An approach to oxazolidin-2-ones from the Baylis-Hillman adducts. Formal synthesis of a chloramphenicol derivative

Article abstract of DOI:10.1016/S0040-4039(02)00351-9

In this communication we describe a straightforward and diastereoselective approach to prepare functionalised oxazolidin-2-ones from Baylis-Hillman adducts. A stereoselective synthesis of a highly substituted vicinal aminoalcohol and a formal synthesis of a chloramphenicol derivative are also described.

Full text of DOI:10.1016/S0040-4039(02)00351-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2797–2800
An approach to oxazolidin-2-ones from the Baylis–Hillman
adducts. Formal synthesis of a chloramphenicol derivative
Fernando Coelho* and Rodrigo C. Rossi
DQO, IQ/Unicamp, PO Box 6154, 13083-970 Campinas, Sa˜o Paulo, Brazil
Received 29 January 2002; accepted 19 February 2002
Abstract—In this communication we describe a straightforward and diastereoselective approach to prepare functionalised
oxazolidin-2-ones from Baylis–Hillman adducts. A stereoselective synthesis of a highly substituted vicinal aminoalcohol and a
formal synthesis of a chloramphenicol derivative are also described. © 2002 Elsevier Science Ltd. All rights reserved.
Oxazolidin-2-ones are a very interesting class of com-
pounds due to their various pharmacological effects.1
They are described as potential neuroleptics with a high
affinity for sigma receptors,2 as psychotropics,3 as
antiallergy agents,4 as antibacterials and antibiotics,5 as
intermediates in the syntheses of renin inhibitors,6 b-
lactams and macrolide antibiotics,7 immunosupres-
sants,8 and in other applications, mainly in synthetic
organic chemistry as chiral auxiliaries.9 Particularly as
synthetic antibacterials, this class of compounds
exhibits activity against many antibiotic-resistant
strains of Gram-positive bacteria.10,11 They represent
the only completely new class of antibiotics licensed
over the past 30 years.12
other hand, vicinal aminoalcohols exhibit interesting
biological activities. For example, chloramphenicol and
derivatives (thiamphenicol and fluoramphenicol) are
aminoalcohols showing therapeutical use as broad-spec-
trum antibiotics.
In an ongoing research program focused on the synthe-
sis of new compounds to be used as candidates for
biological screening as antibiotics, it was necessary to
prepare some modified oxazolidin-2-ones, whose struc-
tural core is depicted in Fig. 1.
Our main interest was focused on evaluating the effect
of substitution at position 5 on membrane transporta-
tion and consequently on biological activity as anti-
biotic agents. Initially we were interested to check the
biological profile of oxazolidin-2-ones with aromatic
substituents in that position, with electron donor
groups on the ring.
Due to these important biological effects and synthetic
uses, several methods of preparing oxazolidin-2-ones
are described in the literature.13 Normally, these com-
pounds can be obtained from a,b-difunctional sub-
strates such as b-aminoalcohols, oxiranes and
aziridines, in the presence of phosgene,14 carbonate,13
isocyanate,1,15 or carbon dioxide.16,17 Strategies based
on the utilisation of solid state chemistry1,10,18 were
recently described as a tool for their preparation.
To accomplish our objective we decided to take advan-
tage of the great potential synthetic versatility exhibited
by a a-methylene-b-hydroxy ester. This class of com-
pounds could be readily prepared through a Baylis–
Hillman reaction.19 This reaction is a very interesting
2-Oxazolidin-2-ones can be easily interconverted into
aminoalcohols and vice-versa. Thus, an approach
directed towards the preparation of highly function-
alised 2-oxazolidin-2-ones could also allow access to
aminoalcohols with varied substitution patterns. On the
Keywords: oxazolidin-2-one; Baylis–Hillman reaction; chlorampheni-
col derivative.
* Corresponding author. Tel.: 55 19 3788-3085; fax: 55 19 3788-3023;
e-mail: coelho@iqm.unicamp.br
Figure 1. Structural core of required oxazolidin-2-ones.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00351-9

2798
F. Coelho, R. C. Rossi / Tetrahedron Letters 43 (2002) 2797–2800
way to form a new CꢀC s bond and can be broadly
defined as a coupling reaction between an aldehyde and
an acrylate derivative in the presence of a tertiary
amine or phosphine.
Owing to the high degree of functionality, these deriva-
tives are predisposed to serve as starting materials for
our purposes. In this communication, we describe pre-
liminary results concerning a new route to function-
alised oxazolidin-2-ones using Baylis–Hillman adducts
as substrates.
From our point of view, the oxazolidin-2-one (1) we
needed could be synthesised according to the retrosyn-
thetic analysis shown in Scheme 1.
Scheme 1. Retrosynthetic analysis for preparation of oxazo-
lidin-2-ones.
Thus, 1 could be obtained through an intramolecular
reaction involving the regioselective attack of the sec-
ondary hydroxyl group on isocyanate 2. To avoid any
competition between the two hydroxyl groups, their
chemical reactivity could be modulated through the
correct manipulation of the protective groups. Isocya-
nate 2 could be secured from hydroxyacid 3, using a
stereospecific Curtius rearrangement. To prepare 3, we
should explore the chemical reactivity of the double
bond presented in the structure of allyl alcohol 4, using
a hydroboration reaction followed by the oxidation of
the primary alcohol to the carboxylic acid. Most proba-
bly, the diastereoselectivity of this sequence could be
controlled in the hydroboration step. Previous results
from our laboratory point in this direction.20 Finally,
access to allyl alcohol 4 could be readily guaranteed
from the Baylis–Hillman adduct 5, using a chemoselec-
tive reduction reaction.
Scheme 2. (a) TIPSOTf, CH2Cl2, 2,6-lutidine, rt, 30 min,
95%; (b) DIBAL-H, CH2Cl2, −78°C, 2 h, 91%; (c) TBSOTf,
CH2Cl2, 2,6-lutidine, rt, 30 min, 100% or (d) TBDPSCl,
imidazole, DMF, rt, 14 h, 90%.
Depending on the success attained with this sequence,
hydrolysis of oxazolidin-2-one (1), under controlled
conditions, allowed the preparation of
a vicinal
aminoalcohol, which could be used as a substrate for
the synthesis of a chloramphenicol derivative.
Our synthesis started with the Baylis–Hillman reaction
between piperonal and methyl acrylate to furnish 5, in
55% yield (73% yield based on recovered aldehyde).21
Protection of the secondary hydroxyl group as TIPS
ether, followed by chemoselective reduction with
DIBAL-H, at −78°C, in dichloromethane gave the allyl
alcohol 6. The primary alcohol was then protected as
TBS ether to provide allyl alcohol 4, in 86% overall
yield (Scheme 2).
Scheme 3. (a) (i) BH3·(CH3)2, THF, 0°C“rt, 16 h; (ii) NaOH
3 M, H2O2 30%, 0°C“rt, 1.5 h; (b) (i) 9-BBN, THF, 0°C“rt,
16 h; (ii) NaOH 3 M, H2O2 30%, 0°C“rt, 1.5 h.
butyldiphenyl, Scheme 2). In addition, 9-BBN was used
with both alcohols (4 and 7) and the results compared
with those obtained with BH3·S(CH3)2 (Scheme 3). As
expected, when we employed a bulky borane we
observed a moderate diastereoselection on the hydrobo-
ration of the allyl alcohol 4. However, the degree of
diastereoselectivity was dramatically increased when a
bulky borane was conjugated with a substrate bearing a
bigger protective group attached to the primary
hydroxyl group.
The allyl alcohol 4 was then treated with BH3·S(CH3)2
in THF to give the triol 8, as
a mixture of
diastereomers (Scheme 3), in 85% yield. Unfortunately,
in this case no diastereoselectivity was observed.
Intrigued by the lack of diastereoselection observed, we
decided to check the eventual influence of steric hin-
drance on the diastereoselectivity of the hydroboration
reaction. Thus, we prepared the allyl alcohol 7, in
which the protective group of the primary hydroxyl
group was replaced by a bulkier silyl ether (t-
Unfortunately,
attempts
to
separate
these
diastereomers, at this stage, failed. To prepare the acid
5, the mixture of diastereomers was then treated with
PDC in DMF.22 Surprisingly, after 20 h we were able

F. Coelho, R. C. Rossi / Tetrahedron Letters 43 (2002) 2797–2800
2799
to isolate a mixture of aldehyde 10 with the required acid
3, in very low concentration (>10%). To drive this
reaction to completion, we increased the reaction time
and PDC concentration. However, after 48 h only
degradation products were detected. The same behaviour
was observed when PDC was replaced by Jones reagent
(diluted reagent at 0°C).23
We tried to prepare the isocyanate 2 by the direct
treatment of acid 3a with diphenylphosphorylazide
(DPPA)27 in refluxing toluene/methanol in the presence
of triethylamine; however, all attempts were unsuccess-
ful. Thus, acid 3a was successively treated with ethyl
chloroformate and sodium azide to provide an interme-
diate acylazide, which was not isolated. Reflux in toluene
gave the isocyanate 2 (not isolated) (Scheme 4).
Due to the difficulties in directly transforming the
mixture of diastereoisomeric alcohols 9a/b into acids
3a/b, we decided to carry it out in two steps. Thus, 9a/b
was treated with tetrapropylammonium perruthenate
(TPAP), in the presence of 4-methylmorpholine N-oxide
(NMO),24 to give the aldehydes 10a/b in 96% yield.
Subsequently these aldehydes were oxidised with sodium
chlorite (Pinnick reaction)25 to furnish the acids 3a/b, in
90% yield. Fortunately, the carboxylic acids were easily
separated by flash column chromatography (Scheme 4).
Isocyanate 2 was then treated with tin tetrachloride in
dichloromethane to furnish oxazolidin-2-one (1) as the
only detectable product, in 30% overall yield (five steps).
This simple and straightforward sequence permitted us
to synthesise the required oxazolidin-2-one in eight steps,
with an overall yield of 26%, from Baylis–Hillman adduct
(5).28
To shorten the synthetic sequence we tried to effect the
Curtius rearrangement directly on the Baylis–Hillman
adduct 5. Unfortunately, under the experimental condi-
tions used, the rearrangement did not work.
To determine the relative stereochemistry obtained in the
hydroboration step, we removed the protective groups
from the separated acids 3a and 3b with
TBAF/THF. The resulting diol-acids were trans-
formed into the corresponding dimethylacetals (2,2-
dimethoxypropane, CSA) and the coupling constant for
the carbinolic protons in both diastereomers was mea-
sured.26 This NMR experiment allowed us to confirm
that, for both cases where we have observed diastereose-
lectivity, the syn diastereomer was preferentially formed.
As far as we know, this is the first report concerning the
utilisation of a Baylis–Hillman adduct as starting mate-
rial for the preparation of oxazolidin-2-ones. This strat-
egy has culminated with the preparation of our target
compound 1, whose biological profile is under
investigation.
Since we had 1 available, we decided to expand the scope
of our synthetic sequence. Chloramphenicol and
derivatives29 are antibacterial agents used against differ-
ent infections. Despite the elevated toxicity of this class
of antibiotics, they are still in wide use topically (occular
bacterial infections) and to combat certain types of
infections (e.g. typhus, dysenthery). Recently, Park et
al.29a have used a similar oxazolidinone as a key interme-
diate for the synthesis of chloramphenicol.
From our point of view, the preparation of 12 (Scheme
4) could be formally considered as achieved, since the
preparation of aminoalcohols from an oxazolidinone and
amidation of the latter are well documented synthetic
methods.
In conclusion, we have developed a new approach for the
preparation of functionalised oxazolidin-2-ones from the
Baylis–Hillman adduct. Despite the moderate
diastereoselectivity attained, this method seems to exhibit
a high synthetic potential. In principle, depending on the
structure of the aldehyde used in the Baylis–Hillman
reaction, it is possible to prepare a wide range of
4,5-disubstituted oxazolidin-2-ones. In addition, if we
simply invert the protective groups it is possible to
exclusively gain access to 4-substituted oxazolidin-2-
ones.
,
Scheme 4. (a) TPAP, NMO, CH2Cl2, MS 4 A, 15 min, rt, 96%;
Additional studies are ongoing in our laboratory with the
objective of generalising and optimising this strategy, to
have a new general method to prepare substituted
oxazolidin-2-ones and vicinal aminoalcohols, with
potential biological activity, from Baylis–Hillman
adduct.
(b) NaClO2, NaH2PO4, t-BuOH, H2O, 2-methyl-but-2-ene, rt,
14 h, 90%, chromatographic separation; (c) (i) ClCO2Et, NEt3,
0°C, 40 min; (ii) NaN3, H2O, 0°C, 2 h; (iii) reflux in toluene;
(d) SnCl4, CH2Cl2, rt, 16 h, 30% overall yield (five steps).

2800
F. Coelho, R. C. Rossi / Tetrahedron Letters 43 (2002) 2797–2800
13. (a) Dyen, M. E.; Swern, D. Chem. Rev. 1967, 67, 197–
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1
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