
4n, 51
Scheme 3. Proposed mechanism for the three-component reaction.
4o, 60
4p, 49
3. Conclusion
4q, 81
In summary, by using
a transision metal-Lewis acid
4r, 52
a
cooperative catalysis strategy, we have realized a highly
stereoselective three-component aldol-type reaction of diazo
compounds and carbamates with aldehydes. The protocol
provides a straightforward and efficient route to access β-
hydroxyl-α-amino acid derivatives in highly stereoselective
manner. This catalytic system accommodates aromatic aldehydes
containing a variety of electron–donating and –withdrawing
groups, heteroaromatic aldehydes, and conjugate aldehydes,
demonstrating wide substrate scope. Efforts to achieve
enantioselective control of this practical method is currently in
progress in our laboratory.
Unless otherwise noted, all reactions were carried out with 0.2 mmol scale,
1 mol % Rh2(OAc)4 and 15 mol % InCl3, and 1a:2a:3a=1.9:1.0:1.2. b Isolated
c
yields were obtained after column chromatography purification. The
diastereomeric ratio was detected by 1H NMR(400 MHz) spectroscopy.

4
Tetrahedron
4. Experimental section
44.46, 44.39; HRMS (ESI) m/z calcd for C H NNaO7
ACCEPTED MANUSCRIPT
25 25
(M+Na)+ 506.1249, found 506.1237.
4.1. General
4.2.4. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-(4-
bromophenyl)-3-hydroxy-2-phenylpropanoate (anti-4d). 1H NMR
(400 MHz, CDCl3) δ 7.49 (d, J = 6.8 Hz, 2H), 7.45–7.34 (m, 8H),
7.32 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 6.32 (s, 1H),
5.97 (s, 2H), 5.21 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H),
3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.16, 157.10,
138.80, 135.86, 135.77, 131.09, 128.70, 128.65, 128.59, 128.49,
128.46, 127.29, 121.90, 75.50, 70.43, 67.79, 53.65; HRMS (ESI)
m/z calcd for C24H22NNaO5Br (M+Na)+ 506.0579, found
506.0582.
HRMS (ESI) Mass spectra were recorded on Bruker
micrOTOF-Q 10198 mass spectrometer. NMR spectra were
recorded on
a Brucker Ascend-400 MHz spectrometer.
Dichloromethane was distilled over calcium hydride. Various
aryl diazo compounds were prepared by the treatment of
corresponding
aryl
acetate
with
p-
acetamidobenzenesulfonylazide (p-ABSA) in the presence of
DBU.12
4.2. General procedure for the three-component reaction of
diazo compounds with carbamates and aldehydes
4.2.5. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(2-nitrophenyl)-2-phenylpropanoate (anti-4e). 1H
NMR (400 MHz, CDCl3 δ ) δ 7.70 (d, J = 7.9 Hz, 1H), 7.44–7.37
(m, 8H), 7.37–7.33 (m, 3H), 7.33–7.27 (m, 2H), 6.75 (d, J = 5.5
Hz, 1H), 6.30 (s, 1H), 6.08 (d, J = 5.4 Hz, 1H), 5.26 (d, J = 12.3
Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H), 3.55 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 171.12, 157.19, 149.27, 135.78, 135.60, 133.04,
131.86, 130.73, 128.81, 128.66, 128.61, 127.02, 123.90, 69.79,
69.43, 68.08, 54.00; HRMS (ESI) m/z calcd for C24H22N2NaO7
(M+Na)+ 473.1325, found 473.1304
To a stirred mixture of Rh2(OAc)4 (1 mol%), InCl3 (15 mol %),
carbamate 1 (0.20 mmol), aldehyde 2 (0.24 mmol), and 4Å-MS
(100 mg) in DCM (1.5 mL) was added diazo compound 3 (0.38
mmol) in DCM (1 mL) in portions at room temperature. After the
addition of diazo compound completes, the reaction mixture was
stirred for 1 h. Then, the reaction mixture was filtered and
concentrated under reduced pressure. The crude product was
subjected to 1HNMR analysis for the determination of
diastereoselectivity. The crude product was purified by column
chromatography on silica gel (eluent: EtOAc /light petroleum =
1:20~1:10) to give the corresponding pure products 4.
4.2.6. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(3-nitrophenyl)-2-phenylpropanoate (anti-4f). 1H
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H),
7.51–7.44 (m, 2H), 7.44–7.34 (m, 10H), 6.31 (s, 1H), 6.22 (s,
1H), 6.13 (s, 1H), 5.21 (d, J = 12.1 Hz, 1H), 5.08 (d, J = 12.1 Hz,
1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.00, 157.28,
147.88, 142.10, 135.58, 135.32, 133.26, 129.00, 128.75, 128.71,
128.66, 128.51, 127.15, 122.95, 121.98, 75.36, 70.43, 68.13,
53.93; HRMS (ESI) m/z calcd for C24H22N2NaO7 (M+Na)+
473.1325, found 473.1311.
4.2.1. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(4-nitrophenyl)-2-phenylpropanoate (anti-4a). 1H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.7 Hz, 2H), 7.47–7.33
(m, 10H), 7.18 (d, J = 8.5 Hz, 2H), 6.26 (s, 1H), 6.10 (s, 2H),
5.22 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 3.73 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 171.09, 157.12, 147.53, 147.19,
135.68, 135.22, 130.50, 129.84, 128.78, 128.72, 128.68, 128.61,
127.89, 127.71, 123.09, 75.36, 70.34, 67.99, 53.87; HRMS (ESI)
m/z calcd for C24H22N2NaO7 (M+Na)+ 473.1308, found
473.1325.
4.2.7. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(4-nitrophenyl)-2-phenylpropanoate (anti-4g). 1H
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.7 Hz, 2H), 7.47–7.36
(m, 10H), 7.18 (d, J = 8.5 Hz, 2H), 6.26 (s, 1H), 6.14–6.02 (m,
2H), 5.22 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz, 1H), 3.73 (s,
3H); 13CNMR (100 MHz, CDCl3) δ 171.09, 157.12, 147.53,
147.19, 135.68, 135.22, 128.78, 128.72, 128.69, 128.61, 127.89,
127.18, 123.09, 75.36, 70.34, 67.99, 53.88; HRMS (ESI) m/z
calcd for C24H22N2NaO7 (M+Na)+ 473.1325, found 473.1308.
4.2.2. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(4-methoxyphenyl)-2-phenylpropanoate (anti-4b). 1H
NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.1 Hz, 2H), 7.45–
7.32(m, 8H), 7.00 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H),
6.36 (s, 1H), 5.95 (d, J = 7.4 Hz, 1H), 5.89 (d, J = 7.3 Hz, 1H),
5.22 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 3.78 (s, 3H),
3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.69, 157.17,
153.95, 142.10, 135.89, 135.78, 128.98, 128.60, 128.54, 128.35,
128.14, 127.30, 110.22, 107.70, 72.18, 69.93, 67.62, 53.94;
HRMS (ESI) m/z calcd for C25H25NNaO6 (M+Na)+ 458.1580,
found 458.1585.
4.2.8.
(2R*,3S*)-methyl
2-(((benzyloxy)carbonyl)amino)-3-
(furan-2-yl)-3-hydroxy-2-phenylpropanoate (anti-4h). 1HNMR
(400 MHz, CDCl3) δ 7.59 (d, J = 7.4 Hz, 2H), 7.33–7.42 (m, 7H),
7.27–7.32 (m, 2H), 6.65 (s, 1H), 6.29 (dd, J = 3.2, 1.9 Hz, 1H),
6.25 (d, J = 3.1 Hz, 1H), 6.16 (d, J = 10.0 Hz, 1H), 6.05 (d, J =
9.9 Hz, 1H), 5.15 (d, J = 12.3 Hz, 1H), 5.03 (d, J = 12.3 Hz, 1H),
3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.25, 159.21,
157.11, 136.23, 136.01, 131.75, 129.48, 128.60, 128.52, 128.45,
128.30, 128.11, 127.39, 113.38, 75.71, 70.72, 67.65, 55.18;
HRMS (ESI) m/z calcd for C22H21NNaO6 (M+Na)+ 418.1267,
found 418.1277.
4.2.3. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(4-(methylsulfonyl)phenyl)-2-phenylpropanoate(anti-
1
4c). H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 2H),
7.33–7.39 (m, 5H), 7.47–7.39, 7.22 (d, J = 8.0 Hz, 2H), 6.27 (s,
1H), 6.08 (s, 2H), 5.20 (d, J = 12.1 Hz, 1H), 5.07 (d, J = 12.1 Hz,
1H), 3.71 (s, 3H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.07, 157.15, 146.18, 139.89, 135.72, 135.31, 128.70, 128.55,
128.03, 127.19, 127.00, 126.44, 77.42, 77.10, 76.78, 75.42, 70.34,
70.11, 68.06, 67.95, 67.84, 53.90, 53.77, 53.63, 53.49, 44.53,

5
4.2.9. (2R*,3S*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-2-phenyl-3-(thiophen-2-yl)propanoate (anti-4i). 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.48–7.31
(m, 8H), 7.24 (d, J = 5.0 Hz, 1H), 6.98–6.89 (m, 1H), 6.82 (d, J =
3.3 Hz, 1H), 6.62 (s, 1H), 6.34 (d, J = 8.1 Hz, 1H), 6.29 (d, J =
8.1 Hz, 1H), 5.19 (d, J = 12.2 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H),
3.71 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 170.73, 157.25,
143.66, 135.86, 128.72, 128.61, 128.49, 128.46, 128.33, 127.22,
126.46, 125.20, 124.89, 73.25, 70.84, 67.86, 53.83; HRMS (ESI)
m/z calcd for C22H21NNaO5S (M+Na)+ 434.1038, found 434.1059.
Hz, 1H), 3.73 (s, 3H), 2.37 (s, 3H);
13C NMR (100 MHz, CDCl3) δ
ACCEPTED MANUSCRIPT
171.25, 157.11, 147.52, 147.29, 138.65, 135.73, 132.23, 129.41,
128.74, 128.67, 128.59, 127.92, 127.03, 123.04, 75.35, 70.16, 67.93,
53.78, 21.09;
HRMS (ESI) m/z calcd for C25H24N2NaO7 (M+Na)+
487.1481, found 487.1490.
4.2.15. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-2-(4-methoxyphenyl)-3-(4-nitrophenyl)propanoate (anti-
1
4n). H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.53
–
7.28 (m, 7H), 7.18 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 6.23
(s, 1H), 6.06 (s, 2H), 5.21 (d, J = 12.1 Hz, 1H), 5.06 (d, J = 12.1 Hz,
1H), 3.82 (s, 3H), 3.73 (s, 3H);
13C NMR (100 MHz, CDCl3) δ
171.28, 159.69, 157.10, 147.50, 147.34, 135.71, 128.75, 128.71,
128.59, 128.44, 127.87, 127.13, 123.07, 114.04, 75.37, 69.94, 67.94,
55.30, 53.78;
HRMS (ESI) m/z calcd for C25H24N2NaO8 (M+H)+
4.2.10. (2R*,3R*,E)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-2,5-diphenylpent-4-enoate (anti-4j). 1H NMR (400 MHz,
CDCl3) δ 7.57 (d, J = 7.6 Hz, 2H), 7.46–7.18 (m, 13H), 6.79–
6.62 (m, 2H), 6.13 (dd, J = 15.7, 4.9 Hz, 1H), 5.61-5.44 (m, 2H),
5.15 (d, J = 12.2 Hz, 1H), 5.05 (d, J = 12.2 Hz, 1H), 3.71 (s, 3H);
13CNMR (100 MHz, CDCl3) δ 171.24, 156.98, 136.56, 136.10,
135.86, 132.52, 128.63, 128.60, 128.54, 128.38, 128.34, 128.14,
127.82, 127.19, 127.11, 126.73, 75.12, 70.25, 67.65, 53.86;
HRMS (ESI) m/z calcd for C26H25NNaO5 (M+H)+ 454.1630,
found 454.1608.
503.1430, found 503.1453.
4.2.16. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(4-
fluorophenyl)-3-hydroxy-3-(4-nitrophenyl)propanoate (anti-4o).
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.59–
7.29 (m, 7H), 7.18 (d, J = 8.3 Hz, 2H), 7.08 (t, J = 8.3 Hz, 2H),
6.28 (s, 1H), 6.13 (s, 1H), 6.06 (d, J = 8.0 Hz, 1H), 5.21 (d, J =
12.1 Hz, 1H), 5.05 (d, J = 12.1 Hz, 1H), 3.75 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.71, 162.67 (d, J = 248.9 Hz), 157.14,
147.59, 147.10 (s), 135.55, 131.23 ((d, J = 2.9 Hz), 129.20 (d, J =
8.3 Hz), 128.85, 128.73, 128.64, 127.68, 123.20, 115.71 (d, J =
21.7 Hz), 75.53, 70.05, 68.10, 53.98; 19F NMR (376 MHz, CDCl3)
δ -112.93 (s) ; HRMS (ESI) m/z calcd for C24H21N2NaO7F
(M+H)+ 491.1230, found 491.1249.
4.2.11. (2 R*,3 S*,E)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-2,5-diphenylpent-4-enoate (syn-4j). 1H NMR (400 MHz,
CDCl3) δ 7.47 (dd, J = 8.2, 1.3 Hz, 2H), 7.40–7.33 (m, 4H),
7.32–7.27 (m, 5H), 7.26-7.20 (m, 5H), 6.63 (d, J = 15.9 Hz, 1H),
6.02 (dd, J = 15.9, 5.3 Hz, 1H), 5.78 (s, 1H), 5.24 (s, 1H), 5.09 (s,
2H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.74, 156.28,
136.47, 136.05, 133.00, 128.67, 128.51, 128.43, 128.23, 128.15,
127.82, 126.62, 126.42, 125.74, 75.70, 69.83, 67.29, 53.26;
HRMS (ESI) m/z calcd for C26H25NNaO5 (M+H)+ 454.1630,
found 454.1617.
4.2.17. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(2-
bromophenyl)-3-hydroxy-3-(4-nitrophenyl)propanoate
1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 7.8 Hz, 1H), 8.22
(m, 2H), 7.59 (dd, J = 7.9, 1.3 Hz, 1H), 7.53 7.46 (m, 1H), 7.44 –
(
anti-4p).
–
8.06
4.2.12. (2R*,3R*)-methyl 2-((tert-butoxycarbonyl)amino)-3-
hydroxy-3-(4-nitrophenyl)-2-phenylpropanoate (anti-4k). 1H
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 7.51–7.30
(m, 7H), 6.36 (s, 1H), 6.12 (d, J = 7.6 Hz, 1H), 6.04 (s, 1H), 3.75
(s, 3H), 1.46 (s, 9H); 13CNMR (100 MHz, CDCl3) δ 171.35,
156.83, 147.75, 147.67, 135.63, 128.57, 128.02, 127.17, 123.04
(s), 81.83, 75.37, 70.28, 53.72, 28.21; HRMS (ESI) m/z calcd for
C21H24N2NaO7 (M+H) + 439.1481, found 439.1477.
–
7.33 (m, 5H), 7.34-7.29 (m, 2H), 7.28 – 7.22 (m, 1H), 6.63 (s, 1H),
6.55 (s, 1H), 5.86 (s, 1H), 5.18 (d, J = 12.2 Hz, 1H), 5.03 (d, J = 12.2
Hz, 1H), 3.63 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.59, 157.60,
147.97, 146.62, 135.89, 135.58, 135.20, 132.06, 130.19, 128.67,
128.65, 128.62, 128.28, 127.78, 123.20, 121.71, 77.46, 70.88, 68.18,
53.90
;
HRMS (ESI) m/z calcd for C24H21N2NaO7Br (M+H)+
551.0430, found 551.0443.
4.2.13.
(2R*,3R*)-methyl
2-((((9H-fluoren-9-
4.2.18. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(3-
yl)methoxy)carbonyl)amino)-3-hydroxy-3-(4-nitrophenyl)-2-
phenylpropanoate (anti-4l). 1H NMR (400 MHz, CDCl3) δ
8.07 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 8.1
Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.43–7.30 (m, 7H), 7.17 (d, J =
8.0 Hz, 2H), 6.15 (s, 1H), 6.07 (d, J = 6.7 Hz, 1H), 6.00 (s, 1H),
4.75–4.60 (m, 1H), 4.59–4.46 (m, 1H), 4.22 (t, J = 5.8 Hz, 1H),
3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.21, 157.11,
147.60, 147.07, 143.28, 141.52, 135.18, 128.73, 128.03, 127.23,
127.18, 127.04, 124.78, 124.69, 123.12, 120.22, 75.26, 70.10,
67.18, 53.83, 47.22; HRMS (ESI) m/z calcd for C31H26N2NaO7
(M+H)+ 561.1638, found 561.1637.
bromophenyl)-3-hydroxy-3-(4-nitrophenyl)propanoate
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 2H), 7.60 (s, 1H),
7.52 7.45 (m, 1H), 7.45-7.37 (m, 4H), 7.36 7.29 (m, 2H), 7.23 (d, J
(anti-4q).
–
–
= 4.1 Hz, 1H), 7.15 (d, J = 8.7 Hz, 2H), 6.25 (s, 1H), 6.13 (d, J = 7.8
Hz, 1H), 6.01 (d, J = 8.3 Hz, 1H), 5.18 (d, J = 12.1 Hz, 1H), 5.04 (d,
J = 12.1 Hz, 1H), 3.73 (s, 3H);
13C NMR (100 MHz, CDCl3) δ
170.30, 157.13, 147.63, 146.91, 137.79, 135.51, 131.91, 130.38,
130.17, 128.84, 128.77, 128.58, 127.68, 126.08, 123.24, 122.86,
75.51, 70.13, 68.17 (s), 54.13
; HRMS (ESI) m/z calcd for
C24H21N2NaO7Br (M+H)+ 551.0430, found 551.0417.
4.2.19. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-2-(4-
bromophenyl)-3-hydroxy-3-(4-nitrophenyl)propanoate(anti-4r).
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz, 2H), 7.52 (d, J =
8.4 Hz, 2H), 7.48–7.41 (m, 3H), 7.41-7.32 (m, 4H), 7.18 (d, J = 8.5
Hz, 2H), 6.28 (s, 1H), 6.16 (d, J = 7.7 Hz, 1H), 6.04 (d, J = 8.4 Hz,
1H), 5.21 (d, J = 12.1 Hz, 1H), 5.04 (d, J = 12.1 Hz, 1H), 3.75 (s,
4.2.14. (2R*,3R*)-methyl 2-(((benzyloxy)carbonyl)amino)-3-
hydroxy-3-(4-nitrophenyl)-2-(p-tolyl)propanoate
NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 2H), 7.48
3H), 7.40 7.35 (m, 2H), 7.32 (d, J = 7.7 Hz, 2H), 7.24 7.13 (m, 4H),
6.24 (s, 1H), 6.08 (s, 2H), 5.22 (d, J = 12.1 Hz, 1H), 5.06 (d, J = 12.1
(
anti-4m). 1H
7.40 (m,
–
–
–

6
Tetrahedron
;
13C NMR (100 MHz, CDCl ) δ 170.38, 157.15, 147.61,
3
10. Qiu, H.; Li, M.; Jiang, L. Q.; Lv, F. P.; Zan, L.; Zhai, C. W.; Doyle, M. P.;
3H)
ACCEPTED MANUSCRIPT
Hu, W. H. Nature chemistry 2012, 4, 733.
146.99, 135.49, 134.63, 131.89, 129.05, 128.87, 128.74, 128.66,
11. Faibish, Neil C.; Park, Yong Sun; Lee, Steven; Beak, Peter; J. Am. Chem.
Soc. 1997, 48, 11561 – 11570.
12. Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic Methods for
OrganicSynthesis with Diazo Compounds; Wiley: New York, 1998.
127.63, 123.24, 123.04, 75.48, 70.24, 68.16, 54.06; HRMS (ESI) m/z
calcd for C24H21N2NaO7F (M+H)+ 491.1230, found 491.12
4.3. (2R*,3R*)-methyl 2-amino-3-hydroxy-3-(4-nitrophenyl)-2-
phenylpropanoate (6)
To a solution of 4k (45 mg, 0.108 mmol) in DCM ( 2 mL) was
added TFA ( 0.5 mL) at room temperature. The reaction mixture
was stirred for 5h, and then solvent was removed in vacuo. The
residue was diluted with DCM. pH was adjusted to about 8 with
a ammonium solution (7M) in methanol and the mixture was
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (eluent: EtOAc /light petroleum =
1:10~1:2) to give the product 6 (34.2 mg, 80% yield) as a white
1
solid. H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.7 Hz, 2H),
7.54 (d, J = 7.9 Hz, 2H), 7.48–7.30 (m, 5H), 5.50 (s, 1H), 3.63 (d,
J = 1.2 Hz, 3H), 1.86 (br, 3H); 13C NMR (100 MHz, CDCl3) δ
174.09, 147.65, 146.59, 138.97, 128.69, 128.45, 126.47, 122.90,
5.87, 68.06, 52.73; HRMS (ESI) m/z calcd for C16H17N2O5
(M+H)+ 317.1137, found 317.1144.
Acknowledgements
We acknowledge generous financial supports from National
NSF of China (21125209, 21332003), and STCSM
(12JC1403800).
Supplementary data
Supplementary data related to this article can be found at
http://www.
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