A new cost-effective Ru-chloramphenicol base derivative catalyst for the asymmetric transfer hydrogenation/dynamic kinetic resolution of N-Boc α-amino-β-ketoesters and its application to the synthesis of the chiral core of vancomycin

Article abstract of DOI:10.1039/c6ra05109j

Herein we describe the application of a series of newly developed Ru-chloramphenicol base derivative complexes as catalysts for the highly diastereo- and enantioselective transfer hydrogenation of N-Boc α-amino-β-ketoesters for the asymmetric synthesis of

Full text of DOI:10.1039/c6ra05109j

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A new cost-effective Ru-chloramphenicol base
derivative catalyst for the asymmetric transfer
hydrogenation/dynamic kinetic resolution of N-
Boc a-amino-b-ketoesters and its application to
the synthesis of the chiral core of vancomycin†
Cite this: RSC Adv., 2016, 6, 37701
*
*
Xinlong Wang, Lingjun Xu, Fangjun Xiong, Yan Wu and Fener Chen
Herein we describe the application of a series of newly developed Ru-chloramphenicol base derivative
complexes as catalysts for the highly diastereo- and enantioselective transfer hydrogenation of N-Boc a-
amino-b-ketoesters for the asymmetric synthesis of anti-N-Boc-b-hydroxy-a-amino esters. This report
highlights the utility of this catalytic methodology for the preparation of pharmaceutical compounds
bearing a N-Boc a-amino-b-hydroxy substructure with two stereocenters.
Received 26th February 2016
Accepted 10th April 2016
DOI: 10.1039/c6ra05109j
www.rsc.org/advances
hydrogenation (ATH) of a-amino-b-keto ester accompanied by
dynamic kinetic resolution (DKR) is considered to be the most
efficient approach.2
Introduction
The stereocontrolled construction of chiral vicinal amino
alcohol motifs remains an active area of research in modern
organic chemistry. Compounds containing this motif not only
represent valuable building blocks, ligands and chiral auxilia-
ries in asymmetric synthesis, but also exhibit a variety of
interesting biological activities. Chiral vicinal amino alcohols
can also be found in a wide range of natural products,
including, for example, (+)-lactacystin, symbioramide, vanco-
mycin antibiotics and sphingosine (Fig. 1).1 Among the
synthetic methods available for the construction of optically
pure vicinal amino alcohol subunits, the asymmetric transfer
In 1989, the Noyori group3 reported the rst asymmetric
transfer hydrogenation of a-acylamino-b-keto esters using a Ru-
(R)-BINAP complex to afford the corresponding syn-selective b-
hydroxyl-a-amino esters with excellent diastereo- and enantio-
selectivity. In a subsequent publication, Genet's group4 reported
the similar results with other sophisticated ligands, such as
MeO-BIPHEP, TsDPEN, SUNPHOS, SYNPHOS. During the last
decade, Hamada and co-workers5 have developed a series of Ru-
catalysts for the anti-selective asymmetric transfer hydrogena-
tion of a-amino-b-keto ester hydrochlorides through a DKR
process to afford the corresponding anti-selective a-amino-b-
hydroxyl esters. Somfai et al.6 recently reported the asymmetric
transfer hydrogenation of a-amido-b-keto esters in water in the
presence of a phase transfer catalyst with an expensive (S,S)-
BnDPAE ligand. Although vicinal amino alcohol can be
prepared in good yields using an ATH/DKR process with high
diastereo- and enantioselectivity, the application of this process
has been limited by its required for expensive ligand. The
development of readily available and in expensive ligands for
preparation of b-hydroxy-a-amino esters via ATH/DKR under
mild reaction conditions is therefore highly desired.
(1S,2S)-2-Amino-1-(4-nitrophenyl)-propane-1,3-diol (chlor-
amphenicol base), which is produced as a chiral waste product
during the manufacture of chloramphenicol,7 has a similar
structure to that of (S,S)-BnDPAE. We previously reported the
use of chloramphenicol base derivatives as a chiral ligand for
the synthesis of orfenicol.8 As part of our ongoing interest in
the stereoselective synthesis of vicinal amino alcohol using an
ATH/DKR approach, we set out to achieve the anti-selective
transfer hydrogenation of a-amido-b-ketoesters with high
Fig. 1 Examples of biologically active molecules containing an anti-
vicinal amino alcohol fragments.
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
People's Republic of China. E-mail: rfchen@fudan.edu.cn; wywin8@163.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra05109j
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Table 1 Screening of the asymmetric transfer hydrogenation of 1a
diastereo- and enantioselectivity using Ru-chloramphenicol
base derivative complex as a catalyst.
with chiral [RuCl2(arene)]2-chloramphenicol base derivative catalystsa
Herein, we describe our recent work towards the use of Ru-
chloramphenicol base derivative complexes as catalysts for
the preparation of anti-N-Boc b-hydroxyl-a-amino esters.
Notably, the transfer hydrogenation strategy described in this
paper was successfully applied to the synthesis of a key inter-
mediate of vancomycin.
Results and discussion
Our initial investigation focused on evaluating various Ru-
chloramphenicol base derivative complexes as catalysts for
the asymmetric transfer hydrogenation of racemic of N-Boc a-
amino-b-ketoesters 1a in the presence of sodium formate (10
equiv.) and Tween 20 (20%) in water at 40 ꢀC (Table 1). All of the
catalysts evaluated in this screen performed effectively to afford
2a with excellent diastereoselectivity (up to 91%) and moderate
enantioselectivity (66%) with high isolated yield. The relative
and absolute stereochemistry of 2a was conrmed by high-
performance liquid chromatography (HPLC) analysis based on
a comparison with an authentic sample.8 The results clearly
showed that the stereochemistry outcome of the reaction is
affected by the nature of chiral ligand. We initially investigated
the impact of the R2 substituent of the ligand on the stereo-
chemical outcome of the reaction. The introduction of an
electron-withdrawing or electron-donating group at the R2
position of the phenyl ring did not lead to an increase in the
diastereo- or enantioselectivity of the reaction (Table 1, entries
1–5). This result could be attributed to unfavored steric
hindrance between the R2 group of ligand and 1a during the
reaction. We subsequently proceeded to investigate the impact
of changing the R1 group to a bulky OTr group. Ligand L8
bearing a proton at R2 led to low level of asymmetric induction
(Table 1, entry 8).
Arene/
Ligand
Temp.
(ꢀC)
Yieldb
(%)
dec
(anti)
eec
(anti, %)
Entry
1
2
3
4
5
6
7
8
9
10
p-Cymene/
L1
p-Cymene/
L2
p-Cymene/
L3
p-Cymene/
L4
p-Cymene/
L5
p-Cymene/
L6
p-Cymene/
L7
p-Cymene/
L8
40
40
40
40
40
40
40
40
40
40
40
82
81
82
82
86
81
74
80
85
88
80
91
88
90
86
87
84
82
85
88
87
82
58
60
66
64
61
60
48
55
43
60
62
Notably, the introduction of [RuCl2(benzene)]2 as a pre-
catalyst led to a slight decrease in the stereoselectivity of 2a
(Table 1, entry 11). Among these catalysts, [RuCl2(p-cymene)]2-
L3 was found to be the most effective for the ATH reaction of 1a,
affording the product 2a with 90% de and 66% ee in 82% yield
(Table 1, entry 3).
p-Cymene/
L9
p-Cymene/
L10
Encouraged by these results, we proceeded to investigate the
effect of varying the phase transfer catalyst (PTC), temperature
and catalyst loading, with the aim of improving the enantio-
selectivity (Table 2). It has been reported that phase transfer
catalysts played a critical role in determining the diastereo- and
enantioselectivity in ATH/DKR reactions.9 several phase trans-
fer catalysts were examined in this transformation in an
attempt to enhance the diastereo- and enantioselectivity. The
addition of PEG-400 or PEG-600 had very little impact on the
stereoselectivity, with the latter leading to a considerable
decrease in the yield (Table 2, entries 4 and 5). Several other
PTCs were also screened, but found to have an adverse impact
on the reaction. We then examined the effect of temperature on
the outcome of reaction and found that reducing the temper-
ature to 25 ꢀC led to an increase in the enantioselectivity of 2a
increased to 74% with [RuCl2(p-cymene)]2-L3 as the catalyst
11
Benzene/L3
a
All of these reactions were carried out with 1a (2 mmol), HCOONa (5
b
c
equiv.) and catalyst (10%) for 48 h. Isolated yield. The diastereo-
and enantioselectivity were determined by HPLC analysis with
a Daicel Chiralcel AD-H column.
(Table 2, entries 8–11). However, further reducing of the
temperature to 20 C led to a slight decrease in the de, ee and
ꢀ
yield of 2a. Decreasing of the catalyst loading lead to a signi-
cant decrease of the enantioselectivity. It is noteworthy that
increasing the catalyst loading caused nearly no increase of the
enantioselectivity of the reaction (Table 2, entries 12 and 13).
It has been shown that the pH value can affect the reaction
rate and stereoselectivity of ATH in water.10 Under present
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Table 2 Optimization of the reaction conditions for the ATH of 1a with [RuCl2(p-cymene)]2-L3 complexa
Entry
PTC
Temp. (ꢀC)
Catalyst loading
Yieldb (%)
dec (anti)
eec (%)
1
2
3
4
5
6
7
8
Tween 20
SDS
CTAB
PEG-400
PEG-600
TBAB
40
40
40
40
40
40
40
35
30
25
20
25
25
10
10
10
10
10
10
10
10
10
10
10
5
82
60
54
75
52
35
41
74
75
80
76
76
80
90
70
80
87
86
72
80
92
88
92
91
90
92
66
40
51
63
61
42
55
69
72
74
71
64
75
TEBAC
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
9
10
11
12
13
20
a
b
c
All of these reactions were carried out with 1a (2 mmol), HCOONa (5 equiv.) and catalyst (10%) for 48 h. Isolated yield. The diastereo- and
enantioselectivity were determined by HPLC analysis with a Daicel Chiralcel AD-H column.
Table 3 Effect of initial pH values of the solution on the ATH of 1a
using a series of different a-amido-b-ketoesters 1a–m (Table
catalyzed by [RuCl2(p-cymene)]2-L3 complexa
4). All of these substrates reacted efficiently to afford the
corresponding chiral vicinal amino alcohol 2a–m as the anti-
Entry
pH
Conv. (%) (h)
dec (%)
eec (%)
products in good yield with excellent diastereoselectivity and
good enantioselectivity. Notably, the introduction of
a methyl group at the ortho- or meta-position of the phenyl
ring of the substrate resulted in a signicant decrease in the
enantioselectivity (Table 4, entries 2–4). This decrease in the
enantioselectivity was attributed to steric hindrance between
the catalytic complex and the substituents at these positions.
Notably, the introduction of a bulky tert-butyl group at the
para-position of the phenyl ring had very little impact on the
diastereoselectivity and enantioselectivity (Table 4, entries 4
and 5). Electron-withdrawing and electron-donating
substituents at the para-position both resulted in high
yields and good enantioselectivities (Table 4, entries 6–9).
Specically, the 4-bromo substrate 1h gave the highest ee
value of all of the substrates tested in the current study (up to
87%, Table 4, entry 8). However, the replacement of the 4-
bromo group with a more strongly electron-withdrawing 4-
nitro group led to a slightly lower enantioselectivity (Table 4,
entry 9). The cyclohexyl substrate 1j (Table 4, entry 10) gave
a slightly lower yield and enantioselectivity than its aromatic
counterpart 1a.
1
2
3
4
5
6
7
2.0
3.0
4.0
5.0
6.0
7.0
8.0b
15 (48 h)
60 (48 h)
72 (48 h)
90 (12 h)
99 (12 h)
95 (24 h)
86 (24 h)
—
—
80
94
96
93
92
—
—
70
75
79
74
71
a
All of these reaction were carried out with substrate (2 mmol), catalyst
(10%), tween 20 (20%) in water with a HCOOH–HCOONa buffer. b This
reaction was carried out at pH 8.0 in HCOONa–NaOH buffer.
c
Determined by HPLC analysis with a Daicel Chiralcel AD-H.
conditions, the initial pH value of the reaction mixture was
about 7 and this transfer hydrogenation of 1a was sluggish. So
we intend to improve the reaction rate of 1a by adjusting pH
value and the results were shown in Table 3. We found that the
reaction rate of 1a was indeed strongly affected by the pH values
of the solution, with the maximum conversion in 12 h observed
at pH 6.0 (Table 3, entry 5) and little compromise in stereo-
selectivity. Deviating from pH 6.0 for [RuCl2(p-cymene)]2-L3
resulted in rapid decrease in the reduction rates.
Based on these results, the optimized reaction conditions
were determined to be as follows: 10 mol% of [RuCl2(p-
cymene)]2-L3 as the catalyst, Tween 20 as the phase transfer
catalyst with HCOOH–HCOONa buffer (pH 6.0) at 25 ꢀC for 12 h.
With optimized conditions in hand, we proceeded to
examine the scope of this Ru-catalyzed ATH/DKR reaction
Heteroaromatics substrates performed poorly under the
optimized conditions, as exemplied by the furan and thio-
phene substrates 1l and 1m, which both resulted in low dia-
stereoselectivity observed in these cases could be explained by
the heteroatoms of these ring forming six-membered cyclic
intermediate in combination with the Ru-chloramphenicol base
derivative complex.4g
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Table 4 anti-Selective asymmetric hydrogenation catalyzed by Ru-L3
complexa
Entry
1
ATH product 2
Yieldb (%)
80
dec (anti)
eed (anti, %)
96
79
2
3
79
80
93
96
43
68
4
5
6
7
8
85
80
92
88
85
90
94
89
94
90
73
79
71
78
87
Scheme 1 Reagent and conditions: (a) SOCl2, DMF (cat.), DCM, reflux.,
3 h; (b) glycine ethyl ester hydrochloride, Na2CO3, EA/H2O, r.t., 2 h; (c)
Boc2O, DMAP (cat.), CH3CN, r.t., 10 h; (d) t-BuOK, THF, 10 ꢀC, 1 h, 63%
(over 4 steps); (e) [RuCl2(p-cymene)]2, Tween 20, HCOONa, H2O, 25
ꢀC, 48 h, 88%, 76% of ee and 95% of de; (f) TFA, DCM, 0 to 20 ꢀC, 4 h,
91%, 99% of ee and 99% of de after crystallized from MTBE.
antibiotic agent vancomycin12,13 (Scheme 1). Briey, 4-
(benzyloxy)-3-chlorobenzoic acid 4 was prepared according to
a literature procedure.12 The subsequent treatment of 4 with
thionyl chloride in reuxing dichloromethane in the presence
of a catalytic amount of DMF afforded the corresponding acyl
chloride 5. The treatment of 5 with glycine, followed by the N-
Boc-protection of the resulting amide gave the N-Boc a-amino-
b-ketoesters 8.11 The ATH/DKR reaction of 8 under our opti-
mized condition afford compound 9 with 76% ee and 95% of
de in 88% yield. The optical purity of 9 was improved to 92%
by recrystallized from petroleum ether/ethyl acetate (1/1, v/v).
The subsequent deprotection of the Boc group in 9 with TFA
in dichloromethane at room temperature to give the anti-
(2S,3S) amino alcohol 3 in 91% yield. Aer crystallized from
MTBE, the desired 3 was obtained with 99% of ee and
99% of de.
9
88
96
67
10
11
12
81
87
85
82
94
63
68
82
60
13
79
80
66
Conclusions
a
All of these reactions were carried out with substrate 1a–m (2 mmol),
catalyst (10%), Tween 20 (20%) HCOONa–HCOOH (pH 6.0, 5 equiv.) at
In conclusion, we have successfully developed a novel series of
readily available Ru-chloramphenicol base derivative complexes
as catalysts for the ATH/DKR of N-Boc a-amino-b-ketoester to
afford anti-selective N-Boc b-hydroxyl-a-amino esters with
excellent diastereoselectivity and good enantioselectivity. This
protocol showed good functional group tolerance towards
a wide variety of aromatic, heteroaromatic and alkyl substrates.
The utility of this methodology was demonstrated by its appli-
cation to the stereoselective synthesis of a key building block in
the preparation of the antibiotic vancomycin.
25 ꢀC for 12 h. Isolated yield. Determined by 1H NMR analysis.
b
c
d
Determined by HPLC analysis with a Daicel Chiralcel AD-H or OD-H
column.
To demonstrate the utility of the methodology developed in
this study, we investigated its application to the synthesis of 3,
which is a key building block in the construction of the
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Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butyl)phenyl)-
Experimental section
3-oxopropanoate (1e). The compound 1e was prepared in 69%
ꢀ
All reagents and solvent were obtained from commercial sour- yield as a white solid. Mp 118.0–120.3 C. FT-IR (ATR): n 3341,
ces and used without further purication. 1H (400 MHz) and 13
C
2972, 1757, 1674, 1603, 1518, 1288, 1155, 1053, 842, 615. 1H
(100 MHz) NMR were recorded on a Bruker Avance 400 spec- NMR (400 MHz, CDCl3): d ¼ 8.06 (d, J ¼ 8.4 Hz, 2H), 7.51 (d, J ¼
trometer using TMS or CDCl3 as internal standards, IR spectra 8.4 Hz, 2H), 5.95 (s, 2H), 4.17–4.20 (m, 2H), 1.47 (s, 9H), 1.36 (s,
were recorded on a Nicolet iS5 FT-IR spectrometer, optical 9H), 1.16 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼
rotations were measured by a JASCO P1020 digital polarimeter. 191.0, 167.0, 158.1, 154.8, 131.3, 129.8, 129.3, 125.5, 125.2, 80.3,
EI-MS were recorded on an Agilent 6890N/5975 spectrometer 62.0, 59.1, 35.1, 30.9, 30.8, 28.0, 13.7. HRMS (ESI) calcd for
and ESI-MS were recorded on a Waters Micromass Quattro
Micro spectrometer. The pH values were recorded on a PHS-3C.
HRMS were recorded on a Bruker microTOF spectrometer.
C
20H29NNaO5 [M + Na]+ 386.1943, found 386.1943.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)-3-
oxopropanoate (1f). The compound 1f was prepared in 74%
yield as a white solid. Mp 60.1–62.3 ꢀC. FT-IR (ATR): n 3324,
2977, 1748, 1674, 1600, 1535, 1266, 1158, 1033, 947, 840, 587. 1H
NMR (400 MHz, CDCl3): d ¼ 8.10 (d, J ¼ 8.8 Hz, 2H), 6.96 (d, J ¼
8.8 Hz, 2H), 5.95 (d, J ¼ 7.6 Hz, 1H), 5.88 (d, J ¼ 8.0 Hz, 1H),
4.16–4.19 (m, 2H), 3.89 (s, 3H), 1.46 (s, 9H), 1.16 (t, J ¼ 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): d ¼ 189.3, 166.7, 163.9, 154.4,
131.4, 126.4, 113.3, 79.8, 61.6, 58.5, 54.9, 27.6, 13.3. HRMS (ESI)
calcd for C17H23NNaO6 [M + Na]+ 360.1423, found 360.1434.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-(methylthio)phenyl)-
3-oxopropanoate (1g). The compound 1g was prepared in 70%
yield as a white solid. Mp 83.0–84.5 ꢀC. FT-IR (ATR): n 3324,
2977, 1748, 1674, 1600, 1535, 1266, 1158, 1033, 947, 840, 587. 1H
NMR (400 MHz, CDCl3): d ¼ 8.02 (d, J ¼ 8.4 Hz, 2H), 7.29 (d, J ¼
8.8 Hz, 2H), 5.88–5.93 (m, 2H), 4.17–4.20 (m, 2H), 2.55 (s, 3H),
1.47 (s, 9H), 1.17 (t, J ¼ 7.2 Hz, 3H) 13C NMR (100 MHz, CDCl3):
d ¼ 189.9, 166.6, 154.4, 147.4, 129.3, 124.2, 79.9, 61.7, 58.6, 27.7,
14.0, 13.3. HRMS (ESI) calcd for C17H23NNaO5S [M + Na]+
376.1195, found 376.1196.
General procedure for the preparation of transfer
hydrogenation substrates 1a–m
1a–m was synthesized according to known procedure from the
corresponding acid.11
Ethyl-2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropa-
noate (1a). The compound 1a was prepared in 70% yield as
a white solid. Mp 68.0–69.2 ꢀC. FT-IR (ATR): n 3358, 2980, 2946,
1751, 1680, 1521, 1288, 1158, 1030, 942, 891, 698, 590. 1H NMR
(400 MHz, CDCl3): d ¼ 7.49–8.13 (m, 5H), 5.95 (s, 2H), 4.16–4.20
(m, 2H), 1.47 (s, 9H), 1.14 (t, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d ¼ 191.3, 166.4, 154.4, 133.6, 128.9, 128.1, 79.9, 61.7,
58.8, 27.6, 13.2. HRMS (ESI) calcd for C16H21NNaO5 [M + Na]+
330.1317, found 330.1310.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-oxo-3-(o-tolyl)prop-
anoate (1b). The compound 1b was prepared in 68% yield as
a white solid. Mp 56.0–58.0 ꢀC. FT-IR (ATR): n 3355, 2969, 1754,
1680, 1515, 1331, 1280, 1158, 1013, 729, 584. 1H NMR (400 MHz,
CDCl3): d ¼ 7.86 (d, J ¼ 7.6 Hz, 1H), 7.25–7.44 (m, 3H), 5.92 (d, J
¼ 6.8 Hz, 1H), 5.79 (d, J ¼ 7.6 Hz, 1H), 4.05–4.16 (m, 2H), 2.45 (s,
3H), 1.45 (s, 9H), 1.05 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d ¼ 194.8, 166.7, 154.8, 139.0, 134.8, 132.1, 131.6, 129.4,
125.5, 80.3, 61.9, 53.2, 28.0, 20.7, 13.6. HRMS (ESI) calcd for
Ethyl-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)-3-
oxopropanoate (1h). The compound 1h was prepared in 78%
yield as a white solid. Mp 101.0–102.8 C. FT-IR (ATR): n 3329,
ꢀ
1
2983, 1757, 1677, 1586, 1527, 1288, 1158, 1055, 950. H NMR
(400 MHz, CDCl3): d ¼ 7.97 (d, J ¼ 8.4 Hz, 2H), 7.65 (d, J ¼ 8.4
Hz, 2H), 5.89 (s, 2H), 4.17–4.20 (m, 2H), 1.46 (s, 9H), 1.16 (t, J ¼
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 191.0, 166.6, 154.8,
132.9, 131.9, 130.7, 129.5, 80.6, 62.3, 59.2, 28.0, 13.7. HRMS
(ESI) calcd for C16H20BrNNaO5 [M + Na]+ 408.0423, found
408.0429.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)-3-
oxopropanoate (1i). The compound 1i was prepared in 78%
yield as a yellow solid. Mp 62.0–64.5 ꢀC. FT-IR (ATR): n 3327,
2986, 1751, 1677, 1524, 1334, 1155, 1058, 868, 851, 703, 598. 1H
NMR (400 MHz, CDCl3): d ¼ 8.34 (d, J ¼ 8.8 Hz, 2H), 8.26 (d, J ¼
8.8 Hz, 2H), 5.88 (s, 2H), 4.20–4.22 (m, 2H), 1.46 (s, 9H), 1.16 (t, J
¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 191.2, 166.0,
154.7, 150.6, 138.9, 130.2, 123.6, 80.8, 62.6, 61.1, 59.5, 28.0, 13.6.
HRMS (ESI) calcd for C16H20N2NaO7 [M + Na]+ 375.1168, found
375.1188.
C
17H23NNaO5 [M + Na]+ 344.1474, found 344.1489.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-oxo-3-(m-tolyl)prop-
anoate (1c). The compound 1c was prepared in 75% yield as
a white solid. Mp 70.2–72.1 ꢀC. FT-IR (ATR): n 3344, 2977, 1757,
1683, 1521, 1282, 1197, 1152, 953, 729. 1H NMR (400 MHz,
CDCl3): d ¼ 7.91 (s, 2H), 7.39–7.45 (m, 3H), 5.95 (s, 2H), 4.14–
4.19 (m, 2H), 2.43 (s, 3H), 1.47 (s, 9H), 1.15 (t, J ¼ 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): d ¼ 191.8, 166.9, 154.8, 138.4,
134.9, 134.0, 129.8, 128.4, 126.6, 80.4, 62.1, 59.3, 28.0, 21.1, 13.7.
HRMS (ESI) calcd for C17H23NNaO5 [M + Na]+ 344.1474, found
344.1467.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-oxo-3-(p-tolyl)prop-
anoate (1d). The compound 1d was prepared in 70% yield as
a white solid. Mp 92.6–94.0 ꢀC. FT-IR (ATR): n 3327, 2983, 1757,
1677, 1603, 1527, 1291, 1160, 1055, 947, 828, 737, 621. 1H NMR
(400 MHz, CDCl3): d ¼ 8.01 (d, J ¼ 8.0 Hz, 2H), 7.29 (d, J ¼ 8.0
Hz, 2H), 5.93 (s, 2H), 4.14–4.19 (m, 2H), 2.44 (s, 3H), 1.46 (s, 9H),
1.15 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 191.3,
167.5, 155.3, 145.7, 131.9, 129.9, 129.6, 80.7, 62.5, 59.6, 28.5,
22.0, 14.1. HRMS (ESI) calcd for C17H23NNaO5 [M + Na]+
344.1474, found 344.1482.
Ethyl-2-((tert-butoxycarbonyl)amino)-3-cyclohexyl-3-oxopro-
panoate (1j). The compound 1j was prepared in 66% yield as
a oil. FT-IR (ATR): n 3358, 2975, 1748, 1660, 1518, 1197, 1053,
947, 723, 587. 1H NMR (400 MHz, CDCl3): d ¼ 5.70 (d, J ¼ 6.8 Hz,
1H), 5.12 (d, J ¼ 7.6 Hz, 1H), 4.21–4.27 (m, 2H), 2.76–2.79 (m,
1H), 1.97–1.93 (m, 1H), 1.69–1.78 (m, 5H), 1.46 (s, 9H), 1.26–1.30
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(m, 7H). 13C NMR (100 MHz, CDCl3): d ¼ 189.9, 167.1, 155.1, yield as a white solid. Mp 88.0–89.2 ꢀC. HPLC (Daicel AD-H,
80.6, 62.5, 62.4, 48.5, 43.0, 28.4, 25.9, 25.3, 14.2. HRMS (ESI) hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225 nm,
calcd for C16H27NNaO5 [M + Na]+ 336.1787, found 336.0883.
30 ꢀC): anti: tR (major) ¼ 14.1 min, tR (minor) ¼ 15.1 min; syn: tR
Ethyl-3-(benzo[d][1,3]dioxol-5-yl)-2-((tert-butoxycarbonyl) ¼ 16.4 min, tR ¼ 17.4 min. FT-IR (ATR): n 3466, 3321, 2975, 1723,
amino)-3-oxopropanoate (1k). The compound 1k was prepared 1677, 1504, 1294, 1186, 1158, 1007, 871, 703. 1H NMR (400 MHz,
in 52% yield as a white solid. Mp 100.0–101.0 ꢀC. FT-IR (ATR): n CDCl3): d ¼ 7.28–7.35 (m, 5H), 5.33 (d, J ¼ 6.0 Hz, 1H), 5.21 (s,
3321, 2977, 1762, 1669, 1532, 1441, 1370, 1263, 1158, 1030, 930, 1H), 4.71 (s, 1H), 4.13–4.19 (q, 2H), 4.07 (s, 1H), 1.45 (s, 9H), 1.19
837, 567. 1H NMR (400 MHz, CDCl3): d ¼ 7.79 (d, J ¼ 8.0 Hz, 1H), (t, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 169.7, 156.3,
7.55 (s, 1H), 6.89 (d, J ¼ 8.4 Hz, 1H), 6.08 (s, 1H), 5.92 (d, J ¼ 8.0 139.2, 128.1, 126.0, 80.5, 75.0, 61.6, 59.7, 28.2, 13.9. HRMS (ESI)
Hz, 1H), 5.83 (d, J ¼ 8.4 Hz, 1H), 4.17–4.21 (m, 2H), 1.46 (s, 9H), calcd for C16H23NNaO5 [M + Na]+ 332.1474, found 332.1473.
1.18 (t, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 189.9,
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(o-
167.5, 155.3, 153.2, 148.6, 129.1, 126.9, 109.1, 108.3, 102.4, 80.8, tolyl)propanoate (2b). The compound 2b was prepared in 80%
ꢀ
62.5, 59.4, 28.5, 14.2. HRMS (ESI) calcd for C17H25NNaO7 [M + yield afford 2b (3.3 g, 85%) as a white solid. Mp 90.0–91.5 C.
Na]+ 374.1216, found 374.1218.
HPLC (Daicel AD-H, hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1
,
Ethyl-2-((tert-butoxycarbonyl)amino)-3-(furan-2-yl)-3-oxopro- detection at 225 nm, 30 ꢀC): tR (major) ¼ 13.3 min, tR (minor) ¼
panoate (1l). The compound 1l was prepared in 76% yield as 16.4 min. FT-IR (ATR): n 3471, 3381, 2983, 1697, 1515, 1376,
a white solid. Mp 84.2–85.7 ꢀC. FT-IR (ATR): n 3366, 3139, 2989, 1189, 1160, 1061, 752, 519. 1H NMR (400 MHz, CDCl3): d ¼ 7.39–
1748, 1657, 1512, 1329, 1158, 1050, 777, 590. 1H NMR (400 MHz, 7.41 (m, 1H), 7.13–7.21 (m, 3H), 5.56 (d, J ¼ 7.2 Hz, 1H), 5.27 (s,
CDCl3): d ¼ 7.70 (s, 1H), 7.49 (s, 1H), 6.60 (t, J ¼ 1.6 Hz, 1H), 5.83 1H), 4.56 (s, 1H), 3.99–4.07 (m, 2H), 3.51 (s, 1H), 2.37 (s, 3H),
(d, J ¼ 7.6 Hz, 1H), 5.68 (d, J ¼ 8.0 Hz, 1H), 4.17–4.22 (m, 2H), 1.44 (s, 9H), 1.04 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
1.45 (s, 9H), 1.18 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 170.3, 155.3, 137.4, 134.6, 130.2, 127.5, 125.6, 80.0, 71.4,
d ¼ 179.7, 166.5, 154.7, 150.1, 147.9, 120.7, 112.6, 80.4, 62.2, 61.1, 57.7, 53.2, 28.0, 18.8, 13.5. HRMS (ESI) calcd for
59.2, 28.0, 13.7. HRMS (ESI) calcd for C14H19NNaO6 [M + Na]+
320.1110, found 320.1117.
C
17H25NNaO5 [M + Na]+ 346.1630, found 346.1620.
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(m-
Ethyl-2-((tert-butoxycarbonyl)amino)-3-oxo-3-(thiophen-2-yl) tolyl)propanoate (2c). The compound 2c was prepared in 76%
propanoate (1m). The compound 1m was prepared in 75% yield yield as a white solid. Mp 75.4–76.8 ꢀC. HPLC (Daicel AD-H,
as a white solid. Mp 74.0–75.5 C. (Lit.3 mp 75.5–76 C). FT-IR hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225 nm,
(ATR): n 3358, 2975, 1748, 1660, 1518, 1197, 1053, 947, 723, 30 ꢀC): tR (major) ¼ 13.3 min, tR (minor) ¼ 16.4 min. FT-IR
587. 1H NMR (400 MHz, CDCl3): d ¼ 8.07 (d, J ¼ 3.6 Hz, 1H), 7.77 (ATR): n 3466, 3335, 2977, 1731, 1677, 1512, 1370, 1291, 1158,
ꢀ
ꢀ
1
(d, J ¼ 4.8 Hz, 1H), 7.18 (t, J ¼ 4.8 Hz, 1H), 5.90 (d, J ¼ 7.6 Hz, 1016, 791. H NMR (400 MHz, CDCl3): d ¼ 7.21–7.25 (m, 1H),
1H), 5.75 (d, J ¼ 8.4 Hz, 1H), 4.19–4.24 (m, 2H), 1.46 (s, 9H), 1.20 7.06–7.11 (m, 3H), 5.33 (d, J ¼ 6.4 Hz, 1H), 5.18 (s, 1H), 4.67 (s,
(t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 183.9, 166.7, 1H), 4.14–4.19 (m, 2H), 4.05 (s, 1H), 2.35 (s, 3H), 1.46 (s, 9H),
154.7, 140.8, 135.8, 134.9, 128.3, 80.4, 62.3, 60.1, 28.0, 13.7. 1.19 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 169.6,
HRMS (ESI) calcd for C14H19NNaO5S [M + Na]+ 336.0882, found 156.2, 139.0, 137.6, 128.5, 127.9, 126.5, 122.9, 80.3, 74.9, 61.4,
336.0888.
59.6, 53.2, 28.0, 21.2, 13.8. HRMS (ESI) calcd for C17H25NNaO5
[M + Na]+ 346.1630, found 346.1612.
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(p-
tolyl)propanoate (2d). The compound 2d was prepared in 84%
General procedure for the ATH/DKR procedure (2a–m)
A mixture of [RuCl2(p-cymene)]2 (31 mg, 0.05 mmol), ligand L3 yield as a white solid. Mp 94.0–95.1 ꢀC. HPLC (Daicel AD-H,
(42 mg, 0.1 mmol), Tween 20 (69 mg, 0.2 mmol) and water (5 hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225 nm,
mL) were stirred at 40 C under N2 for 2 h and cooled to room 30 ꢀC): tR (major) ¼ 13.7 min, tR (minor) ¼ 15.2 min. FT-IR
ꢀ
temperature, 1a–m (1 mmol) and HCOOH–HCOONa buffer (pH (ATR): n 3471, 3332, 2975, 1725, 1680, 1521, 1370, 1291, 1160,
6.0, 5 mmol) were added. The reaction mixture was stirred at 25 1010, 825, 541. 1H NMR (400 MHz, CDCl3): d ¼ 7.16 (s, 4H), 5.30
ꢀC for 12 h. Ethyl acetate (10 mL) was added to the reaction (d, J ¼ 6.0 Hz, 1H), 5.17 (s, 1H), 4.68 (s, 1H), 4.14–4.19 (q, 2H),
mixture and stirred for 30 min. The organic layer was separated, 4.00 (s, 1H), 2.34 (s, 3H), 1.45 (s, 9H), 1.20 (t, J ¼ 7.2 Hz, 3H). 13
C
the aqueous layer was extracted with ethyl acetate (10 mL ꢁ 3), NMR (100 MHz, CDCl3): d ¼ 169.3, 155.8, 137.0, 135.6, 128.4,
and the combined organic layers were washed with brine (20 128.3, 125.4, 79.9, 74.3, 61.1, 59.2, 27.6, 20.5, 13.4. HRMS (ESI)
mL), dried over MgSO4, ltered, and evaporated in vacuo, and calcd for C17H25NNaO5 [M + Na]+ 346.1630, found 346.1640.
the crude product was puried by ash chromatography
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-(tert-butyl)
(petroleum ether/ethyl acetate 3 : 1, v/v) to give 2a–m (Y ¼ 79– phenyl)-3-hydroxypropanoate (2e). The compound 2e was
92%).
prepared in 80% yield as a oil. HPLC (Daicel AD-H, hexane/i-
For the synthesis of the racemic amino alcohols for the ee PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225 nm, 30 C): tR
ꢀ
assay, the TsDPEN ligand (0.2 equiv.) and [RuCl2(p-cymene)]2 (major) ¼ 11.6 min, tR (minor) ¼ 13.5 min. FT-IR (ATR): n 3437,
(0.1 equiv.) were used as the catalyst and the reaction was run at 2963, 1697, 1510, 1365, 1251, 1158, 1021, 859, 573. 1H NMR (400
45 C following the procedure outlined above.6
MHz, CDCl3): d ¼ 7.34 (d, J ¼ 8.0 Hz 2H), 7.21 (d, J ¼ 7.6 Hz 2H),
ꢀ
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3- 5.33 (s, 1H), 5.15 (s, 1H), 4.67 (s, 1H), 4.11–4.17 (m, 2H), 3.86 (d,
phenylpropanoate (2a). The compound 2a was prepared in 90% J ¼ 4.4 Hz 1H), 1.44 (s, 9H), 1.31 (s, 9H), 1.15 (t, J ¼ 7.2 Hz, 3H).
37706 | RSC Adv., 2016, 6, 37701–37709
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13C NMR (100 MHz, CDCl3): d ¼ 171.1, 169.9, 156.1, 150.8, hexane/i-PrOH ¼ 90/10, 0.6 mL minꢂ1, detection at 210 nm,
136.1, 125.7, 80.3, 74.7, 61.5, 60.3, 59.5, 34.4, 31.2, 28.2, 20.9, 30 ꢀC): tR (major) ¼ 14.0 min, tR (minor) ¼ 17.0 min. FT-IR
13.8. HRMS (ESI) calcd for C20H31NNaO5 [M + H]+ 388.2100, (ATR): n 2929, 2853, 1697, 1498, 1365, 1254, 1160, 1027, 553.
found 388.2097.
1H NMR (400 MHz, CDCl3): d ¼ 5.56 (d, J ¼ 6.8 Hz, 1H), 4.43 (d, J
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4- ¼ 4.8 Hz, 1H), 4.15–4.27 (m, 2H), 3.50 (s, 1H), 2.79 (s, 1H), 2.02
methoxyphenyl)propanoate (2f). The compound 2f was (s, 1H), 1.66–1.76 (m, 4H), 1.43 (s, 9H), 0.99–1.28 (m, 8H). 13C
prepared in 92% yield as a white solid. Mp 101.5–102.0 ꢀC. NMR (100 MHz, CDCl3): d ¼ 171.0, 155.4, 79.8, 61.2, 55.6, 40.5,
HPLC (Daicel AD-H, hexane/i-PrOH ¼ 90/10, 0.6 mL minꢂ1
,
28.0, 26.0, 25.5, 13.9. HRMS (ESI) calcd for C16H29NNaO5 [M +
detection at 254 nm, 30 ꢀC): tR (major) ¼ 30.1 min, tR (minor) ¼ H]+ 338.1943, found 338.1958.
31.0 min. FT-IR (ATR): n 3361, 2983, 1746, 1688, 1612, 1512,
(2S,3S)-Ethyl-3-(benzo[d][1,3]dioxol-5-yl)-2-((tert-butoxyca-
1362, 1246, 1155, 999, 828, 539. 1H NMR (400 MHz, CDCl3): d ¼ rbonyl)amino)-3-hydroxypropanoate (2k). The compound 2k
ꢀ
7.20 (d, J ¼ 8.4 Hz, 2H), 6.86 (d, J ¼ 8.4 Hz, 2H), 5.29 (d, J ¼ 7.6 was prepared in 86% yield as a white solid. Mp 70.3–72.3 C.
Hz, 1H), 5.15 (s, 1H), 4.66 (s, 1H), 4.14–4.19 (q, 2H), 3.96 (s, 1H), HPLC (Daicel AD-H, hexane/i-PrOH ¼ 85/15, 0.8 mL minꢂ1
,
3.80 (s, 3H), 1.45 (s, 9H), 1.21 (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 detection at 230 nm, 30 ꢀC): tR (major) ¼ 16.5 min, tR (minor) ¼
MHz, CDCl3): d ¼ 170.1, 159.6, 156.6, 113.9, 80.8, 74.9, 61.9, 17.0 min. FT-IR (ATR): n 3466, 3321, 2980, 1720, 1686, 1504,
1
60.0, 55.5, 28.5, 14.3. HRMS (ESI) calcd for C17H25NNaO6 [M + 1370, 1229, 1158, 1030, 1007, 925. H NMR (400 MHz, CDCl3):
Na]+ 362.1580, found 362.1587.
d ¼ 6.80 (s, 1H), 6.71–6.75 (m, 2H), 5.94 (s, 2H), 5.32 (d, J ¼ 7.2
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4- Hz 1H), 5.10 (s, 1H), 4.62 (s, 1H), 4.10–4.19 (m, 2H), 1.44 (s, 9H),
(methylthio)phenyl)propanoate (2g). The compound 2g was 1.21 (t, J ¼ 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 171.1,
prepared in 88% yield as a brown solid. Mp 116.0–117.4 ꢀC. 169.6, 156.3, 147.5, 147.1, 133.2, 119.4, 107.8, 106.7, 100.9, 80.5,
HPLC (Daicel OD-H, hexane/i-PrOH ¼ 95/5, 0.5 mL minꢂ1
,
74.7, 61.6, 60.3, 59.7, 28.1, 20.9, 13.9. HRMS (ESI) calcd for
detection at 254 nm, 30 ꢀC): tR (major) ¼ 18.5 min, tR (minor) ¼
C
17H23NNaO7 [M + H]+ 376.1372, found 376.1366.
19.8 min. FT-IR (ATR): n 3364, 2980, 1740, 1686, 1510, 1248,
(2S,3R)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-(furan-2-yl)-
1
1152, 1001, 820, 666. H NMR (400 MHz, CDCl3): d ¼ 7.21 (s, 3-hydroxypropanoate (2l). The compound 2l was prepared in
4H), 5.31 (d, J ¼ 6.0 Hz, 2H), 5.17 (s, 1H), 4.67 (s, 1H), 4.14–4.19 85% yield as a oil. HPLC (Daicel AD-H, hexane/i-PrOH ¼ 90/10,
(q, 2H), 4.11 (s, 1H), 2.48 (s, 3H), 1.45 (s, 9H), 1.20 (t, J ¼ 7.2 Hz, 0.6 mL minꢂ1, detection at 210 nm, 30 C): tR (major) ¼ 19.2
ꢀ
3H). 13C NMR (100 MHz, CDCl3): d ¼ 169.9, 156.7, 138.4, 136.4, min, tR (minor) ¼ 21.2 min. FT-IR (ATR): n 3403, 2977, 1703,
1
126.9, 80.9, 75.0, 62.0, 60.0, 28.5, 16.0, 14.3. HRMS (ESI) calcd 1504, 1370, 1163, 1058, 1027, 740. H NMR (400 MHz, CDCl3):
for C17H25NNaO5S [M + Na]+ 378.1351, found 378.1349.
d ¼ 7.34 (d, J ¼ 6.4 Hz, 2H), 6.30–6.32 (m, 2H), 5.44 (d, J ¼ 6.8
(2S,3S)-Ethyl-3-(4-bromophenyl)-2-((tert-butoxycarbonyl) Hz, 1H), 5.17 (s, 1H), 4.72 (s, 1H), 4.16–4.20 (m, 2H), 1.43 (s, 9H),
amino)-3-hydroxypropanoate (2h). The compound 2h was 1.20 (t, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 169.4,
prepared in 88% yield as a white solid. Mp 123.0–124.2 ꢀC. 156.2, 152.7, 152.5, 142.1, 110.0, 107.4, 80.4, 69.2, 68.3, 61.6,
HPLC (Daicel OD-H, hexane/i-PrOH ¼ 95/5, 0.5 mL minꢂ1
,
58.0, 28.0, 13.8. HRMS (ESI) calcd for C14H21NNaO6 [M + Na]+
detection at 254 nm, 30 ꢀC): tR (major) ¼ 15.4 min, tR (minor) ¼ 322.1267, found 322.1263.
16.4 min. FT-IR (ATR): n 3389, 2986, 1697, 1515, 1251, 1158,
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-
1030, 1004, 823. 1H NMR (400 MHz, CDCl3): d ¼ 7.46 (d, J ¼ 8.0 (thiophen-2-yl)propanoate (2m). The compound 2m was
ꢀ
Hz, 2H), 7.16 (d, J ¼ 8.0 Hz, 1H), 5.33 (d, J ¼ 6.4 Hz, 1H), 5.18 (s, prepared in 79% yield as a oil. Mp 70.0–71.1 C. HPLC (Daicel
1H), 4.67 (s, 1H), 4.27 (s, 1H), 4.15–4.20 (q, 2H), 1.45 (s, 9H), 1.21 AD-H, hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225
(t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 169.7, 156.8, nm, 30 ꢀC): tR (major) ¼ 16.3 min, tR (minor) ¼ 17.9 min. FT-IR
138.7, 131.5, 128.1, 122.1, 81.1, 74.9, 62.2, 59.9, 28.5, 14.3. (ATR): n 3446, 3324, 2977, 1723, 1680, 1524, 1291, 1160, 999,
HRMS (ESI) calcd for C16H22BrNNaO5 [M + Na]+ 410.0579, found 703. H NMR (400 MHz, CDCl3): d ¼ 7.26–7.27 (m, 1H), 6.90–
1
410.0563.
7.05 (m, 2H), 5.48 (s, 1H), 5.41–5.42 (m, 1H), 4.76 (s, 1H), 4.53 (s,
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(4- 1H), 4.18–4.24 (m, 2H), 1.46 (s, 9H), 1.25 (t, J ¼ 7.2 Hz, 3H). 13
C
nitrophenyl)propanoate (2i). The compound 2i was prepared in NMR (100 MHz, CDCl3): d ¼ 170.3, 169.0, 156.6, 142.6, 126.4,
ꢀ
95% yield as a yellow solid. Mp 107.7–108.4 C. HPLC (Daicel 124.9, 124.0, 80.7, 71.8, 70.4, 61.8, 61.6, 59.4, 28.0, 13.8. HRMS
OD-H, hexane/i-PrOH ¼ 90/10, 0.8 mL minꢂ1, detection at 225 (ESI) calcd for C14H21NNaO5S [M + H]+ 338.1038, found
ꢀ
nm, 30 C): tR (major) ¼ 8.9 min, tR (minor) ¼ 10.9 min. FT-IR 338.1047.
(ATR): n 3392, 2989, 1686, 1515, 1348, 1246, 1155, 1033, 840,
Ethyl-2-(4-(benzyloxy)-3-chlorobenzamido)acetate (6). To
709, 573. 1H NMR (400 MHz, CDCl3): d ¼ 8.20 (d, J ¼ 8.4 Hz, 2H), a stirred suspension of Na2CO3 (4.0 g, 37.7 mmol) in water (60
7.48 (d, J ¼ 8.4 Hz, 1H), 5.40 (d, J ¼ 6.4 Hz, 1H), 5.34 (s, 1H), 4.72 mL) and ethyl acetate (50 mL) was added glycine ethyl ester
(s, 1H), 4.55 (s, 1H), 4.18–4.23 (q, 2H), 1.46 (s, 9H), 1.22 (t, J ¼ 7.2 hydrochloride (4.8 g, 34.3 mmol) at 0 ꢀC in portions over 30 min.
Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 168.7, 156.4, 146.7, Aer stirring for an additional 30 min, 5 (8.8 g, 31.4 mmol) was
126.9, 123.1, 81.0, 74.5, 62.0, 59.7, 28.0, 13.8. HRMS (ESI) calcd then added in portions over 30 min. The reaction mixture was
for C16H22N2NaO7 [M + Na]+ 377.1325, found 377.1311.
warmed to room temperature and formed homogenous
(2S,3S)-Ethyl-2-((tert-butoxycarbonyl)amino)-3-cyclohexyl-3- biphasic solution. The separated organic phase was dried over
hydroxypropanoate (2j). The compound 2j was prepared in 80% anhydrous Na2SO4 and evaporated in vacuo to afford 6 as a white
yield as a white solid. Mp 75.4–76.8 ꢀC. HPLC (Daicel AD-H, solid, which could be used in the next step without further
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ꢀ
purication. Mp 97.0–98.1 C. FT-IR (ATR): n 3295, 1753, 1634, ether/ethyl acetate 3 : 1, v/v) to give 9 (0.79 g, 88%) as a white
1542, 1491, 1260, 1196, 995, 918, 646. 1H NMR (400 MHz, solid. The ee value of 9 was improved to 92% aer a crystalli-
CDCl3): d ¼ 7.88 (s, 1H), 7.65 (d, J ¼ 6.4 Hz, 1H), 7.35–7.47 (m, zation from petroleum ether/ethyl acetate (1/1, v/v). Mp 92.0–
5H), 6.96 (d, J ¼ 8.4 Hz, 1H), 6.75 (br, 1H), 5.21 (s, 2H), 4.24–4.29 94.6 ꢀC. [a]D20.8 ¼ +70.4(c 1.0, CHCl3). FT-IR (ATR): n 3295, 1753,
(q, 2H), 4.20 (d, J ¼ 5.2 Hz, 2H), 1.32 (t, J ¼ 7.2 Hz, 3H). 13C NMR 1634, 1542, 1491, 1260, 1196, 995, 918, 646. HPLC (Daicel AD-H,
(100 MHz, CDCl3): d ¼ 170.1, 165.7, 156.7, 135.7, 129.4, 128.6, hexane/i-PrOH ¼ 85/15, 0.8 mL minꢂ1, detection at 225 nm, 30
128.1, 127.0, 126.9, 123.2, 113.0, 70.7, 61.6, 41.8, 14.1. HRMS ꢀC): tR (minor) ¼ 19.8 min, tR (major) ¼ 24.2 min. 1H NMR (400
(ESI) calcd for C18H18ClNNaO4 [M + Na]+ 370.0822, found MHz, CDCl3): d ¼ 7.33–7.48 (m, 6H), 7.08 (d, J ¼ 7.6 Hz, 1H),
370.0814.
6.92 (d, J ¼ 8.8 Hz, 1H), 5.37 (d, J ¼ 6.8 Hz, 1H), 5.16 (s, 2H), 4.64
Ethyl-2-(4-(benzyloxy)-N-(tert-butoxycarbonyl)-3-chloroben- (d, J ¼ 3.2 Hz, 1H), 4.28 (s, 1H), 4.15–4.21 (q, 2H), 3.22 (s, 1H),
zamido)acetate (7). The crude 6 (6.94 g, 20 mmol) and DMAP 1.46 (s, 9H), 1.21 (t, J ¼ 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3):
(122 mg, 1.0 mmol) were dissolved in acetonitrile (60 mL) under d ¼ 169.3, 156.3, 153.6, 136.2, 132.7, 128.4, 128.1, 127.8, 126.8,
N2. Boc2O (5.2 g, 24 mmol) was added at 0 ꢀC dropwise over 1 h. 125.1, 122.9, 113.4, 80.6, 74.1, 72.6, 64.1, 61.7, 59.6, 49.2, 28.0,
The reaction mixture was stirred at room temperature for 3 h, 26.7, 25.1, 13.8. HRMS (ESI) calcd for C23H28ClNNaO6 [M + Na]+
and the solvent was evaporated under reduced pressure to give 472.1503, found 472.1501.
crude 7 as a light yellow solid, which was used in the next step
(2S,3S)-Ethyl-2-amino-3-(4-(benzyloxy)-3-chlorophenyl)-3-
without further purication. Mp 87.2–88.4 ꢀC. FT-IR (ATR): n hydroxypropanoate (3). To a solution of 9 (0.89 g, 2 mmol) in
ꢀ
2979, 1738, 1669, 1597, 1500, 1357, 1320, 1212, 1146, 1008, 731. dichloromethane (10 mL) was added TFA (1 mL) at 0 C under
1H NMR (400 MHz, CDCl3): d ¼ 7.71 (s, 1H), 7.53 (d, J ¼ 6.8 Hz, N2. The reaction mixture was allowed to warm to room
1H), 7.32–7.48 (m, 5H), 6.97 (d, J ¼ 8.4 Hz, 1H), 5.25 (s, 2H), 4.51 temperature and stirred for 2 h. The reaction mixture was
(s, 2H), 4.22–4.27 (q, 2H), 1.31 (t, J ¼ 6.8 Hz, 3H), 1.22 (s, 9H). 13
C
quenched with sat. NaHCO3 (10 mL) and diluted with
NMR (100 MHz, CDCl3): d ¼ 171.0, 168.7, 156.3, 152.5, 135.6, dichloromethane (20 mL). The organic layer was separated and
130.3, 129.8, 128.5, 128.0, 126.8, 122.5, 112.6, 83.5, 70.5, 61.3, the aqueous phase was extracted with dichloromethane (10 mL
46.4, 27.2, 13.9. HRMS (ESI) calcd for C23H26ClNNaO6 [M + Na]+ ꢁ 3). The combined organic layers were dried over anhydrous
470.1346, found 470.1325.
Na2SO4 and concentrated under reduced pressure to afford 3
Ethyl-3-(4-(benzyloxy)-3-chlorophenyl)-2-((tert-butoxycarbonyl) (0.64 g, 91%) as a white solid with 92% ee, which was upgraded
amino)-3-oxopropanoate (8). A solution of t-BuOK (2.4 g, 21.6 to 99% de and 99% ee aer recrystallized from MTBE. Mp 99.5–
mmol) in THF (20 mL) was added to a solution of crude 7 (8.0 g, 100.8 ꢀC. FT-IR (ATR): n 3291, 2857, 1718, 1504, 1255, 1189,
ꢀ
18 mmol) in THF (80 mL) at 0 C dropwise over 1 h under N2. 1014, 940, 816, 728, 693. HPLC (Daicel AD-H, hexane/i-PrOH ¼
Aer aging at 0–10 ꢀC for 1 h, then adjusted to pH ¼ 7 with 10% 75/25, 0.8 mL minꢂ1, detection at 225 nm, 30 ꢀC): tR (minor) ¼
citric acid, and the organic layer was washed with brine (50 mL 10.0 min, tR (major) ¼ 11.7 min. [a]2D5 ¼ ꢂ6.6 (c 1.0, CHCl3). 1H
ꢁ 3), the combined organic layers were dried over anhydrous NMR (400 MHz, CDCl3): d ¼ 7.32–7.48 (m, 6H), 7.11 (d, J ¼ 8.4
Na2SO4, ltered, and concentrated in vacuo. Recrystallized from Hz, 1H), 6.92 (d, J ¼ 8.4 Hz, 1H), 5.16 (s, 2H), 4.89 (d, J ¼ 5.2 Hz,
MTBE afforded 8 (5.6 g, 63%, over three steps) as a white solid. 1H), 4.12–4.18 (q, 2H), 3.77 (d, J ¼ 5.2 Hz, 1H), 2.37 (br, 2H), 1.24
Mp 78.0–80.5 C. FT-IR (ATR): n 3363, 2936, 1751, 1683, 1522, (t, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 172.7, 153.7,
ꢀ
1493, 1271, 1157, 1057, 1016, 734, 583. 1H NMR (400 MHz, 136.2, 133.2, 128.2, 127.8, 126.9, 125.5, 123.0, 113.5, 73.0, 70.6,
CDCl3): d ¼ 8.19 (s, 1H), 8.02 (d, J ¼ 7.2 Hz, 1H), 7.36–7.48 (m, 61.1, 59.5, 13.9. HRMS (ESI) calcd for C18H20ClNNaO4 [M + Na]\
5H), 7.04 (d, J ¼ 8.8 Hz, 1H), 5.91 (d, J ¼ 8.0 Hz, 1H), 5.85 (d, J ¼ 372.0979, found 372.0975.
8.0 Hz, 1H), 5.27 (s, 2H), 4.18–4.21 (m, 2H), 1.47 (s, 9H), 1.17 (t, J
¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 189.5, 167.1,
Notes and references
158.9, 155.1, 135.5, 131.9, 130.3, 127.1, 123.9, 112.8, 80.7, 71.0,
62.5, 59.3, 28.4, 14.0. HRMS (ESI) calcd for C23H26ClNNaO6 [M +
Na]+ 470.1346, found 470.1344.
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stirred at 40 C under N2 for 2 h and cooled to room tempera-
ture, compound 8 (0.89 g, 2 mmol) and HCOOH–HCOONa
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