Facile removal of 4-phenyl-oxazolidinethione auxiliary with EtSH mediated by DBU

Article abstract of DOI:10.1016/j.tetlet.2004.08.113

N-Acyl-β-hydroxy-4-phenyl-oxazolidinethiones could be rapidly converted into thioesters in high yields by treatment with EtSH/DBU at 0°C.

Full text of DOI:10.1016/j.tetlet.2004.08.113

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7715–7717
Facile removal of 4-phenyl-oxazolidinethione auxiliary
with EtSH mediated by DBU
Yikang Wu,* Qi Hu, Ya-Ping Sun and Yong-Qing Yang
State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 14 July 2004; revised 11 August 2004; accepted 13 August 2004
Abstract—In methylene chloride at 0°C N-acyl-b-hydroxy-4-phenyl-oxazolidinethiones could be rapidly converted into correspond-
ing ethyl thioesters in high yields by treatment with EtSH in the presence of a catalytic amount of DBU.
Ó 2004 Elsevier Ltd. All rights reserved.
Removal of the auxiliary after completion of the chiral
induction is an inevitable operation in most auxiliary-
based asymmetric syntheses. Whether the auxiliary can
be cleaved successfully under mild conditions may
decide the fate of a particular synthetic route. Hence,
the importance of developing new methods for cleavage
of the auxiliaries can never be over emphasized.
oxazolidinethiones auxiliaries are apparently far too
few. Here in this communication we wish to report a
novel method for cutting off the 4-phenyl-oxazolidinethi-
one auxiliary, which allows for smooth transformation
of the corresponding N-acyl-b-hydroxy-oxazolidinethi-
ones into ethyl thioesters under very mild conditions.
The reactions were carried out at 0°C in CH2Cl2 (such
substrates are much less soluble in other common org-
anic solvents). In the presence of a catalytic amount of
DBU (which has never been used in removal of any chi-
ral auxiliary up to now), the auxiliary could be cleanly
and non-destructively removed by treatment with ca.
2equiv of EtSH. The main results are outlined in Table
1. For those substrates carrying a methyl group on the
a-carbon, the reactions proceeded rather fast and the
yields of the thioesters were usually high (entries 1–4).
Chiral 4-monosubstituted oxazolidinethiones1 derived
from those inexpensive amino acids (such as phenyl-
glycine, valine, and phenylalanine) are a class of auxilia-
ries that attract2 more and more attention in recent years,
presumably because they are remarkably easier2 to be
cleaved than corresponding oxazolidinones while being
highly effective in inducing new chiral centers. However,
the cleavage in most cases was realized by reduction, with
the N-acyl group being reduced to an alcohol. The only
example2a,b of non-reductive cleavage of 4-monosubsti-
tuted oxazolidinethione auxiliaries we can find in the lit-
erature to date is an aminolysis with MeNHOMe leading
to a Weinreb amide. The examples of removing other
types of oxazolidinethiones are also scant. The only
relevant examples appear to be those reported by Yan
and co-workers,3 which employed DMAP-catalyzed
transesterifications to remove a camphor-derived auxil-
iary (yielding esters as products) from two non-hindered
substrates. Compared with the related (Evans) oxazolidin-
ones and thiazolidinethiones2b auxiliaries, the docu-
mented methods for cleaving 4-monosubstituted
When the substituents on the auxiliary and the b-carbon
were not so bulky, a substituent moderately larger than
methyl group on the a-carbon could be tolerated (entries
5–7). However, when the phenyl group on the auxiliary
and the methyl group on the a-carbon of 1c were chang-
ed into i-Pr and n-Bu groups, respectively, the excessive
steric hindrance around the N-acyl group changed the
reaction course completely (entry 3 vs entry 8).
Compounds 1i and 1j also failed to give the expected
thioesters (entries 9 and 10), in sharp contrast to the
clean reactions observed with 1b, 1k, and 1l (entries 2,
11, and 12). Perhaps when both the a- and b-chains
are all linear simple alkyls, some unexpected steric
hindrance was generated by aggregation of the alkyl
chains and led to the excessive side reactions.
Keywords: Chiral auxiliaries; Cleavage; Aldols; Synthesis; Thioesters.
*
Corresponding author. Fax: +86 21 64166128; e-mail: yikangwu@
mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.113

7716
Y. Wu et al. / Tetrahedron Letters 45(2004) 7715–7717
Table 1. Conversion of 1 to 2 in CH2Cl2 at 0°C by treatment with EtSH in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)a
Entry
1
Substrate
EtSH (equiv)
2.0
DBU (equiv)
0.19
Time (min)
30
Product
O
Yield (%)
92
S
O
OH
Ph
OH
Ph
2a
O
O
N
1a
EtS
Ph
S
O
OH
Pentyln
O
OH
Pentyln
2b
3b
4
1b
2.7
2.3
2.5
2.2
2.7
2.1
3.0
2.4
1.9
2.3
2.5
0.25
0.23
0.25
0.21
0.25
0.21
0.19
0.20
0.27
0.21
0.25
60
60
30
60
30
30
90
60
90
60
30
2b
2c
87
89
87
89
85
90
—
—
—
82
76
N
EtS
Ph
O
S
S
OH
O
OH
Pentyln
Ph
O
O
N
1c
2
EtS
Ph
O
S
2
OH
OH
O
S
2
OH
N
S
1d
2d
S
EtS
Ph
O
S
S
S
O
OH
5
1e
2e
O
O
O
N
N
EtS
Bun
Bun
Ph
O
OH
Ph
O
O
OH
6
1f
2f
Ph
EtS
EtS
—
Bun
Bun
Ph
O
OH
Ph
OH
Ph
N
7
1g
2g
Ph
Ph
Ph
S
S
S
S
O
OH
Ph
8c
9c
10c
11
12
1h
O
O
O
O
N
2
Bun
Pri
O
OH
Pentyln 1i
Bun
N
—
—
Ph
O
OH
N
Pentyln 1j
Bun
Bn
O
OH
Pentyln
O
OH
Pentyln
N
1k
2k
EtS
EtS
Ph
OH
Ph
Ph
O
S
S
2
O
S
OH
1l
2l
O
N
S
S
2
Ph
Ph
Ph
a For the general procedure, see Ref. 11.
b The reaction was probably already finished within 30min.
c With disappearance of the starting material, extensive formation of side products was observed.
It should be mentioned that using DMAP (which was effec-
tive3 in converting a camphor-related N-acyloxazolidinethi-
one into esters) or NEt3 to replace the DBU led to much
slower reactions under otherwise identical conditions.

Y. Wu et al. / Tetrahedron Letters 45(2004) 7715–7717
7717
2. (a) See, for example: Crimmins, M. T.; King, B. W.; Tabet,
E. A. J. Am. Chem. Soc. 1997, 119, 7883–7884; (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary,
K. J. Org. Chem. 2001, 66, 894–902; (c) Crimmins, M. T.;
King, B. W. J. Am. Chem. Soc. 1998, 120, 9084–9085; (d)
Crimmins, M. T.; Katz, J. D.; McA tee, L. C.; Tabet, E. A .;
Kirincich, S. J. Org. Lett. 2001, 3, 949–952; (e) Crimmins,
M. T., P. J.; McDougall, P. J. Org. Lett. 2003, 5, 591–594; (f)
Zhang, W.; Carter, R. G. J. Org. Chem. 2004, 69, 2569–2572.
3. (a) Su, D.-W.; Wang, Y.-C.; Yan, T.-H. Tetrahedron Lett.
1999, 40, 4197–4198; (b) Wang, Y.-C.; Su, D.-W.;
Lin, C.-M.; Tseng, H.-L.; Li, C.-L.; Yan, T.-H. J. Org.
Chem. 1999, 64, 6495–6498.
4. Kumamoto, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1968, 41, 2111–2114.
5. Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiy-
ama, T. Chem. Lett. 1998, 831–832.
6. Hoffmann, R. W.; Polachowski, A. Chem. Eur. J. 1998, 4,
1724–1730.
Thioesters are known to be more reactive than corre-
sponding esters. They can be, for instance, easily con-
verted into esters (without complication caused by the
exocyclic attack at the auxiliary, a common side reaction
if the auxiliary is not removed) under essentially neu-
tral conditions by treatment with a proper alcohol in
the presence of NBS4 or Ag(OCOCF3),5 or reduced
to aldehydes with DIBAL-H5 or Me2SiH2/Pd–C.6 They
7
can also be reduced to alcohols with NaBH4 or trans-
formed into ketones through reactions with organo-
zinc,8 copper,9 or boron10 reagents in the presence of a
proper palladium catalyst. It is thus possible to manipu-
late the b-hydroxyl group before further elaboration of
the carboxylic group (note that masking the OH before
cleavage of the auxiliary often makes the auxiliary
removal much more difficult).
In summary, we have described a novel very mild and
convenient procedure for removing 4-phenyl-oxazolidin-
ethione auxiliary. The N-acyl-b-hydroxy-4-phenyl-oxaz-
olidinethiones can thus be readily converted in high
yields into the corresponding thioesters, a class of com-
pounds that are more reactive than esters and thus make
further elaborations much easier.
7. (a) Liu, H.-J.; Luo, W. Can. J. Chem. 1992, 70, 128–134;
(b) Liu, H.-J.; Luo, W. Synth. Commun. 1981, 11, 599–604;
(c) Liu, H.-J.; Wynn, H. Tetrahedron Lett. 1982, 23, 3151–
3154.
8. Tokuyama, H.; Yokoshina, S.; Yamashita, T.; Fukuyama,
T. Tetrahedron Lett. 1998, 39, 3189–3192.
9. Tokuyama, H.; Miyazaki, T.; Yokoshima, S.; Fukuyama,
T. Synlett 2003, 1512–1514.
10. Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554–
3557.
Acknowledgements
11. General procedure: a solution of the substrate (1mmol),
EtSH (2–2.7mmol), and DBU (cat. amounts) in CH2Cl2
(5mL) was stirred at 0°C for 30–90min. When TLC
showed completion of the reaction, the mixture was
diluted with ether, washed in turn with 2N HCl, aq
NaHCO3, H2O and brine, and dried over Na2SO4.
Removal of the solvent and chromatography on silica
gel (eluting with EtOAc/hexanes) afforded the pure
product (with the auxiliary recovered in near quantita-
tive yields). Note that due to the presence of an excess
of EtSH (a stronger acid than the proton at the a-
position of the N-acyl group), the possibility of epime-
rization caused by a catalytic amount of DBU at 0°C
within a relatively short reaction period is practically
negligible.
This work has been supported by the National Science
Foundation of China (20025207, 20272071, 20372075,
20321202), the Chinese Academy of Sciences (Knowl-
edge Innovation Project, KGCX2-SW-209), and the
Major State Basic Research Development Program
(G2000077502).
Referencesand notes
1. For a very practical procedure for preparing these
auxiliaries, see: Wu, Y.-K.; Yang, Y.-Q.; Hu, Q. J. Org.
Chem. 2004, 69, 3990–3992.