Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of (-)-Chloramphenicol, (-)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride

Article abstract of DOI:10.1021/acs.joc.0c02181

The asymmetric synthesis of (-)-chloramphenicol, (-)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride, (+)-florfenicol, is reported. This approach toward the amphenicol antibiotic family features two key steps: (1) a cinchona alkaloid derived urea-catalyzed aldol reaction allows highly enantioselective access to oxazolidinone gem-diesters and (2) a continuous flow diastereoselective decarboxylation of thermally stable oxazolidinone gem-diesters to form the desired trans-oxazolidinone monoesters with two adjacent stereocenters that provide the desired privileged scaffolds of syn-vicinal amino alcohols in the amphenicol family.

Full text of DOI:10.1021/acs.joc.0c02181

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Article
Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis
of (−)-Chloramphenicol, (−)-Azidamphenicol, and
(+)-Thiamphenicol and Its (+)-3-Floride
Jinxin Liu, Yaling Li, Miaolin Ke, Minjie Liu, Pingping Zhan, You-Cai Xiao,* and Fener Chen*
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ABSTRACT: The asymmetric synthesis of (−)-chloramphenicol,
(−)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride,
(+)-florfenicol, is reported. This approach toward the amphenicol
antibiotic family features two key steps: (1) a cinchona alkaloid
derived urea-catalyzed aldol reaction allows highly enantioselective
access to oxazolidinone gem-diesters and (2) a continuous flow
diastereoselective decarboxylation of thermally stable oxazolidinone
gem-diesters to form the desired trans-oxazolidinone monoesters with
two adjacent stereocenters that provide the desired privileged
scaffolds of syn-vicinal amino alcohols in the amphenicol family.
pathogens during the last decades.2 In addition, (+)-florfenicol,
as a (+)-thiamphenicol derivative, is a low toxic, highly efficient
and safe veterinary drug which has become one of the most
used veterinary antibiotics worldwide.
INTRODUCTION
■
(−)-Chloramphenicol (1), (−)-azidamphenicol (2), and
(+)-thiamphenicol (3) and its (+)-3-fluride, (+)-florfenicol,
(4) are a family of amphenicol antibiotics with a structure
comprising the syn-(1R, 2R)-amino alcohol subunit (Figure
1).1 These antibiotics show a wide range of remarkable
The concise asymmetric synthesis of these amphenicol
antibiotics has remained of great interest to the synthetic
community for more than 60 years because of their potent
antibacterial properties and presentation of stereochemistry
within their core structure. To date, a variety of elegant
asymmetric strategies such as Corey’s chiral diazaborolidine-
mediated bromoacetate aldol condensation via a chiral boron
enolate,3 Hajra’s catalytic halohydroxylation,4 Wuff”s catalytic
aziridination,5 Rao6 an Wu’s7 catalytic Sharpless-epoxydation,
Dixon’s silver-catalyzed isocyanoacetate aldol cyclization,8
Ratovelomanana-Vidal’s Ruthenium9 and Chen’s enzyme-
catalyzed reductive dynamic kinetic resolution,10 Lin’s
enzyme-catalyzed hydrogenation,11 etc. have been developed
for the synthesis of the family of amphenicol antibiotics.
Despite the fruitful achievements in this area, to the best of our
knowledge, none of these syntheses appears to have a
commercially advantage over the long used chemical resolution
process of (−)-chloramphenicol (1) and (+)-thiamphenicol
(3) developed by Hoechst AG in 1957 and Sumitomo
chemical company in 1975, respectively.12 However, these
Figure 1. Structures of representative amphenicol antibiotics (1−4).
activities against both gram negative and positive micro-
organisms, which have been used in clinic for the treatment of
serious bacterial infections in both human and veterinary
medicine. In the family of amphenicol antibiotics, (−)-chlor-
amphenicol has long been put aside because of its side effects,
and has only been used as eye drops and ointment since 1980s
along with (−)-azidamphenicol. However, (−)-chlorampheni-
col represents a great comeback in clinical practice because of
its potential role in the treatment of intra-abdominal and
respiratory tract infections caused by multidrug-resistant
Received: September 9, 2020
https://dx.doi.org/10.1021/acs.joc.0c02181
© XXXX American Chemical Society
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environmentally inefficient industrial processes in today’s green
manufacturing leave much to be desired. As a consequence,
developing a practical, general asymmetric strategy that can
access these antibiotics is urgently in great demand. In
continuation of our studies on asymmetric synthesis of
amphenicol antibiotics,13 we herein report a general strategy
that allows the asymmetric synthesis of these four amphenicols
(1−4) using the organocatalytic enantioselective aldol
approach.
would provide the desired oxazolidinone gem-diesters 9 with
requisite stereoselectivity.
RESULTS AND DISCUSSION
Our synthetic journey began with the preparation of the dialkyl
isocyanatomalonates 11a-c as illustrated in Scheme 2
■
Scheme 2. Improved Synthesis of Dialkyl
Isocyanatomalonates 11a-c
One of the expected challenges in the design of the
asymmetric synthetic pathway leading to the amphenicol
family is the stereocontrol of two (1R, 2R) adjacent
stereocenters on a vicinalamino alcohol framework in which
the stereochemistry at the C1 and C2-position of this skeleton
is syn-relationship. Tactically, the silver-catalyzed asymmetric
isocyanoacetate aldol reaction by Dixon’s group is a powerful
method for the construction of privileged syn-(1R, 2R)-vicinal
amino alcohol moieties in excellent enantioselective fashion.8
However, toxic silver salt was used in this reaction. Recent
studies from Takemoto’s laboratory demonstrated the utility of
thiourea-catalyzed aldol condensation of an aldehyde with an
isocyanoacetate diester for the construction of chiral
oxazolidinone scaffolds14 with a high degree of enantioselec-
tivity and its application in the total synthesis of caprazamycin
A.15 The distinct advantage of the asymmetric aldol reaction
prompted us to investigate its scope and its potential in the
asymmetric synthesis of amphenicol antibiotics. Our synthetic
approach toward amphenicol (1−4) is outlined in a
retrosynthetic formation in Scheme 1. (−)-Chloramphenicol
according to a modification of a procedure reported by
Pedro and co-workers.16 Submission of dialkyl malonates 12a-
c to oximation reactions with NaNO2 under acidic conditions
at room temperature afforded the corresponding oximes 13a-c,
which were directly reduced via catalytic transfer hydro-
genation by treatment of zinc dust and AcOH in MeOH,
smoothly providing amines 14a-c in 60−76% yields over two
steps. The crude products 14a-c were treated with triphosgene
(BTC) in boiling toluene under activated charcoal catalysis to
give dialkyl isocyanatomalonates 11a-c in 67−80% yields.
With dialkyl isocyanatomalonates 11a-c in hand, we
investigated the key enantioselective organocatalytic aldol
reactions of the three nucleophiles with different electrophiles
10a-b, and the results are summarized in Table 1. Initially, the
aldol reaction between 4-methylsulfonyl benzaldehyde 10a and
isocyanatomalonate 11a was chosen to probe reactivity and
stereoselectivity using different cinchona alkaloid derived
thiourea 15a-c as organocatalysts. As expected, in the presence
of 10 mol% of 15a containing two electron-withdrawing
trifluromethyl group, the reaction proceeded smoothly in
CH2Cl2 at room temperature, and the desired aldol adduct 9a
was obtained in 80% yield and 71% ee (entry 1). The thiourea
catalyst 15b and 15c were also not proficient for this
transformation, and similar results in terms of yield and
enantioselectivity were obtained (entries 2 and 3). Urea
catalyst 15d bearing two trifluromethyl groups led to the
corresponding product in 88% yield and 83% ee (entry 4),
while changing the trifluromethyl group to other electron-
withdrawing or donating group showed an decrease of the ee
value (entries 5−8), which indicated that the nature properties
of aryl group of the catalyst had a significant effect on reaction
stereocontrol. Various solvents, including DCE, CHCl3,
toluene, MTBE and THF, were screened subsequently,
which indicated that CHCl3 was the best solvent (entries 9−
13). In addition, dropping the reaction temperature to −20
and −60 °C, respectively, resulted in the increase in both yields
and enantioselectivities (entries 14−15). Similar to electro-
phile 10a, the aldol reaction of 10b and 11a enabled by catalyst
Scheme 1. Retrosynthetic Analysis of Amphenicol (1−4)
(1) and its related congener (2−4) could be accessed from
chiral trans-oxazolidinone monoester 8 through several stand-
ard chemical transformations. The trans-oxazolidinone ester 8
would be generated by a thermodynamic controlled decarbox-
ylation of 9 using a continuous-flow setup. As the key strategy-
level step, a highly organocatalytic enantioselective known
isocyanatoma−lonate diester aldol reaction of the aryl
aldehydes 10 using a cinchona alkaloid derived urea catalyst
B
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ster 9a and 9b, as shown in Table 2. Our initial attempts to
one-step decarboxylation of 9a into the thermodynamically
Table 1. Condition Screening for the Enantioselective
Catalytic Aldol Reaction
a b
,
Table 2. Synthesis of Oxazolidinone Monoesters 8a and 8b
a
under Different Conditions
c
temp. (°C),
time (h)
yield
d
entry 11a-c cat.
sol.
(%)
ee (%)
b
d
yield
(%)
trans: ee
c
entry
1
conditions
time
24 h
cis
(%)
1
2
3
4
5
6
7
8
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
15a
15b
15c
15d
15e
15f
15 g
15 h
15d
15d
15d
15d
15d
15d
15d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
Tol.
MTBE
THF
rt, 24
rt, 24
rt, 24
rt., 24
rt, 24
rt, 24
rt, 18
rt, 24
rt, 20
rt, 24
rt, 16
rt, 24
rt, 18
−20, 36
−60, 36
9a, 80
9a, 80
9a, 78
9a, 88
9a, 88
9a, 80
9a, 80
9a, 75
9a, 85
9a, 82
9a, 68
9a, 78
9a, 83
9a, 86
9a,
71
73
70
83
60
76
73
80
82
85
83
70
61
85
Et2NH, reflux in batch
8a,
mess
8a,
mess
2
3
4
LiCl, DMSO, H2O, 170 °C in
48 h
48 h
batch
LiOH, H2O, reflux in batch
8a,
mess
8a, 56
0.3 M KOH, THF, 0 °C; then
DBU, THF, 70 °C in batch
3.5 h;
30
min
3.5 h;
30
min
4:1
99
99
9
5
0.3 M KOH, THF, 0 °C; then
imidazole , THF, 70 °C in
batch
0.3 M KOH, THF, 0 °C; then
imidazole , THF, 70 °C in flow
0.3 M KOH, THF, 0 °C; then
DBN, THF, 70 °C in flow
0.3 M KOH, THF, 0 °C; then
TEA, THF, 70 °C in flow
8a, 67
4.5:1
10
11
12
13
14
15
6
7
8
9
10 min; 8a, 71
4.5:1
2.5:1
2:1
99
99
99
97
8 min
10 min; 8a, 55
CHCl3
CHCl3
e
8 min
87(99)
10 min; 8a, 35
90(64)
9b,
85(60)
9c, 85
9d, 78
g
f
8 min
16
11a
15d
CHCl3
−60, 72
86(97)
0.3 M KOH, THF, 0 °C; then
imidazole, THF, 70 °C in flow
10 min; 8b, 69 4.5:1
8 min
17
18
11b
11c
15d
15d
CHCl3
CHCl3
−60, 60
−60, 60
86
71
a
Reaction conditions: 9 (0.567 mmol), 0.3 M KOH (0.68 mmol),
THF (5.6 mL); then, base (0.567 mmol), THF (5.6 mL), 70 °C in
batch or flow. Isolated yield of trans-isomer. Determined by H
a
Reaction conditions: Unless otherwise noted, the reactions were
carried out with 10a (0.115 mmol), 11 (0.126 mmol), catalyst 15
(0.0115 mmol) in 1.2 mL of solvent at a specified temperature for a
specified time. Values in parentheses represent recrystallized yields
and enantiomeric ratios. Isolated yield. Determined by chiral HPLC
analysis. ee after recrystallization from ethyl acetate. ee after
recrystallization from isopropanol. 10b was used instead of 10a.
b
c
1
d
NMR of crude reaction mixture. Determined by chiral HPLC
analysis.
b
c
d
e
f
stable trans-oxazolidinone monoester 8a, using boiling
Et2NH,17 LiCl/DMSO, and LiOH18 led to the decomposition
of starting substrates (Table 2, entries 1−3). Armed with these
failure results, we decided to conduct a stepwise decarbox-
ylation process. A hydrolysis of compound 9a followed by
treatment of DBU gave 8a in moderate yield and
diastereoselectivity (entry 4). The reaction yield and
diastereoselectivity can be improved by changing DBU to
imidazole (67% yield, 4.5:1 dr, entry 5). To further improve
the reaction yield and stereoselectivity, we turned our attention
to flow technology using coil-based reaction units.19 To our
delight, the reaction yield could be increased to 71% in much
shorter times compared with batch process (entry 6). We also
tried other bases such as DBN and TEA in flow, but no
improvement in product yield and diastereoselectivity occurred
(entries 7−8). Finally, trans-oxazolidinone monoester 8b could
be obtained in 69% yield and 4.5:1 dr under the optimized
condition (entry 9).
g
15d provided the desired oxazolidinone gem-diester 9b in 85%
yield and 86% ee (entry 16). To further heighten both the
yield and enantioselectivity, we turned our attention to
changing the R group of dialkyl isocyanatoma-lonates 11.
Under the reaction of entry 15, when the R group of the
diester was changing from ethyl to methyl or iso-propyl group,
the enantioselectivities of the expected products were
decreased to 86 and 71%, respectively (entries 17−18),
suggesting that the ester group on the dialkyl isocyanatomal-
onates 11 may have a significant influence on the reactivity and
selectivity. Nevertheless, the ee value of 9a and 9b can be
increased to 99 and 97%, respectively, after recrystallization of
the enantioselective aldol reaction product.
Returning to the task at hand, we entered into the
diastereoselective decarboxylation of oxazolidinone gem-die-
C
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Scheme 3. Asymmetric Synthesis of Amphenicol Antibiotics 1−4
After optimizing the decarboxylation of oxazolidinone gem-
diester 9a and 9b, we conducted the asymmetric synthesis of
amphenicol antibiotics 1−4 (Scheme 3). First, nitro-
substituted oxazolidinone gem-diester 9b could be obtained
in 60% yield and 97% ee after recrystallization of the
enantioselective aldol reaction product. Then, subjecting 9b
to a diastereoselective decarboxylation in continuous flow
afforded trans-oxazolidinone monoester 8b. After transforming
the ester group of 8b to the corresponding alcohols 6b under
mild conditions, (−)-chloramphenicol (1, 6 steps from 10b,
24% total yield), and (−)-azidamphenicol (2, 6 steps from
10b, 26% total yield) could be obtained in high overall yields
by hydrolysis and acylation reaction.20 Similarly, (+)-thiam-
phenicol (3) could be synthesized in 6 steps with 24 overall
yields by simply replacing the nitro group to methylsulfonyl
group. Meanwhile, we extend this new synthetic route to the
synthesis of florfenicol. The alcohol group of 6a could directly
be converted to fluoro by DAST reagent.21 Then, ring opening
of fluorinated derivative 7 followed by acylation could afford
(+)-florfenicol (4) in 56% yield along with 99% ee.
CONCLUSIONS
■
In conclusion, we have developed a highly enantioselective
aldol reaction for the construction of chiral oxazolidinones by
the coupling of an isocyanoacetate diester with an aldehyde via
a cinchona alkaloid derived urea catalyst. The corresponding
aldol reaction products have been subsequently used for the
synthesis of the syn-vicinal amino alcohol scaffold through a
continuous flow diastereoselective decarboxylation, and new
general synthetic route to the asymmetric synthesis of
amphenicol antibiotics (1−4) could be accomplished in high
overall yields and stereoselectivities. The synthetic application
of this novel strategy to the synthesis of other structurally
related compounds and analogues is under investigation in our
laboratory.
EXPERIMENTAL SECTION
■
General Experimental Details. The heat source of all reactions
that require heating is an oil bath. Unless otherwise specified, all
reagents and solvents were purchased from commercial sources and
1
used as received. H (400 MHz) and 13C (100 MHz) NMR were
recorded on a Bruker Avance 400 spectrometer in CDCl3 using
D
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tetramethylsilane as internal standards. Coupling constant (J) values
are given in Hz. Multiplicities are designated by the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; hept, heptet;
br, broad; m, multiplet. Products were purified by flash column
chromatography on silica gel purchased from Qingdao Haiyang
Chemical Co., Ltd. Optical rotations were measured using a Rudolph
AUTOPOL Ι Automatic Polarimeter. HRMS were recorded on a
Bruker microTOF spectrometer. HPLC analysis was performed with
Daicel Chiralpak AD column (25 cm × 4.0 mm × 5 μm), IC column
(25 cm × 4.0 mm × 5 μm). The coil reactors and collection lines
were constructed from perfluoroalkoxy (PFA) tubing (Valco Ins. Co.
Inc.). Syringe pumps (Fusion 4000) was purchased from Chemyx Inc.
Diethyl 2-aminomalonate hydrochloride (14a).16 A 250 mL
round bottom flask containing dialkyl malonates 12a (10.0 g) was
cooled to 0 °C. Water (20 mL) was added followed by AcOH (15.2
mL, 264.9 mmol). NaNO2 (18.3 g, 264.9 mmol) was added in
portions over 1 h. The mixture was stirred at room temperature. After
24 h, water was added and the mixture was extracted four times with
diethyl ether. The combined organic layers were cautiously treated
with an equal volume of saturated aqueous sodium bicarbonate. Solid
sodium bicarbonate was then added until the aqueous layer turned to
yellow. The organic layer was dried over sodium sulfate and
concentrated under reduced pressure to give crude oxime. The
resulting crude oxime was dissolved in AcOH (75 mL), and zinc dust
(24.7 g, 378.5 mmol) was added slowly while maintaining the internal
temperature near 15 °C. The mixture was stirred at room temperature
until no remaining oxime was observed (TLC). The mixture was
filtered through celite to remove the zinc dust and saturated NaHCO3
was added until basic pH, the mixture was extracted five times with
ethyl acetate. The combined organic layers were dried over sodium
sulfate and concentrated under reduced pressure gave crude product.
The above crude product was salinized by HCl (g)/Et2O (1.5 M, 80
oxazolidinones 9a (34.7 mg, 90% yield, 87% ee) as a white solid. The
product was subsequently recrystallized from diethyl ether affording
crystalline 9a (24.6 mg, 64% yield, 99% ee). [α]25 + 47.9 (c 0.2,
D
1
CHCl3); H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.7 Hz, 2H),
7.67 (d, J = 8.5 Hz, 2H), 6.27 (s, 1H), 6.04 (s, 1H), 4.51−4.23 (m,
2H), 3.89−3.57 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.1 Hz,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3): δ 166.1, 165.6, 155.8,
148.5, 140.5, 127.9, 123.5, 79.4, 71.2, 63.7, 63.2, 13.9, 13.5 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H20NO8S 386.0910,
found 386.0913; HPLC[CHIRA LPAK AD, hexane/2-propanol = 80/
20, 0.8 mL/min, λ = 254 nm, retention times: (major) 25.1 min,
(minor) 28.6 min].
(R)-diethyl 5-(4-nitrophenyl)-2-oxooxazolidine-4,4-dicarbox-
ylate (9b). 9b was prepared from 10b according to the procedure
of 9a after flash column chromatography (petroleum ether/ diethyl
ether = 3:1) to give 9b as a white solid (29.9 mg, 85% yield, 86% ee).
The product was subsequently recrystallized from isopropyl alcohol
affording crystalline 9b (21.2 mg, 60% yield, 97% ee). The absolute
configuration was determined by comparison to the reported
26
literature.[α]25 + 41.9 (c 0.31, CHCl3) {Lit.[15a] [α]D = −20.7 (c
D
2.1, CHCl3, 91% ee) for (S)-enantiomer}; 1H NMR (400 MHz,
CDCl3) δ 8.24 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 6.27 (s,
1H), 6.04 (s, 1H), 4.51−4.23 (m, 2H), 3.89−3.57 (m, 2H), 1.34 (t, J
= 7.1 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 166.1, 165.6, 155.8, 148.5, 140.5, 127.9, 123.5, 79.4,
71.2, 63.7, 63.2, 13.9, 13.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H17N2O8 353.0985, found 353.0980; HPLC [CHIR-
ALPAK AD, hexane/2-propanol = 85:15, 0.8 mL/min, λ = 220 nm,
(major) 19.8 min, (minor) 24.2 min].
(R)-dimethyl-5-(4-(methylsulfonyl)phenyl)-2-oxooxazolidine-4,4-
dicarboxylate (9c). 9c was prepared from 11b according to the
procedure of 9a after flash column chromatography (petroleum
1
ether/ diethyl ether = 3:1) to obtain 9c as a white solid (30.0 mg, 85%
mL) to obtain amines 14a as a white solid (10.1 g, 77% yield). H
1
yield, 86% ee): [α]25 + 42.5 (c 0.36, CHCl3); H NMR (400 MHz,
NMR (400 MHz, DMSO-d6) δ 9.22 (s, 2H), 4.98 (s, 1H), 4.32−4.16
D
CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 6.56 (d, J
= 5.0 Hz, 1H), 6.25 (s, 1H), 3.91 (s, 3H), 3.25 (s, 3H), 3.06 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 166.0, 156.2, 141.6,
139.6, 127.7, 127.5, 79.6, 71.4, 54.2, 53.4, 44.4 ppm; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H16NO8S 358.0597, found
358.0592; HPLC [CHIRALPAK AD, hexane/2-propanol = 80/20,
1.0 mL/min, λ = 254 nm, retention times: (major) 27.3 min, (minor)
34.8 min].
(m, 4H), 1.22 (t, J = 7.1 Hz, 6H).
Dimethyl 2-aminomalonate hydrochloride (14b).16 The above
procedure was used to obtain dimethyl 2-aminomalonate hydro-
1
chloride 14b as a white solid (10.4 g, 75% yield). H NMR (400
MHz, DMSO-d6) δ 9.24 (s, 2H), 5.04 (s, 1H), 3.78 (s, 6H).
Diisopropyl 2-aminomalonate hydrochloride (14c).16 The above
procedure was used to obtain diisopropyl 2-aminomalonate hydro-
chloride 14c as a white solid (7.6 g, 60% yield). 1H NMR (400 MHz,
DMSO-d6) δ 9.08 (s, 2H), 5.10−4.99 (m, 2H), 4.96 (s, 1H), 1.25
(dd, J = 14.4, 6.2 Hz, 12H).
(R)-diisopropyl-5-(4-(methylsulfonyl)phenyl)-2-oxooxaoldine-
4,4-dicarboxylate (9d). 9d was prepared from 11c according to the
procedure of 9a after flash column chromatography (petroleum
Diethyl 2-isocyanatomalonate (11a).16 To a mixture of 14a (11.5
g, 54.5 mmol) in toluene (55 mL) was added activated charcoal (40.0
mg) and triphosgene (16.2 g, 54.5 mmol) at 0 °C. The reaction
mixture was stirred at 80 °C for 1 h and then refluxed overnight. The
reaction mixture was cooled to room temperature and filtered through
celite. The filtrate was concentrated under reduced pressure. The
resultant oil was distilled by using an oil pump (126 °C, 140 Pa) to
give the dimethyl 2-isocyanatomalonate 11a as a colorless oil (8.8 g,
ether/ diethyl ether = 4:1) to obtain 9d as a white solid (32.2 mg,
1
78% yield, 71% ee): [α]25 + 35.7 (c 0.34, CHCl3); H NMR (600
D
MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H),
6.26 (s, 1H), 6.23 (s, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 4.59 (hept, J =
6.3 Hz, 1H), 3.04 (s, 3H), 1.34 (d, J = 6.3 Hz, 3H), 1.29 (d, J = 6.3
Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.56 (d, J = 6.3 Hz, 3H) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ 165.7, 165.3, 156.1, 141.6,
139.8, 128.1, 127.5, 79.4, 71.8, 71.6, 71.1, 44.3, 21.5, 21.3, 21.2, 20.5
ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H24NO8S
414.1223, found 414.1227; HPLC[CHIRALPAK AD, hexane/2-
propanol = 85/15, 0.8 mL/min, λ = 235 nm, retention times: (major)
36.1 min, (minor) 49.8 min].
1
80% yield). H NMR (400 MHz, CDCl3) δ 4.52 (s, 1H), 4.38−4.23
(m, 4H), 1.31 (t, J = 7.1 Hz, 6H).
Dimethyl 2-isocyanatomalonate (11b).16 The above procedure
was used to obtain dimethyl 2-isocyanatomalonate 11b as a colorless
1
oil (7.6 g, 67% yield). H NMR (400 MHz, CDCl3) δ 4.56 (s, 1H),
3.85 (s, 6H).
Ethyl (4S,5R)-5-(4-(methylsulfonyl)phenyl)-2-oxooxazolidine-4-
carboxylate (8a). The flow system adopted a two-feed microreactor
consisting of a 4 mL piece of PFA tube with an internal diameter of
0.8 mm (1/16″ outer diameter) and a length of 800 cm. 9a (218 mg,
0.567 mmol) was dissolved in THF (5.6 mL) and pumped into the
microreactor through the feed A (flow rate: 560 μL/min), while the
KOH (0.3 M 2.3 mL) was introduced into the microreactor through
the feed B (flow rate: 230 μL/min). The streams (feed A and feed B)
met in a T-mixer before entering the PFA reactor and reacting at
room temperature with a 10 min residence time. The back pressure
regulator was attached to the output line to maintain a stable system
pressure of 10 bar. The reaction mixture was collected in a separate
100 mL output round-bottom flask and quenched with 1 M aqueous
Diisopropyl 2-isocyanatomalonate (11c).16 The above procedure
was used to obtain product 11c as a colorless oil (401 mg, 70% yield).
1H NMR (400 MHz, CDCl3) δ 5.17−5.06 (m, 2H), 4.43 (s, 1H),
1.28 (dd, J = 9.0, 6.3 Hz, 12H).
(R)-Diethyl-5-(4-(methylsulfonyl)phenyl)-2-oxooxazolidine 4, 4-
dicarboxylate (9a). To a mixture of 4-methylsulphonyl benzaldehyde
10a (18.4 mg, 0.1 mmol) and urea catalyst 15d (5.9 mg, 0.01 mmol)
in CHCl3 (0.5 mL) was added a solution of isocyanatomalonate 11a
(24.2 mg, 0.12 mmol) in CHCl3 (0.5 mL) at −60 °C. After being
stirred at the same temperature for 60 h, the reaction mixture was
concentrated in vacuo. The resulting residue was purified by silica gel
chromatography (petroleum ether/ diethyl ether = 3:1) to give
E
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HCl (2 mL). The mixture was extracted with diethyl ether (3 × 15
mL), and washed with brine. The organic layer was dried over with
Na2SO4. Filtration and concentration afforded a crude carboxylic acid
as a light brown solid.
vacuum. The crude compound was taken in methyl dichloroacetate (2
mL) and heated at 90 °C for 3 h. The excess ester was removed under
reduced pressure and the residuum was purified by silica gel column
chromatography (CH2Cl2/MeOH = 20:1) affording chloramphenicol
To a solution of the above crude carboxylic acid (0.567 mmol) in
THF (5.6 mL) was added imidazole (19.3 mg, 0.284 mmol) at room
temperature and pumped into the PFA reactor through the feed A
(flow rate: 700 μL/min). The back pressure regulator was attached to
the output line to maintain a stable system pressure of 10 bar. The
reaction mixture was pumped at an overall flow rate of 700 μL/min
and heating at 70 °C with a 8 min residence time. The reaction
mixture was collected in a 100 mL output conical flask and
concentration under reduced pressure, purification by silica gel
column chromatography (petroleum ether / diethyl ether = 2:1)
afforded trans-isomer 8a (126 mg, 71% yield for two steps, 99% ee, dr
(29 mg, 70% yield for two steps, 97% ee) as a light yellow solid:
1
[α]25 − 16.2 (c 0.68, EtOH); H NMR (400 MHz, DMSO-d6) δ
D
8.32 (d, J = 9.2 Hz, 1H), 8.20−8.11 (d, J = 8.6 Hz, 2H), 7.59 (d, J =
8.6 Hz, 2H), 6.47 (s, 1H), 6.05 (d, J = 4.4 Hz, 1H), 5.06 (dd, J = 4.6,
2.4 Hz, 1H), 4.99 (dd, J = 6.2, 4.9 Hz, 1H), 3.98−3.89 (m, 1H),
3.63−3.55 (m, 1H), 3.37−3.34 (m, 1H) ppm; HPLC[CHIRALPAK
AD, hexane/2-propanol = 90/10, 1.0 mL/min, λ = 235 nm, retention
times: (major) 11.5 min, (minor) 17.7 min].
(−)-Azidamphenicol (2). 6b (30 mg, 0.13 mmol) was suspended in
aqueous NaOH (1 M in water 0.5 mL) and heated under reflux for 30
min, Then the reaction was extracted with CHCl3 (5 × 6 mL). The
combined organic layers were washed with brine and dried over
Na2SO4. After filtration and concentration under reduced pressure,
the resulting residue was dissolved in MeOH (1 mL) and methyl 2-
azidoacetate was added (45 mg, 38 μL) at 0 °C. After addition, the
vessel was heated at 40 °C and monitored by TLC. After 9 h, the
reaction mixture was cooled to room temperature and concentrated in
vacuo, and the cooled mixture was purified by silica gel column
chromatography (CH2Cl2/MeOH = 10:1) to afford (−)-azidamphe-
nicol (28.8 mg, 75% yield for two steps, 97% ee) as a light yellow
solid: [α]25D − 10.2 (c 0.21, EtOH); 1H NMR (400 MHz, DMSO-d6)
δ 8.02 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.4
Hz, 2H), 5.76 (d, J = 4.6 Hz, 1H), 4.93−4.87(m, 1H), 4.81−4.75 (m,
1H), 3.92−3.82 (m, 1H), 3.62−3.52 (m, 2H), 3.48−3.39 (m, 1H),
3.26−3.17 (m, 1H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ
167.4, 151.8, 146.6, 127.5, 123.1, 69.5, 60.7, 56.4, 50.7 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C11H13N5O5Na 318.0814,
found 318.0808; HPLC[CHIRALPAK AD, hexane/2-propanol = 90/
10, 1.0 mL/min, λ = 235 nm, retention times: (major) 16.3 min,
(minor) 21.4 min].
= 4.5:1) as a yellow solid. (The dr ratio was determined by 1H NMR
1
of crude reaction mixture): [α]25 + 25.8 (c 0.6, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 8.01 (dd, J = 8.4, 2.3 Hz, 2H), 7.66 (dd, J = 8.3,
2.3 Hz, 2H), 6.37 (d, J = 4.4 Hz, 1H), 5.74 (dd, J = 5.3, 2.3 Hz, 1H),
4.41−4.28 (m, 2H), 4.24 (dd, J = 5.3, 2.3 Hz, 1H), 3.07 (d, J = 2.4
Hz, 3H), 1.42−1.30 (m, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 169.1, 157.4, 144.1, 141.3, 128.2, 126.3, 78.2, 62.9, 61.0,
44.4, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H16NO6S 314.0698, found 314.0694; HPLC [CHIRALPAK AD,
hexane/2-propanol = 70/30, 0.7 mL/min, λ = 220 nm, retention
times: (major) 32.8 min, (minor) 30.4 min].
Ethyl (4S,5R)-5-(4-nitrophenyl)-2-oxooxazolidine-4-carboxy-late
(8b). 8b was prepared from 9b according to the procedure of 8a after
flash column chromatography (petroleum ether/ diethyl ether = 3:1)
to obtain 8b (109 mg, 69% yield for two steps, 97% ee, dr = 4.5:1) as
1
a yellow solid (The dr ratio was determined by H NMR of crude
reaction mixture): [α]25D + 25.6 (c 0.2, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.29 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 6.55 (s,
1H), 5.76 (d, J = 5.2 Hz, 1H), 4.41−4.32 (m, 2H), 4.25 (d, J = 5.2
Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 169.1, 157.6, 148.3, 144.9, 126.3, 124.3, 78.1, 63.0, 61.1,
14.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H12N2O6Na 303.0593, found 303.0594; HPLC [CHIRALPAK
AD, hexane/2-propanol = 70/30, 0.7 mL/min, λ = 220 nm, retention
times: (major) 15.1 min,(minor) 19.7 min].
(+)-Thiamphenicol (3).22 6a (30 mg 0.11 mmol) was suspended in
aqueous NaOH (1 M 0.5 mL) and heated under reflux for 30 min.
The reaction mixture was filtered and the filtrate concentrated in
vacuum. The crude compound was taken in methyl dichloroacetate (2
mL) and heated at 90 °C for 3 h. The excess ester was removed under
reduced pressure and the residuum was purified by silica gel column
chromatography (CH2Cl2/MeOH = 20:1) affording thiamphenicol
(4R,5R)-4-(hydroxymethyl)-5-(4-(methylsulfonyl)phenyl)oxaz-oli-
din-2-one (6a).22 8a (50 mg, 0.16 mmol) was dissolved in methanol
(2 mL) and the solution cooled using an ice bath. A solution of
NaBH4 (36 mg, 0.96 mmol) in methanol (1 mL) was added dropwise
with stirring. After the addition was complete the ice bath was
removed and the mixture stirred for 60 min. The methanol was
removed under reduced pressure. 1 M HCl (0.2 mL) added followed
by water (15 mL). The remaining aqueous solution extracted with
diethyl ether (6 × 5 mL). The combined organic layers were washed
with brine and dried over Na2SO4. After filtration and concentration
under reduced pressure, purification by silica gel column chromatog-
(24 mg, 62% yield for two steps, 99% ee) as a white solid: [α]25
+
D
11.8 (c 0.88, EtOH); 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J =
9.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 6.46
(s, 1H), 5.94 (d, J = 4.4 Hz, 1H), 4.99 (dd, J = 4.5, 2.7 Hz, 1H), 4.95
(dd, J = 6.1, 4.8 Hz, 1H), 3.93−3.84 (m, 1H), 3.59−3.49(m, 1H),
3.32−3.27 (m, 1H), 3.13 (s, 3H) ppm; HPLC [CHIRALPAK AD,
hexane/2-propanol = 90/10, 1.0 mL/min, λ = 234 nm, retention
times: (major) 21.8 min, (minor) 31.7 min].
(4S,5R)-4-(fluoromethyl)-5-(4-(methylsulfonyl)phenyl)oxazoli-
din-2-one (7).23 To a flask containing 6a (65 mg 0.24 mmol) was
added anhydrous THF (8 mL) under an argon atmosphere. DAST
(89 mg 73 μL) was added slowly at −60 °C. The mixture was allowed
to warm to room temperature during 9 h and stirred at this
temperature for another 12 h. The reaction was quenched with
saturated aqueous NaHCO3 (2 mL) and extracted with diethyl ether
(4 × 10 mL). The combined organic layers were washed with brine
and dried over Na2SO4. After filtration and concentration under
reduced pressure, purification by silica gel column chromatography
(CH2Cl2/MeOH = 60:1) afforded 7 (53 mg, 81% yield) as a white
solid: [α]25D + 25.7 (c 0.46, DMF); 1H NMR (400 MHz, Acetone-d6)
δ 8.07−7.99 (m, 2H), 7.78−7.68 (m, 2H), 7.16 (s, 1H), 5.61 (d, J =
4.0 Hz 1H), 4.77 (d, J = 4.0 Hz, 1H), 4.65 (d, J = 4.0 Hz, 1H), 4.16−
3.96 (m, 1H), 3.15 (s, 3H) ppm; 13C{1H} NMR (100 MHz, Acetone-
d6) δ 158.4, 146.2, 142.6, 128.9, 127.5, 84.3 (d, J = 172.1 Hz), 78.0 (d,
J = 5.7 Hz), 60.4 (d, J = 20.5 Hz), 44.3 ppm.
raphy (CH2Cl2/MeOH = 25:1) afforded 6a as a white solid (36 mg,
1
85%yield). [α]25 + 7.69 (c 0.37, MeOH); H NMR (400 MHz,
D
DMSO-d6) δ 7.94 (d, J = 8.2 Hz, 2H), 7.91 (s, 1H), 7.58 (d, J = 8.1
Hz, 2H), 5.41 (d, J = 4.2 Hz, 1H), 5.16 (d, J = 5.3 Hz, 1H), 3.59−
3.46 (m, 3H), 3.18 (s, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-
d6) δ 157.8, 145.8, 140.6, 127.6, 126.4, 77.6, 62.4, 61.1, 43.5 ppm.
(4R,5R)-4-(hydroxymethyl)-5-(4-nitrophenyl)oxazolidin-2-one
(6b).22 6b was prepared from 8b according to the procedure of 6a
after flash column chromatography (CH2Cl2/MeOH = 25:1) to give
6b (34.8 mg, 82% yield) as a yellow oil. The absolute configuration
was determined by comparison to the reported literature. [α]25
−
D
25
1
3.39 (c 0.52, EtOH) {Lit.[22] [α]D = −4.08 (c 1.1, EtOH)}; H
NMR (400 MHz, Acetone-d6) δ 8.31 (d, J = 8.4 Hz, 2H), 7.73 (d, J =
8.4 Hz, 2H), 6.97 (s, 1H), 5.59 (d, J = 3.4 Hz, 1H), 4.55−4.49 (m,
1H), 3.85−3.75 (m, 3H) ppm; 13C{1H} NMR (100 MHz, Acetone-
d6) δ 158.5, 148.7, 148.4, 127.4, 124.6, 78.8, 63.8, 62.2 ppm.
(+)-Florfenicol (4).23 A solution of 7 (52 mg, 0.19 mmol) in EtOH
(2 mL) was added 1 N NaOH (4 mL). The mixture was heated at 80
°C for 3 h. The mixture was cooled to room temperature, and the
product was extracted with diethyl ether (4 × 10 mL). The organic
(−)-Chloramphenicol (1).22 6b (30 mg, 0.13 mmol) was
suspended in aqueous NaOH (1 M, 3.8 eq) and heated under reflux
for 30 min. The reaction mixture was filtered and concentrated in
F
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layer was washed with brine and dried, and the solvent was
evaporated. The resulting residue was dissolved in THF (3 mL)
and added at 0 °C to a saturated aqueous of NaOAc (3 mL). After the
mixture was stirred for 10 min, dichloroacetyl chloride (27 μL, 0.28
mmol) was added dropwise, and stirring was continued at 25 °C for 5
h. Then the reaction was extracted with diethyl ether (4 × 10 mL),
The combined organic layers were washed with brine and dried over
Na2SO4. After filtration and concentration under reduced pressure,
purification by silica gel column chromatography (CH2Cl2/MeOH =
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Fundamental Research Funds
for the Central Universities (Grants Nos. YJ201853 and
YJ201805) and the National Natural Science Foundation
(Grant No. 21907072).
60:1) to furnish florfenicol 38 mg (0.11 mmol, 56% yield two steps,
1
99% ee) as a white solid: [α]25 + 14.6 (c 0.52, EtOH); H NMR
D
REFERENCES
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(400 MHz, DMSO-d6) δ 8.62 (d, J = 8.9 Hz, 1H), 7.91−7.77 (m,
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Corresponding Authors
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You-Cai Xiao − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China;
Email: xiaoliguo1987@scu.edu.cn
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;
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Authors
Jinxin Liu − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Yaling Li − Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China
Miaolin Ke − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China
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Minjie Liu − Engineering Center of Catalysis and Synthesis for
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Pingping Zhan − Engineering Center of Catalysis and
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Complete contact information is available at:
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