E. Cleator et al. / Tetrahedron Letters 47 (2006) 4245–4248
4247
O
19b. It has been shown that anions a to a sulfonyl
moiety are able to racemize via interaction with the
sulfur d-orbitals,13 hence 19a and 19b are in equilibrium.
This racemization occurs at a faster rate than ring
closure. Cyclization of intermediate 19a is expected to
be faster as, in this case, the bulky R groups are anti
and not eclipsed as in 19b. Sultam 20a is, therefore,
observed as the major product.
O
O
O
O
S
S
O
S
O
NBn
HO
NBn
O
O
S
a
b
BnN
O
O
O
S
c
O
12
13
14
Scheme 6. Reagents and conditions: (a) 1,4-dioxane, K2CO3
(10 mol %), tetraethylammonium chloride (10 mol %), 4 (R = Bn),
100 °C, 88%; (b) MsCl (1.2 equiv), pyridine, DMAP (cat.), rt and (c) n-
BuLi, (2.2 equiv), THF, ꢀ78 °C ! rt, 2 h, 97% over two steps.
In summary, we have developed an efficient synthesis of
N-alkylated-4-substituted isothiazolidine-1,1-dioxides
starting from readily available epoxides. Furthermore,
the use of an enantiomerically enriched epoxide provides
access to the corresponding enantiomerically enriched
sultam. We have also demonstrated the extension of this
method to the synthesis of trisubstituted isothiazolidine-
1,1-dioxides.
used as the starting material (Table 1, entries 4 and 5),
the chirality was faithfully translated to the product
through inversion at the sulfonate-bearing carbon.12
This indicated that the cyclization was occurring exclu-
sively via an SN2 process.
Acknowledgements
Attempts to expand this methodology to 1,2-dialkyl
epoxides were generally unsuccessful, presumably due
to steric hindrance. However, the ring opening of the
bicyclic cyclohexene oxide 12 with N-benzylmethane-
sulfonamide gave the desired trans-amino alcohol 13 in
good yield (Scheme 6). Conversion of 13 to the corre-
sponding mesylate 14 was uneventful; however, when
treated with n-BuLi, 14 was found to revert exclusively
to alcohol 13. This is thought to be a consequence of
14 having both functionalities in equatorial positions,
and thus being unable to attain the correct conforma-
tion for a SN2 reaction. Attempts to cyclize the corre-
sponding besylate were also unsuccessful.
We would like to thank Sophie Strickfuss from the
MSD analytical research group at Hoddesdon for the
chiral HPLC analyses.
References and notes
1. Bowman, W. C.; Ram, M. J. Textbook of Pharma-
cology, 2nd ed.; Blackwell: London, 1979; Chapter
34.
2. Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D.
G.; Furfine, E. S.; Hazen, R. J.; Kazmierski, W. M.;
Salituro, F. G.; Tung, R. D.; Wright, L. R. Bioorg. Med.
Chem. Lett. 2000, 11, 1159.
3. Merten, S.; Fro¨hlich, R.; Kataeva, O.; Metz, P. Adv.
Synth. Cat. 2005, 6, 754.
4. (a) White, E. H.; Lim, H. M. J. Org. Chem. 1987, 52, 2162;
(b) Bliss, A. D.; Cline, W. K.; Hamilton, C. E.; Sweeting,
O. J. Org. Chem. 1963, 28, 3557.
5. Lee, J.; Zhong, Y. L.; Reamer, R. A.; Askin, D. Org. Lett.
2003, 5, 4175.
6. Cooper, G. F. Synthesis 1991, 10, 859.
7. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 936–938.
8. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
9. Baker, B. R.; Kadish, A. F.; Querry, M. V. J. Org. Chem.
1950, 2, 400.
The scope of this methodology was further extended to
the synthesis of trisubstituted isothiazolidine-1,1-di-
oxides: N-benzylpropylsulfonamide 15 was added to (R)-
1,2-epoxyhex-5-ene 16 to give amino alcohol 17 in excel-
lent yield (Scheme 7). The amino alcohol was then con-
verted to the benzenesulfonate 18 which, upon treatment
with n-BuLi, afforded the isothiazolidine-1,1-dioxides
20a and 20b in 52% yield as a 3:1 mixture of diastereo-
mers, respectively.
The observed diastereoselectivity is believed to be a con-
sequence of differing steric environments in the transi-
tion states during the cyclization. Abstraction of the
a-sulfonamide proton generates intermediates 19a and
O
R
O
O
O
S
S
N
PrSO2NHBn
R
H
NBn
OLG
O
O
-
O
O
15
R
S
H
S
NBn
Pr
NBn
20a
a
b
c
19a
+
PhO2SO
HO
O
O
O
R
O
S
O
S
N
H
NBn
H
18
17
-
OLG
16
R
R
20b
19b
Scheme 7. Reagents and conditions: (a) 1,4-dioxane, K2CO3 (10 mol %), tetraethylammonium chloride (10 mol %), 15, 100 °C, 87%; (b) PhSO2Cl
(1.2 equiv), pyridine, DMAP (cat.), 50 °C and (c) n-BuLi, (2.2 equiv), THF, ꢀ78 °C ! rt, 2 h, 52% over two steps.