Catalytic asymmetric transfer hydrogenation/dynamic kinetic resolution: an efficient synthesis of florfenicol

Article abstract of DOI:10.1016/j.tet.2016.02.045

A robust and practical method has been developed for the synthesis of florfenicol (1) starting from commercial available 4-(methylsulfonyl) benzoic acid. The key step in this synthesis was the Ru-chloramphenicol base catalyzed asymmetric transfer hydrogenation of N-Boc α-amino-β-ketoester 5 through a dynamic kinetic resolution, which afforded the key chiral building block, anti-(2S,3S)-α-Boc-amino-β-hydroxyl ester 4, with high diastereoselectivity (92% de) and enantioselectivity (78% ee). The synthesis of a series of novel chloramphenicol base ligands L1–L10 is also included. This protocol could also be used for the asymmetric synthesis of fully synthetic analogs of florfenicol.

Full text of DOI:10.1016/j.tet.2016.02.045

Accepted Manuscript
Catalytic Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution: an
Efficient Synthesis of Florfenicol
Xinlong Wang, Lingjun Xu, LingJie Yan, Haifeng Wang, Sheng Han, Yan Wu, Fener
Chen
PII:
S0040-4020(16)30107-7
10.1016/j.tet.2016.02.045
TET 27515
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 January 2016
Revised Date: 18 February 2016
Accepted Date: 22 February 2016
Please cite this article as: Wang X, Xu L, Yan L, Wang H, Han S, Wu Y, Chen F, Catalytic Asymmetric
Transfer Hydrogenation/Dynamic Kinetic Resolution: an Efficient Synthesis of Florfenicol, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.02.045.
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Catalytic Asymmetric Transfer
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Hydrogenation/Dynamic Kinetic Resolution:
an Efficient Synthesis of Florfenicol
Xinlong Wang, Lingjun Xu, LingJie Yan, Haifeng Wang, Sheng Han, Yan Wu, and Fener Chen,
Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China

1
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Tetrahedron
journal homepage: www.elsevier.com
Catalytic Asymmetric Transfer Hydrogenation/Dynamic Kinetic Resolution: an
Efficient Synthesis of Florfenicol
Xinlong Wang, Lingjun Xu, LingJie Yan, Haifeng Wang, Sheng Han, Yan Wu, and Fener Chen,
Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A robust and practical method has been developed for the synthesis of florfenicol (1) starting
from commercial available 4-(methylsulfonyl) benzoic acid. The key step in this synthesis was
the Ru-chloramphenicol base catalyzed asymmetric transfer hydrogenation of N-Boc α-amino-β-
ketoester 5 through a dynamic kinetic resolution, which afforded the key chiral building block,
anti-(2S,3S)-α-Boc-amino-β-hydroxyl ester 4, with high diastereoselectivity (92% dr) and
enantioselectivity (78% ee). The synthesis of a series of novel chloramphenicol base ligands L1-
L10 is also included. This protocol could also be used for the asymmetric synthesis of fully
synthetic analogs of florfenicol
Available online
Keywords:
florfenicol
asymmetric transfer hydrogenation
dynamic kinetic resolution
chloramphenicol base
inversion
2009 Elsevier Ltd. All rights reserved
.
———
Corresponding author. e-mail: wywin8@163.com (Yan Wu);
Corresponding author. Tel.: +86-21-65643811; fax: +86-21-65643811; e-mail: rfchen@fudan.edu.cn (Fener Chen)

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
Florfenicol (1), which was discovered in 1979 by Schering-
Plough as a 3’-fluorinated derivative of thiamphenicol (2), has
attracted considerable interest from synthetic organic chemists
because of its broad-spectrum antibacterial activity.1 A variety of
synthetic routes have been reported to date for the preparation of
1 involving several different strategies for controlling the two
adjacent stereocenters.2 However, to the best of our knowledge,
none of these routes has a commercial advantage over the
existing industrial synthesis developed by the Sumitomo
Company in 1969, which uses racemic material and a chemical
resolution step.3
Scheme 1. Retrosynthetic approach to florfenicol (1).
For the preparation of the N-Boc α-amino-β-ketoester 5
(Scheme 2), commercially available 4-(methylsulfonyl)benzoic
acid (6) was treated with thionyl chloride in refluxing
dichloromethane in the presence of a catalytic amount of
anhydrous DMF according to the literature method.7 The
resulting crude acyl chloride 7 was then subjected to a Schotten–
Baumann reaction with glycine ethyl ester hydrochloride in the
presence of Na2CO3 in ethyl acetate at room temperature to give
amide 8. The subsequent protection of the amide with Boc2O
under DMAP catalysis in acetonitrile at room temperature
afforded the N-Boc amide 9 in 99% yield over the two steps. The
N-Boc amide 9 was then subjected to a base-promoted
intramolecular N→C benzoyl migration reaction under Xu’s
conditions (t-BuOK/THF/10 °C)6d to afford 5 in an isolated yield
of 71%, together with 23% of the C→C cleavage product 4-
(methylsulfonyl) benzoic acid (6). In an attempt to promote the
desired N→C migration of 9, we screened several other bases,
including LDA, LiHMDS, NaOEt, and K2CO3, as well as a
variety of different solvents such as EtOH, toluene, DMF, and
MTBE. However, none of these changes led to an improved yield
of the desired product (Table 1, entries 2–9).
Figure. 1 Structures of florfenicol (1) and thiamphenicol (2)
The development of a step-economical synthetic route
involving asymmetric catalysis, as well as low cost reaction and
purification stages, would therefore provide a valuable alternative
to the troublesome resolution process described above. The
catalytic asymmetric transfer hydrogenation of α-amino-β-
ketoesters can be conducted in conjunction with a dynamic
kinetic resolution in water. This tandem process therefore
represents a powerful and elegant one-pot method for the
construction of chiral α-amino-β-hydroxyl esters bearing two
adjacent
stereocenters
with
high
several
diastereo-
syntheses
and
have
enantioselectivity.4
Recently,
beendescribed towards florfenicol or thiamphenicol using
5
asymmetric transfer hydrogenation in the literature . However,
most of the reported routes need expensive chiral ligands or
require harsh conditions. As part of our ongoing interest in the
synthesis of this commercially important antibiotic, we recently
investigated the use of this strategy as a practical and economic
approach for the synthesis of 1.
Herein, we report the full details of our recent efforts towards
the development of a novel catalytic process for the diastereo-
and enantioselective synthesis of 1 starting from commercially
available 4-(methylsulfonyl) benzoic acid.
2. Results/Discussion
Our retrosynthetic plan hinged upon the formation of the key
intermediate amino alcohol 3 (Scheme 1). It was envisaged that
this compound could be synthesized from 4 by the inversion of
the configuration at C-2, as previously reported by our group.
The Ru-catalyzed asymmetric transfer hydrogenation/dynamic
kinetic resolution of N-Boc α-amino-β-ketoester 5 would provide
the required anti-(2S,3S)-α-Boc-amino-β-hydroxyl ester 4. The
N-Boc α-amino-β-ketoester 5 could then be readily prepared
from 4-(methylsulfonyl)benzoic acid (6) via an intramolecular
N→C benzoyl migration pathway.6
Scheme 2. Reagents and conditions: a) SOCl2, cat. DMF,
CH2Cl2, reflux,
2 h, quant.; b) glycine ethyl ester
hydrochloride, Na2CO3, EtOAc/H2O, r.t., 1 h; c) Boc2O, cat.
DMAP, CH3CN,r.t., 3 h; d) t-BuOK, THF, 10 °C, 1 h, 71%
(from 6 to 5)
Table 1 N-C benzoyl migration reaction of 9 using different
bases and solvents a
Entry
1
Base
Solvent
THF
Time(h)
1
Yield(%)
71
t-BuOK

3
L1 and ligand L6, which contain one electron-withdrawing
2
3
4
5
6
7
8
9
LDA
THF
1
2
2
2
1
1
1
1
ACCE62PTED MANUSCRIPT
group at the para position of the aromatic ring, but these ligands
afforded 4 with a lower enantioselectivity. When RuCl2(p-
cymene)2 was used as a precatalyst, ligand L3 afforded 4 in 85%
yield with 92% dr and 78% ee. (Table 2, entry 12). The ee value
of 4 was improved to 85% after recrystallization from ethyl
acetate. With RuCl2(p-cymene)2-L3 as the catalyst, we optimized
other reaction conditions such as temperature, reaction time and
so on, but had not significantly increased both of dr and ee. It is
noteworthy that the ligand was recovered in 94% yield by salting
out the reaction with 20% citric acid, followed by neutralization
with saturated NaHCO3 and back extraction with
dichloromethane.
LiHMDS
NaOEt
K2CO3
THF
N.R.c
N.R.
N.R.
65
THF
THF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
MTBE
EtOH
Toluene
DMF
40
62
58
a
All reactions were performed on 4.0-mmol scale and 1.3
equiv of bases. b Isolated yield. c No reaction
Table 2. Catalytic asymmetric transfer hydrogenation/
dynamic kinetic resolution reaction of 5 using different
RuCl2(arene)2 catalyst/ligand combinations a
Preparation of ligands L1-L10 is shown in Scheme 3,
chloramphenicol base, a by-product in the manufacture of
chloramphenicol,9 was condensation with various aromatic
aldehydes in the presence of a catalytic amount of anhydrous
CuSO4 to afford the corresponding Schiff bases (S,S)-1a-e in 65-
90% yield, which was subjected to reduction with sodium
borohydride in THF/MeOH to afford the corresponding (S,S)-2a-
e in 60-75% yield. Protection of primary alcohol at C-3 in (S,S)-
2a-e with tert-butyldimethylsilyl chloride (TBDMSCl) gave L1-
L5 in 59-80% yield, and with triphenylmethane chloride (TrCl)
afforded L6-L10 in 65-85% yield.
Entry Arene/Ligand
Temp Yield
(°C)
25
d.r
e.e.
(%)c
55
(%) b
84
(%)c
85
1
Benzene/(S,S)-2c
Benzene/L1
2
25
25
25
25
25
25
25
25
25
25
25
81
90
80
78
79
82
88
87
80
76
85
80
24
82
64
87
86
67
47
65
77
92
58
67
76
71
66
57
64
62
70
68
78
3
Benzene/ L2
Benzene/ L3
Benzene/ L4
Benzene/ L5
Benzene/ L6
Benzene/ L7
Benzene/ L8
Benzene/ L9
p-cymene/ L10
p-cymene/ L3
4
5
Scheme 3 Reagent and conditions: a) ArCHO (1.0 equiv.),
CuSO4 (0.05 equiv.), MeOH, reflux.3-5 h, 65-90%; b) NaBH4
(3.0 equiv.), THF/MeOH, reflux., 2-10 h, 60-75%; c)
TBDMSCl (1.2 equiv.), imidazole (2.5 equiv.), DMF, r.t. 3-8
h, 59-80%; d) TrCl (1.5 equiv.), Et3N (1.8 equiv.), CH2Cl2,
r.t., 3-8 h, 65-85%
6
7
8
9
10
11
12
With the protected α-amino-β-ketoester 5 in hand, we
proceeded to investigate the construction of the anti-(2S,3S)- α-
Boc-amino-β-hydroxyl ester 4 using the catalytic asymmetric
transfer hydrogenation/dynamic kinetic hydrogenation. The
reaction proceeded smoothly to afford 4 using catalyst (10%),
Tween 20 (20%), and HCOONa (5.0 eq) in water at 25 °C (Table
2, entry 1) 5e. The absolute configuration of 4 was unambiguously
confirmed after deprotection by comparison with an authentic
sample using HPLC analysis.8 Encouraged by this result, we
optimized the reaction conditions and found that the combination
of ligand L3 with the RuCl2(benzene)2 provided 82% dr and
moderate ee (76%) (Table 2, entry 4). In contrast, the use of
ligand L8, which bears a bulky OTr group led to low level
asymmetric induction (Table 2, entry 9). We also tested ligand
a
All reactions were carried out with 5 (1 mmol) and catalyst
b
c
(10%). Isolated yield The diastereo- and enantiomeric ratios
were measured by HPLC on a chiralpak AD-H column with
hexane/i-PrOH 85:15, (0.4 mL/min), UV (λ = 225 nm) detection
T = 30 °C. Anti: tR (major) = 58 min, tR (minor) = 60 min; Syn:
tR (2R,3S) = 69 min, tR (2S,3R) = 73 min.
The inversion of the configuration at C-2 in 4 was achieved
using our previously reported protocol.2f,10 The treatment of 4
(85% ee) with MsCl/Et3N in dichloromethane at 10 °C afforded

4
Tetrahedron
sulfonate 10 in 100% yield with 85% ee, which was upgraded
shown in Table 3, the use of Deoxo-Fluor in CH2Cl2 at room
ACCEPTED MANUSCRIPT
to 99% ee and 99% dr in 94% yield following a simple trituration
with MTBE. The subsequent reduction of the resulting secondary
sulfonate 10 with LiBH4, which was prepared in situ from the
reaction of KBH4 and anhydrous LiCl in THF at 70 °C, provided
the anti-(1S,2R)-amino alcohol 11 in 81% yield. The inversion of
the C-2 position in 11 was achieved via the SN2 reaction of the
benzylic mesylate with DBU/AcOH (1:2.2, molar ratio) in
toluene at 90 °C, which afforded the syn-(1R,2R)-amino alcohol
12 in 74% yield. The diastereoselectivity of 12 was determined to
be higher than 20:1 by chiral HPLC (Scheme 4).Compound 12
was then hydrolyzed with K2CO3 in MeOH at room temperature
to give the syn-(1R,2R) amino alcohol 13 in 90% yield. The
subsequent deprotection of the Boc group in 13 with TFA
afforded the key intermediate 3 in excellent yield. The spectral
data and physical characteristics of 3 were in complete agreement
with the reported values.1c
temperature allowed for the fluorination of 14 in 93% yield
(Table 3, entry 5), albeit after an extended reaction time (14 h)
Table 3. Optimization of the fluorination reaction conditions
of 14a
Entry Fluorinating reagent
Temp Time
Yield
(%)c
72
(°C)
(h)
4
1
2
3
4
5
Ishikawa’s reagent
100b
r.t.
r.t.
r.t.
r.t.
4
55
82
33
93
PBSF/Et3N
Fluolead
·3HF
4.5
4
XtalFluor-E
Deoxo-Fluor
Scheme 4 Reagent and conditions: a) MsCl, Et3N, CH2Cl2, 0
–10 °C, 1 h, 94%; b) LiBH4, THF, r.t., 3 h, 81%; c)
DBU/AcOH (1:2.2), toluene, 90 °C, 15 h, 74%; d) K2CO3,
MeOH, r.t.,2 h, 90%.
Compound 3 was then subjected to a condensation reaction
with p-tolunitrile in the presence of K2CO3 according to a
modified version of the procedure developed by Schumacher et
al,2a which afforded oxazoline 14 in 88% yield (Scheme 5).
14
a All reactions were carried out with 14 (2 mmol), fluorinating
b
reagents (1.5 equiv.); for Deoxo-Fluor (3.0 equiv.).
This
reaction was carried out in a sealed reactor. c Isolated yield
The fluorination of 14 was initially conducted with Ishikawa’s
reagent under the standard conditions developed by
Schumacher’s group,2a which gave the desired product 15 in
moderate yield (72%). We also tested PBSF/Et3N·3HF and
XtalFluor-E,11 but these both very poor yields (Table 3, entries 2
12
and 4). Deoxo-Fluor was therefore identified as the optimum
fluorinating agent. Hydrolysis of 15 proceeded smoothly in 6N
HCl at 100 °C for 8 h to give amine 16 in 90% yield, which was
subjected to acetylation with methyl dichloroacetate following
slightly improved procedure of Lin et al2i to afford florfenicol (1)
in 96% yield.
3. Conclusion
In summary, we have successfully established an efficient
protocol for the asymmetric synthesis of florfenicol (1) staring
from commercial available 4-(methylsulfonyl) benzoic acid. The
most notable feature of this process is the one-pot catalytic
asymmetric transfer hydrogenation/dynamic kinetic resolution of
the α-amino-β-ketoester intermediate to deliver the key chiral α-
Scheme 5 Reagents and conditions: a) TFA, CH2Cl2, r.t.,2 h,
92%; b) p-tolunitrile, K2CO3, glycerol, 100 °C, 5 h, 88%; c)
Deoxo-Fluor, CH2Cl2, 0 °C to r.t., 14 h, 93%; d) 6 N HCl, 100
°C, 8 h, 90%; e) Cl2CHCOOMe, MeOH, Et3N, 40 °C, 16 h,
96%.
amino-β-hydroxyl
ester
with
high
diastereo-
and
enantioselectivity. The scalability and convenience of this
process make it a highly practical procedure for the preparation
florfenicol (1) and its analogues. Studies aimed at exploring the
synthesis other analogues such as chloramphenicol are in
progress.
The conversion of 14 to the corresponding fluoride 15 was
accomplished using a variety of different fluorinating agents. As

5
4. Experimental section
After the aqueous phase was adjusted to pH 2-3 with 1N
ACCEPTED MANUSCRIPT
aqueous HCl, the white precipitate was collected by filtration to
afford the starting material 6 (4.5 g, 23%) as a white crude solid,
mp 265-268oC.(lit 13 mp 264-265 oC).
All reagents and solvent were obtained from commercial
sources and used without further purification. H (400 MHz) and
1
13C (100 MHz) NMR were recorded on a Bruker Avance 400
spectrometer using TMS or CDCl3 as internal standards, IR
spectra were recorded on a Nicolet iS5 FT-IR spectrometer,
Optical rotations were measured by a JASCO P1020 digital
polarimeter. EI-MS were recorded on an Agilent 6890N/5975
spectrometer and ESI-MS were recorded on a Waters Micromass
Quattro Micro spectrometer. HRMS were recorded on a Bruker
microTOF spectrometer
4.4. (2S,3S)-ethyl-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-
(4-(methylsulfonyl)phenyl)propanoate (4).
A mixture of [RuCl2(p-cymene)]2 (0.61 g, 1.0 mmol), ligand
L3 (125 mg, 0,3 mmol), Tween 20 (0.69 g, 2.0 mmol) and water
(30 mL) were stirred at 40 oC under N2 for 2 h and cooled to
room temperature, 5 (3.85 g, 10 mmol) and HCOONa (3.4 g, 50
mmol) were added. The reaction mixture was stirred at room
temperature for 48 h. Ethyl acetate (30 mL) and 20% citric acid
(30 mL) were added to the reaction mixture and stirred for 30
min. the organic layer was separated, the aqueous layer was
extracted with ethyl acetate (30 mL × 3), and the combined
organic layers were washed with brine (40 mL), dried over
MgSO4, filtered, and evaporated in vacuo, and the crude product
was purified by flash chromatography (petroleum ether/ ethyl
acetate 1:1, V/V, Rf = 0.48) to give 4 (3.3 g, 85%) as a white
solid. The ee value of 4 was improved to 85% after a
crystallization from petroleum ether/ ethyl acetate (1/1). mp
159.8-161.5 oC. [ꢀ]ꢂꢁꢃ.ꢄ = + 25.1(c 1.0, EtOH). FT-IR (ATR): ν
3384, 2976, 2934, 1690, 1508, 1302, 1141, 1026, 956, 838, 771,
659. HPLC (Daicel AD-H, hexane/ i-PrOH = 85/15, 0.4 mL/min,
detection at 225 nm, 30 oC): tR (major) = 58.1 min, tR (minor) =
4.1. Ethyl-2-(4(methylsulfonyl)benzamido)acetate (8).
To a stirred suspension of Na2CO3 (12.7 g, 0.12 mol) in water
(120 mL) and ethyl acetate (120 mL) was added glycine ethyl
ester hydrochloride (15.4 g, 0.11 mol) at 0 oC in portions over 30
min. After stirring for an additional 30 min, 7 (21.8 g, 0.1 mol)
was then added in portions over 30 min. The reaction mixture
was warmed to room temperature and formed homogenous
biphasic solution. The separated organic phase was dried over
anhydrous Na2SO4 and evaporated in vacuo to afford 8 as a white
solid, which could be used in the next step without further
o
purification. mp 118.6-121.0 C. FT-IR (ATR): ν 3314, 2926,
1741, 1642, 1538, 1371, 1283, 1200, 1141, 1087. H NMR (400
1
MHz, CDCl3): δ = 7.99 (s, 4H), 6.99 (bs, 1H), 4.24-4.30 (m, 4H),
3.08 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ = 170.3, 166.3, 143.9, 139.3, 128.8, 128.4, 62.5, 44.9,
42.6, 14.7. HRMS (ESI) calcd for C12H15NNaO5S [M+Na]+
308.0569, found 308.0562.
1
60.3 min. H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.0 Hz,
2H), 7.50 (d, J = 8.0 Hz, 2H), 5.32 (dd, J = 6,8 Hz, 4.4 Hz, 2H),
4.72 (d, J = 2.0 Hz, 1H), 4.48 (d, J = 2.0 Hz, 1H), 4.19 (q, 2H),
3.06 (s, 3H), 1.46 (s, 9H), 1.24 (t, J = 8.4 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ = 169.3, 157.5, 156.7, 146.2, 140.1, 127.5, 81.4,
75.0, 62.4, 60.1, 44.7, 28.5, 14.3. HRMS (ESI) calcd for
C17H25NNaO7S [M+Na]+ 410.1249, found 410.1243.
4.2. Ethyl 2-(N-(tert-butoxycarbonyl)-4-(methylsulfonyl)
benzamido)acetate (9).
The crude 8 (29.4 g, 0.1 mol) and DMAP (61 mg, 0.5 mmol)
were dissolved in acetonitrile (150 mL) under N2. Boc2O (24.0 g,
0.11 mol) was added at 0 oC dropwise over 1 h. The reaction
mixture was stirred at room temperature for 3 h, and the solvent
was evaporated under reduced pressure to give crude 9 as a light
yellow solid, which was used in the next step without further
purification. mp 96.4-99.2 oC. FT-IR (ATR): ν 2978, 1757, 1730,
The aqueous layer was neutralized with saturated NaHCO3
(10 mL), then extracted with dichloromethane (10 mL × 3), the
combined organic layers were washed with brine (10 mL), dried
over MgSO4, filtered, and evaporated in vacuo, to afford the
ligand L3 (0.11 g, 94%) as a yellow oil.
4.5. (2S,3S)-ethyl2-((tert-butoxycarbonyl)amino)-3-
((methylsulfonyl)-oxy)-3-(4-(methylsulfonyl)phenyl) propanoate
(10).
1
1667, 1412, 1364, 1326, 1205, 1147, 986, 751; H NMR (400
MHz, CDCl3): δ = 8.02 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz,
2H), 4.57 (s, 2H), 4.24-4.29 (q, 2H), 3.08 (s, 3H), 1.31 (t, J = 7.2
Hz, 3H), 1.20 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 171.4,
168.9, 152.2, 142.7, 128.4, 127.5, 84.9, 62.0, 46.4, 44.7, 27.7,
14.4. HRMS (ESI) calcd for C17H23NNaO7S [M+Na]+ 408.1093,
found 408.1086.
To
a stirred solution of 4 (0.77 g, 2.0 mmol) in
dichloromethane (15 mL) was added Et3N (0.4 g, 4.0 mmol) at
o
room temperature under N2 and cooled to 0 C. Methanesulfonyl
chloride (0.27 g, 2.4 mmol) was added to the reaction mixture
o
dropwise over 30 min. Stirring was continued at 5-10 C for an
4.3. Ethyl-2-((tert-butoxycarbonyl)amino)-3-(4-(methylsulfonyl)
additional 1 h. The reaction mixture was quenched with brine (20
mL) and the organic layer was separated. The aqueous layer was
extracted with dichloromethane (15 mL × 3), and the combined
organic layers were dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was triturated with MTBE (20 mL ×
3) to afford 10 (0.87 g, 93.5%) as a white solid. mp 119.5-121.2
oC. [ꢀ]ꢂꢁꢅ.ꢆ = + 30.0 (c 1.0, MeOH, ee >99%). HPLC (Daicel
AD-H, hexane/ i-PrOH = 80/20, 0.5 mL/min, detection at 225
nm, 30 oC): tR (major) = 71.8 min, tR (minor) = 73.9 min. FT-IR
(ATR): ν 3461, 3362, 3003, 2926, 1674, 1513, 1355, 1288, 1146,
956, 844, 774, 640. 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J =
8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 6.06 (s, 1 H), 5.40 (d, J =
6.8 Hz, 1H), 4.77 (d, J = 2.0 Hz, 1H), 4.15 (q, 2H), 3.08 (s, 6 H),
1.44 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ = 167.0, 127.1, 126.9, 79.9, 61.8, 57.8, 43.8, 38.2,
27.6, 13.4. HRMS (ESI) calcd for C18H27NNaO9S2 [M+Na]+
488.1025, found 488.1017.
phenyl) -3-oxopropanoate (5).
A solution of t-BuOK (14.4 g, 0.13 mol) in THF (150 mL)
was added to a solution of crude 9 (38.0 g, 0.1 mol) in THF (200
o
o
mL) at 0 C dropwise over 1 h under N2. After aging at 0-10 C
for 1 h, then adjusted to pH = 7 with 10% citric acid, and the
organic layer was washed with brine (50 mL × 3), the combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Recrystallized from MTBE afforded 5
(27.1 g, 71%, over three steps) as a colorless solid. mp 100.6-
o
102.7 C. FT-IR (ATR): ν 3354, 2982, 2931, 1736, 1680, 1511,
1
1278, 1149, 1004, 961, 777, 728. H NMR (400 MHz, CDCl3): δ
= 8.30 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 5.89 (dd, J =
6.8 Hz, 17.6 Hz, 2H), 4.20 (q, 2H), 3.10 (s, 3H), 1.45 (s, 9H),
1.16 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 192.7,
167.3, 155.9, 146.0, 139.6, 131.2, 128.8, 82.0, 63.8, 60.7, 45.3,
29.2, 14.9. HRMS (ESI) calcd for C17H23NNaO7S [M+Na]+
408.1093, found 408.1086.

6
Tetrahedron
4.6. (1S,2R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-1-(4-
4.9. (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-
ACCEPTED MANUSCRIPT
(methylsulfonyl)phenyl)propyl methanesulfonate (11).
diol (3).
A mixture of KBH4 (0.81 g, 15 mmol) and LiCl (0.64 g, 15
mmol) was stirred in boiling anhydrous THF (40 mL) under N2
for 2 h. The reaction mixture was cooled to room temperature,
and a solution of 10 (2.32 g, 5.0 mmol) in THF (20 mL) was
added dropwise at 0 oC over 1 h., Stirring was continued at room
temperature for an additional 3 h, then water (30 mL) was added
and stirred for 1 h, and extracted by dichloromethane (20 mL ×
3). The combined the organic layers were washed with brine (30
mL), dried over anhydrous MgSO4, filtered, and evaporated in
vacuo. The crude product was recrystallized from petroleum
ether/ ethyl acetate (1:1, V/V) to afford 11 (1.7 g, 80.9%) as a
white needle. mp 140.0-141.5 oC. [ꢀ]ꢁꢂꢅ.ꢆ = + 33.5 (c 1.0,
MeOH,). FT-IR (ATR): ν 3461, 3362, 3003, 2928, 1674, 1513,
To a solution of 13 (1.03 g, 3 mmol) in dichloromethane (10
mL) was added TFA (1 mL) at 0 C under N2. The reaction
o
mixture was allowed to warm to room temperature and stirred for
2 h. The reaction mixture was quenched with sat. NaHCO3 (10
mL) and diluted with dichloromethane (20 mL). The organic
layer was separated and the aqueous phase was extracted with
dichloromethane (20 mL × 5). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure to afford 3 (0.67 g, 92%) as a light yellow solid. mp
144-145.5 oC. [ꢀ]ꢂꢁꢃ.ꢈ = -21.2 (c 1.0, EtOH).(lit 1c mp 141-142oC,
1
[ꢀ]ꢂꢁꢅ -19.8 (c 1.0, EtOH)). H NMR (400 MHz, CD3OD): δ =
8.02 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 5.03 (d, J = 7.6
Hz, 1H), 3.70 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 3.56-3.60 (m, 1H),
3.48-3.53 (q, 1H), 3.29 (s, 3H). HRMS (ESI) calcd for
C15H23NNaO6S [M+Na]+ 246.0722, found 246.0794.
1
1358, 1291, 1149, 1066, 961, 846, 779. H NMR (400 MHz,
CDCl3): δ = 7.98 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H),
5.95 (d, J = 4.4 Hz, 1H), 5.07 (d, J = 9.2 Hz, 1H), 4.06 (bs, 1H),
3.60-3.70 (q, 2H), 3.08 (s, 3H), 2.98 (s, 3H), 1.36 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ = 146.5, 140.6, 127.8, 81.8, 75.4,
62.8, 60.5, 45.1, 28.8, 14.6. HRMS (ESI) calcd for
C16H25NNaO8S2 [M+Na]+ 446.0919, found 446.0901.
4.10. ((4R,5R)-5-(4-(methylsulfonyl)phenyl)-2-(p-tolyl)-4,5-
dihydrooxazol-4-yl)methanol (14).
A mixture of glycerol (10 mL), K2CO3 (0.43 g, 3.1 mmol) and
3 (5.0 g, 20.4 mmol) was stirred at 100 oC for 30 min, p-
tolunitrile (3.95 g, 33.8 mmol) was added and stirred for an
additional 5 h. The reaction mixture was cooled and diluted with
water (50 mL). The product was collected by filtration, washed
with cold water and dichloromethane (30 mL/30 mL), ethyl
acetate (30 mL × 3), and dried in vacuo to afford 14 (6.2 g, 88%)
4.7. (1R,2R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-1-(4-
(methylsulfonyl)phenyl)propyl acetate (12).
A solution of DBU (1.52 g, 10 mmol) and AcOH (1.32 g, 22.0
mmol) in anhydrous toluene (20 mL) was stirred at room
temperature for 1 h. 11 (2.1 g, 5 mmol) was added, and the
reaction mixture was stirred at 90 oC for 15 h and cooled to room
temperature, diluted with dichloromethane (30 mL) and washed
with 2N HCl (20 mL), sat. NaHCO3 (30 mL × 3), and brine (30
mL). The organic layers were dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/ ethyl acetate 1:1, V/V) to
afford 12 (1.43 g, 74.1%) as a white power. mp 128.2-129.4 oC.
[ꢀ]ꢂꢁꢅ.ꢃ = - 0.47 (c 1.0, EtOH). d.r. >20:1 (1H NMR does not
show the erythro isomer’s signals). FT-IR (ATR): ν 3529, 3373,
2977, 1721, 1693, 1511, 1283, 1255, 1141, 1055, 765. HPLC
(Daicel AD-H, hexane/ i-PrOH = 70/30, 1.0 mL/min, detection at
o
as a white solid. mp 230.0-231.5 C. [ꢀ]ꢂꢁꢅ.ꢃ = - 67.5 (c 0.8,
DMF). FT-IR (ATR): ν 3185, 2918, 2861, 1645, 1302, 1278,
1
1141, 1082, 991, 771, 675. H NMR (400 MHz, DMSO-d6): δ =
7.95 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0
Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.66 (d, J = 6.4 Hz, 1H), 5.11
(bs, 1H), 4.08-4.09 (m, 1H), 3.77-3.79 (m, 1H), 3.59-3.61 (m,
1H), 3.21 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3): δ =
162.0, 147.1, 141.6, 140.1, 129.1, 127.9, 127.4, 126.0, 124.2,
81.5, 76.9, 72.4, 63.0, 62.9, 43.4, 21.0. HRMS (ESI) calcd for
C18H20NO4S [M+H]+ 346.1113, found 346.1109.
4.11. (4S,5R)-4-(fluoromethyl)-5-(4-(methylsulfonyl)phenyl)-2-
(p-tolyl)-4,5-dihydrooxazole (15).
o
1
225 nm, 30 C): tR (minor) =6.09 min, tR (major)=6.80 min. H
NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.4 Hz, 2H), 7.55 (d, J
= 8.0 Hz, 2H), 4.95 (q, 2 H), 4.31-4.36 (m, 1H), 4.09-4.13 (q,
1H), 4.03 (bs, 1H), 3.77 (bs, 1H), 3.02 (s, 3H), 2.12 (s, 3H), 1.32
(s, 9H). 13C NMR (100 MHz, CDCl3): δ = 171.9, 147.8, 140.3,
127.7, 80.8, 72.4, 64.0, 63.9, 55.4, 45.1, 28.7, 21.4. HRMS (ESI)
calcd for C17H25NNaO7S [M+Na]+ 410.1249, found 410.1241.
To a stirred suspension of 14 (0.69 g, 2 mmol) in dry
dichloromethane (10 mL) was added Deoxo-Fluor (1.32 g, 6
mmol) dropwise at 0 oC over 30 min. The reaction mixture was
warmed to room temperature and stirred for 14 h under N2. The
o
reaction mixture was cooled to 0 C, sat. NaHCO3 was added
slowly until pH = 5-6. The organic layer was separated. The
aqueous phase was extracted with dichloromethane (20 mL × 2).
The combined organic layers were washed with brine and then
evaporated in vacuo and the residue was purified by flash
chromatography (petroleum ether/ ethyl acetate 3:1, V/V) to
afford 15 (0.64 g, 93%) as a light yellow solid. mp 107.4-110.2
oC. [ꢀ]ꢂꢁꢅ.ꢆ = - 86.7 (c 0.8, dichloromethane). FT-IR (ATR): ν
4.8. Tert-butyl ((1R,2R)-1,3-dihydroxy-1-(4-
(methylsulfonyl)phenyl) propan-2-yl)carbamate (13).
To a solution of 12 (1.93 g, 5 mmol) in MeOH (20 mL) was
added K2CO3 (1.38 g, 10 mmol), the reaction mixture was stirred
at room temperature for 2 h., The solvent was evaporated in
vacuo and the residue extracted with dichloromethane (20 mL ×
3). The combined organic layers were washed with brine (10 mL
× 3), dried with Na2SO4, the residue was recrystallized from
(petroleum ether/ ethyl acetate 1:1, V/V) to afford 13 (1.55 g,
90%) as a white solid.12. mp 130.4-132.4 oC. [ꢀ]ꢂꢁꢃ.ꢇ = -17.5 (c
1.0, EtOH). FT-IR (ATR): ν 3543, 3398, 2921, 1666, 1518, 1412,
1292, 1144, 1085, 750. 1H NMR (400 MHz, CDCl3): δ = 7.82 (d,
J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 5.28 (d, J = 8.8 Hz,
1H), 5.11 (bs, 1H), 4.26 (bs, 1H), 3.69-3.79 (m, 2H), 3.01 (s,
3H), 1.28 (s, 9H). 13C NMR (100 MHz, CDCl3): δ = 155.6, 147.5,
138.7, 126.6, 126.5, 79.4, 72.9, 63.2, 56.0, 43.9, 27.5. HRMS
(ESI) calcd for C15H23NNaO6S [M+Na]+ 368.1144, found
368.1129.
1
2950, 1647, 1300, 1141, 1060, 1015, 963, 885, 771, 723. H
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 2H), 7.93 (d, J
= 8.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.28 (d, J =7.6 Hz,
2H),5.66 (d, J = 6.8 Hz, 1H ), 4.56-4.86 (m, 2H), 4.35-4.41 (m,
1H), 3.07 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ =
164.9, 146.5, 142.7, 140.4, 129.2, 128.4, 128.0, 126.1, 123.8,
84.5, 82.7, 81.8, 75.0, 74.8, 44.4, 21.5. HRMS (ESI) calcd for
C18H19FNO3S [M+H]+ 348.1070, found 348.1077.
4.12. 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-
(methylsulfonyl)phenyl)propan-2-yl)acetamide (1).
A stirred solution of 15 (3.47 g, 10 mmol) in dichloromethane
(10 mL) was added 6N HCl (100 mL) at room temperature, the

7
reaction mixture was heated under stirring at refluxed
temperature for 8 h. The mixture was cooled and extracted with
dichloromethane (30 mL × 3). The aqueous phase was adjusted
to pH = 11, extracted with dichloromethane (40 mL × 5). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to afford 16 as a crude yellow
solid, which was used in the next step without purification.
Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 4.66
ACCEPTED MANUSCRIPT
(d, J = 7.2 Hz, 1H), 3.75-3.78 (m, 2H), 3.59 (d, J = 13.2 Hz, 1H),
3.39 (dd, J = 7.6, 3.2 Hz, 1H), 2.65-2.66 (m, 1H), 0.94 (s, 9H),
0.09 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 149.7, 147.1,
138.2, 131.3, 129.5, 127.3, 123.2, 120.9, 71.6, 64.1, 59.6, 50.7,
25.6, 17.9. HRMS (ESI) calcd for C22H32BrN2O4Si [M+H]+
495.1236, found 495.1309.
A solution of crude product 16 in dry MeOH (30 mL), Et3N
(2.8 mL, 20 mmol) and methyl dichloroacetate (4.29 g, 30 mmol)
was stirred at 40 oC for 6 h. The solvent was evaporated in vacuo
and the residue was purified by flash chromatography (petroleum
ether/ ethyl acetate 2:1, V/V) to afford 1 (3.4 g, 86%) as a white
(1S,2S)-3-((tert-butyldimethylsilyl)oxy)-2-((4-
methylbenzyl)amino)-1-(4-nitrophenyl)propan-1-ol L4.
The compound L4 was prepared in 59% yield as a yellow
oil. [ꢀ]ꢂꢁꢅ.ꢆ = + 47.4 (c 1.0, CHCl3,). FT-IR (ATR): ν 2928, 2856,
1604, 1522, 1465, 1345, 1255, 1109, 1075, 839, 782. H NMR
(400 MHz, CDCl3): δ = 8.21 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4
Hz, 2H), 7.15-7.16 (m, 4H), 4.65 (d, J = 7.2 Hz, 1H), 3.61-3.80
(m, 3H), 3.38 (dd, J = 7.2, 3.6 Hz, 1H), 2.66-2.68 (m, 1H), 2.36
(s, 3H), 0.95 (s, 9H), 0.10 (s, 6H). 13C NMR (100 MHz, CDCl3):
δ = 150.1, 147.2, 136.8, 136.3, 129.1, 128.0, 127.5, 123.2, 71.6,
64.3, 60.2, 59.6, 51.3, 25.7, 20.9, 18.0, 14.0. HRMS (ESI) calcd
for C22H35N2O4Si [M+H]+ 431.2288, found 431.2361.
1
o
1c
solid. mp 153-154 C. [ꢀ]ꢂꢁꢂ.ꢈ = - 18.2 (c 0,4, DMF) (lit mp
o
151-152 C. [ꢀ]ꢂꢁꢅ.ꢃ = - 18.4 (c 0.4, DMF)). FT-IR (ATR): ν
3445, 3314, 2931, 1680, 1530, 1270, 1146, 1012, 964, 803, 763.
1H NMR (400 MHz, DMSO-d6): δ = 8.61 (d, J = 8.8 Hz, 1H)
7.84 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H),
6.15 (d, J = 4.4 Hz, 1H), 4.99 (d, J = 2.8 Hz, 1H), 4.57-4.73 (m,
1H), 4.26-4.32 (m, 2H), 3.16 (s, 3 H). 13C NMR (100 MHz,
DMSO-d6): δ = 163.8, 148.0, 139.7, 127.2, 126.6, 83.3, 81.6,
69.5, 69.4, 66.4, 54.6, 43.7. HRMS (ESI) calcd for
C12H15Cl2FNO4S [M+H] + 358.0083, found 358.0083.
(1S,2S)-3-((tert-butyldimethylsilyl)oxy)-2-((4-
methoxybenzyl)amino)-1-(4-nitrophenyl)propan-1-ol L5.
4.13. General procedure: Synthesis of the ligands L1-L5.
The compound L5 was prepared in 80% yield as a yellow
oil. [ꢀ]ꢂꢁꢅ.ꢆ = + 58.4 (c 1.0, CHCl3,). FT-IR (ATR): ν 2930, 2858,
1606, 1514, 1461, 1347, 1244, 1175, 1107, 1072, 837, 776. H
(1S,2S)-2-(benzylamino)-3-((tert-butyldimethylsilyl)oxy)-1-(4-
nitrophenyl)propan-1-ol L3.
1
NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.8 Hz, 2H), 7.53 (d, J
= 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H),
4.64 (d, J = 6.8 Hz, 1H), 3.81 (s, 3H), 3.58-3.76 (m, 3H), 3.38
(dd, J = 7.6, 3.6 Hz, 1H), 2.65-2.67 (m, 1H), 2.36 (s, 3H), 0.95 (s,
9H), 0.09 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 158.8, 150.3,
147.3, 131.5, 129.3, 127.5, 123.3, 113.9, 71.7, 64.3, 59.7, 55.2,
51.0, 25.8, 21.0, 18.1, 14.1. HRMS (ESI) calcd for C22H35N2O4Si
[M+H]+ 447.2237, found 447.2321.
TBDMSCl (1.8 g, 12 mmol) and imidazole (1.7 g, 25 mmol)
were added to a solution of (S,S)-2c (3.0 g, 10 mmol) in DMF (20
mL) and the mixture was stirred overnight at room temperature.
Water (100 mL) was added to the mixture and extracted with
ethyl acetate (30 mL × 3). The organic layer was washed with
brine (40 mL), dried over anhydrous Na2SO4 and evaporated in
vacuo, and the crude product was purified by flash
chromatography (petroleum ether/ ethyl acetate 5:1, V/V) to give
L3 (3.0 g, 72%) as a yellow oil. [ꢀ]ꢂꢁꢅ.ꢆ = + 43.3 (c 1.0, CHCl3,).
FT-IR (ATR): ν 2934, 2858, 1608, 1525, 1345, 1259, 1109,
1070, 841. 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz,
2H), 7.55 (d, J = 8.8 Hz, 2H), 7.26-7.35 (m, 5H), 4.66 (d, J = 6.8
Hz, 1H), 3.81 (d, J = 13.2 Hz, 1H), 3.74 (dd, J = 6.8, 3.2 Hz, 1H),
3.66 (d, J = 12.8 Hz, 1H), 3.40 (dd, J = 6.8, 3.2 Hz, 1H), 2.67-
2.70 (m, 1H), 0.96 (s, 9H), 0.10 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 150.0, 147.1, 139.3, 128.4, 127.9, 127.3, 123.2, 71.6,
64.3, 59.5, 51.5, 25.6, 18.0. HRMS (ESI) calcd for C22H32N2O4Si
[M+H]+ 417.2131, found 417.2226.
4.14. General procedure: Synthesis of the ligands L6-L10.
(1S,2S)-2-(benzylamino)-1-(4-nitrophenyl)-3-(trityloxy)propan-1-
ol L8.
Triphenylmethane chloride (4.2 g, 15 mmol) and Et3N (1.8 g, 18
mmol) were added to a solution of (S,S)-2c (3.0 g, 10 mmol) in
dichloromethane (40 mL) and the mixture was stirred overnight
at room temperature. Water (50 mL) was added to the mixture
and extracted with dichloromethane (30 mL × 3). The organic
layer was washed with brine (40 mL), dried over anhydrous
Na2SO4 and evaporated in vacuo, and the crude product was
purified by flash chromatography (petroleum ether/ ethyl acetate
3:1, V/V) to give L8 (3.5 g, 65%) as a yellow solid. mp 67.1-68.4
oC. [ꢀ]ꢂꢁꢅ.ꢆ = + 89.9 (c 1.0, CHCl3,). FT-IR (ATR): ν 3061, 3020,
2875, 1598, 1518, 1518, 1447, 1342, 1064, 999, 743, 696, 631.
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.8 Hz, 2H), 7.40
(d, J = 8.0 Hz, 2H), 7.28-7.35 (m, 20H), 4.76 (d, J = 8.0 Hz, 1H),
3.77 (d, J = 12.8 Hz, 1H), 3.49-3.57 (m, 2H), 2.92 (dd, J = 7.2,
2.8 MHz, 1H), 2.60-2.60 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ = 149.3, 147.0, 143.0, 139.0, 128.4, 127.8, 127.2, 123.1, 86.6,
71.9, 63.8, 59.0, 51.5. HRMS (ESI) calcd for C35H32N2O4
[M+H]+ 545.2362, found 545.2439.
(1S,2S)-3-((tert-butyldimethylsilyl)oxy)-2-((4-nitrobenzyl)amino)-
1-(4-nitrophenyl)propan-1-ol. L1.
The compound L1 was prepared in 78% yield as a yellow
oil. [ꢀ]ꢂꢁꢅ.ꢆ = + 45.8 (c 1.0, CHCl3,). FT-IR (ATR): ν 2930, 2854,
1682, 1602, 1518, 1465, 1342, 1255, 1085, 839, 778, 735. H
NMR (400 MHz, CDCl3): δ = 8.18-8.23 (m, 4H), 7.55 (d, J = 8.4
Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 6.8 Hz, 1H), 3.74-
3.95 (m, 4H), 3.45 (dd, J = 7.6, 3.2 Hz, 1H), 2.68-2.70 (m, 1H),
0.94 (s, 9H), 0.10 (s, 6H). 13C NMR (100 MHz, CDCl3): δ =
149.5, 147.2, 147.1, 146.8, 128.4, 127.3, 123.6, 123.3, 72.0, 64.2,
59.8, 50.6, 25.6, 18.0. HRMS (ESI) calcd for C22H32BrN3O6Si
[M+H]+ 462.1982, found 462.2076.
1
(1S,2S)-2-((4-nitrobenzyl)amino)-1-(4-nitrophenyl)-3-
(trityloxy)propan-1-ol L6.
(1S,2S)-2-((4-bromobenzyl)amino)-3-((tert-
butyldimethylsilyl)oxy)-1-(4-nitrophenyl)propan-1-ol L2.
The compound L6 was prepared in 82% yield as a yellow
solid. mp 136-138.2 oC. [ꢀ]ꢁꢂꢅ.ꢆ = + 92.1 (c 1.0, CHCl3,). FT-IR
(ATR): ν 3059, 2915, 1735, 1600, 1516, 1490, 1447, 1340, 1072,
1001, 850, 751, 698, 627. H NMR (400 MHz, CDCl3): δ = 8.19
(d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.30-7.41 (m, 19H),
4.85 (d, J = 7.6 Hz, 1H), 3.77 (d, J = 14.0 Hz, 1H), 3.59 (d, J =
The compound L2 was prepared in 70% yield as a yellow
oil. [ꢀ]ꢂꢁꢅ.ꢆ = + 50.2 (c 1.0, CHCl3,). FT-IR (ATR): ν 2928, 2852,
1
1
1602, 1518, 1471, 1345, 1252, 1068, 1011, 839, 778. H NMR
(400 MHz, CDCl3): δ = 8.18 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8

8
Tetrahedron
ACCEPTED MANUSCRIPT
Jommi. G, Pagliarin. R, Chiarino. D, Fantucci. M, Gazz. Chim. Ital.
1985, 115, 653-658.
14.0 Hz, 1H), 3.48 (dd, J = 7.2, 3.2 Hz, 1H), 2.99 (dd, J = 7.6,
2.8 Hz, 1H), 2.60-2.62 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
= 148.9, 147.3, 146.8, 143.0, 129.1, 128.5, 128.0, 127.4, 123.7,
123.3, 87.0, 72.4, 64.0, 60.3, 59.3, 50.8, 21.0, 14.1 HRMS (ESI)
calcd for C35H32N3O6 [M+H]+ 590.2213, found 590.2286.
2. (a) Schumacher. D. P, Clark. J. E, Murphy. B. L, Fischer. P. A, J. Org.
Chem., 1990, 55, 5291-5294. (b) Wu. G. Z, Schumacher. D. P,
Tormos. W, Clark. J. E, Murphy. B. L, J. Org. Chem., 1997, 62, 2996-
2998. (c) Bhaskar. G, Kumar. G. V. S, Rao. B. V, Tetrahedron:
Asymmetry 2004, 15, 1279-1283. (d) George. S, Narina. S. V, Sudalai.
A, Tetrahedron, 2006, 62, 10202-10207. (e) Li. F, Wang. Z. H, Zhao.
L, Chen. F. E, Synlett, 2011, 19, 2883-2885. (f) Li. F, Wang. Z. H,
Zhao. L, Xiong. F. J, He. Q. Q, Chen. F. E, Tetrahedron: Asymmetry,
2011, 22, 1337-1341. (g) Clark. J. E, Fischer. P. A, Schumacher. D. P,
Synth, 1991, 10, 891-894. (h) Steinreiber. J, Fesko. K, Reisinger. C,
Schurmann. M, Assema. F. V, Wolgerg. M, Mink. D, Griengl. H,
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(1S,2S)-2-((4-bromobenzyl)amino)-1-(4-nitrophenyl)-3-
(trityloxy)propan-1-ol L7.
The compound L7 was prepared in 85% yield as a yellow
solid. mp 72.1-74.5 oC. [ꢀ]ꢁꢂꢅ.ꢆ = + 109.5 (c 1.0, CHCl3,). FT-IR
(ATR): ν 3462, 2913, 1600, 1514, 1486, 1345, 1068, 999, 864,
1
743, 694, 633. H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.4
Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.14-7.41 (m, 19H), 4.78 (d, J
= 7.6 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.47-3.50 (m, 2H), 2.93
(dd, J = 7.2, 2.8 Hz, 1H), 2.58-2.60 (m, 1H). 13C NMR (100
MHz, CDCl3): δ = 149.2, 147.2, 143.1, 138.2, 131.6, 129.7,
128.5, 127.9, 127.4, 127.3, 123.2, 121.2, 86.8, 72.1, 63.8, 60.3,
59.2, 50.9, 21.0, 14.1. HRMS (ESI) calcd for C35H32BrN2O4
[M+H]+ 623.1467, found 623.1540.
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Tian. W. J, Sun. Z. Y, CN101941927. 2011. (e) Makino. k, Goto. T,
Hiroki. Y, Hamada. Y, Angew. Chem., Int. Ed., 2004, 43, 882-884. (f)
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Dev., 1998, 2, 10-17. (b) Peng. Y. W, Tian. W. J, Sun. Z. Y,
CN102827042. 2012. (c) Perez. M, Echeverria. P. G, Arripe. E. M,
Zoubir. M. E, Touati. R, Zhang. Z.G, Genet. J. P, Phansavath. P, Ayad.
T, Vidal. V. R, Eur. J. Org. Chem. 2015, 27, 5949-5958. (d) Seashore-
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Dewynter, G, Org. Biomol. Chem., 2008, 6, 3989-3996. (d) Xu. F,
Chung. J. Y. L, Moore. J. C, Liu. Z. Q, Yoshikawa. N, Hoerrner. R. S,
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(1S,2S)-2-((4-methylbenzyl)amino)-1-(4-nitrophenyl)-3-
(trityloxy)propan-1-ol L9.
The compound L9 was prepared in 74% yield as a yellow
solid. mp 55.2-56.7 oC. [ꢀ]ꢁꢂꢅ.ꢆ = + 99.4 (c 1.0, CHCl3,). FT-IR
(ATR): ν 2911, 1606, 1510, 1447, 1347, 1238, 1068, 999, 860,
821, 745, 698, 629. 1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J =
8.8 Hz, 2H), 7.41 (d, J = 7.2 Hz, 6H), 7.19-7.35 (m, 15H), 4.77
(d, J = 8.0 Hz, 1H), 3.75 (d, J = 12.8 Hz, 1H), 3.50-3.55 (m, 2H),
2.91 (dd, J = 7.2, 2.8 Hz, 1H), 2.58-2.60 (m, 1H), 2.39 (s, 3H).
13C NMR (100 MHz, CDCl3): δ = 149.4, 147.0, 143.0, 136.9,
136.0, 129.0, 128.4, 128.0, 127.8, 127.2, 123.0, 86.6, 71.8, 63.7,
58.9, 51.3, 20.9, 14.1. HRMS (ESI) calcd for C36H35N2O4
[M+H]+ 559.2519, found 559.2595.
(1S,2S)-2-((4-methoxybenzyl)amino)-1-(4-nitrophenyl)-3-
(trityloxy)propan-1-ol L10.
The compound L10 was prepared in 82% yield as a yellow
solid. mp 130.1-132.7 oC. [ꢀ]ꢁꢂꢅ.ꢆ = + 115.7 (c 1.0, CHCl3,). FT-
IR (ATR): ν 3570, 3083, 2909, 1608, 1510, 1445, 1345, 1234,
1171, 1064, 999, 696, 629. 1H NMR (400 MHz, CDCl3): δ = 8.00
(d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.2 Hz, 6H), 7.29-7.36 (m, 11H),
7.21 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.76 (d, J = 8.0
Hz, 1H), 3.84 (s, 3H), 3.73 (d, J = 8.8 Hz, 1H), 3.50 (d, J = 12.4
Hz, 2H), 2.91 (dd, J = 7.2, 2.8 Hz, 1H), 2.60-2.62 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ = 158.9, 149.5, 147.1, 143.1, 131.3,
129.3, 128.6, 127.9, 127.3, 123.2, 113.9, 86.7, 71.9, 63.7, 59.1,
55.2, 51.0. HRMS (ESI) calcd for C36H35N2O5 [M+H]+ 575.2468,
found 575.2540.
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Supplementary data
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Huffman. Org. Lett., 2004, 6, 1465-1468. (b) T. Umemoto, R. P.
Singh, Y. Xu, N. Saito, J. Am. Chem. Soc., 2010, 132, 18199-18205.
(c) P. Zhou, X. Z. Zhou, Z. H. Peng, G. B. Sun, F. Bian,
CN102491953, 2012
Supplementary data (NMR spectra for all new compounds)
associated with this article can be found in the online version
12. D. E. Shuster, S. Hecker, T. G. Glinka, R. Singh, Z. Y. Su, WO
2005066119, 2005.
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References and notes
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