Synthesis of 3-sulfanylpropanols containing three consecutive stereocenters via tandem Michael-aldol reaction of enoylthioamides with acetals as key reaction

Article abstract of DOI:10.1016/j.tetlet.2005.08.085

(2S,3S,1′R)-2-(α-Methoxybenzyl)-3-phenyl-3- sulfanylpropionamides were diastereoselectively prepared by the reactions of N-cinnamoyl-4S-isopropyl-5,5-dimethyloxazolidinethione with acetals in the presence of SnCl₄. The absolute configuration of the three newly created contiguous stereocenters was determined by the X-ray analysis of the disulfide. The amides were transformed into propanols by the reductive removal of the oxazolidinone moiety.

Full text of DOI:10.1016/j.tetlet.2005.08.085

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7155–7158
Synthesis of 3-sulfanylpropanols containing three consecutive
stereocenters via tandem Michael–aldol reaction of
enoylthioamides with acetals as key reaction
Hironori Kinoshita,a Natsuko Takahashi,a Tatsunori Iwamura,a Shin-ichi Watanabe,a
Tadashi Kataoka,a,* Osamu Muraokab and Genzoh Tanabeb
aGifu Pharmaceutical University, 6-1 Mitahora-higashi 5-chome, Gifu 502-8585, Japan
bFaculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
Received 19 July 2005; revised 11 August 2005; accepted 18 August 2005
Available online 6 September 2005
Abstract—(2S,3S,10R)-2-(a-Methoxybenzyl)-3-phenyl-3-sulfanylpropionamides were diastereoselectively prepared by the reactions
of N-cinnamoyl-4S-isopropyl-5,5-dimethyloxazolidinethione with acetals in the presence of SnCl4. The absolute configuration of
the three newly created contiguous stereocenters was determined by the X-ray analysis of the disulfide. The amides were transformed
into propanols by the reductive removal of the oxazolidinone moiety.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Efficiency and elegance are valued characteristics of
tandem reactions. Even more appealing are those tan-
dem processes which form carbon–carbon bonds and
thereby generate new chiral centers stereoselectively.
One of them is the Morita–Baylis–Hillman (tandem
Michael–aldol–retro Michael) reaction,1 which is an
atom-economical, carbon–carbon bond-forming reac-
tion involving the coupling of the a-position of activated
alkenes with electrophiles (usually aldehydes) under the
influence of Lewis bases such as DABCO,1 Ph3P,1 chal-
cogen species,2 and proazaphosphatrane sulfide.3 This
reaction is traditionally very slow, so we4 and other
groups5 independently developed the TiCl4–mediated
tandem Michael–aldol reaction, to overcome this
drawback. Recently, we succeeded in the simultaneous
synthesis of four chiral centers by the tandem
Michael–aldol reaction of N-cinnamoyl-4S-methyl-5R-
phenyloxazolidinethione with aldehydes.6 This reaction
gave the chiral product with good to high diastereoselec-
tivity, and we further investigated the chiral auxiliary,
which induces the high diastereoselectivity and gives
the stereochemically pure products easily. On the other
hand, we have reported a simple procedure for the a-
alkoxyalkylation of enones via the tandem Michael–
aldol reaction of chalcogenide-enones with acetals using
BF3ÆEt2O.2d Herein, we describe the reaction of N-cin-
namoyl-4S-isopropyl-5,5-dimethyloxazolidinethione (1)
with acetals in the presence of a Lewis acid and transfor-
mation of the products into 2-(a-methoxybenzyl)-3-phe-
nyl-3-sulfanylpropanols.
First, we used BF3ÆEt2O as a Lewis acid for the reactions
of 1 with benzaldehyde dimethyl acetal (2a) and ob-
tained a complex mixture.2d Then, SnCl4 was used in-
stead of BF3ÆEt2O6 because the chloride ion generated
from SnCl4 would react with the iminium intermediate
to give a more stable chloroamine intermediate. The
reaction of 1 with 2a afforded the adduct 3a in good
chemical yield and with excellent diastereoselectivity.7
Although no difference of the yields was observed be-
tween quenching the reaction mixture with water and
with satd NaHCO3, we worked up the reaction with sat-
urated aqueous NaHCO3 to avoid decomposition of the
products with an acid (Table 1, entries 1 and 2). Reac-
tions with 4-chloro 2b and 4-methoxy derivative 2c sim-
ilarly gave 3b and 3c with excellent diastereoselectivity
(entries 3 and 4). Reaction with 4-nitrobenzaldehyde di-
methyl acetal (2d) formed 3d with excellent diastereo-
selectivity but in a low chemical yield because of
lability of the p-nitrobenzyl carbenium ion (entry 5).
Keywords: Tandem Michael–aldol reaction; Asymmetric synthesis;
Oxazolidinethione; Acetal; Sulfanylpropanol.
*
Corresponding author. Tel.: +81 58 237 8571; fax: +81 58 237
5979; e-mail: kataoka@gifu-pu.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.085

7156
H. Kinoshita et al. / Tetrahedron Letters 46 (2005) 7155–7158
Table 1. Reaction of N-cinnamoylthioamide 1 with acetals 2a–d
O
5
S
O
OMe
O
2'
3'
OMe
OMe
SnCl4 (3 equiv.)
O
N
4
R
O
N
Ph
1'
CH2Cl2, -40°C, 24 h
R
Me
Me
Ph
SH
Me
iPr
Me
iPr
1 (1 equiv.)
2 (2 equiv.)
3
Entry
Acetal 2
Yield (%)a
deb
1
2a (R = Ph)
2a (R = Ph)
2b (R = p-ClC6H4)
2c (R = p-MeOC6H4)
2d (R = p-NO2C6H4)
3a (79)
3a (82)
3b (87)
3c (66)
3d (45)
>95%
>95%
>95%
>95%
>95%
2c
3
4
5
a Isolated yield after the recycling HPLC.
b Determined by 1H NMR.
c Quenched with water instead of aqueous saturated NaHCO3.
O
methoxycarbenium ion. A plausible mechanism is
shown in Scheme 2.
O
OMe
(S)
Ph
(R)
I
2 (1 equiv.)
O
N
3a
CCl4, rt , 1.5 h
Me
)
2
S
(S)
Ph
(S)
Intramolecular Michael addition of the thioamide group
of 1 to the enone moiety activated by SnCl4 forms cyclic
chloroamine 7 rather than iminium chloride 6 via tin
enolate 5, because the absolute configuration of the benz-
ylic position a to the sulfur atom of 3 is different from
that of the product obtained from the reaction with
aldehydes using BF3ÆEt2O.6 Since the Si-face is sterically
more crowded than the Re-face and the SnCl3 moiety
occupies the opposite side of isopropyl, methyl, and phe-
nyl groups, the chloride anion of 6 attacks the iminium
carbon from the Re-face to form chloroamine 7. Steric
repulsion among the phenyl, methyl, and isopropyl
groups of 7B is quite strong on the Si-face. The chlorine
atom interferes with the Re-face attack of the meth-
oxycarbenium ion to the enolate ion. The other isomer
7A has a pseudoequatorial phenyl group and this
conformation relaxes the steric hindrance between the
Me
iPr
4 (79%)
Scheme 1. Synthesis of dimer 4.
Unfortunately, the expected reaction did not proceed in
the case of aliphatic acetals.
An X-ray structural analysis of crystalline compound 4,
obtained by the oxidative dimerization of 3a, allowed us
to assign the configurations of the newly created stereo-
genic centers as shown in Scheme 1 (Fig. 1).8
Stereoselection would be effected in the steps of the
Michael addition of the thiocarbonyl group to the enone
moiety and the aldol reaction of the tin enolate with a
1
SnCl4
Ph
Ph
Ph
Cl-
iPr
S
S
S
Me
Me
N
Cl3SnO
H
O
Me
Me
N
OSnCl3
Cl-
O
N
OSnCl3
Cl-
O
N
OSnCl3
O
Me
Me
iPr
Me
iPr
H
S
Me
iPr
Cl
6A
5
6B
7B
iPr
Si
Me
O
Me
Me
Me
H
N
Cl3SnO
H
O
O
O
OMe
R
OMe
Cl
R
O
(S)
iPr
H
S
O
N
R
(R)
Cl
Re
(S)
Ph
Me
Cl3Sn
N
S
Me
(S)
SH
Me iPr
R
OMe
O
Ph
7A
8
3
Scheme 2. Reaction mechanism for the formation of 3.

H. Kinoshita et al. / Tetrahedron Letters 46 (2005) 7155–7158
7157
Figure 1. ORTEP drawing of 4.
Table 2. Nondestructive cleavage of 3a–d
O
O
O
OMe
R
OMe
1
(S)
(R)
(R)
LiAlH4 (4 equiv.), THF
0°C then rt, 30 min
O
N
O
NH
(S)
iPr
(R)
HO
Ph
R
2
(S)
Ph
3
Me
Me
Me
(S)
SH
SH
(S)
Me iPr
3
9
10
Entry
Sulfanylalcohol 3
Yield (%)
1
2
3
4
3a (R = Ph)
9a (68), 10 (94)
9b (60), 10 (98)
9c (59), 10 (98)
9d (31), 10 (82)
3b (R = p-ClC6H4)
3c (R = p-MeOC6H4)
3d (R = p-NO2C6H4)
phenyl group and the isopropyl or methyl group and is
more stable than 7B. The methoxy carbenium ions can
attack from the Si-face to form the Michael–aldol prod-
uct 3 via cyclic transition state 8. The phenyl group and
the chloro substituent block the Re-face approach of the
carbenium ion.
propanols 9 and chiral auxiliary 10 in good yields.
Utilization of chiral products 3 and 9 is currently under
investigation.
Acknowledgments
This work was supported in part by a Grant-in-Aid (No.
16390009) from the Japan Society for the Promotion of
Science.
Reductive removal of the chiral auxiliary from adduct
3a with lithium aluminum hydride in THF gave rise to
2-(a-methoxybenzyl)-3-sulfanylpropanol 9a in an iso-
lated yield of 68% along with oxazolidinone 10 in an iso-
lated yield of 94% (Table 2, entry 1).9 Regeneration of
oxazolidine-2-thione from the recovered oxazolidinone
has been achieved by treatment with Lawessonꢀs
reagent.10
References and notes
1. For reviews of the Morita–Baylis–Hillman reaction: (a)
Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–
4670; (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001–8062; (c) Ciganek, E. In
Organic Reactions; Paquette, L. A., Ed.; Wiley: New
York, 1997; Vol. 51, pp 201–350; (d) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049–3052; (e) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–
891.
2. (a) Kataoka, T.; Kinoshita, S.; Kinoshita, H.; Fujita, M.;
Iwamura, T.; Watanabe, S. Chem. Commun. 2001, 1958–
1959; (b) Kataoka, T.; Kinoshita, H.; Kinoshita, S.;
Iwamura, T. J. Chem. Soc., Perkin Trans. 1 2002, 2043–
2045; (c) Kataoka, T.; Kinoshita, H.; Kinoshita, S.;
Iwamura, T. Tetrahedron Lett. 2002, 43, 7039–7041; (d)
Kinoshita, H.; Osamura, T.; Kinoshita, S.; Iwamura, T.;
Other products 3b,c were similarly transformed into 3-
sulfanylpropanols 9b,c in good yields. However, nitro
derivative 3d gave sulfanylpropanol 9d in low yield prob-
ably due to the reduction of the nitro group by LiAlH4.
In conclusion, we have developed an asymmetric tan-
dem Michael–aldol reaction of N-cinnamoylthioamide
1 with acetals 2. This reaction furnishes diastereomeri-
cally pure 2-(a-methoxybenzyl)-3-phenyl-3-sulfanylprop-
ionamides 3, which contain three contiguous chiral
centers. The reductive removal of the chiral auxiliary
from the adducts 3 provides 2-alkoxybenzyl-3-sulfanyl-

7158
H. Kinoshita et al. / Tetrahedron Letters 46 (2005) 7155–7158
Watanabe, S.; Kataoka, T.; Muraoka, O.; Tanabe, G.
3H; Me of –CHMe2), 1.02 (d, J = 6.8 Hz, 3H; Me of
–CHMe2), 1.04 (s, 3H; 5-Me), 1.44 (s, 3H; 5-Me), 2.05–
2.12 (m, 1H; –CHMe2), 2.37 (d, J = 9.6 Hz, 1H; SH), 2.96
(s, 3H; OMe), 4.10 (d, J = 2.0 Hz, 1H; 4-H), 4.15
(d, J = 7.5 Hz, 1H; –CHOMe), 4.21 (t, J = 9.6 Hz, 1H;
–CHSH), 5.37 (dd, J = 7.5 and 9.6 Hz, 1H; 20-H), 7.14–
7.31 (m, 9H; ArH); 13C NMR (100 MHz; CDCl3) d = 16.5
(q), 21.2 (q), 21.5 (q), 27.7 (q), 29.9 (d), 43.6 (d), 55.1 (d),
56.7 (d), 66.9 (d), 82.4 (s), 83.4 (d), 127.2 (d), 127.6 (d),
128.5 (d), 129.0 (d), 133.7 (s), 137.1 (s), 141.8 (s), 153.9 (s),
172.6 (s). A methyl carbon and four aromatic carbons are
overlapped; IR (KBr): m = 2976 (SH), 1771 (C@O),
1693 cmÀ1 (C@O); MS (FAB; NBA) m/z (%): 476 (18)
[M++H], 154 (100); elemental analysis calcd (%) for
C25H30ClNO4S (476.03): C, 63.08; H, 6.35; N, 2.94.
Found: C, 62.87; H, 6.28; N, 2.89.
J. Org. Chem. 2003, 68, 7532–7534; (e) Walsh, L. M.;
Winn, C. L.; Goodman, J. M. Tetrahedron Lett. 2002, 43,
8219–8222.
3. You, J.; Xu, J.; Verkade, J. G. Angew. Chem., Int. Ed.
2003, 42, 5054–5056.
4. (a) Kataoka, T.; Iwama, T.; Tsujiyama, S. Chem. Com-
mun. 1998, 197–198; (b) Kataoka, T.; Iwama, T.; Tsujiy-
ama, S.; Iwamura, T.; Watanabe, S. Tetrahedron 1998, 54,
11813–11824; (c) Kataoka, T.; Kinoshita, H.; Iwama, T.;
Tsujiyama, S.; Iwamura, T.; Watanabe, S.; Muraoka, O.;
Tanabe, G. Tetrahedron 2000, 56, 4725–4731; (d) Kat-
aoka, T.; Iwama, T.; Kinoshita, H.; Tsujiyama, S.;
Tsurukami, Y.; Iwamura, T.; Watanabe, S. Synlett 1999,
197–198; (e) Kataoka, T.; Iwama, T.; Kinoshita, H.;
Tsurukami, Y.; Tsujiyama, S.; Fujita, M.; Honda, E.;
Iwamura, T.; Watanabe, S. J. Organomet. Chem. 2000,
611, 455–462; (f) Kataoka, T.; Kinoshita, H.; Kinoshita,
S.; Iwamura, T.; Watanabe, S. Angew. Chem., Int. Ed.
2000, 39, 2358–2360; (g) Kinoshita, S.; Kinoshita, H.;
Iwamura, T.; Watanabe, S.; Kataoka, T. Chem. Eur. J.
2003, 9, 1496–1502; (h) Kataoka, T.; Kinoshita, H. Eur. J.
Org. Chem. 2005, 45–58.
5. For TiCl4-mediated reactions: (a) Li, G.; Hook, J. D.;
Wei, H. X. Recent Res. Devel. Org. Bioorg. Chem. 2001, 4,
49–61; (b) Karur, S.; Hardin, J.; Headley, A.; Li, G.
Tetrahedron Lett. 2003, 44, 2991–2994; For TiCl4–ammo-
nium salt-mediated reactions: (c) Taniguchi, M.; Hino, T.;
Kishi, Y. Tetrahedron Lett. 1986, 27, 4767–4770; (d)
Uehira, S.; Han, Z.; Shinokubo, H.; Oshima, K. Org. Lett.
1999, 1, 1383–1385; (e) Han, Z.; Uehira, S.; Shinokubo,
H.; Oshima, K. J. Org. Chem. 2001, 66, 7854–7857; (f)
Yagi, K.; Turitani, T.; Shinokubo, H.; Oshima, K. Org.
Lett. 2002, 4, 3111–3114.
8. Crystal structure data for 8: C50H60N2O8S2, Mr = 881.15,
orthorhombic, space group: P212121, a = 20.404(4),
3
˚
˚
b = 23.153(3), c = 11.679(3) A, V = 5517(1) A , T =
296.2 K, Z = 4, Dcalcd = 1.061 g/cm3, l(MoKa) = 1.43
cmÀ1, R = 0.243, Rw = 0.288. CCDC-229571 contains
the supplementary crystallographic data for this letter.
These data can be obtained free of charge via www.
ccdc.cam.au.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data center, 12, Union
Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-
033; or deposit@ccdc.cam.au.uk).
9. Typical procedure for the transformation of 3 into 9 and
10: To a stirred solution of 2-(a-methoxybenzyl)-3-sulfa-
nylamide (3a) (178 mg, 0.4 mmol) in dry THF (3.2 mL)
was added LiAlH4 (16 mg, 0.4 mmol) at 0 ꢁC. The mixture
was stirred at room temperature for 30 min and then
quenched by the addition of aqueous NH4Cl. The aqueous
layer was extracted with AcOEt (5 mL · 3). The extract
was washed with saturated aqueous NaCl, dried (MgSO4),
and concentrated under reduced pressure. The residue was
purified by PTLC (hexane/AcOEt/i-PrOH = 30:10:1, v/v)
to give 9a as a colorless oil and 10 as a yellow solid.
6. Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Osamura, T.;
Watanabe, S.; Iwamura, T.; Muraoka, O.; Tanabe, G.
Angew. Chem., Int. Ed. 2003, 42, 2889–2891.
7. Typical procedure for the synthesis of 3: To a stirred
solution of N-cinnamoyl-4S-isopropyl-5,5-dimethyloxaz-
olidinethione (1) (152 mg, 0.5 mmol) and p-chlorobenzal-
dehyde dimethyl acetal (2b) (187 mg, 1.0 mmol) in dry
CH2Cl2 (1.6 mL) was added dropwise a solution of SnCl4
(176 lL, 1.5 mmol) at À40 ꢁC. The mixture was stirred at
the same temperature for 24 h and then quenched by the
addition of saturated aqueous NaHCO3 (2 mL). The
resulting solution was allowed to warm to room temper-
ature and was stirred until the solution became clear. The
aqueous layer was extracted with CH2Cl2 (5 mL · 2) and
the combined organic layers were washed with brine. The
extract was dried (MgSO4) and evaporated under reduced
pressure. The residue was purified by recycling preparative
HPLC, eluting with chloroform to give 3b as a white
24
Compound 9a: Colorless oil; ½aꢀD À117.1 (c 1.0, CHCl3);
1H NMR (400 MHz; CDCl3; TMS) d = 2.02–2.04 (m, 1H;
2-H), 2.11 (d, J = 5.9 Hz, 1H; SH), 3.05–3.07 (m, 1H;
OH), 3.10 (s, 3H; OMe), 3.83–3.86 (m, 1H; CH2), 3.94–
3.99 (m, 1H; CH2), 4.16 (d, J = 3.4 Hz, 1H; –CHOMe),
4.49 (dd, J = 5.9 and 9.8 Hz, 1H; –CHSH), 7.15
(d, J = 6.8 Hz, 2H; ArH), 7.25–7.40 (m, 8H; ArH); 13C
NMR (100 MHz; CDCl3) d = 42.4 (d), 54.1 (d), 57.7 (q),
59.6 (t), 84.8 (d), 126.0 (d), 127.4 (d), 127.5 (d), 127.6 (d),
128.5 (d), 128.9 (d), 136.7 (s), 143.3 (s). Four aromatic
carbons are overlapped; IR (NaCl) m = 3524 (OH),
2560 cmÀ1 (SH); MS (FAB; Gly) m/z (%): 289 (3)
[M++H], 121 (100); HRMS (FAB, Gly); calcd for
C17H20O2S [M++H]: 289.1184; found: 289.1252.
23
1
powder. Mp 47.5–50.0 ꢁC; ½aꢀD +29.9 (c 1.0, CHCl3); H
10. Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A.
J. Am. Chem. Soc. 2001, 123, 5602–5603.
NMR (400 MHz; CDCl3; TMS) d = 0.85 (d, J = 6.8 Hz,