Asymmetric synthesis of 3-methylthio alcohols by intramolecular Michael addition reactions

Article abstract of DOI:10.1016/j.tetlet.2005.02.021

Chiral 3-methylthio alcohols have been synthesized through a known intramolecular sulfur transfer reaction that has been carried out in di- and trisubstituted α,β-unsaturated N-enoyl oxazolidinethiones as substrates, giving rise to syn/anti-diastereomers. The anti-diastereomer is favored and obtained via a highly diastereoselective protonation step.

Full text of DOI:10.1016/j.tetlet.2005.02.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2243–2246
Asymmetric synthesis of 3-methylthio alcohols by
intramolecular Michael addition reactions
a
a
Aurelio Ortiz,a, Hector Hernandez, Guadalupe Mendoza,
*
´
Leticia Quintero and Sylvain Bernes
a
b,
*
`
a
´ ´ ´ ´
Centro de investigacion de la Facultad de Ciencias Quımicas de la Benemerita Universidad Autonoma de Puebla,
´
Puebla Pue. 72570, Mexico
´ ´
Instituto de Ciencias de la Benemerita Universidad Autonoma de Puebla, Puebla Pue. 72570, Mexico
b
´
Received 24 January 2005; revised 2 February 2005; accepted 3 February 2005
Abstract—Chiral 3-methylthio alcohols have been synthesized through a known intramolecular sulfur transfer reaction that has
been carried out in di- and trisubstituted a,b-unsaturated N-enoyl oxazolidinethiones as substrates, giving rise to syn/anti-diastereo-
mers. The anti-diastereomer is favored and obtained via a highly diastereoselective protonation step.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The introduction of a thiol group in the a and b-posi-
tions of carboxylic acid derivatives, has been subject of
extensive researches. SN2substitution has been the
method employed to prepare a-mercapto derivatives
from a-hydroxy or a-halo acids with (RSꢀ) as nucleo-
phile.1 On the other hand nucleophilic addition reac-
tions, such as the Michael addition, have provided b-
mercapto derivatives through the addition of thiols to
achiral2 or chiral3 a,b-unsaturated carboxylic acid deriva-
tives.2 Both methodologies used different kinds of thiols,
which after their addition, were cleavaged for different
reactions carried out in an atmosphere of dry, oxygen-
free nitrogen.1
sulfur transfer in N-enoyl oxazolidinethiones.5 Recently,
this methodology has been applied in the construction
of C–S bonds with a quaternary stereocenter.6
We describe herein the preparation of a series of chiral
methylthio alcohols, which are shown in Figure 1. Their
synthesis was achieved by the intramolecular sulfur
transfer reaction in di- and trisubstituted a,b-unsatu-
rated N-enoyl oxazolidinethiones, followed by protec-
tion of the thiol and removal of the oxazolidinone by
reduction with LiAlH4.
SMe
Me
SMe
SMe
A highly diastereoselective Michael addition of a thiol to
a-substituted a,b-unsaturated derivatives has been de-
scribed based on asymmetric protonation.4 On the other
hand it has also been described that the addition of thi-
ols to trisubstituted E and Z a,b-unsaturated carboxylic
acid derivatives produces stereospecifically erythro and
threo adducts, respectively.2
HO
HO
HO
R
Me
R= Me, Ph
SMe
Ph
SMe
Ph
HO
HO
Me
Me
Palomo et al. have described highly diastereoselective
preparation of such compounds through intramolecular
Figure 1.
The chiral auxiliary oxazolidinethione employed was
prepared from (S)-valine7 and the N-enoyl oxazolidine-
thiones (1a–c) were prepared as previously described5,7
in yields of 70–79%, all of them as E-isomers. The
*
Corresponding authors. Tel.: +52 222 2295500 7518; fax: +52 222
2295584 (A.O.); tel.: +52 222 2295500 7297; fax: +52 222 2295551
(S.B.); e-mail addresses: jaortizm@siu.buap.mx; sylvain_bernes@
hotmail.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.021

2244
A. Ortiz et al. / Tetrahedron Letters 46 (2005) 2243–2246
intramolecular sulfur transfer reaction of these N-enoyl
oxazolidinethiones was performed using SnCl4 and
NbCl5, as promoters, to afford the desired b-mercapto
adducts (2a–c) as shown in Scheme 1. The results and
reaction conditions are listed in Table 1.
S
O
O
SH
R2
O
SH
R2
a
O
N
R2
Xc
+
Xc
R1
R1
R1
2 (a-c)
2 (a'-c')
1a R1=CH3 R2=CH3
1b R1=CH3 R2=Ph
1c R1= R2= -(CH2)4
2a=2a' R1=CH3 R2=CH3
2b=2b' R1=CH3 R2=Ph
2c=2c' R1= R2= -(CH2)4
Figure 3. Molecular structure of the b-mercapto compound 2c.
Scheme 1. Reagents: (a) SnCl4 or NbCl5, CH2Cl2, H2O.
The intramolecular sulfur transfer reaction in 1b pro-
vides an anti/syn-diastereomeric mixture in a ratio 84/
16 for adducts 2b/2b0. Their isolation gives anti-diaste-
reomer 2b as a liquid compound and syn-diastereomer
2b0 as a solid compound. For 2b0 the absolute configura-
tion at the newly formed stereogenic centers (C-12, C-
13) are R and S, respectively, as established by X-ray
analysis (Fig. 4).11
Table 1. Intramolecular sulfur transfer reaction of the N-enoyl
oxazolidinethiones
Products
Promoter
T (ꢁC)/t (h)a
Yieldb (%)
anti/synd
2a/2a0
2b/2b0
2b/2b0
2c/2c0
SnCl4
NbCl5
SnCl4
SnCl4
ꢀ78/14
ꢀ30/7293
0/60
40
98:2
84:16e
84:16e
c
70c
5296:4
ꢀ78/14
a T = temperature, t = time.
b Purified yield.
c Yield of the diastereomeric mixture.
d Diastereomeric isomer ratios were determined by HPLC on the crude
products.
e Ratio determined by NMR.
From the data in Table 1, for adducts 2b and 2b0 the use
of different reaction conditions provides the same diaste-
reomeric ratio. This reaction at ꢀ78 ꢁC and large reac-
tion times provided starting material. The formation
of new chiral centers in compounds 2a and 2c is highly
diastereoselective and the E-isomers (1a–c) provide the
anti-diastereomers (2a–c) mainly.
Figure 4. Molecular structure of the b-mercapto compound 2b0.
The configuration at the newly formed stereogenic cen-
ters (C-12, C-13) are S and R, respectively, for both
compound 2a, and 2c as established by X-ray analysis
(Figs. 2and 3 ).8,9
The sense of stereodirection is the same for principal
compounds as shown in Table 2.
Table 2. Physical properties of the b-mercapto compounds
Compound
Mp (ꢁC)
[a]D (c)a
2a-(S,R)
2b-(S,S)
2b0-(R,S)
2c-(S,R)
70–72
—
145
ꢀ43.2(1.25)
ꢀ58.1 (1.60)
+14.1 (1.05)
ꢀ65.2(1.10)
92–93
a Determined in CHCl3 at 25 ꢁC.
This diastereoselective can be explained by cyclization
between the sulfur atom and the C(b) atom of the a,b-
unsaturated system, to form a six-membered ring as
shown in Figure 5. A posterior diastereoselective pro-
tonation gave the anti-diastereomer mainly.
Figure 2. Molecular structure of the b-mercapto compound 2a.

A. Ortiz et al. / Tetrahedron Letters 46 (2005) 2243–2246
2245
H
O
S
CH
3
N
CH
3
L
n-1
MO
Figure 5.
Subsequently, the compounds 2(a–c) and 2(d–e)7 were
treated with CH3I and Et3N in MeOH to provide the
methylthio adducts 3(a–e) in excellent yields (93–99%).
The removal of the oxazolidinone moiety was carried
3a
out with LiAlH4 in THF at 0 ꢁC, to give the chiral
methylthioalcohols 4(a–e) in good yields and to recover
the oxazolidinone in yields of 80–82% as shown in
Scheme 2.
Figure 6. Molecular structure of the sulfoxide compound 5b.
O
SCH3
R2
SCH3
R2
LiAlH4
Acknowledgements
Xc
HO
THF
0 oC
R1
R1
We thank CONACyT (Project J35098-E), grant to H.H.
from Promep, and Professors C. Palomo and M. Oiar-
bide (U.P.V.) for their help.
3a R1=CH3 R2=CH3
4a R1=CH3 R2=CH3
3b R1=CH3 R2=Ph (S, S)
3b´ R1=CH3 R2=Ph (R, S)
3c R1= R2= -(CH2)4
4b R1=CH3 R2=Ph (S, S)
4b´ R1=CH3 R2=Ph (R, S)
4c R1= R2= -(CH2)4
3d R1=H
3e R1=H
R2=CH3
R2= Ph
4d R1=H
4e R1=H
R2=CH3
R2= Ph
References and notes
1. (a) Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51,
3664–3671; (b) Chen, J. G.; Zhu, J.; Skonezny, P. M.;
Rosso, V.; Venit, J. J. Org. Lett. 2004, 6, 3233–3235; (c)
Ward, R. S.; Pelter, A.; Goubet, D.; Pritchard, M. C.
Tetrahedron: Asymmetry 1995, 6, 469–498; (d) Sohda, T.;
Mizuno, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.;
Kawamatsu, Y. Chem. Pharm. Bull. 1982, 30, 3563–
3573; (e) Sohda, T.; Mizuno, K.; Imamiya, E.; Sugiyama,
Y.; Fujita, T.; Kawaamatsu, Y. Chem. Pharm. Bull. 1982,
30, 3580–3600.
Scheme 2.
The sulfoxide 5b was prepared from anti-diastereomer
3b as described elsewhere12 using MCPBA to afford a
diastereomeric mixture of 5b as shown in Scheme 3. It
was possible to isolate crystals of this mixture. X-ray
crystallographic analysis permitted the assignment of
absolute configuration at the newly formed stereogenic
centers (C-12, C-13) as S and S, respectively, to com-
pound 5b (Fig. 6).13
2. (a) Field, L.; Giles, P. M., Jr. J. Med. Chem. 1970, 13, 317–
319; (b) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.;
Date, T.; Okamura, K.; Inagaki, S. J. Org. Chem. 1991,
56, 6556–6564.
3. (a) Wu, M.-J.; Wu, C.-C.; Tseng, T.-C. J. Org. Chem.
1994, 59, 7188–7189; (b) Tseng, T.-C.; Wu, M.-J. Tetra-
hedron: Asymmetry 1995, 6, 1633–1640.
4. Nishide, K.; Ohsugi, S.-I.; Shiraki, H.; Tamakita, H.;
Node, M. Org. Lett. 2001, 3, 3121–3124.
O
O
SCH3
Ph
O
SCH3
Ph
MCPBA
CH Cl
Xc
Xc
5. Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A.
J. Am. Chem. Soc. 2001, 123, 5602–5603.
2
2
Me
Me
o
50 min, 0
C
´
6. Palomo, C.; Oiarbide, M.; Dias, F.; Lopez, R.; Linden, A.
Angew. Chem., Int. Ed. 2004, 43, 3307–3310.
5b
3b
7. Preparation of (S)-4-isopropyl-5,5-dimethyl-1,3-oxazoli-
dinethione is described in: Ortiz, A.; Quintero, L.;
Scheme 3.
´
`
Hernandez, H.; Maldonado, S.; Mendoza, G.; Bernes, S.
Tetrahedron Lett. 2003, 44, 1129–1132.
8. Crystal data for 2a: C13H23NO3S, M = 273.38, colorless
irregular block, 0.65 · 0.60 · 0.36 mm3, space group
P212121, cell parameters a = 7.2713 (7), b = 11.4320 (7),
In conclusion we have applied the intramolecular sulfur
transfer reaction to trisubstituted a,b-unsaturated N-en-
oyl oxazolidine-2-thiones. This study shows that the
anti-diastereomer is favored and obtained via a highly
diastereoselective protonation step. Furthermore this
methodology was applied to synthesize 3-methylthio
alcohols. The absolute configuration to compound 2b
was confirmed from compound 5b.
c = 18.4288 (12) A, Z = 4, Dc = 1.185 g cmꢀ3. Reflections
˚
(4683) collected on a Bruker P4 diffractometer at room
˚
temp, with the Mo-Ka radiation (k = 0.71073 A) in the
range 2h = 4.20–59.98ꢁ, of which 4019 are unique
(Rint = 0.0192). Variables (163) refined:10 R1 = 0.0679
[2731 data with I > 2r(I)] and wR2 = 0.2197 [all data].
Absolute configuration was determined starting from

2246
A. Ortiz et al. / Tetrahedron Letters 46 (2005) 2243–2246
the known configuration at C4 and confirmed by the
Absolute configuration was determined starting from the
known configuration at C4 and confirmed by the refine-
ment of a Flack parameter, x = 0.09 (12), 903 Friedel pairs
measured. Complete data have been deposited with the
CCDC, reference 257399. Structure factors and raw files
are available on request to authors.
refinement of a Flack parameter, x = ꢀ0.22 (18), 1470
Friedel pairs measured. Complete data have been depos-
ited with the CCDC, reference 257397. Structure factors
and raw files are available on request to authors.
9. Crystal data for 2c: C15H25NO3S, M = 299.42, colorless
block, 0.60 · 0.40 · 0.28 mm3, space group P21, cell
parameters a = 6.7361 (4), b = 8.3096 (5), c = 15.2470
12. Crich, D.; Mataka, J.; Zakharov, L. N.; Rheingold, A. L.;
Wink, D. J. Am. Chem. Soc. 2002, 124, 6028–
6036.
(10) A, b = 95.207 (6)ꢁ, Z = 2 ,Dc = 1.170 g cmꢀ3. Reflec-
˚
tions (5907) collected on a Bruker P4 diffractometer at
˚
13. Crystal data for 5b: Crystallization of this compound
revealed to be problematic. After several attempts, we only
produced poor-quality single-crystals, which were how-
room temp, with the Mo-Ka radiation (k = 0.71073 A) in
the range 2h = 5.36–59.96ꢁ, of which 2956 are unique
10
˚
(Rint = 0.0194). Variables (182) refined:
R1 = 0.0413
ever suitable for a low resolution (1.0 A) X-ray study,
allowing the determination of the absolute configuration
for chiral centers with a good level of confidence.
[2290 data with I > 2r(I)] and wR2 = 0.1224 [all data].
Absolute configuration was determined starting from the
known configuration at C4 and confirmed by the refine-
ment of a Flack parameter, x = 0.22 (13), 317 Friedel pairs
measured. Complete data have been deposited with the
CCDC, reference 257398. Structure factors and raw files
are available on request to authors.
C19H27NO4S,
M = 365.48,
colorless
irregular,
0.42 · 0.40 · 0.08 mm3, space group P212121, cell param-
eters a = 7.0592(16), b = 11.460 (4), c = 24.972 (10) A,
˚
Z = 4, Dc = 1.202 g cmꢀ3. Reflections (3559) collected on a
Bruker P4 diffractometer at room temp, with the Mo-Ka
˚
10. Sheldrick, G. M. SHELXL97, University of Go¨ttingen,
Germany, 1997.
radiation (k = 0.71073 A) in the range 2h = 3.92–42.06ꢁ, of
which 2174 are unique (Rint = 0.0573). Variables (255)
refined:10 R1 = 0.0546 [1547 data with I > 2r(I)] and
wR2 = 0.1353 [all data]. Absolute configuration was deter-
mined starting from the known configuration at C4 and
confirmed by the refinement of a Flack parameter,14
x = ꢀ0.2(2), 881 Friedel pairs measured. Complete data
have been deposited with the CCDC, reference 257400.
Structure factors and raw files are available on request to
authors.
11. Crystal data for 2b0: C18H25NO3S, M = 335.45, colorless
plate, 0.40 · 0.20 · 0.08 mm3, space group C2, cell param-
eters a = 19.831 (3), b = 6.4460 (10), c = 16.786 (2) A
˚
b = 117.522 (9)ꢁ, Z = 4, Dc = 1.171 g cmꢀ3. Reflections
(3400) collected on a Bruker P4 diffractometer at room
˚
temp, with the Mo-Ka radiation (k = 0.71073 A) in the
range 2h = 4.16–50.00ꢁ, of which 2753 are unique
(Rint = 0.0194). Variables (211) refined:10 R1 = 0.0455
[2034 data with I > 2r(I)] and wR2 = 0.1094 [all data].
14. Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.