Regioselective synthesis of N-substituted-4-substituted isothiazolidine-1,1-dioxides

Article abstract of DOI:10.1016/j.tetlet.2006.04.038

A novel and efficient synthesis of a range of racemic and enantioenriched N-substituted-4-substituted isothiazolidine-1,1-dioxides from epoxides and sulfonamides is described. The critical choice of the activating group for the cyclization event is discussed. The application of this methodology to the synthesis of N-substituted-4,5-disubstituted derivatives is also described.

Full text of DOI:10.1016/j.tetlet.2006.04.038

Tetrahedron Letters 47 (2006) 4245–4248
Regioselective synthesis of N-substituted-4-substituted
isothiazolidine-1,1-dioxides
Ed Cleator,* Faye J. Sheen, Matthew M. Bio, K. M. Jos Brands,
Antony J. Davies and Ulf-H. Dolling
Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon,
Hertfordshire, EN11 9BU, UK
Received 26 November 2005; revised 2 April 2006; accepted 7 April 2006
Available online 4 May 2006
Abstract—A novel and efficient synthesis of a range of racemic and enantioenriched N-substituted-4-substituted isothiazolidine-1,
1-dioxides from epoxides and sulfonamides is described. The critical choice of the activating group for the cyclization event is dis-
cussed. The application of this methodology to the synthesis of N-substituted-4,5-disubstituted derivatives is also described.
Ó 2006 Elsevier Ltd. All rights reserved.
Sulfonamides are prevalent structural features of many
pharmaceutical agents.1 The corresponding cyclic sul-
fonamides (sultams) have therefore been pursued as po-
tential pharmaceutical scaffolds in their own right.2 The
synthetic strategies towards these important building
blocks have, with very few exceptions,3 relied upon
intramolecular cyclization of the corresponding halo-
alkylsulfonyl chlorides. This approach generally
requires multi-step reaction sequences and/or the use
of noxious reagents (Cl2, PCl5, Bu3SnH/AIBN).4
available starting materials and mild reaction condi-
tions. The cyclization is also found to be stereoselective,
when enantioenriched starting materials are used. The
methodology has also been applied to the synthesis of
4,5-disubstituted isothiazolidin-1,1-dioxides.
During the course of a research project, a number of
N-alkylated-4-substituted isothiazolidine-1,1-dioxides 3
were required. We envisaged that these compounds
could be prepared by addition of sulfonamides to epox-
ides and subsequent ring closure (Scheme 2). Many
epoxides are commercially available in both racemic
and enantioenriched forms, which makes them very
attractive precursors. Additionally, nonracemic epox-
ides can be readily prepared using methods such as the
Jacobsen hydrolytic kinetic resolution (HKR)7 and the
Sharpless epoxidation (SAE).8
Lee et al. have recently shown that substituted sultams
can be effectively prepared from a-amino alcohols 1,
and used this protocol to generate a range of 3-substi-
tuted isothiazolidine-1,1-dioxides 2 in good yields
(Scheme 1).5 A similar strategy had previously been used
by Cooper to produce 3,4-disubstituted isothiazolidine-
1,1-dioxides, starting from the corresponding 1,2-disub-
stituted amino alcohols.6
Ms
O
Ms
O
Whilst this method has proven general for 3- and 3,4-
substituted cyclic sulfonamides there are, to date, no
general methods for the preparation of the 4-substituted
analogues. Herein we report a novel, efficient and regio-
selective synthesis of these compounds, using readily
HO
R
NR''
R'
Cl
NR''
R'
MsO
R
NR''
R'
S
c
b
R''
a
N
R
R
R'
1
2
d
R = alkyl, phenyl, H
R' = alkyl, phenyl, H
R'' = H
Keywords: Sulfonamides; Epoxides; Cyclizations; Ring opening
Scheme 1. Reagents and conditions: (a) MsCl, THF, 0 °C; (b) NaCl,
DMF, 80 °C; (c) LDA, THF, ꢀ50 °C ! rt and (d) n-BuLi, (2.2 equiv),
THF, ꢀ10 °C ! rt, 2 h.
reactions.
*
Corresponding author. Tel.: +44 (0)1992 452179; fax: +44 (0)1992
470437; e-mail: edward_cleator@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.038

4246
E. Cleator et al. / Tetrahedron Letters 47 (2006) 4245–4248
O
O
O
O
O
O
O
S
OH
OH
S
S
O
S
S
O
-
NR
NR
NHR
+
BnO
BnO
BnO
R
Path b
Path a
O
NBn
NBn
R'
R'
OA
S
NBn
3
4
S
O
O
O
O
R = R' = alkyl, phenyl
A = activating group
O
O
6
7
6
Scheme 2. Retrosynthetic approach to 4-substituted isothiazolidine-
1,1-dioxides 3.
O
S
S
O
O
9
O
Scheme 4. Potential pathways for the formation of 6 from 7 upon
treatment with n-BuLi.
The ring opening of epoxides with sulfonamides has
been outlined in the literature.9 Adapting the conditions
of Albanese et al.,10 we found that heating a solution of
a secondary sulfonamide 411 (R = Bn) and an epoxide 5
in 1,4-dioxane at 100 °C gave the desired amino alcohol
6 in good yield. Subsequent activation of the alcohol
prior to intramolecular cyclization was accomplished
upon treatment of 6 with methanesulfonyl chloride
(MsCl) in pyridine at room temperature. The resulting
O
O
O
S
O
O
O
S
Bn
O
OH
S
N
OA
S
N
NHR'
N
O
O
R
R
Bn
R
Bn
R
methanesulfonate (mesylate)
7 could, after acidic
10
11
work-up, be directly cyclized by treatment with n-butyl-
lithium (n-BuLi) in THF (Scheme 3).
Scheme 5. General approach to N-substituted-4-substituted isothiazol-
idine-1,1-dioxides. A = Ms (methanesulfonyl), Bs (benzenesulfonyl).
This procedure gave a modest 48% yield of the cyclized
product 8. The remaining material was found to be alco-
hol 6, resulting from the loss of the mesyl group from 7.
This was ascribed to the decomposition of the methane-
sulfonate by the action of n-BuLi.
Table 1. N-Alkyl-4-substituted isothiazolidine-1,1-dioxides 11 produced
via Scheme 5
Entry
R
R0 Yield of Aa Yield 11 over
10 (%)
two steps (%)
This decomposition could either take place by nucleo-
philic attack of the organometallic species at the sulfur
to give alcohol 6 and sulfone 9 (Scheme 4, path a), or
by deprotonation of the a-hydrogen and elimination of
a sulfene (Scheme 4, path b). Changing the base to LDA
also gave a mixture of 6 and 8, suggesting that path b
was operative. Further evidence for path b was obtained
using an activating group with no a-hydrogens. The
alcohol 6 was converted to the corresponding benzene-
sulfonate (besylate) by treatment with benzenesulfonyl
chloride (BsCl) in pyridine at 50 °C. Treatment of this
benzenesulfonate analogue with n-BuLi led to the for-
mation of the desired N-benzylated-4-substituted iso-
thiazolidine-1,1-dioxide in an improved 76% overall
yield. In this case, no alcohol 6 was observed.
1
2
3
4b
5b
6
Ph
Ph
Bn
Bn
Bn
87
87
88
94
94
97
86
Ms
Bs
Bs
Ms
Bs
Bs
Bs
42
78
83
51
82
81
72
CH2OPh
(R)–(CH2)2CHCH2 Bn
(R)–(CH2)2CHCH2 Bn
(CH2)2CHCH2
Ph
Bn
Ph
7
a Ms = Methanesulfonyl, Bs = benzenesulfonyl.
b Commercially available chiral epoxide (97.4% ee). The chirality was
transferred to the product 11.
In all cases, the overall yield for the two-step activation-
cyclization was greatly enhanced when the benzenesulf-
onates were used as activated intermediates.
Chiral 4-substituted isothiazolidine-1,1-dioxides were
also easily accessed using this methodology. When the
chiral epoxide (R)-1,2-epoxyhex-5-ene (97.4% ee) was
A range of N-substituted-4-substituted isothiazolidine-
1,1-dioxides were prepared using this method (Scheme
5, Table 1).
O
O
N
O
O
S
O
Bn
OH
S
N
OMs
S
N
O
O
c
a
b
Bn
Bn
OBn
OBn
OBn
OBn
5
6
7
8
Scheme 3. Initial preparation of 4-substituted isothiazolidine-1,1-dioxide: Reagents and conditions: (a) 1,4-dioxane, K2CO3 (10 mol %),
tetraethylammonium chloride (10 mol %), 4 (R = Bn), 100 °C, 91%; (b) MsCl (1.2 equiv), pyridine, DMAP (cat.), rt and (c) n-BuLi, (2.2 equiv),
THF, ꢀ78 °C ! rt, 2 h, 48% over two steps.

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.
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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.

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E. Cleator et al. / Tetrahedron Letters 47 (2006) 4245–4248
10. Albanese, D.; Landini, D.; Penso, M.; Petricci, S. Tetra-
hedron 1999, 20, 6387.
11. For initial studies, N-benzyl methanesulfonamide (4,
R = Bn) was prepared in almost quantitative yield by
reaction of benzylamine and methanesulfonyl chloride in
THF, in the presence of triethylamine.
12. Determined by chiral HPLC. Conditions, Column—Chi-
ral AD; eluant 20% iso-propyl alcohol in hexanes con-
taining 0.1% TFA; Retention times—major = 30.5 min,
minor = 34.0 min.
13. Corey, E. J.; Kaiser, E. T. J. Am. Chem. Soc. 1961, 83,
490.