Catalytic Syn-Selective Nitroaldol Approach to Amphenicol Antibiotics: Evolution of a Unified Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, (+)-Thiamphenicol, and (+)-Florfenicol

Article abstract of DOI:10.1021/acs.joc.1c01124

A unified strategy for an efficient and high diastereo- and enantioselective synthesis of (-)-chloramphenicol, (-)-azidamphenicol, (+)-thiamphenicol, and (+)-florfenicol based on a key catalytic syn-selective Henry reaction is reported. The stereochemistry of the ligand-enabled copper(II)-catalyzed aryl aldehyde Henry reaction of nitroethanol was first explored to forge a challenging syn-2-amino-1,3-diol structure unit with vicinal stereocenters with excellent stereocontrol. Multistep continuous flow manipulations were carried out to achieve the efficient asymmetric synthesis of this family of amphenicol antibiotics.

Full text of DOI:10.1021/acs.joc.1c01124

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Article
Catalytic Syn-Selective Nitroaldol Approach to Amphenicol
Antibiotics: Evolution of a Unified Asymmetric Synthesis of
(−)-Chloramphenicol, (−)-Azidamphenicol, (+)-Thiamphenicol, and
(+)-Florfenicol
Yingqi Xia, Meifen Jiang, Minjie Liu, Yan Zhang, Hongmin Qu, Tong Xiong, Huashan Huang,
Dang Cheng, and Fener Chen*
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ABSTRACT: A unified strategy for an efficient and high diastereo-
and enantioselective synthesis of (−)-chloramphenicol, (−)-azi-
damphenicol, (+)-thiamphenicol, and (+)-florfenicol based on a
key catalytic syn-selective Henry reaction is reported. The
stereochemistry of the ligand-enabled copper(II)-catalyzed aryl
aldehyde Henry reaction of nitroethanol was first explored to forge
a challenging syn-2-amino-1,3-diol structure unit with vicinal
stereocenters with excellent stereocontrol. Multistep continuous
flow manipulations were carried out to achieve the efficient
asymmetric synthesis of this family of amphenicol antibiotics.
last few decades, which stand for a serious public health
emergency, currently, this class of amphenicol antibiotics has
been reintroduced as antibacterial therapy for some infectious
diseases,3 despite their undesirable side effects to patients. Once
further evidence supports the broad clinical use of these older
antibiotics for the bacterial infections caused by MDR
microorganisms, the bulk supply of the active pharmaceutical
ingredients for cost-effective and highly stereocontrolled
manufacture of these amphenicol antibiotics would be an urgent
concern.4 Structurally, these amphenicol antibiotics (1−4)
share a common chiral syn-2-amino-1,3-diol subunit, harboring
two adjacent stereocenters, which presents a huge challenge to
large-scale synthesis. Thus, this came as a driving force for the
development of a variety of strategies for the construction of this
highly functionalized syn-2-amino-1,3-diol moiety bearing
(1R,2R)-vicinal stereocenters existing in this family of
amphenicol antibiotics. To date, a number of asymmetric
synthetic approaches toward the targeted amphenicol molecules
have been reported.5 Typical methods include Corey’s chiral
diazaborolidine-mediated asymmetric aldol reaction,5a Hajra’s
INTRODUCTION
■
Amphenicols are a class of important synthetic antibiotics, which
exhibit a broad spectrum of activity against both Gram-negative
and Gram-positive microorganisms, such as Streptococcus spp.,
Staphylococcus spp., Pasteurella spp. etc.1 (−)-Chloramphenicol
(1), (−)-azidamphenicol (2), (+)-thiamphenicol (3), and
(+)-florfenicol (4) (Figure 1) are typical members of this family
of antibiotics. They have been used effectively for the treatment
of susceptible and serious bacterial infections in both human and
livestock.2 Due to the lack of treatment options for multidrug-
resistant (MDR) bacterial infections with a global spread in the
Received: May 13, 2021
Figure 1. Structure of amphenicol antibiotics (1−4).
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Scheme 1. Previous Asymmetric Approaches Toward Amphenicol Antibiotics (1−4)
Scheme 2. Retrosynthetic Analysis of 1−4
catalytic halohydroxylation,5b Wulff’s catalytic asymmetric
aziridination,5c Rao5d and Wu’s5e catalytic Sharpless epoxida-
tion, Dixon’s silver-catalyzed isocyanoacetate aldol cyclization,5f
Ratovelomanana-Vidal’s Ruthenium,5g and Chen’s5h enzyme-
catalyzed dynamic reductive kinetic resolution, Lin’s enzyme-
catalyzed hydrocynation,5i etc (Scheme 1). However, synthetic
efficiency and stereoselectivities still need to be improved from
the viewpoint of practical synthesis.
Our group has also developed several new synthetic strategies,
including Sharpless6 and vanadium-catalyzed7 asymmetric
epoxidation of allylic alcohol, Sharpless asymmetric dihydrox-
ylation of acrylic esters,8 ruthenium-catalyzed asymmetric
transfer hydrogenation/dynamic kinetic resolution of N-Boc-
B
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a
Table 1. Optimization of Reaction Conditions on the Copper-Catalyzed Asymmetric Henry Reaction of 8b with 9
a
Unless noted otherwise, reactions were performed with 8b (0.2 mmol), 9 (0.6 mmol), Cu(OAc)2·H2O (10 mol %), and L (10 mol %) in a solvent
b
c
d
e
f
(0.8 mL) at 25 °C for 24 h. Isolated yield. The syn/anti ratio and ee determined by chiral HPLC. At 0 °C. At −5 °C. 9 (4.0 equiv) in 0.3 mL
THF. With Cu(OAc)2·H2O (5 mol %), L9 (5 mol %).
g
α-amino-β-ketoester,9 thiourea-catalyzed asymmetric aldol
reaction of aldehydes with isocyanatomalonate,10 catalytic
asymmetric Wulff-type aziridination of benzhydryl imine for
the assembly of the syn-(1R,2R)-2-amino-1,3-diol framework,11
and applied these techniques to the enantioselective synthesis of
these amphenicol antibiotics. However, a significant drawback
C
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a
Table 2. Substrate Scope of Aryl Aldehydes
a
Reaction conditions: 8 (1.0 mmol), 9 (4.0 mmol), Cu(OAc)2·H2O (10 mol %), and L9 (10 mol %) in THF (1.5 mL) at 0 °C for 72−120 h. The
b
isolated yield was provided. The syn/anti ratio and the ee value were determined by chiral HPLC analysis. Conversion yield determined by HPLC.
associated with these platforms is the synthetic difficulty in the
stereochemical control of the syn-relationship between the C-1
and C-2 stereocenters during the construction of highly
functionalized chiral scaffolds in their structures. To resolve
this problem, it would be desirable to establish a practical and
flexible strategy (i.e., short steps, facile reaction conditions,
cheap commercially available starting materials, and excellent
stereoselectivity) leading to the asymmetric synthesis of all of
the amphenicol antibiotics and their analogues in this family
bearing syn-2-amino-1,3-diol with vicinal stereocenters.
An attractive alternative, especially considering atom and step
economy,12 would be via Chen’s ligand-controlled copper(II)-
catalyzed diastereo- and enantioselective nitroaldol (Henry
reaction) process that could open the opportunity for the
construction of the syn-2-nitro-1,3-diol unit possessing vicinal
stereocenters.13 Although Chen’s method is limited to only
aliphatic substrates, this elegant catalytic syn-selective enantio-
selective nitroaldol approach caught our attention. Had this
been the case, a catalytic syn-selective enantioselective nitroaldol
reaction14 could be expected, allowing access to the syn-2-nitro-
1,3-diol motif with two adjacent stereocenters required for the
enantioselective synthesis of (−)-chloramphenicol (1), (−)-azi-
damphenicol (2), (+)-thiamphenicol (3), and (+)-florfenicol
(4). Based on this idea, a retrosynthetic analysis of 1−4 is
depicted in Scheme 2. We envisioned that syn-2-amino-1,3-diols
6a and 6b are the advanced intermediates for the enantiose-
lective synthesis of amphenicol antibiotics 1−2 and 3−4, which
can be accessed from the corresponding syn-2-nitro-1,3-diols 7a
and 7b via catalytic hydrogenation under continuous flow
conditions, respectively. To access compounds 7a and 7b, a
D
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Scheme 3. Completion of Enantioselective Synthesis of Amphenicol Antibiotics (1−4) in Continuous Flow
challenging syn-selective and enantioselective Henry reaction of
4-nitrobenzaldehyde (8a) or 4-methylsulfonyl benzaldehyde
(8b) with 2-nitroethanol (9), three compounds being
commercially available, would wait for us to achieve.
RESULTS AND DISCUSSION
■
Having designed the novel route to amphenicol antibiotics (1−
4), we first investigated the copper(II)-catalyzed asymmetric
E
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Henry reaction of 4-methylsulfonyl benzaldehyde (8b) and 2-
nitroethanol (9), and the results are summarized in Table 1. The
desired syn-adduct product 7b was obtained in 68% yield and
with a moderate dr (syn/anti) of 73:27 and an excellent
enantioselectivity of 97% ee when using 10 mol % of Cu(OAc)2·
H2O, 10 mol % of noncyclic chiral amino alcohol ligand L1,
commonly used in copper-catalyzed asymmetric Henry
reactions, in THF at room temperature for 24 h (entry 1).
Other ligands for the Cu(II) catalyst were then investigated,
including the known13,15 1,2-nonsubstituted diphenyl β-amino
alcohol ligands L2−L5 and our newly developed disubstituted-
1,2-diphenyl amino alcohol ligands L6 and L7, tetrasubstituted-
1,2-diphenyl amino alcohol ligand L8, and 1,2-di-biphenyl-
substituted amino alcohol ligands L9−L11 (see the Supporting
Information for details). The reaction proceeded smoothly with
the use of pyrrolidine-derived ligand L2, giving a result similar to
the case of using ligand L1 (76%, syn/anti = 75:25, 97% ee)
(entry 2). The yield could be improved to 95% using piperidine-
derived ligand L3 in place of ligand L2, but a poor
enantioselectivity was observed (entry 3). The ligand L4 bearing
a morpholino group showed no reactivity under the reaction
conditions (entry 4). The reaction with the ligand L5, derived
from (R)-binaphthylazepine, was also less effective, providing
syn-adduct 7b in only 36% yield with a poor enantioselectivity of
22% ee (entry 5). Subsequent investigations were focused on the
pyrrolidine-derived chiral ligands L6−L11, which feature a 1,2-
di or tetrasubstituted diphenyl group and a 1,2-dibiphenyl group
bearing different electronic and steric properties. It was found
that all of the reactions using L6−L11 as the ligands produced
syn-adduct 7b in good yields with good syn-selectivity and
excellent enantioselectivity (entries 6−11). The reaction using
L9 as the ligand showed the best result, leading to the desired
product 7b in 81% yield with 80:20 dr (syn/anti) and 97% ee
(entry 9). Further optimization of reaction conditions indicated
that some reaction parameters, including solvent, temperature,
the molar ratio of 8b to 9, concentration, and the catalyst loading
amount, have an impact on this Henry reaction. The use of other
solvents, such as MeCN, DCM, DCE, and DMF, could improve
the yield (90−95%), but the poor diastereo- and enantiose-
lectivities were observed (entries 12−15), and THF remained
the best choice for this reaction. Notably, the diastereoselectivity
was remarkably increased to 97:3 (syn/anti), albeit with 23%
yield without affecting the enantioselectivity when the reaction
proceeded at 0 °C (entry 16). Further decreasing the reaction
temperature to −5 °C, slightly lower yield and diastereo- and
enantioselectivities were observed (entry 17). Furthermore,
increasing the loading of 9 to 4.0 equivalents relative to that of
8b and concentration from 0.25 M to 0.67 M under the identical
reaction conditions (THF, 0 °C) led to a 98% yield of syn-adduct
7b with 97:3 dr (syn/anti) and 97% ee after prolonged reaction
time (3 days, entry 18). Interestingly, when the catalyst loading
was reduced to 5 mol %, the same result could be obtained (96%
yield, 94:6 dr, 97% ee), albeit with an even longer reaction time
(5 days, entry 19). With a systematic survey, the optimal
reaction conditions were determined, as shown in entry 18 of
Table 1.
sulfonyl, nitro, trifluoromethyl, nitrile, ester, methoxy, and
methylthio, were tolerated under the reaction conditions to give
the desired products (7a−7t) in good to excellent yields (76−
99%) with good to excellent diastereoselectivities (87:13 to 97:3
dr) and excellent enantioselectivities (95−99% ee). For
benzaldehyde with disubstituents at any position of the phenyl
ring, the reaction proceeded smoothly to generate 7u−7w in
good to excellent yields (82−96%) with good to excellent
diastereoselectivities (82:18 to 93:7 dr), and excellent
enantioselectivities (95−99% ee). These results indicated that
the electronic properties and steric hindrance exert little effect
on this reaction. The trisubstituted benzaldehyde, 2,4,6-
trimethoxybenzaldehyde (8x), was also suitable for this reaction,
delivering the desired syn-adduct product 7x in 98% yield with
excellent diastereo- and enantioselectivity (99:1 dr, >99% ee). In
addition to benzaldehydes, fused aryl (2-naphthyl) and fused
heterocyclic aldehydes (8y, 8z, and 8aa) were also good
substrates for this reaction providing the corresponding
products (7y−7aa) with high efficiency (82−98% yield, 89:11
to 95:5 dr, 97−98% ee).
After the synthetic route to access the syn-2-nitro-1,3-diols has
been established, we proceeded to develop multigram-scale
continuous-flow processes for the enantioselective synthesis of
amphenicol antibiotics (1−4) (Scheme 3).16 We began with
syn-adduct 7a (95% ee) and syn-adduct 7b (97% ee) in our
endeavor to develop the continuous-flow process. First, the
continuous flow hydrogenation17 of crude 7a was conducted in a
fixed bed reactor (MF-200, Shenzhen E-Zheng Tech Co., Ltd.)
containing 10% of Pd(OH)2/C dispersed in SiO2 (5 mL internal
volume) at 25 °C and 15 bar back-pressure, giving syn-2- amino-
1,3-diol 6a in 76% yield in a residence time of 10 min.
Remarkably, the catalytic system was found to be stable at room
temperature for at least 10 days without reducing the catalytic
activity. The syn-2-amino-1,3-diol 6a was combined with methyl
dichloroacetate (10a) and methyl 2-azidoacetate (10b)
pumped, respectively, into a 1.0 mL PTFE reactor coil (i.d. =
0.8 mm) at 40 °C with a residence time of 3.5 min to afford the
corresponding 5a and 5b in 80% yield and 81% yield. The
solution of 5a in H2O/acetone and aqueous NaHCO3/NaOH
buffer was combined at a T-mixer with a stream of oxone in
aqueous EDTA, and the oxidation reaction proceeded smoothly
in a PTFE reactor coil with a residence time of 1.5 min to furnish
(−)-chloramphenicol (1) in 62% yield after recrystallization
from AcOEt/petroleum ether. It is noted that the flow protocol
was optimized by operating the first half of the flow reactor at 0
°C, while the second half of the flow reactor at room
temperature.
In addition to (−)-chloramphenicol (1), (−)-azidamphenicol
(2) could also be efficiently prepared in 64% yield from 5b under
exactly the same reaction conditions using the same flow setup.
Next, we continued with continuous flow synthesis of
(+)-thiamphenicol (3) and (+)-florfenicol (4). At the outset,
catalytic hydrogenation of 7b delivered the desired product 6b
in 82% yield under the same flow conditions. This flow reaction
could be continuously operated for over 72 h without any
clogging issues along with a throughput of 0.18 g·h−1 (i.e., 4.3 g·
day−1). The syn-2-amino-1,3-diol 6b could serve as a common
intermediate for the asymmetric synthesis of target molecules (3
and 4) by subsequent transformations. A methanol solution of
6b, methyl dichloroacetate (10a), and Et3N was streamed
through a PTFE reactor coil, and the acylation was found to
proceed at 30 °C with 10 min residence time, affording
(+)-thiamphenicol (3) in 84% yield.
With the optimized reaction conditions in hand, the
substituted scope of the aryl aldehydes was then investigated,
and the results are shown in Table 2. A variety of benzaldehydes
(8a−8t) bearing monosubstituents at any position of the phenyl
ring were initially surveyed. Both electron-withdrawing and
donating groups were compatible with this transformation, and a
diverse array of functional groups, such as halogen, methyl-
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a
Table 3. Optimization of the Fluorination Reaction Conditions in Flow
b
entry
conditions
yield (%)
1
2
3
4
5
6
Deoxo-Fluor (2.0 equiv), DCM, 25 °C, 10 min
DAST (2.0 equiv), THF, 25 °C, 10 min
XtalFluor-E (2.0 equiv), DCM, 25 °C, 10 min
Fluolead (2.0 equiv), DCM, 25 °C, 10 min
52
36
20
24
89
95
PBSF (1.5 equiv), Et3N (3.0 equiv), Et3N·3HF (3.0 equiv), THF, 40 °C, 10 bar, 40 min
Ishikawa’s reagent (1.1 equiv), DCM, 100 °C, 10 bar, 2.5 min
a
b
Reaction conditions: 11 (1.0 mmol) and solvent (5 mL) in flow. Isolated yield.
For the preparation of (+)-florfenicol (4), a solution of 6b in
product 12 in excellent yield (95%, entry 6). Finally, the crude
product 12 was then dissolved in iPrOH/H2O and subsequently
streamed into another reactor coil at 100 °C and 10 bar back-
pressure. This flow protocol achieved 81% yield of (+)-florfe-
nicol (4) in a residence time of 2.5 min.
MeOH and a solution of dichloroacetonitrile in MeOH with a
catalytic amount of conc. HCl were pumped separately into a
reactor coil using two syringe pumps at 70 °C and 10 bar back-
pressure with a residence time of 10 min to afford the oxazolyl
alcohol 11 in 88% yield. With access to the oxazolyl alcohol 11,
the introduction of fluorine functionality to 11 in flow was at
hand (Table 3). Initially, oxazolyl alcohol 11 was subjected to
fluorination with Deoxo-Fluor (F1) into a reactor coil at 25 °C
with 10 min residence time, which generated 52% yield of the
desired oxazolyl fluoride 12, along with large amounts of
unreacted 11 (entry 1). Further optimization studies were
undertaken for this fluorination reaction. Other fluorination
reagents (F2−F6) under reaction conditions illustrated in
entries 2−6 of Table 3 were investigated. To our dismay, DAST
(F2), XtalFluor-E (F3), and Fluolead (F4) only showed poor
reactivity (entries 2−4). In contrast, PBSF (F5) performed
better to provide the desired product 12 in 89% yield with a
residence time of 40 min (entry 5). Further screening indicated
that Ishikawa’s reagent (F6) under flow conditions (100 °C, 10
bar back-pressure, and 2.5 min residence time) was the best
fluorinating agent and cleanly produced the corresponding
CONCLUSIONS
■
In conclusion, we have successfully developed a unique and
general strategy that allows the enantioselective synthesis of the
amphenicol antibiotics, including (−)-chloramphenicol (1),
(−)-azidamphenicol (2), and (+)-thiamphenicol (3) and its 3-
fluoro derivative, (+)-florfenicol (4), without the requirement
for any protecting chemistry. The novel synthetic strategy was
enabled by the key copper(II)-chiral biphenyl-substituted
amino alcohol complex catalyzed Henry reaction, which allows
efficient and high diastereo- and enantioselective construction of
the common syn-2-amino-1,3-diol moiety. Our strategy can
provide a platform for the straightforward and asymmetric
synthesis of other pharmacologically important molecules and
biologically active natural products containing the syn-2-amino-
1,3-diol subunit with two vicinal stereocenters.
G
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rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 22.550 min,
EXPERIMENTAL SECTION
■
t
minor = 27.981 min; syn isomer: tmajor = 41.961 min, tminor = 55.233 min.
General Information. All aldehydes (8a−8z and 8aa), 2-
nitroethanol (9), and solvents were commercially available. Amino
alcohol ligands L1−L5 were prepared according to the literature
procedures.13,15 NMR data (1H, 13C, and 19F) were recorded on Bruker
Avance III 600 and 400 spectrometers. Chemical shifts were referred to
as TMS. HRMS were measured on a Bruker micro TOF Q III.
Ultraviolet light (UV) detection was monitored at 254 nm. The
procedure of continuous flow was monitored by thin-layer chromatog-
raphy (TLC) and LC−MS (Agilent 6545 LC/Q-TOF, Agilent 1260
Infinity II, Eclipse Plus C18, RRHD 1.8 μm, 2.1 × 50 mm2). Column
chromatography was performed on silica gel (200−300 mesh), eluting
with dichloromethane/methanol and petroleum ether/ethyl acetate.
Melting points were measured on an SRS-optic melting point
apparatus. In each case, syn/anti ratio and enantiomeric ratio were
determined by HPLC analysis on a chiral column in comparison with
authentic racemate, using a Daicel Chiralpak IC Column (250 × 4.6
mm2), Chiralpak AS-H Column (250 × 4.6 mm2), or Chiralpak AD-H
Column (250 × 4.6 mm2).
General Procedure for the Racemic Henry Reactions. To a
mixture of aldehydes 8 (1 mmol, 1.0 equiv) and 2-nitroethanol 9 (3
mmol, 3.0 equiv) in THF (2 mL) was added TBAF (1 mL, 1.0 equiv, 1
M solution in THF) dropwise at room temperature and the mixture was
stirred at room temperature for 36 h. Water (2 mL) was added, and the
aqueous phase was extracted twice with ethyl acetate (2 × 3 mL). The
organic layer was combined and washed with brine (3 mL), then dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by silica gel flash column chromatography (DCM/MeOH
= 100:2) to give the corresponding racemic products rac-7.
(1R,2R)-1-(4-Chlorophenyl)-2-nitropropane-1,3-diol (7d). Pale
1
yellow oil, 108 h, 93% yield, 215.4 mg, syn/anti = 94:6; H NMR
(400 MHz, CD3OD): δ 7.40−7.35 (m, 4H), 5.02 (d, J = 9.2 Hz, 1H),
4.82−4.76 (m, 1H), 3.83 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H), 3.41 (dd, J1
= 12.4 Hz, J2 = 3.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CD3OD):
δ 139.6, 135.2, 129.7, 129.4, 96.1, 72.6, 61.5 ppm. ESI HRMS: calcd. for
C9H10ClNO4+Na 254.0196, found 254.0192; [α]D25 = −21.9 (c =1.76,
EtOH). The enantiomeric excess of product 7d was determined by
chiral HPLC: 98% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 9.847 min,
t
minor = 11.750 min; syn isomer: tmajor = 16.376 min, tminor = 19.956 min.
(1R,2R)-1-(4-Bromophenyl)-2-nitropropane-1,3-diol (7e). Pale
1
yellow oil, 108 h, 87% yield, 240.2 mg, syn/anti = 87:13; H NMR
(400 MHz, CD3OD): δ 7.54 (d, J = 8.4 Hz, 2H, syn), 7.50 (d, J = 8.4 Hz,
2H, anti), 7.33 (d, J = 8.4 Hz, 2H, syn), 7.30 (d, J = 8.4 Hz, 2H, anti),
4.99 (d, J = 9.2 Hz, 1H), 4.77 (td, J1 = 9.6 Hz, J2 = 3.2 Hz, 1H), 4.18 (dd,
J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 3.99 (dd, J1 = 12.0 Hz, J2 = 2.8 Hz,
1H, anti), 3.82 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, syn), 3.40 (dd, J1 =
12.0 Hz, J2 = 3.2 Hz, 1H, syn) ppm; 13C{1H} NMR (100 MHz,
CD3OD): δ 139.2 (anti), 138.9 (syn), 131.5 (syn), 131.2 (anti), 128.5
(syn), 128.2 (anti), 122.1 (syn), 121.8 (anti), 94.9 (syn), 94.2 (anti),
71.6 (anti), 71.5 (syn), 60.3 (syn), 59.9 (anti) ppm. ESI HRMS: calcd.
for C9H10BrNO4+Na 297.9691, found 297.9695; [α]D25 = −15.3 (c =
0.77, EtOH). The enantiomeric excess of product 7e was determined
by chiral HPLC: 97% ee (CHIRALPAK IC, hexane/i-PrOH = 95/5,
flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 33.386
min, tminor = 41.268 min; syn isomer: tmajor = 64.533 min, tminor = 80.172
min.
General Procedure for the Asymmetric Henry Reactions. A
solution of Cu(OAc)2·H2O (0.1 mmol, 10 mol %) and L9 (0.1 mol, 10
mol %) in THF (1.5 mL) was stirred for 1 h at room temperature. Then,
aldehyde 8 (1.0 mmol, 1.0 equiv) and 2-nitroethanol 9 (4.0 mmol, 4.0
equiv) were added into the reaction flask at 0 °C. The mixture was
stirred for 72−120 h at 0 °C and then quenched with 1 M HCl (2 mL).
The resulting mixture was extracted with ethyl acetate (3 × 10 mL).
The organic layer was combined and washed with brine (5 mL). The
organic phase was dried with Na2SO4 and evaporated in a vacuum. The
resulting residue was purified by silica gel chromatography (DCM/
MeOH = 50:1) to give the corresponding syn-2-nitro-1,3-diols 7.
(1R,2R)-1-(4-(Methylsulfonyl)phenyl)-2-nitropropane-1,3-diol
(7b). White solid, mp 136−138 °C, 60 h, 269.8 mg, 98% yield, syn/anti
= 97:3; 1H NMR (400 MHz, DMSO): δ 7.93 (d, J = 8.0 Hz, 2H), 7.71
(d, J = 8.4 Hz, 2H), 6.35 (d, J = 4.8 Hz, 1H), 5.28 (dd, J1 = 6.4 Hz, J2 =
4.4 Hz, 1H), 5.06 (dd, J1 = 8.8 Hz, J2 = 4.8 Hz, 1H), 4.80 (td, J1 = 9.2 Hz,
J2 = 3.2 Hz, 1H), 3.84−3.77 (m, 1H), 3.25 (dt, J1 = 12.4 Hz, J2 = 4.0 Hz,
1H), 3.21 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO): δ 146.5,
141.1, 128.4, 127.6, 95.4, 71.2, 60.5, 43.9 ppm. ESI HRMS: calcd. for
(1R,2R)-2-Nitro-1-(4-(trifluoromethyl)phenyl)propane-1,3-diol
(7f). Colorless oil, 84 h, 262.5 mg, 99% yield, syn/anti = 89:11; 1H NMR
(400 MHz, CD3OD): δ 7.70 (d, J = 8.0 Hz, 2H, syn), 7.66 (d, J = 8.4 Hz,
2H, anti), 7.62 (d, J = 8.0 Hz, 2H, syn), 7.59 (d, J = 8.0 Hz, 2H, anti),
5.13 (d, J = 9.2 Hz, 1H), 4.82 (td, J1 = 9.2 Hz, J2 = 3.2 Hz, 1H), 4.21 (dd,
J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 4.00 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz,
1H, anti), 3.86 (dd, J1 = 12.0 Hz, J2 = 8.8 Hz, 1H, syn), 3.45 (dd, J1 =
12.4 Hz, J2 = 3.2 Hz, 1H, syn) ppm; 13C{1H} NMR (100 MHz,
CD3OD): δ 142.9 (anti), 142.6 (syn), 128.8 (q, J = 32 Hz), 125.8 (syn),
125.4 (anti), 123.7 (q, J = 4 Hz, syn), 123.4 (q, J = 4 Hz, anti), 122.6 (q, J
= 269 Hz), 93.2 (syn), 92.6 (anti), 70.0 (anti), 69.9 (syn), 58.7 (syn),
58.2 (anti) ppm. ESI HRMS: calcd. for C10H10F3NO4 + Na 288.0460,
found 288.0465; [α]D25 = −14.7 (c = 2.32, EtOH). The enantiomeric
excess of product 7f was determined by chiral HPLC: 97% ee
(CHIRALPAK IC, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, T
= 30 °C, 220 nm), anti isomer: tmajor = 6.902 min, tminor = 7.896 min; syn
isomer: tmajor = 10.885 min, tminor = 12.577 min.
4-((1R,2R)-1,3-Dihydroxy-2-nitropropyl)benzonitrile (7g). White
solid, mp 110−111 °C, 60 h, 217.8 mg, 98% yield, syn/anti = 92:8; 1H
NMR (400 MHz, CD3OD): δ 7.77−7.74 (m, 2H), 7.63−7.61 (m, 2H),
5.14 (d, J = 8.8 Hz, 1H), 4.83−4.78 (m, 1H), 3.86 (dd, J1 = 12.4 Hz, J2 =
8.8 Hz, 1H), 3.48 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H) ppm; 13C{1H}
NMR (100 MHz, CD3OD): δ 143.8, 130.7, 126.1, 116.5, 110.5, 92.9,
69.8, 58.7 ppm. ESI HRMS: calcd. for C10H10N2O4 + Na 245.0538,
found 245.0569; [α]D25 = −36.4 (c = 0.45, EtOH). The enantiomeric
excess of product 7g was determined by chiral HPLC: 96% ee
(CHIRALPAK IC, hexane/i-PrOH = 90/10, flow rate: 0.8 mL/min, T
= 30 °C, 220 nm), anti isomer: tmajor = 33.155 min, tminor = 35.837 min;
syn isomer: tmajor = 59.506 min, tminor = 50.737 min.
25
C10H13NO6S + Na 298.0361, found 298.0362; [α]D = −32.6 (c =
0.29, EtOH). The enantiomeric excess of product 7b was determined
by chiral HPLC: 97% ee (CHIRALPAK IC, hexane/i-PrOH = 65/35,
flow rate: 0.7 mL/min, T = 30 °C, 210 nm), anti isomer: tmajor = 17.918
min, tminor = 20.068 min; syn isomer: tmajor = 30.064 min, tminor = 22.175
min.
(1R,2R)-1-(4-Fluorophenyl)-2-nitropropane-1,3-diol (7c). Color-
less oil, 84 h, 96% yield, 206.6 mg, syn/anti = 94:6; 1H NMR (400 MHz,
CD3OD): δ 7.46−7.38 (m, 2H), 7.15−7.05 (m, 2H), 5.02 (d, J = 7.2
Hz, 1H, anti), 5.01 (d, J = 9.2 Hz, 1H, syn), 4.79 (td, J1 = 9.2 Hz, J2 = 3.2
Hz, 1H), 4.18 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 4.03 (dd, J1 =
12.0 Hz, J2 = 2.8 Hz, 1H, anti), 3.82 (dd, J1 = 12.0 Hz, J2 = 9.2 Hz, 1H,
syn), 3.38 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H, syn) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 162.8 (d, J = 244.4 Hz, syn), 162.7 (d, J = 243.8
Hz, anti), 135.9 (d, J = 3.2 Hz, anti), 135.7 (d, J = 3.1 Hz, syn), 128.6 (d,
J = 8.2 Hz, syn), 128.3 (d, J = 243.8 Hz, anti), 115.1 (d, J = 21.8 Hz, syn),
114.8 (d, J = 21.8 Hz, anti), 95.1 (syn), 94.4 (anti), 71.6 (anti), 71.5
(syn), 60.4 (syn), 60.1 (anti) ppm. ESI HRMS: calcd. for
(1R,2R)-2-Nitro-1-phenylpropane-1,3-diol (7h). Pale yellow oil,
1
132 h, 167.6 mg, 85% yield, syn/anti = 94:6; H NMR (400 MHz,
CDCl3): δ 7.41−7.36 (m, 5H), 5.46 (t, J = 4.4 Hz, 1H, anti), 5.24 (dd, J1
= 8.8 Hz, J2 = 3.2 Hz, 1H, syn), 4.81−4.76 (m, 1H, syn), 4.70−4.66 (m,
1H, anti), 4.25−4.07 (m, 2H, anti), 3.83−3.72 (m, 2H, syn), 3.21 (d, J =
4.8 Hz, 1H, anti), 2.85 (d, J = 4.0 Hz, 1H, syn), 2.61 (t, J = 7.2 Hz, 1H,
anti), 2.28 (d, J = 6.0 Hz, 1H, syn) ppm; 13C{1H} NMR (100 MHz,
CDCl3): δ 138.2 (anti), 138.0 (syn), 129.4 (syn), 129.2 (syn), 129.0
(anti), 128.9 (anti), 126.6 (syn), 125.9 (anti), 93.8 (syn), 91.9 (anti),
73.4 (anti), 72.6 (syn), 61.3 (syn), 60.0 (anti) ppm. ESI HRMS: calcd.
for C9H11NO4+Na 220.0586, found 220.0582; [α]D25 = 2.0 (c = 0.79,
25
C9H10FNO4+Na 238.0492, found 238.0497; [α]D = −30.9 (c =
0.61, EtOH). The enantiomeric excess of product 7c was determined by
chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-PrOH = 95/5, flow
H
https://doi.org/10.1021/acs.joc.1c01124
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
EtOH). The enantiomeric excess of product 7h was determined by
chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 13.511 min,
C11H13NO6 + Na 278.0641, found 278.0640; [α]D25 = −17.6 (c = 0.78,
EtOH). The enantiomeric excess of product 7m was determined by
chiral HPLC: 98% ee (CHIRALPAK IC, hexane/i-PrOH = 85/15, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 15.340 min,
minor = 17.904 min; syn isomer: tmajor = 24.200 min, tminor = 28.347 min.
(1R,2R)-1-(2-Fluorophenyl)-2-nitropropane-1,3-diol (7n). Color-
t
minor = 15.645 min; syn isomer: tmajor = 20.455 min, tminor = 27.789 min.
(1R,2R)-2-Nitro-1-(p-tolyl)propane-1,3-diol (7i). Pale yellow oil,
t
1
156 h, 173.2 mg, 82% yield, syn/anti = 88:12; H NMR (400 MHz,
CD3OD): δ 7.29−7.16 (m, 4H), 4.99 (d, J = 7.2 Hz, 1H, anti), 4.94 (d, J
= 9.6 Hz, 1H, syn), 4.80 (td, J1 = 9.6 Hz, J2 = 3.2 Hz, 1H), 4.20 (dd, J1 =
12.4 Hz, J2 = 9.6 Hz, 1H, anti), 4.05−4.00 (m, 1H, anti), 3.82 (dd, J1 =
12.4 Hz, J2 = 10.0 Hz, 1H, syn), 3.34 (dd, J1 = 12.0 Hz, J2 = 2.8 Hz, 1H,
syn), 2.34 (s, 3H, syn), 2.32 (s, 3H, anti) ppm; 13C{1H} NMR (100
MHz, CD3OD): δ138.5 (syn), 138.0 (anti), 136.8 (anti), 136.5 (syn),
129.1 (syn), 128.7 (anti), 126.5 (syn), 126.1 (anti), 95.3 (syn), 94.5
less oil, 72 h, 210.9 mg, 98% yield, syn/anti = 96:4; 1H NMR (400 MHz,
CD3OD): δ 7.55 (td, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H), 7.43−7.37 (m, 1H),
7.26 (t, J = 7.6 Hz, 1H), 7.17−7.13 (m, 1H), 5.36 (dd, J1 = 9.2 Hz, J2 =
3.2 Hz, 1H), 4.96−4.93 (m, 1H), 3.96 (td, J1 = 12 Hz, J2 = 2.8 Hz, 1H),
3.96 (dt, J1 = 12 Hz, J2 = 3.6 Hz, 1H) ppm; 13C{1H} NMR (100 MHz,
CD3OD): δ 160.9 (d, J = 244.0 Hz, syn), 160.9 (d, J = 244.1 Hz, anti),
131.3 (d, J = 8.5 Hz, syn), 131.0 (d, J = 7.7 Hz, anti), 129.3 (d, J = 3.9 Hz,
syn), 129.2 (d, J = 3.8 Hz, anti), 127.6 (d, J = 13.2 Hz), 125.6 (d, J = 3.4
Hz, syn), 125.2 (d, J = 3.4 Hz, anti), 116.1 (d, J = 21.4 Hz, syn), 116.0 (d,
J = 21.7 Hz, anti), 95.6 (d, J = 2.5 Hz, syn), 93.5 (anti), 67.6 (anti), 66.9
(syn), 61.2 (syn), 40.4 (anti) ppm. ESI HRMS: calcd. for
(anti), 72.2, 60.5 (syn), 60.1 (anti), 19.8 (syn), 19.8 (anti) ppm. ESI
25
HRMS: calcd. for C10H13NO4+Na 234.0742, found 234.0738; [α]D
=
−11.4 (c = 0.56, EtOH). The enantiomeric excess of product 7i was
determined by chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-
PrOH = 90/10, flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti
25
C9H10FNO4+Na 238.0492, found 238.0487; [α]D = −12.0 (c =
isomer: tmajor = 14.779 min, tminor = 18.756 min; syn isomer: tmajor
24.737 min, tminor = 35.048 min.
=
0.52, EtOH). The enantiomeric excess of product 7n was determined
by chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10,
flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 12.327
min, tminor = 15.067 min; syn isomer: tmajor = 16.038 min, tminor = 20.773
min.
(1R,2R)-1-(4-Methoxyphenyl)-2-nitropropane-1,3-diol (7j). Color-
less oil, 144 h, 184 mg, 81% yield, syn/anti = 93:7; 1H NMR (400 MHz,
CD3OD): δ 7.34−7.32 (m, 2H), 6.97−6.95 (m, 2H), 4.94 (d, J = 9.6
Hz, 1H), 4.84−4.78 (m, 1H), 3.83−3.79 (m, 4H), 3.36 (dd, J1 = 12.0
Hz, J2 = 3.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ
161.3 (syn), 161.0 (anti), 132.9 (anti), 132.6 (syn), 129.0 (syn), 128.7
(anti), 115.0 (syn), 114.6 (anti), 96.6 (syn), 95.7 (anti), 73.2 (anti),
(1R,2R)-1-(2-Chlorophenyl)-2-nitropropane-1,3-diol (7o). Pale
1
yellow oil, 108 h, 222.3 mg, 96% yield, syn/anti = 92:8; H NMR
(400 MHz, CD3OD): δ 7.63 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H), 7.47−
7.34 (m, 3H), 5.57 (d, J = 8.4 Hz, 1H), 4.99−4.94 (m, 1H), 4.14 (dd, J1
= 12.0 Hz, J2 = 9.6 Hz, 1H), 3.51 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H)
ppm; 13C{1H} NMR (100 MHz, CD3OD): δ 138.2, 133.1, 130.6,
130.2, 129.2, 128.4, 96.0, 69.0, 61.1 ppm. ESI HRMS: calcd. for
C9H10ClNO4+Na 254.0196, found 254.0193; [α]D25 = −11.4 (c = 1.15,
EtOH). The enantiomeric excess of product 7o was determined by
chiral HPLC: 97% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 15.711 min,
73.1 (syn), 61.7 (syn), 61.4 (anti), 56.0 (anti), 55.5 (syn) ppm. ESI
25
HRMS: calcd. for C10H13NO5+Na 250.0691, found 250.0683; [α]D
=
−6.9 (c = 0.79, EtOH). The enantiomeric excess of product 7j was
determined by chiral HPLC: 96% ee (CHIRALPAK IC, hexane/i-
PrOH = 90/10, flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti
isomer: tmajor = 19.900 min, tminor = 25.022 min; syn isomer: tmajor
36.504 min, tminor = 46.255 min.
=
(1R,2R)-1-(4-(Methylthio)phenyl)-2-nitropropane-1,3-diol (7k).
t
minor = 14.266 min; syn isomer: tmajor = 17.139 min, tminor = 21.539 min.
(1R,2R)-1-(2-Bromophenyl)-2-nitropropane-1,3-diol (7p). White
1
Pale yellow oil, 96 h, 228.7 mg, 94% yield, syn/anti = 89:11; H
NMR (400 MHz, CD3OD): δ 7.35−7.23 (m, 4H), 5.01 (d, J = 7.2 Hz,
1H, anti), 4.96 (d, J = 9.6 Hz, 1H, syn), 4.84−4.78 (m, 1H), 4.20 (dd, J1
= 12.0 Hz, J2 = 9.2 Hz, 1H, anti), 4.03 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H,
anti), 3.83 (dd, J1 = 12.0 Hz, J2 = 9.2 Hz, 1H, syn), 3.39 (dd, J1 = 12.4 Hz,
J2 = 3.2 Hz, 1H, syn), 2.48 (s, 3H, syn), 2.46 (s, 3H, anti) ppm; 13C{1H}
NMR (100 MHz, CD3OD): δ 139.7 (syn), 139.1 (anti), 136.4 (anti),
136.1 (syn), 127.1 (syn), 126.8 (anti), 126.1 (syn), 125.9 (anti), 95.2
(syn), 94.4 (anti), 72.0 (anti), 71.9 (syn), 60.5 (syn), 60.1 (anti), 14.1
(anti), 14.0 (syn) ppm. ESI HRMS: calcd. for C10H13NO4S+Na
solid, mp 70−73 °C, 108 h, 270.6 mg, 98% yield, syn/anti = 92:8; 1H
NMR (400 MHz, CD3OD): δ 7.61 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
7.57 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H), 7.43 (td, J1 = 7.6 Hz, J2 = 1.2 Hz,
1H), 7.25 (td, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H), 5.49 (d, J = 8.4 Hz, 1H),
4.92−4.89 (m, 1H), 4.15−4.09 (m 1H), 3.43 (dd, J1 = 12 Hz, J2 = 3.2
Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ 139.0, 132.6,
129.9, 128.5, 127.9, 122.1, 95.3, 70.4, 60.2 ppm. ESI HRMS: calcd. for
C9H10BrNO4+Na 297.9691, found 297.9689; [α]D25 = −3.3 (c = 0.33,
EtOH). The enantiomeric excess of product 7p was determined by
chiral HPLC: 96% ee (CHIRALPAK IC, hexane/i-PrOH = 95/5, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 44.035 min,
25
266.0463, found 266.0465; [α]D = −22.8 (c = 0.64, EtOH). The
enantiomeric excess of product 7k was determined by chiral HPLC:
98% ee (CHIRALPAK IC, hexane/i-PrOH = 85/15, flow rate: 1.0 mL/
t
minor = 37.405 min; syn isomer: tmajor = 48.952 min, tminor = 65.461 min.
(1R,2R)-2-Nitro-1-(o-tolyl)propane-1,3-diol (7q). Colorless oil, 132
min, T = 30 °C, 220 nm), anti isomer: tmajor = 10.238 min, tminor
12.527 min; syn isomer: tmajor = 17.665 min, tminor = 20.517 min.
=
h, 171.1 mg, 81% yield, syn/anti = 91:9; 1H NMR (400 MHz, CD3OD):
δ 7.48−7.45 (m, 1H, anti), 7.42−7.40 (m, 1H, syn), 7.27−7.14 (m,
3H), 5.34 (d, J = 6.8 Hz, 1H, anti), 5.29 (d, J = 9.6 Hz, 1H, syn), 4.93
(td, J1 = 9.6 Hz, J2 = 3.2 Hz, 1H, syn), 4.28 (dd, J1 = 12.8 Hz, J2 = 9.2 Hz,
1H, anti), 4.02 (dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H, anti), 3.85 (dd, J1 =
12.0 Hz, J2 = 9.6 Hz, 1H, syn), 3.35 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H,
syn), 2.42 (s, 3H, syn), 2.40 (s, 3H, anti) ppm; 13C{1H} NMR (100
MHz, CD3OD): δ 138.9 (anti), 138.6 (syn), 136.6 (syn), 136.3 (anti),
131.6 (syn), 131.4 (anti), 129.2 (syn), 129.0 (anti), 127.6 (syn), 127.4
(syn), 127.2 (anti), 127.0 (anti), 96.7 (syn), 93.9 (anti), 70.1 (anti),
(1R,2R)-1-([1,1′-Biphenyl]-4-yl)-2-nitropropane-1,3-diol (7l).
White solid, mp 122−126 °C, 96 h, 259.6 mg, 95% yield, syn/anti =
93:7; 1H NMR (400 MHz, CD3OD): δ 7.58−7.49 (m, 4H), 7.38 (d, J =
8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.26−7.21 (m, 1H), 4.95 (d, J =
9.2 Hz, 1H), 4.80−4.75 (m, 1H), 3.78 (dd, J1 = 12.0 Hz, J2 = 9.2 Hz,
1H), 3.34 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H) ppm; 13C{1H} NMR (100
MHz, CD3OD): δ 141.5, 140.3, 138.6, 128.5, 127.2, 127.1, 127.0, 126.6,
95.2, 72.1, 60.5 ppm. ESI HRMS: calcd. for C15H15NO4+Na 296.0899,
found 296.0894; [α]D25 = −24.3 (c = 0.68, EtOH). The enantiomeric
excess of product 7l was determined by chiral HPLC: 99% ee
(CHIRALPAK IC, hexane/i-PrOH = 85/15, flow rate: 0.8 mL/min, T
= 30 °C, 220 nm), anti isomer: tmajor = 12.060 min, tminor = 14.489 min;
syn isomer: tmajor = 20.987 min, tminor = 23.151 min.
69.6 (syn), 61.4 (syn), 60.8 (anti), 19.2 (syn), 18.8 (anti) ppm. ESI
25
HRMS: calcd. for C10H13NO4+Na 234.0742, found 234.0733; [α]D
=
−4.3 (c = 1.62, EtOH). The enantiomeric excess of product 7q was
determined by chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-
PrOH = 90/10, flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti
4-((1R,2R)-1,3-Dihydroxy-2-nitropropyl)phenyl acetate (7m).
1
Colorless oil, 132 h, 194.0 mg, 76% yield, syn/anti = 94:6; H NMR
isomer: tmajor = 15.559 min, tminor = 14.526 min; syn isomer: tmajor
18.721 min, tminor = 24.451 min.
=
(400 MHz, CD3OD): δ 7.46−7.44 (m, 2H), 7.15−7.13 (m, 2H), 5.04
(d, J = 9.2 Hz, 1H), 4.84 (td, J1 = 9.2 Hz, J2 = 3.2 Hz, 1H), 3.85 (dd, J1 =
12.4 Hz, J2 = 9.6 Hz, 1H), 3.42 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 1H), 2.27
(s, 3H) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ 171.0, 152.1,
138.2, 128.8, 122.9, 96.2, 72.7, 61.5, 20.7 ppm. ESI HRMS: calcd. for
(1R,2R)-1-(3-Chlorophenyl)-2-nitropropane-1,3-diol (7r). Color-
less oil, 72 h, 224.7 mg, 97% yield, syn/anti = 95:5; 1H NMR (400 MHz,
CD3OD): δ 7.48 (s, 1H), 7.40−7.34 (m, 3H), 5.10−5.08 (m, 1H, anti),
5.05 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H, syn), 4.84−4.80 (m, 1H), 4.22 (td,
I
https://doi.org/10.1021/acs.joc.1c01124
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
J1 = 12.0 Hz, J2 = 2.4 Hz, 1H, anti), 4.07−4.01 (m, 1H, anti), 3.87 (td, J1
= 12.0 Hz, J2 = 2.4 Hz, 1H, syn), 3.47 (td, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H,
syn) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ 142.2 (anti), 142.0
(syn), 134.3 (syn), 134.1 (anti), 130.0 (syn), 129.7 (anti), 128.5 (syn),
128.1 (anti), 126.6 (syn), 126.3 (anti), 125.0 (syn), 124.7 (anti), 94.8
(syn), 94.1 (anti), 71.5 (anti), 71.5 (syn), 60.4 (syn), 59.9 (anti) ppm.
ESI HRMS: calcd. for C9H10ClNO4+Na 254.0196, found 254.0195;
[α]D25 = −12.1 (c = 1.86, EtOH). The enantiomeric excess of product
7r was determined by chiral HPLC: 99% ee (CHIRALPAK IC, hexane/
i-PrOH = 95/5, flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti
syn), 3.38 (dd, J1 = 12.0 Hz, J2 = 2.8 Hz, 1H, syn) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 148.2 (syn), 148.0 (syn), 147.8 (anti), 147.7
(anti), 133.7 (anti), 133.4 (syn), 120.3 (syn), 120.0 (anti), 107.8 (syn),
107.5 (anti), 106.4 (syn), 106.3 (anti), 101.2 (syn), 101.1 (anti), 95.3
(syn), 94.5 (anti), 72.1, 60.5 (syn), 60.2 (anti) ppm. ESI HRMS: calcd.
for C10H11NO6+Na 264.0484, found 264.0477; [α]D25 = −6.3 (c = 0.49,
EtOH). The enantiomeric excess of product 7v was determined by
chiral HPLC: 95% ee (CHIRALPAK IC, hexane/i-PrOH = 80/20, flow
rate: 0.8 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 10.609 min,
t
minor = 14.754 min; syn isomer: tmajor = 17.166 min, tminor = 18.520 min.
(1R,2R)-1-(2,3-Dimethoxyphenyl)-2-nitropropane-1,3-diol (7w).
isomer: tmajor = 25.832 min, tminor = 30.432 min; syn isomer: tmajor
46.861 min, tminor = 53.726 min.
=
1
Colorless oil, 84 h, 239.2 mg, 93% yield, syn/anti = 93:7; H NMR
(400 MHz, CD3OD): δ 7.12(t, J = 8.0 Hz, 1H), 7.05−6.99 (m, 2H),
5.34 (dd, J1 = 9.2 Hz, J2 = 1.6 Hz, 1H), 4.93−4.88 (m, 1H), 3.96−3.92
(m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.36 (dt, J1 = 12.0 Hz, J2 = 2.8 Hz,
1H) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ 153.7 (syn), 153.6
(anti), 147.5 (syn), 147.2 (anti), 134.0 (anti), 133.9 (syn), 125.5 (syn),
124.9 (anti), 119.9 (syn), 119.8 (anti), 113.7 (syn), 113.6 (anti), 96.4
(syn), 93.8 (anti), 69.1 (anti), 67.8 (syn), 61.7 (syn), 61.1 (syn), 60.9
(anti), 60.2 (anti), 56.0 (syn) ppm. ESI HRMS: calcd. for
(1R,2R)-1-(3-Bromophenyl)-2-nitropropane-1,3-diol (7s). Pale
yellow oil, 84 h, 270.6 mg, 98% yield, syn/anti = 95:5; 1H NMR (400
MHz, CD3OD): δ 7.60 (t, J = 2.0 Hz, 1H), 7.52−7.49 (m, 1H), 7.38
(dt, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 5.03 (t, J = 7.2
Hz, 1H, anti), 5.00 (t, J = 9.2 Hz, 1H, syn), 4.77 (td, J1 = 8.8 Hz, J2 = 3.2
Hz, 1H), 4.18 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 3.99 (dd, J1 =
12.4 Hz, J2 = 2.8 Hz, 1H, anti), 3.83 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H,
syn), 3.43 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H, syn) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 142.6 (anti), 142.3 (syn), 131.4 (syn), 131.0
(anti), 130.2 (syn), 129.9 (anti), 129.6 (syn), 129.3 (anti), 125.5 (syn),
125.1 (anti), 122.3 (syn), 122.0 (anti), 94.8 (syn), 94.1 (anti), 71.5
(anti), 71.4 (syn), 60.3 (syn), 59.8 (anti) ppm. ESI HRMS: calcd. for
C9H10BrNO4+Na 297.9691, found 297.9682; [α]D25 = −11.5 (c = 1.81,
EtOH). The enantiomeric excess of product 7s was determined by
chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow
rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 12.247 min,
25
C11H15NO6+Na 280.0797, found 280.0800; [α]D = 8.0 (c = 1.13,
EtOH). The enantiomeric excess of product 7w was determined by
chiral HPLC: 99% ee (CHIRALPAK IC, hexane/i-PrOH = 80/20, flow
rate: 0.8 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 15.954 min,
t
minor = 14.887 min; syn isomer: tmajor = 17.856 min, tminor = 18.930 min.
(1R,2R)-2-Nitro-1-(2,4,6-trimethoxyphenyl)propane-1,3-diol (7x).
White solid, mp 160−163 °C, 84 h, 281.6 mg, 98% yield, syn/anti =
99:1; 1H NMR (400 MHz, CD3OD): δ 6.27 (s, 2H), 5.51 (d, J = 10.0
Hz, 1H), 5.38 (td, J1 = 10.4 Hz, J2 = 3.6 Hz, 1H), 3.87 (s, 3H), 3.84 (s,
3H), 3.82−3.79 (m, 1H), 3.34−3.32 (m, 1H) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 162.2, 159.2, 106.1, 94.2, 90.6, 64.6, 60.7, 54.9,
54.5 ppm. ESI HRMS: calcd. for C12H17NO7+Na 310.0903, found
310.0910; [α]D25 = 15.4 (c = 0.63, EtOH). The enantiomeric excess of
product 7x was determined by chiral HPLC: >99% ee (CHIRALPAK
AD-H, hexane/i-PrOH = 70/30, flow rate: 0.7 mL/min, T = 30 °C, 220
nm), anti isomer: tmajor = 10.902 min, tminor = 12.330 min; syn isomer:
t
minor = 14.420 min; syn isomer: tmajor = 19.082 min, tminor = 23.252 min.
(1R,2R)-2-Nitro-1-(m-tolyl)propane-1,3-diol (7t). Pale yellow oil,
1
132 h, 185.9 mg, 88% yield, syn/anti = 95:5; H NMR (400 MHz,
CD3OD): δ 7.26 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 2.0 Hz, 1H), 7.20−7.11
(m, 2H), 4.99 (d, J = 6.8 Hz, 1H, anti), 4.92 (d, J = 9.2 Hz, 1H, syn),
4.82−4.76 (m, 1H), 4.19 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 4.00
(dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H, anti), 3.81 (dd, J1 = 12.4 Hz, J2 = 9.6
Hz, 1H, syn), 3.33 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz, 1H, syn), 2.35 (s, 3H,
syn), 2.33 (s, 3H, anti) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ
140.8 (anti), 140.6 (syn), 139.5 (syn), 139.0 (anti), 130.2 (syn), 129.7
(anti), 129.4 (syn), 129.1 (anti), 128.2 (syn), 127.8 (anti), 124.7 (syn),
124.3 (anti), 96.4 (syn), 95.5 (anti), 73.5, 61.6 (syn), 61.0 (anti), 21.1
(anti), 21.1 (syn) ppm. ESI HRMS: calcd. for C10H13NO4+Na
t
major = 15.695 min, tminor = 12.979 min.
(1R,2R)-1-(Naphthalen-2-yl)-2-nitropropane-1,3-diol (7y). Pale
1
yellow oil, 132 h, 202.8 mg, 82% yield, syn/anti = 89:11; H NMR
(400 MHz, CD3OD): δ 7.90−7.81 (m, 4H), 7.55−7.45 (m, 3H), 5.24
(dd, J1 = 7.2 Hz, J2 = 3.2 Hz, 1H, anti), 5.18 (dd, J1 = 9.6 Hz, J2 = 3.2 Hz,
1H, syn), 4.99−4.94 (m, 1H), 4.31−4.25 (m, 1H, anti), 4.10−4.05 (m,
1H, anti), 3.89 (td, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H, syn), 3.38 (dt, J1 = 12.4
Hz, J2 = 2.8 Hz, 1H, syn) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ
137.3 (anti), 137.0 (syn), 133.6 (syn), 133.5 (anti), 133.4 (syn), 133.2
(anti), 128.5 (syn), 128.1 (anti), 127.8 (syn), 127.5 (syn), 127.4, 126.3
(syn), 126.2 (syn), 126.1 (anti), 126.1 (anti), 125.6 (anti), 123.8 (syn),
123.7 (anti), 95.3 (syn), 94.4 (anti), 72.7 (anti), 72.6 (syn), 60.7 (syn),
60.1 (anti) ppm. ESI HRMS: calcd. for C13H13NO4+Na 270.0742,
found 270.0737; [α]D25 = −10.8 (c = 0.68, EtOH). The enantiomeric
excess of product 7y was determined by chiral HPLC: 98% ee
(CHIRALPAK IC, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, T
= 30 °C, 220 nm), anti isomer: tmajor = 16.384 min, tminor = 21.644 min;
syn isomer: tmajor = 28.505 min, tminor = 32.894 min.
25
234.0742, found 234.0733; [α]D = −7.4 (c = 0.75, EtOH). The
enantiomeric excess of product 7t was determined by chiral HPLC:
99% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/
min, T = 30 °C, 220 nm), anti isomer: tmajor = 13.748 min, tminor
17.288 min; syn isomer: tmajor = 21.381 min, tminor = 26.903 min.
=
(1R,2R)-1-(3,4-Dichlorophenyl)-2-nitropropane-1,3-diol (7u).
1
Colorless oil, 96 h, 255.5 mg, 96% yield, syn/anti = 91:9; H NMR
(400 MHz, CD3OD): δ 7.63 (d, J = 2.0 Hz, 1H, syn), 7.56 (d, J = 8.4 Hz,
1H, syn), 7.52 (d, J = 8.4 Hz, 1H, anti), 7.37 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz,
1H, syn), 7.32 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H, anti), 5.07 (d, J = 8.8 Hz,
1H), 4.80 (td, J1 = 8.8 Hz, J2 = 3.2 Hz, 1H), 4.20 (dd, J1 = 12.4 Hz, J2 =
9.2 Hz, 1H, anti), 4.02 (dd, J1 = 12.0 Hz, J2 = 2.8 Hz, 1H, anti), 3.87 (dd,
J1 = 12.4 Hz, J22 = 9.2 Hz, 1H, syn), 3.51 (dd, J1 = 12.0 Hz, J2 = 3.2 Hz,
1H, syn) ppm. 13C{1H} NMR (100 MHz, CD3OD): δ 140.8 (anti),
140.6 (syn), 132.3 (syn), 132.0 (syn), 131.8 (anti), 130.5 (syn), 130.2
(anti), 128.7 (syn), 128.4 (anti), 126.4 (syn), 126.1 (anti), 94.5 (syn),
94.0 (anti), 70.9 (anti), 70.8 (syn), 60.3 (syn), 59.8 (anti) ppm. ESI
(1S,2R)-1-(Benzofuran-2-yl)-2-nitropropane-1,3-diol (7z). Yellow
oil, 60 h, 232.5 mg, 98% yield, syn/anti = 90:10; 1H NMR (400 MHz,
CD3OD): δ 7.58 (d, J = 7.6 Hz, 1H, syn), 7.54 (d, J = 7.6 Hz, 1H, anti),
7.48 (d, J = 8.4 Hz, 1H, syn), 7.45 (d, J = 8.0 Hz, 1H, anti), 7.29 (td, J1 =
7.2 Hz, J2 = 1.6 Hz, 1H), 7.25−7.18 (m, 1H), 6.86 (s, 1H, syn), 6.79 (s,
1H, anti), 5.31 (d, J = 6.8 Hz, 1H, anti), 5.23 (d, J = 9.2 Hz, 1H, syn),
5.16−5.08 (m, 1H), 4.30 (dd, J1 = 12.4 Hz, J2 = 8.8 Hz, 1H, anti), 4.11
(dd, J1 = 12.4 Hz, J2 = 1.6 Hz, 1H, anti), 3.94 (dd, J1 = 12.4 Hz, J2 = 9.2
Hz, 1H, syn), 3.60 (dd, J1 = 12.4 Hz, J2 = 3.6 Hz, 1H, syn) ppm; 13C{1H}
NMR (100 MHz, CD3OD): δ 156.1 (anti), 156.0 (syn), 155.9 (anti),
155.2 (syn), 128.7 (anti), 128.6 (syn), 125.6 (syn), 125.4 (anti), 123.8
(syn), 123.7 (anti), 122.1 (syn), 121.9 (anti), 111.8 (syn), 111.7 (anti),
106.3 (syn), 105.3 (anti), 93.7 (syn), 92.4 (anti), 67.5 (anti), 66.8 (syn),
61.3 (syn), 60.8 (anti) ppm. ESI HRMS: calcd. for C11H11NO5+Na
25
HRMS: calcd. for C9H9Cl2NO4+Na 287.9806, found 287.9808; [α]D
= −22.9 (c = 1.75, EtOH). The enantiomeric excess of product 7u was
determined by chiral HPLC: 97% ee (CHIRALPAK AS-H, hexane/i-
PrOH = 90/10, flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti
isomer: tmajor = 30.273 min, tminor = 19.975 min; syn isomer: tmajor
27.313 min, tminor = 41.672 min.
=
(1R,2R)-1-(Benzo[d][1,3]dioxol-5-yl)-2-nitropropane-1,3-diol
(7v). Yellow oil, 132 h, 197.8 mg, 82% yield, syn/anti = 82:18; 1H NMR
(400 MHz, CD3OD): δ 6.91 (d, J = 1.6 Hz, 1H), 6.89−6.76 (m, 2H),
5.95 (s, 2H, syn), 5.94 (s, 2H, anti), 4.90 (d, J = 9.2 Hz, 1H), 4.79−4.73
(m, 1H), 4.17 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, anti), 4.04 (dd, J1 =
12.8 Hz, J2 = 3.2 Hz, 1H, anti), 3.81 (dd, J1 = 12.0 Hz, J2 = 9.6 Hz, 1H,
25
260.0535, found 260.0532; [α]D = −39.9 (c = 1.0, EtOH). The
enantiomeric excess of product 7z was determined by chiral HPLC:
J
https://doi.org/10.1021/acs.joc.1c01124
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
97% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/
was heated at 40 °C with a 3.5 min residence time. The reaction stream
was collected in a 100 mL flat-bottomed conical flask. The reaction
mixture was concentrated in vacuo. The residue was purified by silica
gel flash column chromatography (DCM/MeOH = 100:5) to afford 5a
(2.35 g, 80%) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ 7.14 (d, J
= 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.28 (s, 1H), 4.83 (s, 1H), 4.01
(q, J = 5.6 Hz, 1H), 3.69 (dd, J1 = 11.2 Hz, J2 = 6.0 Hz, 1H), 3.47 (dd, J1
= 11.2 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz, CD3OD): δ
166.3, 147.5, 132.8, 128.0, 116.3, 72.1, 67.4, 61.9, 58.9 ppm. ESI
HRMS: calcd. for C11H14Cl2N2O3 + Na 315.0279, found 315.0275,
317.0248, 319.2014.
min, T = 30 °C, 220 nm), anti isomer: tmajor = 11.790 min, tminor
31.974 min; syn isomer: tmajor = 20.296 min, tminor = 24.369 min.
=
(1R,2R)-1-(Benzo[b]thiophen-3-yl)-2-nitropropane-1,3-diol
(7aa). Yellow oil, 96 h, 233.0 mg, 92% yield, syn/anti = 95:5; 1H NMR
(400 MHz, CD3OD): δ 8.05 (d, J = 7.6 Hz, 1H, syn), 7.98 (d, J = 8.0 Hz,
1H, anti), 7.91−7.87 (m, 1H), 7.65 (s, 1H, syn), 7.59 (s, 1H, anti),
7.44−7.36 (m, 2H), 5.54 (d, J = 6.4 Hz, 1H, anti), 5.45 (d, J = 9.2 Hz,
1H, syn), 5.21−5.14 (m, 1H, syn), 5.12−5.07 (m, 1H, anti), 4.33 (dd, J1
= 12.8 Hz, J2 = 9.6 Hz, 1H, anti), 4.07 (dd, J1 = 12.4 Hz, J2 = 2.8 Hz, 1H,
anti), 3.92 (dd, J1 = 12.4 Hz, J2 = 9.6 Hz, 1H, syn), 3.41 (dd, J1 = 12.4 Hz,
J2 = 3.6 Hz, 1H, syn) ppm; 13C{1H} NMR (100 MHz, CD3OD): δ
141.9 (syn), 141.8 (anti), 137.9 (syn), 137.8 (anti), 135.8 (anti), 135.5
(syn), 126.0, 125.5 (syn), 125.4 (anti), 125.1 (syn), 125.0 (anti), 123.6
(syn), 123.6 (anti), 123.2 (syn), 122.7 (anti), 95.2 (syn), 93.7 (anti),
69.4 (anti), 68.6 (syn), 61.7 (syn), 60.8 (anti) ppm. ESI HRMS: calcd.
Continuous Flow Synthesis of (−)-Chloramphenicol (1). For
the flow oxidation reaction, the reactor coil consists of a 200 cm
segment of a PTFE tube (i.d. = 0.8 mm, 1.0 mL total volume), a T-
mixer, and a 5 bar back-pressure valve. 5a (2.0 g, 6.8 mmol, 1.0 equiv),
NaHCO3 (5.72 g, 68.0 mmol, 10.0 equiv), and NaOH (322 mg, 8.0
mmol, 1.18 equiv) were dissolved in degassed H2O/acetone (120 mL,
v/v = 2:1) and placed in one syringe. The mixture containing oxone
(10.86 g, 17.7 mmol, 2.6 equiv) and degassed 4 × 10−4 M EDTA
aqueous (60 mL) was placed in another syringe. The 5a syringe was set
to 429.1 μL/min and the oxone syringe was set to 237.5 μL/min. The
flow was initiated with a 1.5 min residence time and cooling down the
first half of the flow reactor to 0 °C, leaving the second half of the flow
reactor length to warm up to room temperature. The reaction stream
was collected in a 250 mL flat-bottomed conical flask and quenched
with sodium bisulfite. The resulting mixture was extracted with ethyl
acetate (3 × 100 mL). The organic layer was combined and washed
with brine (100 mL). Then, the organic solution was dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by silica gel flash column chromatography (DCM/MeOH = 10:1) to
afford (−)-chloramphenicol (1) (1.58 g, 72%) as a white solid. The
25
for C11H11NO4S+Na 276.0306, found 276.0297; [α]D = −7.6 (c =
1.90, EtOH). The enantiomeric excess of product 7aa was determined
by chiral HPLC: 98% ee (CHIRALPAK IC, hexane/i-PrOH = 90/10,
flow rate: 1.0 mL/min, T = 30 °C, 220 nm), anti isomer: tmajor = 15.083
min, tminor = 15.821 min; syn isomer: tmajor = 21.806 min, tminor = 26.908
min.
Continuous Flow Catalytic Hydrogenation Synthesis of 6a.
(1R,2R)-2-Nitro-1-(4-nitrophenyl)propane-1,3-diol (7a). A solution
of Cu(OAc)2·H2O (200 mg, 1.0 mmol, 10 mol %) and L9 (419.6 mg,
1.0 mmol, 10 mol %) in THF (15 mL) was stirred for 1 h at room
temperature. Then, 4-nitrobenzaldehyde 8a (1.51 g, 10.0 mmol, 1
equiv) and 2-nitroethanol 9 (2.88 mL, 40.0 mmol, 4 equiv) were added
into the reaction flask at 0 °C. The mixture was stirred for 72 h at 0 °C
and then quenched with 1 M HCl (30 mL). The resulting mixture was
extracted with ethyl acetate (3 × 60 mL). The organic layer was
combined and washed with brine (3 × 50 mL). Then, the organic
solution was dried over Na2SO4, filtered, and concentrated in vacuo to
afford the crude syn-2-nitro-1,3-diol 7a, which was used in the next step
without further purification. The crude product was analyzed by HPLC
to determine the ratio of syn/anti and enantiomeric excess: syn/anti =
90:10, 95% ee (CHIRALPAK AD-H, hexane/i-PrOH = 80/20, flow
rate: 0.8 mL/min, T = 30 °C, 210 nm), anti isomer: tmajor = 16.378 min,
product was subsequently recrystallized from AcOEt/PE, affording
25
(−)-chloramphenicol (1) (1.37 g, 62%). Mp = 150−151 °C; [α]D
=
−24.1 (c = 1.0, AcOEt); 1H NMR (400 MHz, DMSO): δ 8.33 (d, J =
9.2 Hz, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 6.48 (s,
1H), 6.05 (d, J = 4.4 Hz, 1H), 5.07 (dd, J1 = 4.8 Hz, J2 = 2.4 Hz, 1H),
5.00 (dd, J1 = 6.0 Hz, J2 = 4.8 Hz, 1H), 3.98−3.91 (m, 1H), 3.63−3.57
(m, 1H), 3.40−3.37 (m, 1H); 13C{1H} NMR (100 MHz, DMSO): δ
163.9, 151.7, 146.9, 127.8, 123.3, 69.4, 66.9, 60.7, 57.3 ppm. ESI
HRMS: calcd. for C11H12Cl2N2O5 + Na 345.0021, found 345.0010.
N-((1R,2R)-1-(4-Aminophenyl)-1,3-dihydroxypropan-2-yl)-2-azi-
doacetamide (5b). 5b was prepared from 10b in 81% yield by the same
procedure of 5a. Yellow oil. 1H NMR (400 MHz, CD3OD): δ 7.02 (d, J
= 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 4.66 (d, J = 5.2 Hz, 1H), 3.96 (q,
J = 6.0 Hz, 1H), 3.77 (s, 2H), 3.53 (dd, J1 =11.2 Hz, J2 = 5.6 Hz, 1H),
3.34 (dd, J1 = 11.2 Hz, J2 = 6.0 Hz, 1H); 13C{1H} NMR (100 MHz,
CD3OD): δ 168.8, 146.8, 131.4, 126.9, 115.0, 71.5, 61.1, 57.2, 51.6
ppm. ESI HRMS: calcd. for C11H15N5O3 + Na 288.1073, found
288.1069.
t
minor = 14.816 min; syn isomer: tmajor = 17.846 min, tminor = 28.347 min.
(1R,2R)-2-Amino-1-(4-aminophenyl)propane-1,3-diol (6a). For
the flow hydrogenation reaction, the flow system consists of a gas
flow meter, a micromixer, a micropacked bed, and a 15 bar back-
pressure valve. The mixture containing the above crude 7a and
methanol (333 mL) was delivered by a plunger pump (flow rate: 0.5
mL/min). H2 gas from the high-pressure-resistant cylinder was fed via a
gas flow meter (flow rate: 0.1 L/min). The liquid phase and gas phase
were combined by a T-piece connector, entering a micromixer to
control the reaction temperature at 25 °C. Then, the reaction stream
was passed through a micropacked bed (2.0 g 10% Pd(OH)2/C, 20.0 g
SiO2, and 5 mL internal volume) with 10.0 min residence time. The
reaction stream was then collected in a 500 mL flat-bottomed conical
flask and concentrated in vacuo. The residue was purified by silica gel
flash column chromatography (DCM/MeOH = 3:1) to afford 6a (1.38
Continuous Flow Synthesis of (−)-Azidamphenicol (2).
(−)-Azidamphenicol (2) was prepared from 5b in 75% yield by the
same procedure of (−)-chloramphenicol (1). The product was
subsequently recrystallized from AcOEt/PE, affording (−)-azidam-
1
25
g, 76%, two steps) as a white solid. Mp 135−137 °C. H NMR (400
phenicol (2) in 64% yield. White solid. Mp = 108−109 °C; [α]D
=
−9.8 (c = 1.0, EtOH); 1H NMR (400 MHz, DMSO): δ 8.17 (d, J = 8.8
Hz, 2H), 7.86 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 5.92 (d, J =
4.4 Hz, 1H), 5.04 (dd, J1 = 4.4 Hz, J2 = 2.4 Hz, 1H), 4.92 (dd, J1 = 6.4
Hz, J2 = 4.8 Hz, 1H), 4.03−3.97 (m, 1H), 3.71 (d, J = 2.4 Hz, 2H),
3.59−3.53 (m, 1H), 3.37−3.32 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO): δ 167.6, 152.1, 146.8, 127.7, 123.3, 69.7, 60.9, 56.7, 50.9 ppm.
ESI HRMS: calcd. for C11H13N5O5 + Na 318.0814, found 318.0808.
Continuous Flow Catalytic Hydrogenation Synthesis of 6b.
(1R,2R)-1-(4-(Methylsulfonyl)phenyl)-2-nitropropane-1,3-diol (7b).
A solution of Cu(OAc)2·H2O (200 mg, 1.0 mmol, 10 mol %) and L9
(419.6 mg, 1.0 mmol, 10 mol %) in THF (15 mL) was stirred for 1 h at
room temperature. Then, 4-methylsulfonyl benzaldehyde 8b (1.84 g,
10.0 mmol, 1 equiv) and 2-nitroethanol 9 (2.88 mL, 40.0 mmol, 4
equiv) were added into the reaction flask at 0 °C. The mixture was
stirred for 72 h at 0 °C, then quenched with 1 M HCl (30 mL). The
resulting mixture was extracted with ethyl acetate (3 × 60 mL). The
MHz, DMSO): δ 6.95 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 8.0 Hz, 2H), 4.89
(s, 2H), 4.18 (d, J = 6.8 Hz, 1H), 3.39 (s, 4H), 3.22 (dd, J1 = 10.4 Hz, J2
= 4.4 Hz, 1H), 3.07 (dd, J1 = 10.4 Hz, J2 = 6.4 Hz, 1H), 2.63 (td, J1 = 6.0
Hz, J2 = 4.0 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO): δ 147.8,
131.5, 127.6, 113.8, 73.9, 63.4, 59.5 ppm. ESI HRMS: calcd. for
C9H14N2O2 + Na 205.0953, found 205.0956.
N-((1R,2R)-1-(4-Aminophenyl)-1,3-dihydroxypropan-2-yl)-2,2-di-
chloroacetamide (5a). For the flow amidation reaction, the reactor coil
consists of a 200 cm segment of a PTFE tube (i.d. = 0.8 mm, 1.0 mL
total volume), a T-mixer, and a 5 bar back-pressure valve. Diamine 6a
(1.82 g, 10.0 mmol, 1.0 equiv) was dissolved in degassed MeOH (24
mL) and placed in one syringe. The mixture containing methyl
dichloroacetate 10a (5.72 g, 40.0 mmol, 4.0 equiv) and degassed
MeOH (6 mL) was placed in another syringe. The diamine 6a syringe
was set to 205.2 μL/min, and the methyl dichloroacetate 10a syringe
was set to 80.8 μL/min. The flow was initiated, and the reaction mixture
K
https://doi.org/10.1021/acs.joc.1c01124
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The Journal of Organic Chemistry
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Article
organic layer was combined and washed with brine (3 × 50 mL). Then,
the organic solution was dried over Na2SO4, filtered, and concentrated
in vacuo to afford the crude syn-2-nitro-1,3-diol 7b, which was used in
the next step without further purification. The crude product was
analyzed by HPLC to determine the ratio of syn/anti and enantiomeric
excess: syn/anti = 95:5, 97% ee (CHIRALPAK IC, hexane/i-PrOH =
65/35, flow rate: 0.7 mL/min, T = 30 °C, 210 nm).
(d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 5.75 (d, J = 6.4 Hz, 1H), 5.17 (t, J = 5.6
Hz, 1H), 4.08 (dd, J1 = 10.8 Hz, J2 = 5.6 Hz, 1H), 3.75−3.70 (m, 1H),
3.60−3.55 (m, 1H), 3.23 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
DMSO): δ 161.3, 146.4, 141.0, 128.1, 126.5, 83.3, 76.9, 62.4, 43.9 ppm.
ESI HRMS: calcd. for C12H13Cl2NO4S + Na 359.9840, found 359.9843.
Continuous Flow Synthesis of (+)-Florfenicol (4). (4S,5R)-2-
(Dichloromethyl)-4-(fluoromethyl)-5-(4-(methylsulfonyl)phenyl)-
4,5-dihydrooxazole (12). For the flow fluorination reaction, the reactor
coil consists of a 200 cm segment of a PTFE tube (i.d. = 0.8 mm, 1.0 mL
total volume) and a 10 bar back-pressure valve. Oxazoline 11 (3.38 g,
10.0 mmol, 1.0 equiv) was dissolved in dry DCM (50 mL) and placed in
one syringe. The oxazoline 11 syringe was set to 400 μL/min. The flow
was initiated, and the reaction mixture was heated at 100 °C with a 2.5
min residence time. The reaction stream was collected in a 100 mL flat-
bottomed conical flask. After collection of the organic reaction solution,
the solvent was removed in vacuo to afford product 12, which was used
in the next stage without the need for further purification. White solid.
Mp 123−126 °C. [α]D = −12.2 (c = 0.57, CHCl3). H NMR (400
MHz, CDCl3): δ 8.0 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 6.35
(s, 1H), 5.72 (d, J = 6.8 Hz, 1H), 4.78−4.53 (m, 2H), 4.35−4.26 (m,
1H), 3.05 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 163.1,
145.0, 141.0, 128.3, 126.1, 83.2 (d, J = 4.2 Hz), 82.6 (d, J = 173.1 Hz),
74.6 (d, J = 31.9 Hz), 60.9, 44.4 ppm. ESI HRMS: calcd. for
C12H12Cl2FNO3S + Na 361.9797, found 361.9795.
(1R,2R)-2-Amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol
(6b). For the flow hydrogenation reaction, the flow system consists of a
gas flow meter, a micromixer, a micropacked bed, and a 15 bar back-
pressure valve. The mixture containing the above crude 7b and
methanol (333 mL) was delivered by a plunger pump (flow rate: 0.5
mL/min). H2 gas from the high-pressure-resistant cylinder was fed via a
gas flow meter (flow rate: 0.1 L/min). The liquid phase and gas phase
were combined by a T-piece connector, entering a micromixer to
control the reaction temperature at 25 °C. Then, the reaction stream
was passed through a micropacked bed (2.0 g 10% Pd(OH)2/C, 20.0 g
SiO2, and 5 mL internal volume) with 10.0 min residence time. The
reaction stream was then collected in a 500 mL flat-bottomed conical
flask and concentrated in vacuo. The residue was purified by silica gel
flash column chromatography (DCM/MeOH = 3:1) to afford 6b (2.01
g, 82%, two steps) as a white solid. Mp = 142−143 °C; [α]D25 = −22.4
(c = 0.28, EtOH); 1H NMR (400 MHz, CD3OD): δ 7.93 (d, J = 8.4 Hz,
2H), 7.65 (d, J = 8.4 Hz, 2H), 4.76 (d, J = 5.6 Hz, 1H), 3.53 (dd, J1 =
10.8 Hz, J2 = 5.2 Hz, 1H), 3.39 (dd, J1 = 10.8 Hz, J2 = 6.0 Hz, 1H), 3.12
(s, 3H), 2.90 (dd, J1 = 10.8 Hz, J2 = 5.2 Hz, 1H) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 150.8, 140.7, 128.4, 128.1, 74.0, 63.8, 59.5, 44.2
ppm. ESI HRMS: calcd. for C10H15NO4S + Na 268.0619, found
268.0614.
Continuous Flow Synthesis of (+)-Thiamphenicol (3). For the
flow amidation reaction, the reactor coil consists of a 200 cm segment of
a PTFE tube (i.d. = 0.8 mm, 1.0 mL total volume) and a T-mixer. syn-2-
Amino-1,3-diol 6b (1.23 g, 5.0 mmol, 1.0 equiv) was dissolved in
degassed MeOH (14 mL) and placed in one syringe. The mixture
containing methyl dichloroacetate 10a (2.15 g, 15.0 mmol, 3.0 equiv),
Et3N (1.0 g, 10.0 mmol, 2.0 equiv), and degassed MeOH (3 mL) was
placed in another syringe. The syn-2-amino-1,3-diol 6b syringe was set
to 77.6 μL/min and the methyl dichloroacetate 10a syringe was set to
22.4 μL/min. The flow was initiated, and the reaction mixture was
heated at 30 °C with a 10.0 min residence time. The reaction stream was
collected in a 100 mL flat-bottomed conical flask. The reaction mixture
was concentrated in vacuo. The residue was purified by silica gel flash
column chromatography (DCM/MeOH = 100:10) to afford
(+)-thiamphenicol (3) (1.71 g, 96%) as a white solid. The product
was subsequently recrystallized from MeOH/PE, affording (+)-thiam-
phenicol (3) (1.50 g, 84%). Mp 164−165 °C; [α]D20 = +12.6 (c = 1.0,
EtOH); 1H NMR (400 MHz, CD3OD): δ 7.90 (d, J = 8.4 Hz, 2H), 7.68
(d, J = 8.4 Hz, 2H), 6.25 (s, 1H), 5.16 (d, J = 2.8 Hz, 1H), 4.15 (td, J1 =
6.4 Hz, J2 = 2.8 Hz, 1H), 3.83 (dd, J1 = 10.8 Hz, J2 = 6.8 Hz, 1H), 3.62
(dd, J1 = 10.8 Hz, J2 = 6.0 Hz, 1H), 3.10 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CD3OD): δ 165.1, 149.0, 139.4, 126.9, 126.8, 70.0, 66.0,
60.8, 57.1, 43.0 ppm. ESI HRMS: calcd. for C12H15Cl2NO5S + Na
377.9946, found 377.9941.
25
1
(+)-Florfenicol (4). For the flow hydrolysis reaction, the reactor coil
consists of a 200 cm segment of a PTFE tube (i.d. = 0.8 mm, 1.0 mL
total volume) and a 10 bar back-pressure valve. The above crude 12 was
i
dissolved in PrOH/H2O (40 mL, v/v = 1.86:1) and placed in one
syringe. The syringe was set to 400 μL/min. The flow was initiated, and
the reaction mixture was heated at 100 °C with a 2.5 min residence
time. The reaction stream was collected in a 100 mL flat-bottomed
conical flask. The reaction mixture was concentrated in vacuo. The
residue was purified by silica gel flash column chromatography
(AcOEt/PE = 1:1) to afford (+)-florfenicol (4) (3.26 g, 91%) as a
white solid. The product was subsequently recrystallized from AcOEt/
PE, affording (+)-florfenicol (4) (2.90 g, 81%). Mp 151−152 °C;
[α]D25 = −18.8 (c = 1.0, DMF); 1H NMR (400 MHz, DMSO): δ 8.61
(d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H),
6.45 (s, 1H), 6.14 (d, J = 4.4 Hz, 1H), 4.98 (t, J = 3.6 Hz, 1H), 4.72−
4.57 (m, 1H), 4.58−4.24 (m, 2H), 3.15 (s, 3H); 13C{1H} NMR (100
MHz, DMSO): δ 164.2, 148.3, 140.0, 127.6, 126.9, 82.8 (d, J = 169.0
Hz), 69.8 (d, J = 6.0 Hz), 66.7, 55.0 (d, J = 19.6 Hz), 44.0 ppm. ESI
HRMS: calcd. for C12H14Cl2FNO4S + Na 379.9902, found 379.9908.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01124.
■
sı
Experimental procedures, HPLC data, compound char-
acterization, NMR spectra, and HRMS spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
((4R,5R)-2-(Dichloromethyl)-5-(4-(methylsulfonyl)phenyl)-4,5-di-
hydrooxazol-4-yl)methanol (11). For the flow cyclization reaction, the
reactor coil consists of a 200 cm segment of a PTFE tube (i.d. = 0.8 mm,
1.0 mL total volume), a T-mixer, and a 10 bar back-pressure valve. syn-
2-Amino-1,3-diol 6b (1.23 g, 5.0 mmol, 1.0 equiv) was dissolved in
degassed MeOH (6 mL) and placed in one syringe. The mixture
containing dichloroacetonitrile (616 mg, 5.6 mmol, 1.12 equiv), conc.
HCl (126 μL), and degassed MeOH (1 mL) was placed in another
syringe. The syn-2-amino-1,3-diol 6b syringe was set to 80.6 μL/min
and the dichloroacetonitrile syringe was set to 19.4 μL/min. The flow
was initiated, and the reaction mixture was heated at 70 °C with a 10.0
min residence time. The reaction stream was collected in a 100 mL flat-
bottomed conical flask. The reaction mixture was concentrated in
vacuo. The residue was purified by silica gel flash column
chromatography (DCM/MeOH = 100:10) to afford 11 (1.49 g,
Fener Chen − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China; Engineering
Center of Catalysis and Synthesis for Chiral Molecules,
Department of Chemistry, Fudan University, Shanghai
200433, China; Shanghai Engineering Center of Industrial
Asymmetric Catalysis for Chiral Drugs, Shanghai 200433,
China; orcid.org/0000-0002-6734-3388;
Email: rfchen@fudan.edu.cn
Authors
Yingqi Xia − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
20
88%) as a white solid. Mp 144−145 °C; [α]D = +11.2 (c = 1.0,
EtOH); 1H NMR (400 MHz, DMSO): δ 7.99 (d, J = 8.0 Hz, 2H), 7.60
L
https://doi.org/10.1021/acs.joc.1c01124
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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Meifen Jiang − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan University,
Shanghai 200433, China
Minjie Liu − Shanghai Engineering Center of Industrial
Asymmetric Catalysis for Chiral Drugs, Shanghai 200433,
China
Yan Zhang − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Hongmin Qu − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Tong Xiong − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Huashan Huang − Shanghai Engineering Center of Industrial
Asymmetric Catalysis for Chiral Drugs, Shanghai 200433,
China
Dang Cheng − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan University,
Shanghai 200433, China; orcid.org/0000-0001-5899-
5141
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Fundamental Research Funds
for the Central Universities (YJ201805 and YJ201864).
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