A short asymmetric total synthesis of chloramphenicol using a selectively protected 1,2-diol

Article abstract of DOI:10.1016/j.tetlet.2005.01.039

A general route for the synthesis of chloramphenicol, thiamphenicol and fluoramphenicol is described. Chloramphenicol has been synthesized in 45% overall yield.

Full text of DOI:10.1016/j.tetlet.2005.01.039

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1743–1746
A short asymmetric total synthesis of chloramphenicol
using a selectively protected 1,2-diol
Joshodeep Boruwa, Jagat C. Borah, Siddhartha Gogoi and Nabin C. Barua*
Natural Products Chemistry Division, Regional Research Laboratory, Jorhat 785 006, Assam, India
Received 23 September 2004; revised 16 December 2004; accepted 7 January 2005
Abstract—A general route for the synthesis of chloramphenicol, thiamphenicol and fluoramphenicol is described. Chloramphenicol
has been synthesized in 45% overall yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Optically active amino alcohols are important structural
fragments found in numerous natural products1 and
their stereoselective synthesis has been a subject of
recent interest.2
of methods for their synthesis and protection.6 How-
ever, selective monoprotection of 1,2-diols with a stable
but easily removable protecting group in a single step is
a difficult task.7 Epoxides can be cleaved under acidic or
basic conditions to give alkoxy alcohols but hydrolysis
of alkyl ethers requires drastic conditions not always
compatible with the synthesis of complex natural
products.
Since its discovery more than 50 years ago, the antibiotic
chloramphenicol A3 has been especially effective in the
treatment of typhus, dysentery and ocular bacterial
infections and a number of syntheses have been
described in the literature.4
We have found that when epoxides are treated with
NaNO2 in water in the presence of acetic acid, 1,2-diols
are formed with one hydroxyl group selectively masked
as a nitrite ester (see Scheme 1 and Table 1).
As a part of our work on the synthesis of pharmacologi-
cally important natural products involving ring opening
reactions of epoxides with nucleophiles5 we became
interested in developing a practical synthesis capable
of providing not only chloramphenicol A, but also anti-
biotics such as fluoramphenicol B, thiamphenicol C and
modified analogues (Fig. 1).
It was found that the ONOꢀ nucleophile had a very
strong preference for attack from the less hindered car-
bon of the epoxide, but in the case of styrene oxide the
attack took place exclusively at the benzylic position.
The advantages of this method are (i) it does not require
additional steps for introduction of the protecting group
and (ii) the small size of the protecting group exerts little
1,2-Diols are important structural fragments in numer-
ous natural products and the literature details a number
OH
OH
OH
OH
O
OH
O
OH
HN
HN
HN
O
O2N
MeSO2
O2N
CHF2
Fluoramphenicol B
CHCl2
CHCl2
Chloramphenicol A
Thiamphenicol C
Figure 1.
Keywords: 1,2-Diol; Selective protection; Nitrite ester; Chloramphenicol.
*
Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011; e-mail: ncbarua2000@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.039

1744
J. Boruwa et al. / Tetrahedron Letters 46 (2005) 1743–1746
OH
To assess the general applicability and scope of this
NaNO2, AcOH
water, 0 oC-r.t.
O
method a series of reactions were performed with the
selectively protected 1,2-diol 1a obtained by ring open-
ing of benzoyloxy glycidol.
ONO
ONO
R
R
O
NaNO2, AcOH
water, 0 oC-r.t.
Treatment of alcohol 1a with acetic anhydride and pyr-
idine gave the acetate 1b in quantitative yield. Treatment
of alcohol 1a with CBr4/PPh3 in CH2Cl2 gave bromide
1c in 95% yield, which was converted to the nitro com-
pound 1d in 65% yield by treatment with NaNO2 in
DMF. Oxidation of 1a with PCC in CH2Cl2 yielded
the ketone 1f in 90% yield, which was transformed to
1a by reduction with NaBH4 in methanol. Exposure of
the ketone 1f to CH3MgI in dry ether afforded 1g in
87% yield. In all these reactions the ꢀO–N@Oꢁ masking
group remained unaffected. Deprotection of nitrite
OH
Scheme 1.
steric hindrance for further reactions on the free hydr-
oxyl group. Furthermore, it was observed that the corre-
sponding 2-nitro alcohols were not formed, as indicated
by the IR spectra of the crude reaction mixtures.
Table 1. Selectively protected 1,2-diols from epoxides
Entry
Epoxide
Producta
Reaction time (h)
1.5
Yieldb (%)
90
BnO
ONO
BnO
1
O
OH
1
1a
ONO
O
2
2.0
90 (4)c
Ph
Ph
Ph
2
OH
2a
OH OH
OH
O
3
4
5
6
7
2.0
2.0
2.0
2.0
2.0
92
90
88
88
85
Ph
ONO
3
3a
OH OH
OH
O
O
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
ONO
4a
4
OH OH
OH
p-ClC6H4
ONO
5a
5
OH OH
OH
6
O
O
6a
ONO
OH OH
OH
7a
ONO
7
O
O
8
2.0
87
OH
O
ONO
8
8a
a Products were characterized by IR, 1H NMR and mass spectra.
b Yields of isolated pure products.
c Yield in the parenthesis indicate that of the other isomer.

J. Boruwa et al. / Tetrahedron Letters 46 (2005) 1743–1746
ONO
1745
ONO
iii
i
BnO
BnO
Br
1c
NO2
1d
OH
ONO
ONO
vii
ii
BnO
BnO
BnO
OAc
1e
OAc
1b
ONO
OH
v
1a
OH
OH
ONO
vii
iv
vi
BnO
BnO
BnO
OH
O
1h
1g
1f
Scheme 2. Reagents and conditions: (i) CBr4, PPh3, CH2Cl2, 0 ꢁC, 95%; (ii) acetic anhydride, pyridine, rt, 93%; (iii) NaNO2, DMF, rt, 65%; (iv) PCC,
CH2Cl2, rt, 90%; (v) NaBH4, MeOH, 0 ꢁC, 92%; (vi) CH3MgI, Et2O, 0 ꢁC to rt, 87% ; (vii) NiCl2Æ6H2O/Al, THF, rt, 5–10 min, 90%.
esters is easily effected by catalytic hydrogenation and
photolysis,8 and these methods were incompatible with
other sensitive functional groups. However NiCl2Æ
6H2O/Al in THF,9 a very mild and efficient system for
deprotection of nitrite esters gave the deprotected
products 1e and 1h in around 90% yield. Under these
conditions other protected hydroxy groups, for example,
an acetate, a benzyl group and an ester were unaffected
(Scheme 2).
sired selectively protected diol (+)-1014,15 in 89% yield.
When (+)-10 was treated with diphenyl phosphoryl
azide (DPPA)16 in the presence of DEAD and PPh3 in
THF at 0 ꢁC and then the temperature immediately
raised to room temperature, the azide (+)-1114 was iso-
lated in 82% yield. Catalytic hydrogenation of (+)-11
using 10% Pd–C at 1 atm in methanol afforded (+)-12
in 97% yield. Acetylation under standard conditions
gave the desired product 13 in quantitative yield. Nitra-
tion of the aromatic ring followed by acid hydrolysis of
the acetyl protecting groups and usual basic work-up
generated the free amine. Crystallization (i-PrOH/
CH2Cl2) afforded the pure p-nitrophenyl substituted
amino diol 14 in good yield. The synthesis was com-
pleted by treating 14 with Cl2CHCOOMe using a litera-
ture procedure.17 The spectral and physical properties of
synthetic chloramphenicol were identical with those
reported in the literature.18
We next focused our attention on the regioselectivity of
epoxide ring opening of substituted methyl 2,3-epoxy-3-
phenylpropionates and 2,3-epoxy-3-phenylpropanol. As
expected nucleophilic attack took place predominantly
at the benzylic position, although a trace amount of
the other regioisomer was detected. The regioisomeric
ratio was determined by GC analysis of the crude prod-
uct. Our results are shown in Table 2.
We decided to apply the regioselective epoxide opening
to a synthesis of chloramphenicol (Scheme 3). The requ-
isite epoxide (+)-9 was prepared from methyl cinnamate
following a three step sequence10–12 in 86% yield (over
the three steps) and with 98% ee.13 The epoxide when ex-
posed to NaNO2 and acetic acid in water gave the de-
In conclusion, we have described a novel strategy for the
synthesis of chloramphenicol, which should be applic-
able to related compounds. New methods for deprotec-
tion of nitrite ester groups and further applications of
this strategy in natural product synthesis are being
studied.
Table 2. Regioselectivity of epoxide ring opening
OH
ONO
3
O
R1
R1
R1
NaNO2, AcOH
water, 0 oC-r.t.
R1
+
2
ONO
OH
R
R
R
Entry
R
H
Regioselectivity C3:C2a
Yieldsb (%)
94
1
2
3
4
COOMe
COOMe
COOMe
CH 2OH
89:5
OMe
Cl
91:495
88:5
90:3
93
93
H
a GC ratio of the crude product.
b Combined isolated yields.

1746
J. Boruwa et al. / Tetrahedron Letters 46 (2005) 1743–1746
OH
ONO
O
ONO
O
iii
O
i
ii
O
Ph
OH
OMe
Ph
OMe
OAc
Ph
Ph
OMe
97%
89%
82%
NH2
OH
N3
(2R,3R)-12
9
(2S,3R)-11
(2R,3S)-
(2R,3R)-10
OH
iv
v,vi
69%
vii
OH
Ph
OAc
80%
NH2
(2R,3R)-14
NHAc
O2N
(2R,3R)-13
OH
OH
HN
O
O2N
CHCl2
(2R,3R)-Chloramphenicol A
Scheme 3. Reagents and conditions: (i) NaNO2, AcOH, H2O, 0 ꢁC to rt, 2 h; (ii) DPPA, DEAD, PPh3, THF, 0 ꢁC to rt, 12 h; (iii) 10% Pd–C, MeOH,
1 atm, rt, 12 h; (iv) Ac2O, DMAP, pyridine; (v) HNO3, H2SO4, ꢀ20 ꢁC to rt, 1.5 h; (vi) aqueous 5% HCl, 90 ꢁC; (vii) Cl2CHCOOCH3, 90 ꢁC, 1 h.
13. The enantiomeric excess was measured by HPLC analysis
carried out on a Waters 510 HPLC system. Chiracel OD
packed in a 4.6 mm i.d · 250 mm SS column was used. Iso-
cratic elution was applied with a mobile phase n-hexane
Acknowledgements
The authors are thankful to the Director, RRL, Jorhat
for providing facilities. S.G. and J.B. also thank CSIR
(New Delhi) for Research Fellowships.
90% and isopropanol 10% at
a flow rate of 0.8
mL/min and pressure of 125 psi with UV monitoring at
243 nm.
20
References and notes
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1178, 1030, 834cm ꢀ1 1H NMR (300 MHz, CDCl3):
.
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d = 7.10–7.25 (s, 5H), 5.82 (d, J = 7.7 Hz, 1H), 3.75 (s,
3H), 3.25 (d, J = 7.7 Hz, 1H), 2.85 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d = 53.1, 56.1, 68.0, 73.5, 113.5, 128.0,
129.8, 159.1, 170.3. MS (m/z): 248.0 (M++Na). Anal.
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20
C, 53.38; H, 5.19; N, 6.28. (2S,3R)-11: ½aꢁD +24.8 (c 1.0,
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H, 4.09; N, 22.28.
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added acetic acid (0.25 mL) and the reaction mixture was
allowed to stand at that temperature for 30 min and then
at room temperature for an additional 1–1.5 h. The
reaction mixture was then extracted with CHCl3, the
combined organics washed with H2O, dried (Na2SO4), the
solvent evaporated and the crude residue purified by silica
gel column chromatography.
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