(S)-4-Isopropyl-5,5-dimethyl-1,3-oxazolidinethione as chiral auxiliary for the intramolecular sulfur transfer in α,β-unsaturated N-acylimides, promoted by NbCl5

Article abstract of DOI:10.1016/S0040-4039(02)02837-X

The 1,3-oxazolidinethione 4 has been synthesized from (S)-valine and used in the intramolecular sulfur transfer in its N-enoyl derivatives in the presence of NbCl₅ as catalyst, which, moreover, works as an indicator of the course of the reactio

Full text of DOI:10.1016/S0040-4039(02)02837-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1129–1132
(S)-4-Isopropyl-5,5-dimethyl-1,3-oxazolidinethione as chiral
auxiliary for the intramolecular sulfur transfer in a,b-unsaturated
N-acylimides, promoted by NbCl5
Aurelio Ortiz,a,* Leticia Quintero,a Hector Herna´ndez,a Sotero Maldonado,a Guadalupe Mendozaa
and Sylvain Berne`sb
aCentro de investigacio´n de la Facultad de Ciencias Qu´ımicas, Puebla Pue., 72570, Mexico
bInstituto de Ciencias de la Beneme´rita Universidad Auto´noma de Puebla, Puebla Pue., 72570, Mexico
Received 15 November 2002; revised 14 December 2002; accepted 17 December 2002
Abstract—The 1,3-oxazolidinethione 4 has been synthesized from (S)-valine and used in the intramolecular sulfur transfer in its
N-enoyl derivatives in the presence of NbCl5 as catalyst, which, moreover, works as an indicator of the course of the reaction.
The adducts have subsequently been transformed into the corresponding b-mercapto esters by action of Sm(OTf)3 in methanol.
© 2003 Elsevier Science Ltd. All rights reserved.
Recently, a novel strategy for asymmetric synthesis,
based on the principle of intramolecular atom transfer,
has been described by Palomo and co-workers in which
they report a Lewis acid-promoted sulfur transfer reac-
tion with N-enoyl oxazolidine-2-thiones to yield b-mer-
capto carboxylic acid derivatives.1 Our interest in
finding other promoters for this reaction led us to use
NbCl5 as a new Lewis acid, different to the traditional
type, it is a stable solid, easy to handle and soluble in
organic solvents, but its use in organic syntheses has
been limited.2
tative yield.5 The condensation of the b-amino alcohol
3 with CS2 was carried out by a modification of previ-
ously described method.6 Firstly, the b-amino alcohol 3
was treated with 4 equiv. of CS2 in 100 mL of an
aqueous solution of Na2CO3 and refluxed for 16 h.
After this time, to totally consume the starting material,
added was 2 equiv. of CS2 and refluxed for 4 h to
afford 4 in 80% yield, mp 118–120°C, [h]2D5=−14.3,
c=2, CHCl3.7
In this paper we describe the synthesis of a new oxazo-
lidine-2-thione chiral auxiliary 4 and its application to
the asymmetric synthesis of b-mercapto methyl ester
compounds. Chiral auxiliary 4 was prepared from the
commercially available S-valine through a series of
transformations,3,4 as shown in Scheme 1. In order to
optimize the yield and avoid racemization of the stereo-
genic center by use of excess Grignard reagent, the
amino group in 1 was protected as its trifluoracetamide
using trifluoroacetic anhydride and triethylamine to
give N-trifluoroacetyl S-valine methyl ester 2 in quanti-
Scheme 1. Reagents and conditions: (a) Et3N (2 equiv.),
(CF3CO)2O, −78°C“rt, 3 h, THF, 99.8%; (b) MeMgI (5
equiv.), Et2O, 0°C rt, “12 h; (c) KOH, rt, 78%; (d) CS2 (4
equiv.), Na2CO3 1N, reflux, 16 h, +CS2 (2 equiv.), reflux, 4 h.
* Corresponding author. Tel.: 222-2295500-7481; fax: 222-2295584;
e-mail: jaortizm@siu.buap.mx
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02837-X

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A. Ortiz et al. / Tetrahedron Letters 44 (2003) 1129–1132
Table 1. Synthesis of chiral 1,3-oxazolidine-2-thione 6
N-enoyl oxazolidinethiones did not form the precipi-
tate. TMSCl was also not the Lewis acid of choice
because it required an exceedingly long reaction time to
form the product in good yield.
Compound Yield (%)
Mp (°C)
81–82
[h]D
(c, t °C)
Reference
8
(4R,5S)-6
73.1
87.0
+219.2
(0.4, 20)a
rac
In the case of NbCl5, it gave b-mercapto products in
the mayor yields and its addition did not form the
precipitate in any reactions. NbCl5 has the advantage of
being highly soluble and easy to handle. An additional
improvement of the methodology comes from the fact
that the reaction course is readily followed by the color
change, from red to yellow. All of these advantages
make NbCl5 the most desirable Lewis acid for this
reaction.12 Scheme 3 shows the reaction conditions to
provide the adducts (9a, 9b, 10a, 10b) with NbCl5. The
typical reaction procedure is described for obtention of
10a.13
rac-6
91–92
6
(4S,5R)-6
(4S,5R)-6
100
93
83.4–83.9
80–81
–
9
−218.0
Our study
(2, 25)a
a Determined in CHCl3.
On the other hand, the chiral auxiliary 6 has been
widely studied and prepared by different methods. The
results and its physical properties are shown in Table 1.
The chiral auxiliary 6 was prepared from (1R,2S)
norephedrine 5. It was treated under the same reaction
conditions described above to give the desired chiral
auxiliary 6 in 93% yield (Scheme 2). In both cases,
under these reaction conditions, the formation of thia-
zolidinethione was undetected.6,10
Scheme 2. Reagents and conditions: (a) CS2 (4 equiv.),
Na2CO3 1N, reflux, 16 h, +CS2 (2 equiv.), reflux, 4 h.
Scheme 3. Reagents and conditions: (a) NbCl5, CH2Cl2, −
78°C, H2O.
The N-enoyl oxazolidinethiones 7a, 7b, 8a and 8b were
then prepared from 4 and 6 as previously described.1
Deprotonation of compounds 4 and 6 with NaH in
THF followed by acylation with either crotonyl or
cinnamoyl chloride yielded the desired N-enoyl oxazo-
lidinethiones 7a, 7b and 8a, 8b in a range of 73–91%, all
of them as white solid, after purification by flash
column chromatography using silica gel that had been
previously treated with an aqueous solution of
NaHCO3.11
Table 2. Intramolecular sulfur transfer reaction of the N-
enoyl oxazolidinethiones
Products
Catalyst
T (°C)/t
Yield (%)b Diastereome
ric ratiod
(h)a
9a
10a
9b
10b
10a
10a
NbCl5
NbCl5
NbCl5
NbCl5
SnCl4
−78/6
−78/10
−50/12
−50/24
−78/3
0/336
50
76
95
57c
40
72
98:2
97:3
96:4
63:37
96:4
98:2
The asymmetric intramolecular sulfur transfer reaction
of the N-enoyl oxazolidinethiones 7a, 7b, 8a and 8b was
investigated using three Lewis acids, NbCl5, TMSCl
and SnCl4 to afford the desired b-mercapto products
9a, 9b, 10a, 10b. The results of these reactions are
shown in Table 2. In all cases 2 equiv. of the respective
Lewis acid were used in 300 mL of methylene chloride.
It was found that SnCl4 at −78°C in 3 h gave b-mer-
capto product in 40% yield, moreover when SnCl4 was
added to the N-enoyl oxazolidinethiones, a precipitate
was formed that was soluble at −78°C when R=Me,
for R=Ph it was insolvable at the same temperature.
SnCl4 was not the most desirable Lewis acid for this
reaction because it gave one of the lowest yields for the
desired b-mercapto product. When the reaction was
carried out with TMSCl at 0°C it very slowly gave the
b-mercapto product in 72% yield. The addition to the
TMSCl
a T=temperature, t=time.
b Purified yield.
c Diastereomeric mixture yield.
d Diastereomeric isomer ratios were determined by HPLC on the
crude products.
From the data in Table 2, it was observed that in the
case of products 9b and 10b there is a notable difference
both in the yield and in the diastereomeric ratio. The
presence of the aromatic groups in 7b and 8b has an
important influence in the reaction to give products 9b
and 10b. These compounds were obtained at −50°C in
comparison with products 9a and 10a. When com-
pound 8b was treated with SnCl4 and the mixture was

A. Ortiz et al. / Tetrahedron Letters 44 (2003) 1129–1132
1131
warmed close to room temperature, the elimination
product 11 was obtained in 80% yield as a crystalline
solid. The structure of 11 was determined by X-ray
crystallography14 showing a five-membered ring for the
1,3-oxazolidinone moiety and the carbonyl group at
C-13 anti to carbonyl group at C-2, a conformation
which was previously described for another N-
acylimides15 (Scheme 4).
Scheme 5. Reagents and conditions: (a) Sm(OTf)3 (1.5 equiv.),
MeOH, rt, 24 h.
In conclusion, we have prepared a new chiral auxiliary
1,3-oxazolidinethione 4 that was utilized in the asym-
metric intramolecular sulfur transfer reaction to the
N-enoyl oxazolidinethiones using NbCl5 as a promot-
ing reagent, furthermore this Lewis acid is easy to
handle and makes it possible to follow the course of the
reaction. On the other hand, we applied an esterifica-
tion to remove the modified chiral auxiliary using
Sm(OTf)3 as Lewis acid and CH3OH to produce (R)-
methyl-3-phenyl-3-mercaptopropionate 13.
Scheme 4. Reagents and conditions: (a) SnCl4, CH2Cl2, −78“
25°C, H2O.
The configuration at the newly formed stereogenic cen-
ter (C-15) is R, as established by X-ray analysis16 of
compound 10a, derived from norephedrine (Fig. 1).
The X-ray structure of 10a shows the expected five-
membered ring for the 1,3-oxazolidinone as evidenced
by 13C NMR analysis.17
Acknowledgements
We thank CONACyT (Project I32971-E and Project
J35098-E). The author H.H. acknowledges a grant from
Promep.
References
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1
7. Compound 4: H NMR (400 MHz, CDCl3): l 8.27 (br s,
1H, NH), 3.37 (d, 1H, J=8.0, CH-N), 1.90 (m, 1H,
CHꢀCH3), 1.56 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.04 (d,
3H, J=6.6, CH3ꢀCH), 0.95 (d, 3H, J=6.6, CH3ꢀCH);
13C NMR (100 MHz, CDCl3): l 188.1 (CꢁS), 90.4 (CꢀO),
71.2 (CꢀN), 28.2 (CH3), 28.0 (CH3), 21.0 (CHꢀCH3), 19.8
(2CH3). Anal. calcd for C8H15NOS: C, 55.45; H, 8.73.
Found: C, 55.48; H, 8.69%.
Figure 1. Molecular structure of the b-mercapto adduct 10a,
the first structure obtained by X-ray without blocking the
thiol group. Displacement ellipsoids are drawn at the 30%
probability level.
Our subsequent work focused on finding the conditions
for the cleavage of the adduct 9b. The treatment of 9b
with aqueous lithium hydroxide18 provided the recovery
of oxazolidinone 12 in 85% yield and as elimination
product trans-cinnamic acid instead of the desired
product 13. Therefore, was employed an efficient
method19 for the conversion of 9b to 13 with samarium-
(III) triflate in methanol (10 mL) at room temperature
to provide methyl ester 13 in 75% yield as a dense
liquid, [h]2D5=−46 (c 1.3, CHCl3) and the oxazolidinone
12 in 80% yield (Scheme 5).
8. Nagao, Y.; Kumagai, T.; Yamada, S.; Fujita, E.; Inoue,
Y.; Nagase, Y.; Aoyagi, S.; Abe, T. J. Chem. Soc., Perkin
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11. The N-enoyl oxazolidinethiones (7a, 7b, 8a, 8b) are
unstable in acid media. The purification of these by flash
column chromatography using normal silica gel gave 4 or
6 as deacylation products.

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A. Ortiz et al. / Tetrahedron Letters 44 (2003) 1129–1132
12. NbCl5 is a solid, and highly soluble in CH2Cl2 and none
of the reactions produced a precipitate when it was
added to the solution of N-enoyl oxazolidinethiones.
13. A typical reaction procedure for the asymmetric sulfur
transfer reaction is described. To a solution of 8a (0.3 g,
1.14 mmol) in CH2Cl2 (300 mL) was added NbCl5 (0.62
g, 2.28 mmol) at −78°C under a nitrogen atmosphere.
The reaction mixture was stirred at −78°C until the red
solution turned yellowish (10 h, TLC monitoring). The
reaction was quenched with water, extracted with
CH2Cl2 (3×30 mL) and the combined organic extracts
were washed with brine and dried over Na2SO4. After
removal of solvent, analysis by 1H NMR showed the
tary Material available: Tables of atomic coordinates,
thermal parameters, bond lengths and angles and
observed and calculated structure factors have been
deposited at the Cambridge Crystallographic Data Cen-
tre.
15. Palomo, C.; Berre´e, F.; Linden, A.; Villalgordo, J. M. J.
Chem. Soc., Chem. Commun. 1994, 1861–1862.
16. Crystal data for 10a: C14H17NO3S, M=279.35, colorless
plate, 0.38×0.26×0.14 mm3, space group P212121, cell
parameters
a=10.0428(10),
b=10.6011(10),
c=
13.3494(8) A, Z=4, Dcalcd=1.306 g cm−3. 2442 reflec-
,
tions collected on a Bruker P4 diffractometer at rt, with
,
the Mo Ka radiation (u=0.71073 A) in the range 2q=
formation of b-mercapto adduct 10a as
a (97:3)
3–50°, of which 2115 are unique (Rint=0.0513). 173
variables refined: R1=0.0429 [1374 data with I>2|(I)]
and wR2=0.1088 [all data]. Complete data have been
deposited with the CCDC, reference 197368. Structure
factors and raw files are available on request to authors.
17. The 13C NMR spectrum of 10a showed a signal at l
153 ppm due to carbonyl group (C-2), in agreement
with 13C NMR analysis spectrum of 8a which showed a
signal at l 185.3 ppm for the thiocarbonyl group (C-2).
18. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
diastereomeric mixture (by HPLC). The crude was
purified by flash column chromatography (10% ethylac-
etate in hexane as eluent) to give 10a (0.243 g, 76%
yield) as a white solid mp 108°C, [h]2D5=−42.03 (c 1.5,
CHCl3).
14. Crystal data for 11: C19H17NO3, M=307.34, colorless
block, 0.70×0.34×0.18 mm3, space group P212121, cell
parameters a=6.4224(9), b=12.4092(11), c=20.386(2)
A, Z=4, Dcalcd=1.256 g cm−3. 2296 reflections collected
,
on a Bruker P4 diffractometer at rt, with the Mo Ka
,
radiation (u=0.71073 A) in the range 2q=4–50°, of
19. (a) Chang, G. X.; Lowary, T. L. Org. Lett. 2000, 2,
1505–1508; (b) Sibi, M. P.; Hasegawa, H.; Ghorpade, S.
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which 2105 are unique (Rint=0.0235). 209 variables
refined: R1=0.0522 [1102 data with I>2|(I)] and wR2=
0.1456 [all data]. Complete data have been deposited
with the CCDC, reference 197369. Structure factors and
raw files are available on request to authors. Supplemen-