An efficient enantioselective synthesis of florfenicol based on sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1055/s-0031-1289706

An efficient and highly enantioselective synthesis of florfenicol- via a new intermediate threo-dihydroxy ester, with a Sharpless asymmetric dihydroxylation as the key step, is reported. A ring-opening/reduction strategy avoids the formation of a chlorinated byproduct that occurs in Schumachers phenyloxazoline procedure. The overall yield of florfenicol by this new process is 23% based on 4-(methylsulfonyl)benzaldehyde. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289706

PAPER
699
An Efficient Enantioselective Synthesis of Florfenicol Based on Sharpless
Asymmetric Dihydroxylation
E
nantioselective
h
Synthesis
o
o
f
Florfenicolng-Hua Wang,a Chen Zheng,a Feng Li,a Lei Zhao,b Fen-Er Chen,*a,b Qiu-Qin He*a
a
Department of Chemistry, Fudan University, 220 Handan Road, 200433 Shanghai, P. R. of China
Institute of Biomedical Science, Fudan University, 305 Fenglin Road, 200031 Shanghai, P. R. of China
Fax +86(21)65643811; E-mail: rfchen@fudan.edu.cn
b
Received 23 November 2011; revised 22 December 2011
florfenicol that uses a Sharpless asymmetric dihydroxy-
lation4 as its key step.
Abstract: An efficient and highly enantioselective synthesis of
florfenicol via a new intermediate threo-dihydroxy ester, with a
Sharpless asymmetric dihydroxylation as the key step, is reported.
A ring-opening/reduction strategy avoids the formation of a chlori-
nated byproduct that occurs in Schumacher’s phenyloxazoline pro-
cedure. The overall yield of florfenicol by this new process is 23%
based on 4-(methylsulfonyl)benzaldehyde.
Our retrosynthetic plan for 1 is shown in Scheme 1. We
hypothesized that intermediate fluoro compound 2 might
be synthesized from alcohol 4 by inversion of the config-
uration of the hydroxyl group at the benzylic position via
the intermediate oxazoline 3. The stereocenters of
(2S,3S)-4 could be elaborated through a selective sulfona-
tion/sodium azide substitution strategy.5 The chiral dihy-
droxy ester 5 might be obtained from acrylate 6 by means
of a Sharpless asymmetric dihydroxylation (AD).
Key words: halogenation, heterocycles, asymmetric synthesis, sul-
fones, drugs
As part of our studies on asymmetric syntheses in the field
of chiral pharmaceutical and natural products, the enanti-
oselective synthesis of florfenicol (1), which has a unique
structure and broad-spectrum antibacterial activity, has
been an important target of our group.1 We have recently
developed two different asymmetric approaches to the
synthesis of 1 that feature a vanadium-catalyzed asym-
metric epoxidation2 and an asymmetric catalytic aziridi-
nation strategy,3 respectively. The main problem with
these two strategies is the difficulty in recovering the
chiral ligands that are used in the catalytic asymmetric
transformations and which precludes the application of
these processes in large-scale syntheses of florfenicol.
There remains, therefore, a need for an efficient and eco-
nomic approach to the synthesis of florfenicol. Here, we
report an efficient and highly enantioselective route to
Our enantioselective synthesis of florfenicol (1) com-
menced from commercially available 4-(methylsulfo-
nyl)benzaldehyde (7). Knoevenagel condensation of 7
with malonic acid proceeding smoothly in the presence of
piperidine to give (2E)-3-[4-(methylsulfonyl)phe-
nyl]acrylic acid (8) in high yield (Scheme 2).6 Refluxing
of 8 with thionyl chloride in ethanol or methanol then
gave the corresponding cinnamates 6 and 9 in excellent
yields. When the reaction was carried out at room temper-
ature, the desired products were not detected.
Sharpless asymmetric dihydroxylation of ethyl ester 6
with AD-mix-a reagent (1.4 g/mmol) and 1.0 equivalent
of methanesulfonamide in a 1:1 mixture of tert-butanol
and water at 25 °C for 20 hours gave the dihydroxy com-
pound 5 in 95% yield and 98.7% enantiomeric excess
Ar
OH
F
O
OH
OH
O
N
2
Cl
F
1
OEt
3
O
O
O
O
HN
NH2
NH2
OH
S
Cl
S
S
S
Me
Me
Me
Me
O
O
O
O
O
1
2
3
4
O
OH
O
O
O
O
O
O
O
S
OH
S
S
Me
Me
Me
O
O
O
5
6
7
Scheme 1 Retrosynthetic analysis for florfenicol (1)
SYNTHESIS 2012, 44, 699–704
x
x
.x
x
.2
0
1
2
Advanced online publication: 14.2.2012
DOI: 10.1055/s-0031-1289706; Art ID: F109711SS
© Georg Thieme Verlag Stuttgart · New York

700
Z.-H. Wang et al.
PAPER
O
O
O
a
OH
OR
b
O
O
O
S
S
S
Me
Me
Me
O
O
O
7
8
6 R = Et
9 R = Me
Scheme 2 Reagents and conditions: (a) malonic acid, piperidine, py, reflux, 2 h, 81%; (b) SOCl2, ROH, reflux, overnight, 92% (for 6), 93%
(for 9).
(Table 1, entry 1), whereas similar treatment of the corre- (2R,3S)-5 with 1.0 equivalent of 4-nitrobenzenesulfonyl
sponding methyl ester 9 gave the corresponding dihy- chloride in the presence of 2.0 equivalents of triethyl-
droxy derivative 10 in only 52% yield (after extraction ten amine in dichloromethane at 0–4 °C gave the a-hydroxy
times with ethyl acetate) and 97.8% enantiomeric excess sulfonate 11 in 76% isolated yield (Scheme 4). Subse-
(entry 2). The yield of the methyl ester 10 was much lower quently, sulfonate 11 underwent substitution with 1.2
than that of its ethyl counterpart 5 because of the greater equivalents of sodium azide in dry N,N-dimethylform-
solubility of the former in water; the calculated7 octanol– amide under argon at 55 °C to give the (2S,3S)-a-azido b-
water partition coefficient (log P) of 10 is –1.66 0.41, hydroxy ester 12 and its (2R,3S)-epimer 12¢ in a ratio of
which is much lower than that of 5 (–1.12 0.41).
3:1. Reduction of the mixture of 12 and 12¢ with 10% Pd/C
in ethanol under hydrogen at room temperature for two
hours gave a mixture of the corresponding of amines 4 and
4¢ in a ratio of 3:1. Treatment of this mixture with 4-meth-
oxybenzoyl chloride in dichloromethane with subsequent
separation by column chromatography gave the amides 13
and 13¢ in 65 and 17% yields, respectively.
Because the more acidic a-hydroxy group reacted prefer-
entially to form a monosulfonate,5 selective sulfonation of
O
OH
O
a
OR
OR
O
O
OH
The structure of the (2R,3S)-sulfonate 11 was unambigu-
S
S
Me
Me
ously determined by X-ray crystallography (Figure 1).8
O
O
6 R = Et
9 R = Me
5 R = Et
10 R = Me
Cyclization of amide 13 with thionyl chloride in anhy-
drous chloroform at 45 °C for 0.5 hours gave the trans-
oxazoline 14 in 91% yield (Scheme 5). The inversion of
Scheme 3 Reagents and conditions: (a) AD-mix-a, MeSO2NH2,
t-BuOH–H2O (1:1), r.t., 20 h.
Table 1 Results of the Sharpless AD Reaction of Cinnamates 6 and
9
Entrya
Reactant
R
Products
Yield (%)b ee (%)
1
2
6
9
Et
Me
(2R,3S)-5
(2R,3S)-10
95
52
98.7c
97.8d
a Reaction conditions: cinnamate (8.5 mmol), AD-mix-a and MsNH2
(8.5 mmol), t-BuOH–H2O (1:1), r.t., 20 h.
b Isolated yield after chromatography (silica gel).
c By HPLC [CHIRALPAK AD-H (25 cm × 0.46 cm i.d.); hexane–
i-PrOH (80:20), 1.0 mL/min; UV wavelength: 220 nm; 35 °C].
d By HPLC [CHIRALPAK IA (25 cm × 0.46 cm i.d.); hexane–EtOH–
Et2NH (60:40:0.1), 0.8 mL/min; UV wavelength: 220 nm; 35 °C].
Figure 1 ORTEP diagram for (2R,3S)-sulfonate 11
OH
OH
OH
CO2Et
b
OR1
CO2Et
CO2Et
+
O
O
O
R2
R2
S
S
S
Me
Me
Me
O
O
O
(2R,3S)-5 R1 = H
R2 = N3 12
2 = NH2
2 = PMP-CONH 13
:
12' = 3:1
4' = 3:1
13'
c
a
11 R1 = Ns
R
4
:
d
R
Scheme 4 Reagents and conditions: (a) 4-O2NC6H4SO2Cl, Et3N, CH2Cl2, 0–4 °C, 10 h, 76%; (b) NaN3, DMF, 55 °C, overnight; (c) H2, 10%
Pd/C, EtOH, r.t., 2 h; (d) 4-MeOC6H4COCl, Et3N, CH2Cl2, 0–4 °C, 10 h, 65% for 13; 17% for 13¢ from 11.
Synthesis 2012, 44, 699–704
© Thieme Stuttgart · New York

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Enantioselective Synthesis of Florfenicol
701
the configuration at the benzylic position of this com- Hydrolysis of fluoro compound 16 with 1 M hydrogen
pound from S to R was confirmed from the relationship chloride in tetrahydrofuran at 45 °C for three hours and
between the signals from the H-4 and H-5 protons of 14 in subsequent evaporation of the solvent gave the fluoro
its nuclear Overhauser effect (NOE) NMR spectra amine 17 as its hydrochloride salt,9 which formed a col-
(Figure 2). The cis-oxazoline 14¢ was similarly obtained ored ninhydrin chromophore on thin-layer chromatogra-
by treatment of 13¢ with thionyl chloride, and its configu- phy and gave a precipitate on treatment with silver nitrate
ration was also confirmed by NOE spectroscopy in aqueous solution. Reduction of the free amine 17 with
(Figure 2). The trans-oxazoline 14 could be prepared lithium borohydride (prepared in situ from potassium
from 14¢ in 85% yield (based on 13¢) by treatment with so- borohydride and lithium chloride) in tetrahydrofuran gave
dium ethoxide in a mixture of ethanol and tetrahydrofu- the corresponding amine 2. This mild preparation of
ran.
amine 2 from oxazoline 16 avoids the formation of a chlo-
rinated byproduct that occurs during Schumacher’s phe-
nyloxazoline strategy.10
PMP
N
O
Finally, florfenicol (1) was obtained in 91% yield by ami-
dation of amine 2 with 1.03 equivalents of dichloroacetic
chloride in a mixture of dichloromethane and ethanol at
0 °C for three hours; the total yield for the final three steps
was 75%. The spectral data and physical characteristics of
the product were in complete agreement with the reported
values for florfenicol.10
b
13'
O
OEt
S
O
Me
O
14'
c
PMP
N
PMP
N
In summary, we developed an efficient enantioselective
route to florfenicol (1) in 23% overall yield via a new ad-
vanced intermediate threo-dihydroxy ester 5 and by using
Sharpless AD as the key step.
O
O
d
a
e
13
O
O
OEt
OH
S
S
O
Me
Me
O
O
14
15
Chiral HPLC was performed on a Shimadzu LC 20 with UV detec-
tor SPD-20A. Melting points were determined on a WRS-1 digital
melting-point apparatus and are uncorrected. Optical rotations were
recorded on a JASCO P1020 digital polarimeter. Elemental analy-
ses were performed on a Carlo-Erba 1106 instrument, and the re-
sults of elemental analyses for C, H, N, and S were within 0.4% of
the theoretical values. 1H and 13C NMR spectra were recorded on a
Bruker Avance 400 spectrometer at 400 and 100 MHz, respectively,
in CDCl3, MeOD, or DMSO-d6 using TMS or the solvent (MeOD:
1H, d = 3.31 ppm; 13C, d = 49.0 ppm: DMSO-d6, 1H, d = 2.49 ppm,
13C, d = 39.5 ppm: CDCl3, 13C, d = 77.0 ppm) as the internal stan-
dard. 19F NMR spectra were recorded on a Bruker DMX 500 spec-
trometer (470 MHz) using CCl3F (19F, d = 0.0 ppm) as an external
standard. IR spectra were recorded on a Nicolet FT-IR 4200 spec-
trometer as KBr pellets. Mass spectra were measured on a Waters
Quattro Micromass instrument using electrospray ionization (ESI)
techniques. Unless otherwise noted, all reactions were conducted in
oven-dried glassware under an inert atmosphere of dried argon or
N2. THF was distilled from sodium/benzophenone. Toluene and
CH2Cl2 were distilled from CaH2. Cinnamic acid 8 was prepared ac-
cording to the literature method.6
O
PMP
N
O
O
PMP
g
h
f
2
1
F
O
O
NH2
F
S
S
Me
Me
O
O
16
17
Scheme 5 Preparation of florfenicol from amide 13. Reagents and
conditions: (a) SOCl2, CHCl3, 45 °C, 0.5 h, 91%; (b) SOCl2, CHCl3,
45 °C, 0.5 h; (c) NaOEt, EtOH, THF, r.t., 1 h, 85% (from 13¢); (d)
NaBH4, CaCl2, EtOH, 0 °C to r.t., 5 h, 82%; (e) Ishikawa’s reagent
(F3CCHFCF2NEt2), CH2Cl2, sealed tube, 100 °C, 3 h, 92%; (f) 1 M
HCl, THF, r.t., 3 h; (g) KBH4, LiCl, THF, 50 °C, overnight; (h)
Cl2CHCOCl, NEt3, CH2Cl2, EtOH, 0 °C, 3 h, 75% (three steps).
PMP
PMP
O
O
Me
Me
2
2
3
1
O
S
1
3
S
N
O
N
O
O
O
H
OEt
5
4
5
4
Ethyl (2E)-3-[4-(Methylsulfonyl)phenyl]acrylate (6)
OEt
H
H
H
A mixture of cinnamic acid 8 (22.6 g, 100 mmol) and EtOH (150
mL) was stirred at r.t. and SOCl2 (14.2 mL, 200 mmol) was added
dropwise. The mixture was then refluxed overnight, cooled to r.t.,
and concentrated. The residue was dissolved in CH2Cl2 (130 mL)
and the resulting soln was washed with sat. aq NaCO3 and brine
then dried (Na2SO4), filtered, and concentrated. The residue was
crystallized from EtOH–H2O (1:1) to give yellow needles; yield:
23.3 g (92%); mp 93–94 °C.
O
no NOE
14
NOE
14'
Figure 2 Nuclear Overhauser effect correlation of 14 and 14¢
Reduction of oxazoline 14 with calcium borohydride (pre-
pared in situ from sodium borohydride and calcium chlo-
ride) in ethanol at 0 °C gave the alcohol 15 in 82% yield.
This was converted into the fluoro compound 16 in 92%
FTIR (KBr): 1709, 1644, 1307, 1146, 968, 835, 773, 651, 528 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
yield by fluorination with Ishikawa’s reagent (N,N-dieth- 3.08 (s, 3 H, SO2CH3), 4.29 (q, J = 7.2 Hz, 2 H, CH2), 6.56 (d,
J = 16 Hz, 1 H, COCH), 7.68–7.72 (m, 3 H, ArCH and ArH), 7.96
yl-1,1,2,3,3,3-hexafluoropropylamine) in dichloromethane
(d, J = 8.4 Hz, 2 H, ArH).
in a sealed tube at 100 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 699–704

702
Z.-H. Wang et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 14.29, 44.45, 60.95, 122.17,
ESI-MS: m/z (%) = 275 [M + H]+.
128.02, 128.66, 139.71, 141.47, 142.01, 166.13.
Anal. Calcd for C11H14O6S: C, 48.17; H, 5.14; S, 11.69. Found: C,
48.09; H, 5.11; S, 11.63.
ESI-MS: m/z (%) = 255 [M + H]+.
Anal. Calcd for C12H14O4S: C, 56.68; H, 5.55; S, 12.61. Found: C,
56.60; H, 5.59; S, 12.57.
Ethyl (2R,3S)-3-Hydroxy-3-[4-(methylsulfonyl)phenyl]-2-{[(4-
nitrophenyl)sulfonyl]oxy}propanoate (11)
4-O2NC6H4SO2Cl (2.43 g, 11 mmol) was added to a soln of (2R,3S)-
5 (3.17 g, 11 mmol) and Et3N (2.3 mL, 16.5 mmol) in CH2Cl2 (110
mL) at 0 °C under argon, and the mixture was stirred for 10 h. Ad-
ditional CH2Cl2 (50 mL) was added and the mixture was washed se-
quentially with 1 M aq HCl (3 × 30 mL), sat. aq NaHCO3 (20 mL),
and brine (20 mL). The organic phase was dried (Na2SO4), filtered,
and then concentrated under vacuum. The residue was mixed with
CH2Cl2 (20 mL) and the mixture was refluxed for 2 h, cooled to r.t.,
and filtered to give a white solid; yield: 3.95 g (76%); mp 195–
196 °C; [a]D25 +64.5 (c 1.04, THF).
Methyl (2E)-3-[4-(Methylsulfonyl)phenyl]acrylate (9)
This compound was prepared by the same procedure as 6 to give
yellow needles; yield: 22.3 g (93%): mp 128–129 °C.
FTIR (KBr): 3021, 2955, 2925, 1717, 1639, 1433, 1303, 1149, 966,
770, 651, 530 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.08 (s, 3 H, SO2CH3), 3.84 (s, 3
H, OCH3), 6.56 (d, J = 16.4 Hz, 1 H, COCH), 7.70–7.74 (m, 3 H,
ArCH and ArH), 7.97 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 44.46, 52.04, 121.68, 128.04,
128.70, 139.62, 141.55, 142.32, 166.57.
FTIR (KBr): 3573, 3107, 2991, 2982, 2940, 1746, 1541, 1351,
1310, 1149, 1089, 1036, 836, 743, 535, 418 cm–1.
ESI-MS: m/z (%) = 241 [M + H]+.
1H NMR (400 MHz, DMSO-d6): d = 1.19 (t, J = 7.2 Hz, 3 H, CH3),
3.11 (s, 3 H, SO2CH3), 4.19 (q, J = 7.2 Hz, 2 H, CH2), 5.23 (dd,
J = 5.2, 2.4 Hz, ArCH), 5.41 (d, J = 2.8 Hz, 1 H, CH), 6.34 (d,
J = 5.6 Hz, 1 H, OH), 7.48 (d, J = 8.4 Hz, 2 H, ArH), 7.59 (d, J = 8.4
Hz, 2 H, ArH), 7.78 (d, J = 8.8 Hz, 2 H, ArH), 8.18 (d, J = 8.8 Hz,
2 H, ArH).
Anal. Calcd for C11H12O4S: C, 54.99; H, 5.03; S, 13.35. Found: C,
54.93; H, 5.06; S, 13.31.
Ethyl (2R,3S)-2,3-Dihydroxy-3-[4-(methylsulfonyl)phenyl]pro-
panoate (5)
K3[Fe(CN)6] (8.33 g, 25.5 mmol), K2CO3 (3.50 g, 25.5 mmol),
Sharpless ligand (DHQ)2PHAL (66 mg, 0.085 mmol), and K2OsO4
(6.3 mg, 0.017 mmol) were added to a mixture of t-BuOH (80 mL)
and H2O (80 mL), and the resulting mixture was stirred for 5 min.
Acrylate 6 (2.16 g, 8.5 mmol) and MeSO2NH2 (808 mg, 8.5 mmol)
were added and the mixture was stirred at r.t. for 20 h. NaSO3 (12
g) was then added and the mixture was stirred for an additional 0.5
h. H2O (200 mL) was added and the mixture was extracted with
EtOAc (3 × 150 mL). The combined organic phase was dried
(Na2SO4) and concentrated, and the residue was purified by flash
column chromatography [silica gel, hexane–EtOAc (1:1 to 1:2)] to
give a bright-yellow solid; yield: 2.33 g (95%, 98.7% ee); mp 154–
155 °C; [a]D20 +19.5 (c 0.66, THF).
13C NMR (100 MHz, DMSO-d6): d = 14.40, 43.75, 62.26, 71.75,
82.92, 124.85, 126.79, 127.57, 129.45, 140.19, 140.82, 145.50,
150.88, 166.73.
ESI-MS: m/z (%) = 474 [M + H]+.
Anal. Calcd for C18H19NO10S2: C, 45.66; H, 4.04; N, 2.96; S, 13.54.
Found: C, 45.58; H, 4.09; N, 2.91; S, 13.50.
The structure of 11 was confirmed by X-ray crystallography.8
Ethyl (2S,3S)-3-Hydroxy-2-[(4-methoxybenzoyl)amino]-3-[4-
(methylsulfonyl)phenyl]propanoate (13) and Ethyl (2R,3S)-3-
Hydroxy-2-[(4-methoxybenzoyl)amino]-3-[4-(methylsulfo-
nyl)phenyl]propanoate (13¢)
A soln of disulfone 11 (1.84 g, 3.9 mmol) and NaN3 (305 mg, 4.7
mmol) in anhyd DMF (10 mL) was stirred at 55 °C under N2 over-
night and then the solvent was distilled off. The residue was diluted
with CH2Cl2 (50 mL), washed with brine (2 × 20 mL), dried
(Na2SO4), filtered, and concentrated under vacuum to afford a mix-
ture of the crude azides 12 and 12¢ (3:1 by 1H NMR) as a bright yel-
low oil that was used directly in the next step without further
purification.
FTIR (KBr): 3472, 3053, 3023, 2923, 2856, 1743, 1596, 1408,
1296, 1204, 1147, 1050, 959, 767, 562, 493 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.14 (t, J = 7.2 Hz, 3 H, CH3),
3.18 (s, 3 H, SO2CH3), 4.07 (q, J = 7.2 Hz, 2 H, CH2), 4.21 (dd,
J = 7.2, 3.6 Hz, 1 H, COCH), 4.96 (dd, J = 5.6, 3.6 Hz, 1 H, ArCH),
5.37 (d, J = 7.6 Hz, 1 H, OH), 5.77 (d, J = 5.6 Hz, 1 H, OH), 7.62
(d, J = 8.0 Hz, 2 H, ArH), 7.85 (J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): d = 14.55, 44.08, 60.73, 74.08,
75.44, 126.85, 128.06, 139.88, 148.64, 172.38.
The crude mixture of 12 and 12¢ was dissolved in EtOH (50 mL),
10% Pd/C (200 mg) was added, and the mixture was stirred under
H2 at r.t. for 2 h. The mixture was then filtered and concentrated un-
der vacuum to afford a mixture of crude 4 and 4¢ (3:1 by 1H NMR)
as a bright yellow oil. This mixture was used directly in the next step
without further purification.
ESI-MS: m/z (%) = 289 [M + H]+.
Anal. Calcd for C12H16O6S: C, 49.99; H, 5.59; S, 11.12. Found: C,
49.89; H, 5.56; S, 11.07.
Methyl (2R,3S)-2,3-Dihydroxy-3-[4-(methylsulfonyl)phe-
nyl]propanoate (10)
This compound was prepared by the same procedure as 5 to give a
bright-yellow solid; yield: 1.21 g (52%, 97.8% ee); mp 125–127 °C;
[a]D25 +27.9 (c 1.08, MeOH).
Et3N (1.08 mL, 7.8 mmol) and the mixture of 4 and 4¢ were dis-
solved in EtOH (100 mL) and a soln of 4-MeOC6H4COCl (663 mg,
3.9 mmol) in CH2Cl2 (20 mL) was added at 0 °C. The mixture was
stirred for 10 h and then the solvent was evaporated under vacuum.
The residue was diluted with CH2Cl2 (100 mL) and the soln was
washed sequentially with 0.1 M HCl (40 mL) and brine (40 mL)
then dried (Na2SO4), filtered, and concentrated in a vacuum. The
residue was purified by flash column chromatography [silica gel,
hexane–EtOAc (1:1)] to give 13 [yield: 1.07 g (65% from 11)] and
13¢ [yield: 0.28 g (17%)] as white solids.
FTIR (KBr): 3456, 3368, 3030, 3014, 2929, 1759, 1445, 1299,
1144, 1062, 968, 781, 738, 539 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.18 (s, 3 H, SOCH3), 3.63 (s,
3 H, OCH3), 4.25 (dd, J = 7.2, 3.2 Hz, 1 H, COCH), 4.99 (dd,
J = 5.6, 3.2 Hz, 1 H, ArCH), 5.37 (d, J = 7.6 Hz, 1 H, OH), 5.76 (d,
J = 6.4 Hz, 1 H, OH), 7.63 (d, J = 8.4 Hz, 2 H, ArCH), 7.86 (d,
J = 8.4 Hz, 2 H, ArCH).
13C NMR (100 MHz, DMSO-d6): d = 44.10, 52.05, 73.91, 75.37,
126.84, 128.02, 139.86, 148.65, 172.89.
13
Mp 154–155 °C; [a]D25 +22.3 (c 0.47, THF).
Synthesis 2012, 44, 699–704
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Enantioselective Synthesis of Florfenicol
703
FTIR (KBr): 3497, 3384, 3332, 3223, 3018, 2977, 2925, 1748,
1634, 1607, 1506, 1293, 1263, 1148, 1023, 772, 558 cm–1.
1 h then concentrated under vacuum. The residue was dissolved in
CH2Cl2 (50 mL) and washed successively with 5% aq NaHCO3 (30
mL) and brine (20 mL) then dried (Na2SO4), filtered, and concen-
trated under vacuum. The residue was purified by flash column
chromatography [silica gel, hexane–EtOAc (2:1)] to give a bright
yellow oil [yield: 1.64 g (85% from 13¢), together with 14¢ as a white
solid: yield 36 mg (1.9% yield from 13¢).
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.6 Hz, 3 H, CH3),
3.03 (s, 3 H, SO2CH3), 3.86 (s, 3 H, OCH3), 4.28 (q, J = 7.2 Hz, 2
H, CH2), 5.19 (dd, J = 3.2, 6.4 Hz, 1 H, COCH), 5.35 (d, J = 5.2 Hz,
1 H, ArCH), 5.49 (s, 1 H, OH), 6.86 (d, J = 5.6 Hz, 1 H, NH), 6.94
(d, J = 8.4 Hz, 2 H, ArH), 7.48 (d, J = 8.4 Hz, 2 H, ArH), 7.73 (d,
J = 8.4 Hz, 2 H, ArH), 7.88 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 14.07, 44.45, 55.51, 59.74, 62.36,
74.71, 114.02, 124.82, 127.19, 127.22, 129.19, 139.87, 146.26,
162.97, 168.28, 169.03.
14¢
Mp 209–211 °C, [a]D25 –243.3 (c 1.06, CHCl3).
FTIR (KBr): 3001, 2982, 2907, 2844, 1733, 1645, 1517, 1308,
1261, 1190, 1147, 1086, 1018, 839, 767, 545 cm–1.
ESI-MS: m/z (%) = 422 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 0.84 (t, J = 7.2 Hz, 3 H, CH3),
3.04 (s, 3 H, SO2CH3), 3.63–3.84 (m, 2 H, CH2), 3.90 (s, 3 H,
OCH3), 5.32 (d, J = 10.8 Hz, 1 H, COCH), 5.97 (d, J = 10.8 Hz, 1
H, ArCH), 6.99 (d, J = 8.4 Hz, 2 H, ArH), 7.55 (d, J = 8.0 Hz, 2 H,
ArH), 7.94 (d, J = 8.4 Hz, 2 H, ArH), 8.04 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.67, 44.48, 55.49, 61.13, 74.00,
81.74, 114.00, 118.84, 127.37, 127.57, 130.65, 140.76, 142.56,
162.96, 166.19, 168.75.
Anal. Calcd for C20H23NO7S: C, 57.00; H, 5.50; N, 3.32; S, 7.61.
Found: C, 56.89; H, 5.53; N, 3.28; S, 7.57.
13¢
Mp 165–167 °C, [a]D25 +90.4 (c 1.12, THF).
FTIR (KBr): 3452, 3362, 3020, 2979, 2924, 1728, 1632, 1533,
1504, 1299, 1258, 1147, 1024, 848, 770, 573, 554 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 6.8 Hz, 3 H, CH3),
2.97 (s, 3 H, SO2CH3), 3.82 (s, 3 H, OCH3), 4.06 (s, 1 H, OH), 4.16–
4.26 (m, 2 H, CH2), 5.02 (dd, J = 8.8, 2.8 Hz, 1 H, COCH), 5.42 (d,
J = 2.4 Hz, 1 H, ArCH), 6.89 (d, J = 9.2 Hz, 2 H, ArH), 6.90 (d,
J = 8.8 Hz, 1 H, NH), 7.55 (d, J = 8.0 Hz, 2 H, ArH), 7.62 (d, J = 8.8
Hz, 2 H, ArH), 7.77 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 14.13, 44.51, 55.48, 58.38, 62.22,
73.55, 113.91, 125.50, 127.11, 127.37, 128.97, 139.89, 146.46,
162.70, 167.31, 170.09.
ESI-MS: m/z (%) = 404 [M + H]+.
Anal. Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47; S, 7.95.
Found: C, 59.47; H, 5.21; N, 3.42; S, 7.89.
{(4R,5R)-2-(4-Methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-
4,5-dihydro-1,3-oxazol-4-yl}methanol (15)
NaBH4 (1.12 g, 29.6 mmol) was added to a soln of oxazole 14 (1.49
g, 3.7 mmol) and CaCl2 (1.64 g, 14.8 mmol) in EtOH (80 mL) at
0 °C. The mixture was stirred for 5 h then H2O (20 mL) was added
and the mixture was stirred for a further 1 h. The mixture was then
filtered and the filtrate was concentrated. The residue was diluted
with EtOAc (300 mL), washed with brine (100 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The residue
was purified by flash column chromatography [silica gel hexane–
EtOAc (1:3)] to give a white solid; yield: 1.10 g (82%); mp 153–
154 °C; [a]D25 –143.4 (c 0.203, CHCl3).
ESI-MS: m/z (%) = 422 [M + H]+.
Anal. Calcd for C20H23NO7S: C, 57.00; H, 5.50; N, 3.32; S, 7.61.
Found: C, 56.89; H, 5.45; N, 3.29; S, 7.56.
Ethyl (4S,5R)-2-(4-Methoxyphenyl)-5-[4-(methylsulfonyl)phe-
nyl]-4,5-dihydro-1,3-oxazole-4-carboxylate (14)
Method 1 (from amide 13): Amide 13 (2.02 g, 4.8 mmol) was added
to a soln of SOCl2 (0.67 mL, 9.6 mmol) in CHCl3 (10 mL). The mix-
ture was stirred at 45 °C for 0.5 h then cooled to r.t. and concentrat-
ed. The residue was dissolved in CH2Cl2 (30 mL) and the soln was
carefully poured into a mixture of sat. aq NaHCO3 (30 mL) and ice
(150 mL). The organic phase was separated and the aqueous phase
was extracted with CH2Cl2 (2 × 30 mL). The combined organic
phase was dried (Na2SO4), filtered, and concentrated under vacuum
to give a residue that was purified by flash column chromatography
[silica gel, hexane–EtOAc (2:1)] to give a bright yellow oil; yield:
1.75 g (91%); [a]D25 –71.8 (c 1.24, CHCl3).
FTIR (KBr): 3190, 2957, 2920, 2859, 1645, 1515, 1302, 1259,
1144, 1097, 778, 557, 54 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.20 (s, 3 H, SO2CH3), 3.53–
3.60 (m, 1 H, CHa), 3.73–3.79 (m, 1 H, CHb), 3.82 (s, 3 H, OCH3),
4.03–4.07 (m, 1 H, NCH), 5.08 (t, J = 5.2 Hz, 1 H, OH), 5.64 (d,
J = 6.4 Hz, 1 H, ArCH), 7.04 (d, J = 8.8 Hz, 2 H, ArH), 7.59 (d,
J = 8.4 Hz, 2 H, ArH), 7.90 (d, J = 8.8 Hz, 2 H, ArH), 7.95 (d,
J = 8.4 Hz, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): d = 44.06, 55.91, 63.56, 77.54,
82.08, 114.57, 119.85, 126.63, 128.04, 130.36, 140.74, 147.79,
162.43, 162.45.
FTIR (KBr): 2982, 2929, 1738, 1644, 1608, 1513, 1314, 1257,
1150, 1080, 957, 767, 550 cm–1.
ESI-MS: m/z (%) = 362 [M + H]+.
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.2 Hz, 3 H, CH3),
3.05 (s, 3 H, SO2CH3), 3.86 (s, 3 H, OCH3), 4.29–4.38 (m, 2 H,
CH2), 4.71 (d, J = 7.6 Hz, 1 H, COCH), 5.92 (d, J = 7.6 Hz, 1 H,
ArCH), 6.95 (d, J = 8.8 Hz, 2 H, ArH), 7.59 (d, J = 8.4 Hz, 2 H,
ArH), 7.97 (d, J = 8.4 Hz, 2 H, ArH), 8.01 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 14.24, 44.54, 55.49, 62.20, 77.12,
81.95, 113.96, 118.88, 126.42, 128.13, 130.62, 140.70, 146.08,
162.89, 165.08, 170.62.
Anal. Calcd for C18H19NO5S: C, 59.82; H, 5.30; N, 3.88; S, 8.87.
Found: C, 59.75; H, 5.26; N, 3.83; S, 8.83.
(4S,5R)-4-(Fluoromethyl)-2-(4-methoxyphenyl)-5-[4-(methyl-
sulfonyl)phenyl]-4,5-dihydro-1,3-oxazole (16)
A 50-mL tube was charged with a 23% CH2Cl2 soln of
F3CCHFCF2NEt2 (Ishikawa’s reagent; 12.75 g, 13.5 mmol) and ox-
azole 15 (3.25 g, 9 mmol) at r.t. under N2. The tube was sealed and
heated at 100 °C for 3 h then cooled to r.t. CH2Cl2 (100 mL) was
added and the organic phase was washed successively with sat. aq
NaHCO3 (2 × 30 mL) and brine, dried (Na2SO4), filtered, and con-
centrated under vacuum. The residue was purified by flash column
chromatography [silica gel, hexane–EtOAc (1:1)] to give a white
solid; yield: 3.03 g (92%); mp 117–118 °C; [a]D25 –165.8 (c 1.03,
CHCl3).
ESI-MS: m/z (%) = 404 [M + H]+.
Anal. Calcd for C20H21NO6S: C, 59.54; H, 5.25; N, 3.47; S, 7.95.
Found: C, 59.42; H, 5.18; N, 3.44; S, 7.91.
Method 2 (from amide 13¢): Crude oxazole 14¢ [prepared from 13¢
(2.02 g, 4.8 mmol) by the same procedure as 14] was added to a soln
of NaOEt (326 mg, 0.48 mmol) in a mixture of absolute EtOH (50
mL) and THF (50 mL). The resulting mixture was stirred at r.t. for
© Thieme Stuttgart · New York
Synthesis 2012, 44, 699–704

704
Z.-H. Wang et al.
PAPER
FTIR (KBr): 2954, 2900, 2839, 1653, 1513, 1310, 1255, 1141,
1011, 773, 560, 543 cm–1.
Anal. Calcd for C18H21ClFNO5S: C, 51.74; H, 5.07; N, 3.35; S, 7.67.
Found: C, 51.68; H, 5.02; N, 3.31; S, 7.63.
1H NMR (400 MHz, CDCl3): d = 3.04 (s, 3 H, SO2CH3), 3.86 (s, 3
H, OCH3), 4.29–4.39 (m, 1 H, NCH), 4.51–4.83 (m, 2 H,CH2), 5.62
(d, J = 6.8 Hz, 1 H, ArCH), 6.95 (d, J = 8.8 Hz, 2 H, ArH), 7.54 (d,
J = 8.4 Hz, 2 H, ArH), 7.94–7.98 (m, 4 H, ArH).
13C NMR (100 MHz, CDCl3): d = 44.53, 55.48, 74.98 (d, J = 20.8
Hz, FCH2CH), 81.92 (d, J = 3.3 Hz, FCH2CHCH), 83.93 (d,
J = 172 Hz, FCH2), 114.00, 119.07, 126.27, 128.12, 130.41, 140.53,
146.67, 163.79, 164.70.
2
1H NMR (400 MHz, DMSO-d6): d = 1.42 (br s, 2 H, NH2), 2.98–
3.04 (m, 1 H, NH2CH), 3.18 (s, 3 H, CH3), 4.11–4.44 (m, 2 H,
FCH2), 4.68 (d, J = 3.6 Hz, 1 H, CHOH), 5.68 (br s, 1 H, OH), 7.60
(d, J = 8.0 Hz, 2 H, ArH), 7.86 (d, J = 8.0 Hz, 2 H, ArH).
19F NMR (470 MHz, CDCl3): d = –229.5 to –229.2 (m, 1 F).
1
19F NMR (470 MHz, CDCl3): d = –228.0 (s, 1 F).
ESI-MS: m/z (%) = 364 [M + H]+.
Mp 151–152 °C; [a]D25 –18.3 (c 0.51, DMF).
FTIR (KBr): 3453, 3321, 3033, 2989, 1684, 1535, 1290, 1276,
1149, 1017, 769 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.16 (s, 3 H, SO2CH3), 4.26–
4.78 (m, 3 H, CH2F/NCH), 4.99 (m, 1 H, ArCH), 6.15 (d, J = 4.4
Hz, 1 H, OH), 6.47 (s, 1 H, CHCl2), 7.62 (d, J = 8.4 Hz, 2 H, Ar),
7.85 (d, J = 8.4 Hz, 2 H, Ar), 8.60 (d, J = 8.8 Hz, 1 H, NH).
Anal. Calcd for C18H18FNO4S: C, 59.49; H, 4.99; N, 3.85; S, 8.82.
Found: C, 59.37; H, 4.96; N, 3.81; S, 8.78.
Florfenicol (1; 2,2-Dichloro-N-{(1S,2R)-1-(fluoromethyl)-2-hy-
droxy-2-[4-(methylsulfonyl)phenyl]ethyl}acetamide)
A soln of oxazole 16 (1.82 g, 5 mmol) in THF (20 mL) and 1 M HCl
(10 mL) was stirred at 45 °C for 3 h and then concentrated to give
17 as its hydrochloric acid salt. This salt was dissolved in 5%
NaHCO3 (30 mL) and the soln was extracted with CH2Cl2 (3 × 30
mL). The combined organic phase was washed with brine (40 mL),
dried (Na2SO4), filtered, and concentrated under vacuum. The resi-
due was added to a soln of LiBH4 in THF, prepared in situ from
KBH4 (810 mg) and LiCl (634 mg) in THF (20 mL). The mixture
was stirred overnight at 40 °C, cooled, mixed with H2O (2 mL), and
stirred for an additional 2 h. The solvent was then removed and the
residue was diluted with CH2Cl2 (50 mL). The organic phase was
extracted with 1 M HCl (3 × 30 mL) and the pH of the combined
aqueous phase was adjusted to neutral with concd aq NaHCO3. The
soln was then extracted with CH2Cl2 (3 × 30 mL) and the combined
organic phase was dried (Na2SO4), filtered, and concentrated under
vacuum to give the crude product 2 as a bright-yellow oil.
13C NMR (100 MHz, DMSO-d6): d = 44.1, 55.1 (d, J = 19.4 Hz,
CHCH2F), 66.8, 69.8 (d, J = 6.1 Hz, ArCHCHCH2F), 82.8 (d,
J = 168.9 Hz, CH2F), 127.0, 127.6, 140.0, 148.4, 164.2.
19F NMR (470 MHz, CDCl3): d = –224.4 to –224.1 (m, 1 F).
ESI-MS: m/z (%) = 358 [M + H]+.
Anal. Calcd for C12H14Cl2FNO4S: C, 40.24; H, 3.94; N, 3.91; S,
8.95 Found: C, 40.07; H, 3.97; N, 3.87; S, 8.92.
References
(1) (a) Nagabhushan, T. L. US 4235892, 1982; Chem. Abstr.
1982, 96, 180950. (b) Schumacher, D. P.; Clark, J. E.;
Murphy, B. L.; Fischer, P. A. J. Org. Chem. 1990, 55, 5291.
(c) Giordano, C.; Cavicchioli, S.; Levi, S.; Villa, M. J. Org.
Chem. 1991, 56, 6114. (d) Clark, J. E.; Fischer, P. A.;
Schumacher, D. P. Synthesis 1991, 891.
Crude product 2 and Et3N (2.0 mL, 14.3 mmol) were dissolved in
EtOH (100 mL) and the mixture was stirred at 0 °C. A soln of
Cl2CHCOCl (757 mg, 5.15 mmol) in CH2Cl2 (20 mL) was added
dropwise over 1 h, and the mixture was stirred for an additional 3 h.
The solvent was removed under reduced pressure and the residue
was diluted with CH2Cl2 (100 mL). The resulting soln was washed
successively with 0.1 M HCl (50 mL), 5% aq NaHCO3 (30 mL), and
brine (30 mL). The organic phase was then dried (Na2SO4), filtered,
and concentrated under vacuum to give a residue that was purified
by flash column chromatography [silica gel, hexane–EtOAc (1:1)]
to give 1 as a white solid; yield: 1.34 g (75%).
(2) Li, F.; Wang, Z. H.; Zhao, L.; Xiong, F. J.; He, Q. Q.; Chen,
F. E. Tetrahedron: Asymmetry 2011, 22, 1337.
(3) Wang, Z. H.; Li, F.; Zhao, L.; He, Q. Q.; Chen, F. E.; Zheng,
C. Tetrahedron 2011, 67, 9199.
(4) For reviews of the Sharpless AD reaction, see: (a) Kolb, H.
C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. (b) Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2024. (c) Noe, M. C.; Letavic, M. A.; Snow, S. L.
Org. React. (N. Y.) 2005, 66, 109.
(5) (a) Denis, J. N.; Correa, A.; Greene, A. E. J. Org. Chem.
1990, 55, 1957. (b) Fleming, P. R.; Sharpless, K. B. J. Org.
Chem. 1991, 56, 2869. (c) Boger, D. L.; Patane, M. A.;
Zhou, J. J. Am. Chem. Soc. 1994, 116, 8544.
(6) Wu, G.-Z.; Schumacher, D. P.; Tormos, W. E.; Clark, J. B.;
Murphy, L. J. Org. Chem. 1997, 62, 2996.
(7) Calculated by using ACD ChemSketch software. This
software can be downloaded from http://www.acdlabs.com.
(8) Crystallographic data for compound 11 have been deposited
with the accession number CCDC 830167, and can be
obtained free of charge from the Cambridge
17·HCl
Mp 179–180 °C; [a]D25 +88.8 (c 0.414, MeOH).
FTIR (KBr): 3594, 3455, 2928, 2898, 2849, 2649, 2521, 1704,
1604, 1309, 1262, 1159, 1102, 1024, 771 cm–1.
1H NMR (400 MHz, MeOD): d = 3.15 (s, 3 H, SO2CH3), 3.90 (s, 3
H, OCH3), 4.17–4.80 (m, 3 H, CH2 and NCH), 6.28 (d, J = 9.2 Hz,
1 H, ArCH), 7.06 (d, J = 8.8 Hz, 2 H, ArH), 7.83 (d, J = 8.0 Hz, 2
H, ArH), 8.07 (d, J = 8.0 Hz, 2 H, ArH), 8.14 (d, J = 8.4 Hz, 2 H,
ArH).
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/
conts/retrieving.html.
13C NMR (100 MHz, MeOD): d = 42.85, 54.46 (d, J = 17.7 Hz,
NCH), 54.78, 72.56 (d, J = 5.3 Hz, ArCH), 80.22 (d, J = 171 Hz,
FCH2), 113.71, 120.73, 128.00, 128.19, 131.94, 141.45, 141.86,
164.54, 164.73.
19F NMR (470 MHz, CDCl3): d = –235.2 to –234.9 (m, 1 F).
ESI-MS: m/z (%) = 382 [M – Cl]+.
(9) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.;
Laucher, D. J. Am. Chem. Soc. 1988, 110, 4611.
(10) Lu, W. Y.; Chen, P. R.; Lin, G. Q. Tetrahedron 2008, 64,
7822.
Synthesis 2012, 44, 699–704
© Thieme Stuttgart · New York