Enantiomerically pure trans-3,4-disubstituted tetrahydrothiophenes from diastereoselective thiocarbonyl ylide addition to chiral α,β-unsaturated amides

Article abstract of DOI:10.1021/ol9910565

(matrix presented). Asymmetric 1,3-dipolar cycloadditions of a sulfur-containing 1,3-dipole and α,β-unsaturated camphorsultam amides as dipolarophiles are described. The cycloaddition products, trans-3,4-disubstituted tetrahydrothiophenes, were obtained in high diastereomeric ratios (up to 90:10) and in high yields. Chromatographic removal of the minor diastereomer followed by cleavage of the chiral auxiliary furnished either the enantiomerically pure corresponding alcohol or carboxylic acid.

Full text of DOI:10.1021/ol9910565

ORGANIC
LETTERS
1999
Vol. 1, No. 10
1667-1669
Enantiomerically Pure
trans-3,4-Disubstituted
Tetrahydrothiophenes from
Diastereoselective Thiocarbonyl Ylide
Addition to Chiral r,â-Unsaturated
Amides
Staffan Karlsson and Hans-Erik Ho1gberg*
Department of Chemistry and Process Technology, Mid Sweden UniVersity,
SE-851 70 SundsVall, Sweden
hans-erik.hogberg@kep.mh.se
Received September 16, 1999
ABSTRACT
Asymmetric 1,3-dipolar cycloadditions of a sulfur-containing 1,3-dipole and r,â-unsaturated camphorsultam amides as dipolarophiles are
described. The cycloaddition products, trans-3,4-disubstituted tetrahydrothiophenes, were obtained in high diastereomeric ratios (up to 90:10)
and in high yields. Chromatographic removal of the minor diastereomer followed by cleavage of the chiral auxiliary furnished either the
enantiomerically pure corresponding alcohol or carboxylic acid.
Ylide equivalents containing heteroatoms such as nitrogen1
or sulfur2 are useful intermediates for the addition to
dipolarophiles such as R,â-unsaturated acyl derivatives. Such
1,3-dipolar cycloaddition reactions can result in the formation
of five-membered rings (for example, pyrrolidine or tetrahy-
drothiophene derivatives) in one single step. Moreover,
dipolarophiles linked to chiral auxiliaries react with nitrogen
ylides to form cycloaddition products in favor of one
diastereomer.3 However, auxiliary-induced diastereoselective
cycloadditions between thiocarbonyl ylides and dipolaro-
philes have to our knowledge not been investigated.
Recently we reported the asymmetric 1,3-dipolar cyclo-
addition between nitrogen-containing 1,3-dipoles and chiral
dipolarophiles. Thus, R,â-unsaturated acyl derivatives linked
(2) See, for example: (a) Ye, X.-S.; Wong, H. N. C.; J. Org. Chem.
1997, 62, 1940-1954. (b) Aono, M.; Terao, Y.; Achiwa, K. Heterocycles
1995, 40, 249-260. (c) Tominaga, Y.; Takada, S.; Kohra, S. Tetrahedron
Lett. 1994, 35, 3555-3558. (d) Tominaga, Y.; Ueda, H.; Ogata, K.; Kohra,
S.; Hojo, M.; Ohkuma, M.; Tomita, K.; Hosomi, A.; Tetrahedron Lett. 1992,
33, 85-88. (e) Terao, Y.; Aono, M.; Achiwa, K. Heterocycles 1988, 27,
981-1008. (f) Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1987, 1851-
1852. (g) Terao, Y.; Aono, M.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1987, 35, 1734-1740. (h) Hosomi, A.; Hayashi, S.; Hoashi, K.; Kohra, S.;
Tominaga, Y. J. Org. Chem. 1987, 52, 4423-4424. (i) Huisgen, R.; Mloston,
G.; Langhals, E. J. Am. Chem. Soc. 1986, 108, 6401-6402. (j) Terao, Y.;
Aono, M.; Takahashi, I.; Achiwa, K. Chem. Lett. 1986, 2089-2092. (k)
Terao, Y.; Tanaka, M.; Imai, N.; Achiwa, K. Tetrahedron Lett. 1985, 26,
3011-3014.
(1) See, for example: (a) Plancquaert, M.-A.; Redon, M.; Janousek, Z.;
Viehe, H. G. Tetrahedron 1996, 52, 4383-4396. (b) Be´gue´, J.-P.; Bonnet-
Delpon, D.; Lequeux, T. Tetrahedron Lett. 1993, 34, 3279-3282. (c)
Laborde, E. Tetrahedron Lett. 1992, 33, 6607-6610. (d) Padwa, A.; Dent,
W. J. Org. Chem. 1987, 52, 235-244. (e) Terao, Y.; Kotaki, H.; Imai, N.;
Achiwa, K. Chem. Pharm. Bull. 1985, 33, 2762-2766. (f) Padwa, A.; Chen,
Y.-Y.; Dent, W.; Nimmesgern, H. J. Org. Chem. 1985, 50, 4006-4014.
(g) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117-1120.
(3) See, for example: (a) Pandey, G.; Laha, J. K.; Mohanakrishnan, A.
K. Tetrahedron Lett. 1999, 40, 6065-6068. (b) Ma, Z.; Wang, S.; Cooper,
C. S.; Fung, A. K. L.; Lynch, J. K.; Plagge, F.; Chu, D. T. W.
Tetrahedron: Asymmetry 1997, 8, 883-887. (c) Stack, J. A.; Heffner, T.
A.; Geib, S. J.; Curran, D. P. Tetrahedron 1993, 49, 995-1008.
10.1021/ol9910565 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/10/1999

to various chiral auxiliaries were studied and we found that
camphorsultam is the most efficient auxiliary among those
investigated.4
We now wish to present a similar approach to the
preparation of enantiomerically pure trans-3,4-disubstituted
tetrahydrothiophenes.
CsF-catalyzed5 decomposition of chloromethyl trimethyl-
silylmethyl sulfide 3 furnishes the thiocarbonyl ylide 3#
(Scheme 2). This adds to a variety of dipolarophiles in a
stereoselective manner forming substituted tetrahydrothiophene
rings.6 Thus, when starting from dipolarophiles of the
â-substituted (E)-R,â-unsaturated acyl type, the resulting
products are trans-3,4-disubstituted tetrahydrothiophene de-
rivatives.6 We found that a number of such dipolarophiles
linked to camphorsultam underwent highly diastereoselective
thiocarbonyl ylide additions.
Table 1. Diastereomeric Ratio (dr) in the 1,3-Dipolar
Cycloaddition between 2a-c and the Dipole Precursor 3
temp
(°C)
yield
(%)b
product,
dr 4:5c
entrya
dipolarophile
time
1d
2e
3e
4d
5e
6e
7d
8e
9e
2c
2c
2c
2a
2a
2a
2b
2b
2b
0
20
80
0
20
80
0
4 days
2 days
1 h
4 days
2 days
3 h
3 days
2 days
1 h
89
95
94
92
91
84
95
88
40
89:11
86:14
82:18
90:10
89:11
86:14
90:10
87:13
f
20
80
a To one of the dipolarophiles 2a, 2b or 2c (1 molar equiv) in CH3CN
(8 mL/mmol dipolarophile) were added the dipole precursor 3 (1.3 molar
equiv) and CsF (2-3 molar equiv) under an atmosphere of argon. Quenching
with H2O (20-40 mL/mmol dipolarophile), extractions with EtOAc (3 ×
20-40 mL/mmol dipolarophile), and drying (MgSO4) gives the two
The enantiomerically pure dipolarophiles, i.e., (E)-R,â-
unsaturated sultam amides 2a-c, were prepared according
to Scheme 1. In the presence of the CsF catalyst, the dipole
b
diastereomers 4 and 5 after chromatography. Isolated total yield of 4 and
c
5 after liquid chromatography. Calculated on the crude products by1H
NMR. d Performed on a 3 mmol scale. e Performed on a 0.1 mmol scale.
f Not measured.
Scheme 1. Preparation of Chiral Dipolarophiles 2a-c
three dipolarophiles 2a-c. When the reaction temperature
was increased, a small decrease in selectivity was observed
while the yields remained practically constant. However, at
elevated temperature, the dipolarophile 2b gave the cyclo-
addition products in very low yield and the reaction became
very sluggish (entry 9). When the temperature was kept at 0
°C, all three dipolarophiles reacted cleanly during 4 days to
give the products 4 and 5 in high isolated yields (up to 95%)
and high diastereomeric ratios (up to 90:10), see entries 1,
4, and 7. In all cases, the diastereomers 4 and 5 were easily
separated by liquid chromatography. For example, diastereo-
merically pure 4a was obtained in 84% overall yield.
Nondestructive removal of the chiral auxiliary to give the
corresponding enantiomerically pure carboxylic acid or
alcohol along with recovered camphorsultam was accom-
plished using LiOH in refluxing THF:H2O or LiAlH4,
respectively (Scheme 3). To confirm the configurations at
precursor 3 reacted with compounds 2a-c to give exclusively
the two diastereomeric trans-3,4-disubstituted tetrahydro-
thiophenes 4 and 5 (Scheme 2) in excellent yields and high
diastereoselectivities (Table 1).
Scheme 2. 1,3-Dipolar Cycloaddition between 2a-c and 3
Scheme 3. Cleavage of the Camphorsultam Auxiliary and
Subsequent Reductive Desulfurization
(1S)-(-)-2,10-Camphorsultam was found to be very ef-
ficient as a chiral inducer for this type of cycloaddition
sequence. High diastereoselectivities were observed for all
(4) Karlsson, S.; Han, F.; Ho¨gberg, H.-E.; Caldirola, P. Tetrahedron:
Asymmetry 1999, 10, 2605-2616.
positions 3 and 4 of the tetrahydrothiophene ring, 6a-c were
transformed to their corresponding desulfurized, known
compounds 7a-c using Ra-Ni in refluxing EtOH (Scheme
3). The [R]D values of these compounds were used for the
(5) (a) Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1980, 102, 7993-
7994. (b) Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1979, 101, 6452-
6454.
(6) Hosomi, A.; Matsuyama, Y.; Sakurai, H. J. Chem. Soc., Chem.
Commun 1986, 1073-1074.
1668
Org. Lett., Vol. 1, No. 10, 1999

confirmation of the absolute configurations at C-3 and C-4:
dipole (3#) and R,â-unsaturated (1S)-(-)-camphorsultam
amides as chiral dipolarophiles. We have also demonstrated
that a dipolarophile containing a vinyl ether moiety (i.e. 2b)
can be used as the reactive partner in the cycloaddition
sequence resulting in the enantioselective introduction of a
4-hydroxy equivalent in the tetrahydrothiophene ring.
7a [R]25 ) -38.1 (lit.7 for ent-7a [R]23 ) +40.65); 7b
D
D
[R]25 ) -55.9 (lit.8 [R]20 ) -41.7); 7c [R]25 ) -63.1
D
D
D
(lit.7 for ent-7c [R]21.5 ) +53.1).
D
We also prepared the enantiomerically pure oxazolidinone
dipolarophiles of type 2, where XC in the amides were
derived from 4(S)-tert-butyl- and 4(R)-phenyl-2-oxazolidi-
none. The CsF-catalyzed cycloaddition reactions of these
dipolarophiles with compound 3 were not successful. Al-
though the yields were high, the diastereomeric ratios
obtained were unsatisfactory: 55:45.
In conclusion, enantiomerically pure trans-3,4-disubsti-
tuted tetrahydrothiophenes 6 were obtained via asymmetric
cycloaddition reactions between a sulfur-containing 1,3-
Acknowledgment. This work was supported by the
Swedish Natural Science Research Council (NFR) and the
Swedish Council for Forestry and Agricultural Research
(SJFR).
Supporting Information Available: Text giving experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron 1989, 45, 479-
488.
(8) Baker, R.; Boyes, R. H. O.; Broom, D. M. P.; O′Mahony. M. J.;
Swain, C. J. J. Chem. Soc., Perkin Trans. 1 1987, 1613-1621.
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