A high-yielding low-cost facile synthesis of 2-oxazolidinones chiral auxiliaries

Article abstract of DOI:10.1016/S0957-4166(00)00415-8

The chiral aminol alcohols from reduction of amino acids with NaBH₄/H₂SO₄ were directly treated with EtO₂CCl to give the carbamates, which cyclized in the presence of traces of K₂CO₃ at 100-130°C under vacuum to afford chiral 2-oxazolidinones in high yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00415-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4359–4363
A high-yielding low-cost facile synthesis of 2-oxazolidinones
chiral auxiliaries
Yikang Wu* and Xin Shen
State Key Laboratory of Bio-organic & Natural Products Chemistry
and Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 18 September 2000; accepted 10 October 2000
Abstract
The chiral aminol alcohols from reduction of amino acids with NaBH4/H2SO4 were directly treated
with EtO2CCl to give the carbamates, which cyclized in the presence of traces of K2CO3 at 100–130°C
under vacuum to afford chiral 2-oxazolidinones in high yields. © 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Chiral 2-oxazolidinones1 (especially 1) have been shown to be highly versatile chiral auxiliaries
through numerous elegant syntheses2 by Evans and others. Unfortunately, their broader
application in asymmetric synthesis is seriously hampered by the lack of facile, safe, and
low-cost access to the chiral auxiliaries themselves. To circumvent this problem, many efforts3a–m
have been made since the late 1980s.
As already noted by previous investigators, the original Et2CO3 procedure3a suffered from
such draw-backs as the inconvenience and potential hazards associated with borane, tedious
work up, and inconsistent results.3b The subsequent modifications all aimed at circumventing
3f
3e
these problems. For instance, LiAlH4,3d CaBH4,3e or LiBH4 (formed in situ from CaCl2 or
LiI3f and NaBH4, with the carboxylic acids being transformed into esters before reduction) were
* Corresponding author. E-mail: yikangwu@pub.sioc.ac.cn
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00415-8

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Y. Wu, X. Shen / Tetrahedron: Asymmetry 11 (2000) 4359–4363
employed as reducing agent to replace the borane. Similarly, more reactive (and unfortunately,
more expensive) phosgene derivatives such as Cl3CO2CCl,3b,h Cl3CO2COCCl3,3d PhO2CCl,3c and
BnO2CCl3f were utilized in place of the Et2CO3 to ensure a facile ring closure. More recent
efforts appear to have already given up the base-catalyzed intramolecular ester exchange
ring-closure protocol; some3m chose to utilize urea derivatives (prepared at high temperatures
not easily accessible using oil baths) with an amino group as leaving group after treatment with
nitrite, while others3g,j,l attempted to revert the ester exchange mechanism to the less common
alkylꢀoxygen cleavage ones. Since all these modified procedures, while improving the original
one in some way, introduced other undesired factors such as expensive reagents or inconvenient
conditions, none of them could serve as a clear-cut solution to the aforementioned problem—the
‘bottle-neck’ still remains despite all the exhaustive efforts. The long span of time over which all
those efforts were made and the large number of research groups involved in such endeavors
seem to insinuate that preparing these chiral 2-oxazolidinones in high yields from cheap
phosgene derivatives without problems4 is just impossible.
2. Results and discussion
Now we have found a clear-cut solution (Scheme 1) to the facile access problem. First, we
found from the literature a reduction protocol (NaBH4/H2SO4) reported by Abiko and
Masamune5 in 1992, which is apparently the cheapest procedure applicable in the present
context but has somehow been ignored by previous investigators. Then an alkoxycarbonylation
using EtO2CCl6 is performed without isolating the amino alcohol, directly affording7 the rather
pure carbamates 4a,8 4b,3e,9 and 4c3e in near quantitative yields. More amino alcohols (as shown
by the yields of 4a–c) than previously5 were thus obtained. Finally, the crude carbamates 4a–c
were heated with K2CO3 (0.2–0.5 mol%) at 100–130°C (bath) under aspirator vacuum to afford
rather pure 1a–c (free from any discernible amounts of unreacted starting carbamates or
hydrolysis products) in near quantitative yields in 15–120 min (depending on the quantity of
added K2CO3). The crude oxazolidinones thus obtained could be directly used as chiral auxiliary
without any further purification. The overall yields were above 90%. The vacuum proved to be
necessary for avoiding hydrolysis, especially when using relatively larger amounts of K2CO3.
The cyclization of 4a could be easily achieved even at 100°C, although 120°C was necessary for
4b,c to ensure a fast reaction.
Scheme 1. (a) NaBH4/H2SO4; (b) EtO2CCl/Na2CO3; (c) cat. K2CO3/100–130°C/vacuum

Y. Wu, X. Shen / Tetrahedron: Asymmetry 11 (2000) 4359–4363
4361
As a key step in the synthesis of 2-oxazolidinones, the cyclization of 4 deserves a few more
comments here. Although the inconsistent3b results with the Evans’ procedure and the
difficulty10 with McKillop’s procedure3e are generally believed to be associated with the poor
leaving ability of the ethoxyl in 4, the conformational factors may also contribute to a certain
extent. For instance, in Hintermann and Seebach’s3i carbamates the most stable conformer is the
one shown by A in Fig. 1 regardless of the size of R. Since the cyclization requires the OH syn
(most easily attainable from the gauche conformers) to the NHCO2Et, these carbamates are
expected to undergo easier cyclizations than11 1b (where the gauche conformer B is hardly more
stable than the anti one C, Fig. 1). Replacement of the benzyl with a bulkier isopropyl (which
is also bulkier than NHCO2Et) renders D the most stable one. This explains why 1a cyclized at
a much faster rate than 1b at lower temperatures under otherwise the same conditions.
Figure 1. The Newman projections of C-4 and C-5 of the conformers of some carbamates
As shown in Fig. 2, cyclization of the carbamates relies on an alkoxide cycle: The ethoxide
formed in the ring closure must generate an alkoxide of the starting carbamate to sustain the
reaction. The solvent-free conditions disclosed here no doubt provide a maximal probability for
the ethoxides to encounter starting carbamates and therefore make the ring closure much easier
than in solutions as in the previous procedures. However, it is noteworthy that, even under such
most favorable conditions, the cyclization was completely quenched if the boron-derived
impurities from the reduction was not thoroughly removed (presumably due to annihilation of
the ethoxides by the boric acids, which extinguishes the alkoxide cycle). It appears that complete
hydrolysis of the boron esters derived from NaBH4 and clean isolation of the carbamates 4
through aqueous work up are prerequisites for a successful cyclization and a priori for obtaining
reproducible results using earlier conditions. It should be noted that the solvent-free cyclization
at easily accessible temperatures disclosed here might also be applicable to the cyclization of
similar carbamates, including those12 not related to the auxiliary chemistry.
Figure 2. The initial deprotonation by K2CO3 and the subsequent catalytic cycle of the alkoxides
In brief, we have developed a long awaited high-yielding low-cost simple route to the
2-oxazolidinones 1 using a one-pot NaBH4/H2SO4 reduction and EtO2CCl alkoxycarbonylation,

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Y. Wu, X. Shen / Tetrahedron: Asymmetry 11 (2000) 4359–4363
followed by a solvent-free cyclization. The cost for preparing 1 is thus reduced. The reaction
conditions are mild and easily accessible in both laboratory and industry, and the set-ups as well
as the operations are very simple; the preparation of these auxiliaries is thus no longer a costly
and/or tedious task demanding much experience and great care.
3. Experimental
A typical procedure13 is as follows: (S)-(−)-4-Benzyl-2-oxazolidinone 1b.
L
-Phenylalanine
(33.00 g, 200 mmol) was reduced following (but skipping the addition of MeOH) the literature
procedure5 up to ‘adding 5N NaOH (200 mL used for this work) and heating for 3 h’. The
mixture was cooled to rt with stirring before introducing H2O (150 mL) and NaHCO3 (84.00 g,
1.00 mol), followed by ClCO2Et (21 mL, 210 mmol, cooling with 5°C bath). After stirring at rt
for another 1.5 h the mixture was extracted with EtOAc (100 mL×4). The combined organic
phases were washed with H2O (50 mL) and brine (50 mL), dried over MgSO4. Removal of the
solvent gave rather pure 4b as a white solid (44.26 g, 198 mmol). Powered K2CO3 (140 mg, 1.01
mol) was added and the mixture was heated (125–130°C, bath) with magnetic stirring under
aspirator vacuum (ca. 40 mmHg) until the gas evolving stopped. After cooling down to rt a
white solid (>98% yield for the essentially pure 1b, ee >99% by chiral HPLC) was obtained.
Recrystallization (1:1 EtOAc/hexanes) gave pure 1b in two crops (30.91 g, 87% from -phenyl-
L
alanine; chromatography of the mother liquor raised the overall yield to 95% yield) as white
long prisms: mp 90–91°C; [h]30 −62 (c 1.0, CHCl3) [lit.14 [h]20 −63 (c 1, CHCl3)]; ee >99% (HPLC
n
on Chiralcel OC column eluting with 7:3 hexane/ipropanol at 0.6 mL/min and detection at 211
nm).3b
(S)-(−)-4-Isopropyl-2-oxazolidinone 1a. White needles, 83.9% (from -valine) by recrystalliza-
L
tion (1:7 EtOAc/hexanes, in two crops) or 91% by chromatography; mp 71.5–73°C; [h]30 −17 (c
6.0, EtOH) [lit.14 [h]20 −18 (c 6, EtOH)].
(R)-(−)-4-Phenyl-2-oxazolidinone 1c. White needles, 82% (from -phenylglycine) by recrystal-
D
lization (2:1 EtOAc/hexanes, in two crops) or 91% by chromatography; mp 132–134°C; [h]30 −50
(c 2.0, CHCl3) [lit.14 [h]25 −48 (c 2, CHCl3)]; ee >99%.
Acknowledgements
This work was supported by the Chinese Academy of Sciences (CAS ‘Knowledge Innovation’
Project), the Life Science Special Fund of CAS Supported by the Ministry of Finance (Stz
98-3-03), the Major State Basic Research Development Program (G2000077502), the Ministry of
Science and Technology of China (970211006-06), and the National Natural Science Foundation
of China (29832020).
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i
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in the easily accessible journals, not detailed, or mis-assigned data are listed below. Data for 4a: [h]29 −28.6 (c
1
0.85, CHCl3). Data for 4b: mp 64.5–66.0°C; [h]20 −23.1 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) 7.47–7.33
(m, 5H; aromat.), 5.03 (br s, 1H; NH), 4.22 (q, J=7.1 Hz, 2H; CH2Me), 4.05 (br s, 1H; HCꢀNCO2Et), 3.82 (br
dd, J=3.3, 11 Hz, 1H; CH2OH), 3.72 (br dd, J=5.2, 11 Hz, 1H; CH2OH), 3.00 (br s, 1H; benzylic), 2.98 (br s,
1H; benzylic), 2.69 (vbr s, 1H; OH), 1.35 (t, J=7.1 Hz, 3H; CH3). Data for 4c: Mp 80–82°C; [h]29 −44.6 (c 0.98,
1
CHCl3). Data for 1b: H NMR (300 MHz, CDCl3) 7.38–7.29 (m, 3H; aromat.), 7.17–7.21 (m, 2H; aromat.), 5.51
(br s, 1H; NH), 4.47 (br t, J=8.2 Hz, 1H; H-5), 4.17 (br dd, J=5.5, 8.2 Hz, 1H; H-5), 4.09 (br sextet, 1H; H-4),
2.90 (br s, 1H; benzylic), 2.88 (br s, 1H; benzylic).
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.
.