A facile and efficient asymmetric synthesis of florfenicol

Article abstract of DOI:10.1055/s-0031-1289858

A facile and efficient enantioselective synthesis of flor-fenicol starting from commercially available 4-methylthiobenzaldehyde is described. Key features of the synthesis include a one-step oxidation of allyl and thioether groups in allylic alcohol to form (2S,3S)-epoxide under Sharpless epoxidation conditions and a highly efficient conversion of (1R,2R)-azide into amino alcohol via debenzylation and reduction of an azido moiety in one-pot operation. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289858

LETTER
2883
A Facile and Efficient Asymmetric Synthesis of Florfenicol
S
ynthesis of
F
e
lorfenicol ng Li,a Zhong-Hua Wang,a Lei Zhao,b Fen-Er Chen*a,b
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Institute of Biomedical Science, Fudan University, 305 Fenglin Road, Shanghai 200032, P. R. of China
Fax +86(21)65643811; E-mail: rfchen@fudan.edu.cn
b
Received 8 September 2011
under Sharpless epoxidation conditions as the key reac-
tion.
Abstract: A facile and efficient enantioselective synthesis of flor-
fenicol starting from commercially available 4-methylthiobenzal-
dehyde is described. Key features of the synthesis include a one-
step oxidation of allyl and thioether groups in allylic alcohol to form
(2S,3S)-epoxide under Sharpless epoxidation conditions and a high-
ly efficient conversion of (1R,2R)-azide into amino alcohol via de-
benzylation and reduction of an azido moiety in one-pot operation.
In our retrosynthetic analysis, we reasoned that florfenicol
(1) could be synthesized from amino alcohol 9 via dichlo-
roacetylation of the 2¢-amino groups and fluorination of
the 3¢-hydroxy group (Scheme 1). The intermediate 9
could be obtained from 4 via regio- and stereoselective
epoxide-opening manipulation. The allyl and the thioether
functional group of trans-cinnamyl alcohol 3 could be ox-
idized to give epoxide 4 in a one-step operation under
Sharpless epoxidation conditions. The allylic alcohol 3
could be readily prepared from 4-methylthiobenzalde-
hyde.
Key words: florfenicol, Sharpless asymmetric epoxidation, one-
pot reaction, SN2 nucleophilic substitution, fluorination
There is a considerable interest in the development of an
efficient route for the synthesis of florfenicol (1), a broad-
spectrum antibiotic.1a,c A number of synthetic approaches
towards 1 by utilizing different strategies have been doc-
umented to date.1 Very recently, an efficient enantioselec-
tive synthesis of 1 has been realized through an
asymmetric epoxidation catalyzed by Yamamoto’s vana-
dium catalyst2 in our laboratory.1n However, the limitation
of scaling up of this approach is well known in chemical
process development due to the difficulties in the prepara-
tion and recycling use of the catalyst. Although a highly
enantioselective synthesis of 1 involving the Sharpless
asymmetric epoxidation has been developed by Wu and
co-workers in 1997,1l this key reaction needs large
amounts of solvent to achieve high enantioselectivity and
yield due to the poor solubility of (E)-[4-(methylsulfo-
nyl)phenyl]propenol. As part of our continuous program
on the development of asymmetric synthesis of 1, we
herein report an economical and efficient asymmetric syn-
thesis of 1 by using a one-step oxidation of allyl and thio-
ether group in allylic alcohol 3 to form (2S,3S)-epoxide 4
The trans-cinnamyl alcohol 3 was synthesized in three
straightforward steps (Scheme 2). First, the trans-cinnam-
ic acid ester 2 was prepared by Wittig–Horner reaction of
4-methylthiobenzaldehyde with methyl 2-(diethoxyphos-
phoryl)acetate. The selective reduction of the ester group
of 2 worked well in the presence of LiAlH4 and AlCl3 to
provide trans-cinnamyl alcohol 3 in 90% yield.
O
CHO
a
b
OMe
MeS
MeS
2
O
c
OH
OH
MeS
MeO2S
4
3
Scheme 2 Reagents and conditions: (a) MeO2CCH2P(=O)(OEt)2,
NaH, THF, 0–25 °C, 2.5 h, 92%; (b) LiAlH4, AlCl3, Et2O, 0–25 °C, 2
h, 90%; (c) L-DIPT, Ti(Oi-Pr)4, t-BuOOH, 4 Å MS, CH2Cl2, –40 °C,
70%, 75% ee.
OH
OH
F
OH
NHCOCHCl2
MeO2S
NH2
MeO2S
9
florfenicol (1)
O
CHO
OH
OH
MeO2S
MeS
MeS
4
3
Scheme 1 Retrosynthetic analysis of florfenicol (1)
SYNLETT 2011, No. 19, pp 2883–2885
x
x
.x
x
.2
0
1
1
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289858; Art ID: W17511ST
© Georg Thieme Verlag Stuttgart · New York

2884
F. Li et al.
LETTER
With 3 in hand, the next task was to prepare the key inter-
mediate (2S,3S)-epoxide 4, a key precursor to 1. Fortu-
nately, allylic alcohol 3 could be converted into 4 via a
one-pot oxidation of allyl and thioether group in 3 in good
enantioselectivity and yield by treatment with anhydrous
tert-butyl hydroperoxide under Sharpless epoxidation
conditions.3 In order to increase the enantioselectivity of
this reaction, reaction conditions (solvent, temperature,
and loading of catalyst) were also screened. As summa-
rized in Table 1, it was found that amongst three different
Ph
O
O
5
4
OH
H
H
MeO2S
strong NOE
12
Figure 1 The NOE observed for 12 in the NOESY spectrum
solvents tested (entries 1–3), the optimum solvent in terms Compound 6, upon reaction with MsCl in the presence of
of enantioselectivity was dichloromethane. The enantio- Et3N, afforded the sulfonate 7, which was submitted to the
selectivity of 4 was also found to be strongly dependent nucleophilic SN2 displacement reaction with NaN3 at
upon the reaction temperature. As seen from entries 3–5, 100 °C to afford the (1R,2R)-azide 8 in 75% yield and in
1
a continuous increase in enantioselectivity was observed high diastereoselectivity (dr > 20:1, determined by H
when the reactions were decreased from 0 °C to –40 °C. NMR spectroscopy). Efficient conversion of 8 into the
We subsequently observed that the change of catalyst corresponding amino alcohol 9 was accomplished by de-
loading led to a remarkable improvement in the enantio-
O
O
selectivity (entries 5–7). The absolute configuration of 4
was confirmed by comparison to the optical rotation of
Sharpless epoxidation product using Wu’s procedure.1l
OH
OBn
a
b
MeO2S
MeO2S
4
5
The primary hydroxy group was protected under standard
conditions as its benzyl ether 5, which was then submitted
to BF3·OEt2-mediated regio- and stereoselective ring
opening with benzyl alcohol to afford the desired (1R,2S)-
alcohol 6 in 64% overall yield (over two steps, Scheme 3).
The diastereoselectivity of 6 was determined to be higher
than 20:1 by 1H NMR spectroscopy. After transformation
into 12 via a sequence of catalytic debenzylation in the
presence of 10% Pd/C and acetalation with benzaldehyde,
the configuration of 6 was assigned on the basis of 2D
NOESY experiment of 12, which showed a strong NOE
interaction between C4–H and C5–H confirming their
erythro stereochemisty (Figure 1).
OBn
OBn
OBn
c
OBn
OH
OMs
MeO2S
MeO2S
6
7
OH
OBn
d
e
OH
OBn
NH2
N3
MeO2S
MeO2S
9
8
Scheme 3 Reagents and conditions: (a) BnBr, NaH, DMF, –20 °C,
5 h, 91%; (b) BnOH, BF3·OEt2, r.t., 5 h, 70%; (c) MsCl, Et3N, CH2Cl2,
0–25 °C, 3 h; (d) NaN3, DMF, 100 °C, 10 h, 75% (from 6 to 8); (e)
10% Pd/C, H2, MeOH, r.t., 48 h, 85%.
Table 1 Optimization of Reaction Conditions in the Sharpless Asymmetric Epoxidation of 3a
O
OH
Ti(Oi-Pr)4, (–)-DIPT
t-BuOOH
O
S
OH
Me
Me
S
O
4
3
Entry
Solvent
DCE
Temp (°C)
Catalyst loading (mol%) Time (h)
Yield (%)b
ee (%)c
60
1
2
3
4
5
6
7
–20
–20
–20
0
10
10
10
10
10
5
48
48
48
24
48
48
48
51
60
68
65
66
67
70
THF
66
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
69
40
–40
–40
–40
71
67
20
75
a All reactions were carried out in the presence of (–)-diisopropyl tartrate, Ti(Oi-Pr)4, and t-BuOOH.
b Isolation yields.
c Determined by chiral HPLC analysis using Chiralcel OJ-H column (hexane–i-PrOH–MeCN = 50:50:1, l = 225 nm, 0.5 mL/min).
Synlett 2011, No. 19, 2883–2885 © Thieme Stuttgart · New York

LETTER
Synthesis of Florfenicol
2885
benzylation and reduction of azido moiety in a one-pot Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synlett and can be cited
using the following DOI: 10.4125/pd0021th.
operation. The absolute configuration of 8 was elaborated
by comparison of the specific rotation of known amino al-
cohol 9 with the literature value.4
References and Notes
Transformation of 9 into oxazoline 10 was accomplished
in 87% yield according to slightly improved Wu’s proce-
dure (Scheme 4).1l The Ishikawa reagent5 is an effective
reagent in the scale-up fluorination of 10 into 1,1h,l but its
toxicity and highly corrosive nature made it not environ-
mentally benign from green chemistry perspectives. We
first attempted to use Et3N·3HF as a fluorinating reagent
to fluorinate 10, but this fluorinating reaction was unsuc-
cessful. Gratifyingly, the successful conversion to 1 was
achieved in 62% overall yield by fluorination of its sul-
fonate 11 with Et3N·3HF in refluxing acetonitrile.
(1) (a) Nagabhushan, T. L. EP 14437 A2, 1980; Chem. Abstr.
1981, 94, 139433. (b) Nagabhushan, T. L. US 4311857 A,
1982; Chem. Abstr. 1982, 96, 180950. (c) Jommi, G.;
Pagliarin, R.; Chiarino, D.; Fantucci, M. Gazz. Chim. Ital.
1985, 115, 653. (d) Jommi, G.; Pagliarin, R.; Tavecchia, P.;
Chiarino, D.; Fantucci, M. Gazz. Chim. Ital. 1986, 116, 485.
(e) Jommi, G.; Ripa, A.; Ripa, G.; Sisti, M. Gazz. Chim. Ital.
1988, 118, 75. (f) Jommi, G.; Chiarino, D.; Pagliarin, R. EP
677511 A2, 1995; Chem. Abstr. 1995, 124, 145633.
(g) Tyson, R. Chem. Ind. 1988, 118. (h) Schumacher, D. P.;
Clark, J. E.; Murphy, B. F.; Fischer, P. A. J. Org. Chem.
1990, 55, 5291. (i) Clark, J. E.; Fischer, P. A.; Schumacher,
D. P. Synthesis 1991, 891. (j) Wu, G.-Z.; Tormos, W. I. WO
9414764 A1, 1994; Chem. Abstr. 1994, 121, 133722.
(k) Clark, J. E.; Schumacher, D. P.; Wu, G.-Z. US 5382673
A, 1995; Chem. Abstr. 1995, 122, 187135. (l) Wu, G.-Z.;
Schumacher, D. P.; Tormos, W.; Clark, J. E.; Murphy, B. L.
J. Org. Chem. 1997, 62, 2996. (m) Lu, W.-Y.; Chen, P.-R.;
Lin, G.-Q. Tetrahedron 2008, 64, 7822. (n) Li, F.; Wang,
Z.-H.; Zhao, L.; Xiong, F.-J.; He, Q.-Q.; Chen, F.-E.
Tetrahedron: Asymmetry 2011, 22, 1337.
CHCl2
O
OH
N
a
1
OH
NH2
OH
MeO2S
MeO2S
9
10
b
(2) (a) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.;
Yamamoto, H. Angew. Chem. Int. Ed. 2005, 44, 4389.
(b) Yamamoto, H.; Basak, A.; Zhang, W. US 20050159607
A1, 2005; Chem. Abstr. 2005, 143, 153269.
CHCl2
N
O
c
(3) Experimental Procedure – Preparation of 4
To a stirred suspension of 4 Å MS powder (1 g) in dry
CH2Cl2 (10 mL), (–)-diisopropyl tartrate (0.174 g, 0.74
mmol) and Ti(Oi-Pr)4 (0.216 g, 0.74 mmol) were added
successively at –40 °C under nitrogen atmosphere. After
stirring 1 h at the same temperature, 3 (0.67 g, 3.7 mmol)
and t-BuOOH (3.3 M, 7.5 mL) in toluene was added. The
reaction mixture was stirred for 48 h at –40 °C. Sat. aq
NaHSO3 (10 mL) was added, and stirring was continued for
1 h. The reaction mixture was then allowed to warm to r.t.,
extracted with CH2Cl2 (3 × 10 mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel
(EtOAc–PE = 1:2) to afford 4 (0.59 g, 70% yield, 75% ee)
as a white solid.
OMs
MeO2S
11
Scheme 4 Reagents and conditions: (a) CHCl2CN, HCl, i-PrOH, 70
°C to 50 °C, 16 h, 87%; (b) MsCl, Et3N, CH2Cl2, 0–25 °C, 3 h, 95%;
(c) Et3N·3HF, MeCN, reflux, 10 h, 65%.
In conclusion, a facile and efficient asymmetric synthesis
of florfenicol (1) was accomplished starting from com-
mercially available 4-methylthiobenzaldehyde by utiliz-
ing a one-step oxidation of allyl and thioether group in 3
to form (2S,3S)-epoxide 4 under Sharpless epoxidation
conditions as the key step.
(4) Cutler, R. A.; Stenger, R. J.; Suter, C. M. J. Am. Chem. Soc.
1952, 74, 5475.
(5) Takaoka, A.; Iwagiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn.
1979, 52, 3377.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 19, 2883–2885 © Thieme Stuttgart · New York

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