A novel highly stereoselective synthesis of chiral 5- and 4,5-substituted 2-oxazolidinones

Article abstract of DOI:10.1016/S0957-4166(01)00364-0

A novel highly stereoselective synthesis of chiral mono- and bicyclic 4- and 4,5-substituted 2-oxazolidinones starting from β-keto esters was developed. After bioreduction with S. cerevisiae the resulting homochiral β-hydroxy esters are transformed into their hydrazides. Treatment with NaNO₂/H⁺ then furnishes 2-oxazolidinones in high e.e. (～99%) and d.e. (>99%). The ring formation proceeds via a highly concerted sextet rearrangement with full retention of configuration at the stereocentres. Enantiopure 1,2-amino alcohols can subsequently be obtained by saponification of the 2-oxazolidinone products.

Full text of DOI:10.1016/S0957-4166(01)00364-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2103–2107
A novel highly stereoselective synthesis of chiral 5- and
4,5-substituted 2-oxazolidinones
M. Bertau,a,* M. Bu¨rli,b E. Hungerbu¨hlerc and P. Wagnerb
aInstitut fu¨r Biochemie, Technische Universita¨t Dresden, 01062 Dresden, Germany
bRohner AG, Gempenstraße 6, 4133 Pratteln, Switzerland
cBasel Institute for Applied Sciences, Gru¨ndenstrasse 41, 4132 Muttenz, Switzerland
Received 14 August 2001; accepted 15 August 2001
Abstract—A novel highly stereoselective synthesis of chiral mono- and bicyclic 4- and 4,5-substituted 2-oxazolidinones starting
from b-keto esters was developed. After bioreduction with S. cerevisiae the resulting homochiral b-hydroxy esters are transformed
into their hydrazides. Treatment with NaNO2/H+ then furnishes 2-oxazolidinones in high e.e. (ꢀ99%) and d.e. (>99%). The ring
formation proceeds via a highly concerted sextet rearrangement with full retention of configuration at the stereocentres.
Enantiopure 1,2-amino alcohols can subsequently be obtained by saponification of the 2-oxazolidinone products. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
(the diastereoselectivity of which should benefit from
fixed conformation of the substituents). As the Curtius-
degradation preserves the configuration of the stereo-
genic center a to the carboxylic acid group, this
procedure should also be well suited for the synthesis of
oxazolidinones containing two stereogenic centres.11
In modern drug synthesis chiral oxazolidinones serve as
synthetic tools and also as essential subunits of phar-
macons, as in the antidepressant befloxatone,1–3 and in
fungicides.4 There exist several synthetic methodologies
for the preparation of 5-substituted chiral 2-oxazolidi-
nones.5–8 Herein, with regard to the preparative effort,
we report a new synthetic variant using diastereomeri-
cally pure b-hydroxy esters 1a–1e as easily accessible
chiral synthons (Scheme 1).
The intention was to start with the baker’s yeast reduc-
tion of a b-keto ester to the corresponding b-hydroxy
ester A, and to convert this into its hydrazide B.
Nitrosation would then lead to an intermediary azide,
from which elimination of nitrogen furnishes the isocy-
anate C. The latter can cyclise to the oxazolidinone D
or can give the 1,2-amino alcohol E by decarboxyla-
tion. Reaction conditions which allow for a sufficient
discrimination between intramolecular ring-closure
reaction to afford D and carbamic acid formation to
afford E are key to the success of this synthesis (Scheme
2).
Homochiral b-hydroxy esters are provided with high
stereoselectivity by the baker’s yeast reduction of the
respective b-keto esters and are characterised struc-
turally by an intramolecular proton bridge between the
hydroxyl group and the carbonyl oxygen (Scheme 2).9,10
Thus, this class of ester emerged as an ideal candidate
for an intramolecular Curtius-degradation–cyclisation
Scheme 1.
* Corresponding author. Tel.: +49 351 463-8355; fax: +49 351 463-5506; e-mail: martin.bertau@chemie.tu-dresden.de
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00364-0

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M. Bertau et al. / Tetrahedron: Asymmetry 12 (2001) 2103–2107
Scheme 2.
Many 2-oxazolidinone syntheses require noxious
reagents like phosgene. With the sequence A“D an
elegant approach to diastereomerically pure oxazolidi-
nones which avoids the use of such hazardous reagents
would be at hand.
acidic medium is the key step of the synthesis as the
reaction conditions govern whether intramolecular
cyclisation to the 2-oxazolidinone 6a–6e occurs or
whether the 1,2-amino alcohol 8a–8e is preferred. In
order to demonstrate the effects involved, the process is
exemplified best with the cyclic hydrazide 3e (Scheme
3).
2. Results and discussion
From hydrazide 3e azide 4e is formed by nitrosation.
Accompanied by the liberation of nitrogen gas, the
azide rearranges in a highly concerted process to the
isocyanate 5e. At this stage, temperature has proven to
be essential for the fate of the intermediate. At room
temperature, cyclisation to the 2-oxazolidinone 6e
occurs, while at elevated temperature (up to 50°C), the
reaction is less selective and up to 38% of 1,2-amino
alcohol 8e is formed. When temperature is raised above
50°C, the reaction becomes increasingly unselective.
This is assigned to nitrene formation at elevated tem-
perature levels, while at lower temperature the process
is highly concerted and highly selective. On the other
hand, the rates of the reactions are very low at 0°C.
Chiral b-hydroxy esters 2a–2e were prepared by the
baker’s yeast reduction of the keto esters 1a–e (Table
1).3,9,10,12–15
In the next step the b-hydroxy esters 2a–2e were reacted
with hydrazine hydrate (80%) in ethanol, which fur-
nished the corresponding hydrazides 3a–3e in high
yields with the exception of 3c (Table 2).16 The reasons
for the low yield in the step 2c“3c remain unclear.
Using a less concentrated hydrazine hydrate solution
resulted in a significant decrease in yield.
The conversion of hydrazides 3a–3e with NaNO2 in
Table 1. Enantioselective baker’s yeast reduction of keto esters 1a–1e
Entry
Substrate
Yield (%)a
% e.e.b (conf.)c
% d.e.b (conf.)c
1
2
3
4
5
Ethyl acetoacetate 1a
67
95
35
86
84
98.4 (S)
92.8 (R)
62.1 (R)
99.3 (1R,2S)
93.9 (1R,2S)
–
–
–
Ethyl 4-chloro-acetoacetate 1b
Ethyl 4,4,4-trifluoro-acetoacetate 1c
Ethyl 2-oxocyclopentanecarboxylate 1d
Ethyl 2-oxocyclohexanecarboxylate 1e
97.3 (1R,2S)
97.4 (1R,2S)
a Representative procedure: Baker’s yeast (Saccharomyces cerevisiae)d (250 g) was suspended in a solution of sucrose (250 g) in tap water (2.0 L)
in a 3 L flask. The mixture was maintained at 30°C and stirred for 30 min. 1a (19.53 g, 150 mmol) was added and the suspension was stirred
at 30°C for 20 h (GLC control). The reaction mixture was centrifuged, the yeast was washed with water and the aqueous phase was extracted
with tert-butyl methylether (3×250 mL). Problems due to emulsions were overcome by centrifugation. The organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. Distillation of the crude residue under reduced pressure yielded the carbinols 2a–2e as colourless
liquids.
b Determined by GLC with Macherey&Nagel Lipodex A column.
c Absolute configurations were determined by comparison of specific rotations with literature values.
d Baker’s yeast was the product of Societe´ de levure FALA S.A., Strasbourg, France.

M. Bertau et al. / Tetrahedron: Asymmetry 12 (2001) 2103–2107
2105
tronic and steric factors, the interaction between the
hydroxyl oxygen and NCO-carbon allows for a fast
nucleophilic attack to give the 2-oxazolidinone 6e. The
proton bridging further polarises the NCO-residue, thus
additionally catalyzing the cyclisation step (Scheme 4).
Table 2. Conversion of b-hydroxy esters 2a–2e into
hydrazides 3a–3e
At elevated temperature the rotational freedom of the
substrate is increased due to thermal hydrogen bond
breakage. Hence, the isocyanate possesses the ability to
react either intramolecularly to afford the cyclic
product 6e or to react intermolecularly with water to
give the carbamic acid 7e, which spontaneously decar-
boxylates to the 1,2-amino alcohol product 8e (Scheme
3). This behaviour demonstrates that the intramolecular
process is kinetically highly favoured and therefore very
fast.
Entry
Substrate
Yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
94
92
12
96
97
a Representative procedure: To a solution of 2a (9.91 g, 75 mmol) in
ethanol (6 mL) 80% aqueous hydrazine hydrate (7.3 mL, 120 mmol)
was added. The solution was stirred under reflux conditions until
TLC (CH2Cl2/ethyl acetate, 9:1) showed that conversion was com-
plete (1 h). After cooling to ambient temperature the solution was
concentrated in vacuo (60°C, 25 mbar). The solid residue was
crystallised from methylene chloride, affording 3a (8.39 g, 94%) as
colourless crystals.
A comparison of 2-oxazolidinone yields confirms this
interpretation (Table 3). The cyclic species 6d and 6e
gave the best results, which is probably a result of high
order in the respective transition states.
The high selectivity of this process is shown in the e.e.
(>99%) and d.e. (>99%) of the product 6e.
The selectivity of the intramolecular cyclisation is
affected positively by the conformation of the starting
material and the acidic reaction conditions. It is known
from early studies that there is no change in the
configuration of the stereogenic carbon a to the car-
boxylic acid group during the concerted sextet rear-
rangement 4e“5e (Scheme 4).11 Consequently, the
isocyanate residue will be positioned cis to the hydroxyl
group and the isocyanate oxygen is fixed by hydrogen
bonding in the position nearest to the hydroxyl group.
As a consequence of the acidic conditions, the reso-
nance-stabilised protonated species 5e exhibits a partial
positive charge at the NCO-carbon. Due to these elec-
Alongside 2-oxazolidinone synthesis, an enrichment of
the desired stereoisomer is encountered (Table 3). This
finding is explained by the different reactivities of the
diastereomeric substrates and a depletion of the unde-
sired stereoisomers as a result of the purification steps.
Possibly due to the trifluoromethyl substituent, the
reaction of 3c proceeds essentially unselectively. This
needs further clarification.
Preparation of chiral N-substituted 2-oxazolidinones
such as the N-phenyl derivative 11e using substituted
hydrazines are matters of current research (Scheme
5).17–20
Scheme 3.
Scheme 4.

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M. Bertau et al. / Tetrahedron: Asymmetry 12 (2001) 2103–2107
Table 4. Preparation of 1,2-amino alcohol hydrochlorides
9a, 9d and 9e from 2-oxazolidinones 6a, 6d and 6e
Table 3. Formation of 2-oxazolidinones 6a, 6b, 6d and 6e
from b-hydroxy-hydrazides 3a, 3b, 3d and 3e
Yield (%)a
% e.e.b
(conf.)c
% d.e.b
(conf.)c
Entry
Substrate
Yield (%)a
% e.e.b
(conf.)c
% d.e.b
(conf.)c
Entry
Substrate
1
2
3
6a
6d
6e
27
50
47
98.6 (S)
\99.0 (S)
\99.0 (S)
–
1
2
3
3a
3b
3d
61
71
88
98.9 (S)
99.0 (R)
\99.0
(1R,2S)
\99.0
–
–
99.0 (R)
98.9 (R)
\99.0
(1R,2S)
\99.0
(1R,2S)
a Representative procedure: To a 10% aqueous solution of LiOH (50
mL), 6a (5.06 g, 50 mmol) was added and stirred at 80°C for 15
min. The reaction mixture was saturated with NaCl and extracted
with ethyl acetate (3×30 mL). Total extraction was confirmed by
GLC. After washing the organic extract with water (30 mL) the
volatile components were removed in vacuo. The crude material was
dissolved in ethanol/diethyl ether, 10:1 (10 mL) and HCl gas was
passed through the solution until precipitation was complete. After
filtration and concentration in vacuo 6a (0.98 g, 27%) was obtained
as colourless crystals.
4
3e
89
(1R,2S)
a Representative procedure: At 0°C a solution of NaNO2 (5.5 g, 89
mmol) in 5% aqueous sulfuric acid (110 mL) was added to the
hydrazide 3a (5.91 g, 50 mmol) under an inert gas atmosphere.
While stirring, the solution was allowed to warm up to 20°C within
2 h. After TLC (ethyl acetate/CH2Cl2, 9:1) had shown that conver-
sion was complete, the solution was neutralised by portionwise
addition of Na2CO3 (pH control). NaCl (7.0 g) was added and the
aqueous phase was extracted with methylene chloride (3×50 mL).
The combined organic extracts were washed with water (50 mL),
dried over MgSO4 and concentrated in vacuo. The solid residue was
crystallised from methylene chloride, yielding 6a (2.62 g, 61%) as
colourless crystals.
b Determined by GLC with Macherey&Nagel Lipodex A column.
c Absolute configurations were determined by comparison of specific
rotations with literature values.
b Determined by GLC with Macherey&Nagel Lipodex A column.
c Absolute configurations were determined by comparison of specific
rotations with literature values.
2-oxazolidinone and Lewis acid-assisted nucleophilic
substitution of the halogen by hydroxide, as well as the
aforementioned elimination reactions.
From the diastereomerically pure 2-oxazolidinones 6a,
6d and 6e, the respective chiral 1,2-amino alcohols 8a,
8d and 8e can be obtained by saponification with
aqueous alkali hydroxide. Due to their sensitivities
towards oxygen, the 1,2-amino alcohols 8a, 8d and 8e
were isolated as their amine hydrochloride salts 9a, 9d
and 9e (Table 4).
3. Conclusions
We have presented herein a novel and effective method
for facile and highly stereoselective access to mono- and
bicyclic 2-oxazolidinones starting from b-keto esters.
Subsequent saponification renders this methodology a
facile and efficient process for the preparation of 1,2-
amino alcohols.
However, the isolated yields are rather poor, owing to
side reactions such as elimination. These are favoured
by the highly basic conditions and the strongly elec-
trophilic Li+ cation, which may not only polarise the
carbonyl, but also the carbinolic CꢀO bond. As a
consequence, the enantiopurity of the amino alcohols is
slightly affected (Table 4).
Acknowledgements
The authors wish to thank W. Hohl (Basel Institute for
Applied Sciences, Muttenz, Switzerland) for recording
1H NMR spectra, and P. Eckert (Basel Institute for
Applied Sciences, Muttenz, Switzerland) and U. Klein
(Rohner AG, Pratteln, Switzerland) for GC analyses.
The 3-chloro-amino alcohol 8b was not accessible in
satisfactory yields. This is mainly attributed to a Li+-
catalysed competition between saponification of the
Scheme 5.

M. Bertau et al. / Tetrahedron: Asymmetry 12 (2001) 2103–2107
2107
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This work was supported by the Swiss National Science
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