Synthesis and Diels-Alder reactions of α,β-unsaturated-γ-sultams

Article abstract of DOI:10.1016/S0040-4039(01)00313-6

An efficient synthesis of prop-1-ene 1,3-sultam 4 and its Diels-Alder reactions is reported. Sultams are also prepared as chiral auxiliaries for asymmetric transformations.

Full text of DOI:10.1016/S0040-4039(01)00313-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3121–3124
Synthesis and Diels–Alder reactions of
a,b-unsaturated-g-sultams†
K. F. Ho, Dennis C. W. Fung, W. Y. Wong, W. H. Chan* and Albert W. M. Lee*
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong
Received 11 December 2000; revised 14 February 2001; accepted 21 February 2001
Abstract—An efficient synthesis of prop-1-ene 1,3-sultam 4 and its Diels–Alder reactions is reported. Sultams are also prepared
as chiral auxiliaries for asymmetric transformations. © 2001 Elsevier Science Ltd. All rights reserved.
In the past decade, our team have explored the uses of
different sulfur-based functional groups such as sulfox-
ide, sulfinate and sulfonate as activators of either
acetylenic or vinyl units.1 Several versatile two- or
three-carbon synthons, including chiral acetylenic sul-
foxides and prop-1-ene 1,3-sultone 1,2 have been pre-
pared and have found application in Diels–Alder
reactions and asymmetric synthesis.3 Sulfonamides are
a very common organic functional group.4 Compounds
containing sulfonamides are well known for their wide-
range of biological activities such as antibacterial5 and
peptiomimetic.6 Recently, a,b-unsaturated sulfonamides
were also identified as potent, irreversible inhibitors of
cysteine proteases,7 which are essential to the life cycles
of many pathogenic protozoa. However, the ability of
the sulfonamide group to activate an unsaturated car-
bonꢀcarbon unit as a dieneophile in Diels–Alder reac-
tions has not been studied in detail. The only recent
example found in the literature is the intramolecular
Diels–Alder reactions of vinyl sulfonamides reported by
Metz and co-workers.8 They reported that the electron
withdrawing ability of the sulfonamide group toward
the vinylic unit in intramolecular Diels–Alder reaction
is comparable to that of a sulfonate. Based on our
studies of the chemistry of a,b-unsaturated-g-sultones,
we report in this paper the synthesis and the Diels–
Alder reactions of the a,b-unsaturated-g-sultam, prop-
1-ene 1,3-sultam 4.
O
O
O3SH2C
S
O
n-C4H9NH2
N
n-C4H
9 NH
nC4H9
iii
H
O
O
2
3
O
O
S
O
O
O
O
S
O
S
S
iv
R1
O
CHC6H5
NH2
N C R3
i; ii
+
N
R2
NH
β
γ
R2 = CH2C6H5
CH3
9
R3 = Et
7
4
1
5
R1 = H
(+)-6; (-)-6 R1 = CH3
10 R3 = C6H5
(+)8
(+)8
R2
=
H
C6H5
Scheme 1. Reagents: i. reflux THF; ii. POCl3; iii. (a) HCO2H, 70°C, (b) KOH/EtOH; iv. BuLi; R3COCl.
Keywords: unsaturated sultam; Diels–Alder reaction; chiral auxiliaries.
* Corresponding authors. Fax: (852) 2339 7348; e-mail: alee@hkbu.edu.hk
†
This paper is dedicated to Professor Barry Sharpless on the occasion of his 60th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00313-6

3122
K. F. Ho et al. / Tetrahedron Letters 42 (2001) 3121–3124
Our approach to 4 started from the unsaturated sultone
1. For the unsaturated g-sultone 1, there are two possi-
ble carbon sites for nucleophilic attack, conjugate addi-
tion at the b-carbon or nucleophilic ring opening at the
g-carbon. It was reported that aziridinium betaine 3
was formed when butylamine was reacted with the
unsaturated g-sultone 1 (Scheme 1) presumably via the
conjugate addition intermediate 2. However, we found
that when a slightly more bulky primary amine, such as
benzylamine 5 or a-methylbenzylamine ( )-6, was used
as the nucleophile in THF, only the ring-opened prod-
ucts resulting from nucleophilic attack at the g-carbon
were observed. Without isolation of the ring opened
products, in situ cyclization with POCl3 afforded the
N-alkylated unsaturated g-sultams 7 and 8 in good
overall yield directly from sultone 1 (60% for 5 and 75%
for 6). Debenzylation with formic acid followed by
deformylation in ethanolic KOH afforded a convenient
synthesis of the parent unsaturated g-sultam, prop-1-
ene 1,3-sultam 4.9
To investigate the activating ability of the sulfonamide
group, we studied the Diels–Alder reactions of 4 and
the results are summarized in Table 1. Good yields of
the cycloadducts were obtained but the reactivity of 4 is
much lower than that of the unsaturated sultone 1. It
required days at 110°C to complete the reactions. Sev-
eral Lewis acids were screened to enhance the reactivity
of 4 and we found that Ti(OEt)4 gave the best results.
Although the reaction temperature can be lowered to
60°C in CHCl3, the rate of the reaction is still not very
fast. In the case of cyclopentadiene, the endo/exo ratio
of the cycloadducts were much improved under Lewis
acid conditions (entries 1 and 2). In comparison with
Table 1. Diels–Alder reactions of a,b-unsaturated-g-sultams

K. F. Ho et al. / Tetrahedron Letters 42 (2001) 3121–3124
3123
Scheme 2.
analysis.12 After debenzylation, a new pair of enan-
tiomerically pure chlorine substituted tricyclic sultams
(12a, 12b) were obtained (Scheme 2). Methods for using
these optically pure tricyclic sultams in asymmetric
synthesis are in progress.
the unsaturated sultone, we envisaged that for the
unsaturated sultam, electron withdrawing appending
groups could be attached to the nitrogen atom to
further moderate the reactivity or selectivity of the
unsaturated sultam. Extra coordination sites could also
be created for Lewis acid catalyzed reactions. Two
N-acylated derivatives 9 and 10 were prepared and
subjected to Diels–Alder reactions. However, their reac-
tivities were similar to that of the parent sultam in both
the uncatalyzed and Lewis acid catalyzed reactions
(entries 2, 3, 6, 8 and 10).
Acknowledgements
Financial support from the Faculty Research Grant
and the Research Grant Council (HKBU 2024/00) are
gratefully acknowledged.
Homochiral sultams such as the Oppolzer’s camphor
sultams are important chiral auxiliaries in asymmetric
synthesis.10 We envisaged that if a chiral group is
attached to the sultam’s nitrogen, optically pure tri-
cyclic sultams can be synthesized from the Diels–Alder
cycloadducts. Homochiral unsaturated g-sultam (+)-8
was synthesized using optically pure (S)-(−) a-methyl-
benzylamine (−)-6 in the reaction with the sultone
(Scheme 1). When (+)-8 was subjected to the uncata-
lyzed Diels–Alder reactions with cyclopentadiene, 80%
yield of the diastereomeric cycloadducts with endo/exo
ratio of 7:3 were formed (entry 4). The diastereomeric
ratio of the endo-isomers was 1:1 as determined by
NMR. They can be separated into optically pure forms
by column chromatography. After debenzylation, opti-
cally pure exo- and endo-tricyclic sultams were
obtained. With Ti(OEt)4, the endo-diastereomers were
almost the exclusive product. However, the diastereo-
selectivity was not improved. These tricyclic sultams
had also been previously prepared by us from Diels–
Alder cycloadducts using unsaturated sultone 1 as the
dieneophile.11 The present approach to the synthesis of
these chiral tricyclic sultams with unsaturated g-sultam
(+)-8 as the dieneophile is more convergent. In the
reaction with 5,5-dimethoxy-1,2,3,4-tetrachlorocyclo-
pentadiene, either under uncatalyzed or Lewis acid
catalyzed conditions (entry 11), only the endo-
diastereomers 11a, 11b (1:1) were obtained. The two
endo-diastereomers were separated into optically pure
forms by column chromatography. The structure of one
of the diastereomers 11a was determined by X-ray
References
1. Lee, A. W. M.; Chan, W. H. In Top. Curr. Chem.; Metz,
P., Ed.; Springer, 1997; Vol. 190, pp. 103–129.
2. Lee, A. W. M.; Chan, W. H.; Jiang, L. S.; Poon, K. W.
Chem. Commun. 1997, 611.
3. (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. S.; Mak, T. C.
M. Tetrahedron: Asymmetry 1997, 8, 2501–2504; (b) Lin,
J.; Chan, W. H.; Lee, A. W. M.; Wong, W. Y. Tetra-
hedron 1999, 55, 13983–13998.
4. Tanaka, K. In The Chemistry of Sulphonic Acid, Esters
and Their Derivatives; Patai, S.; Rappoport, Z., Eds.;
Wiley: New York, 1991; pp. 401–452.
5. Vree, T. B.; Hekstar, Y. A. Antibiol. Chemother. 1987, 37,
1.
6. (a) Gennari, C.; Salom, B.; Potenza, D.; Williams, A.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2067; (b) Gennari,
C.; Nestlei, H. P.; Salom, B.; Still, W. C. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1763.
7. Roush, W. R.; Gwaltney, II, S. L.; Cheng, J.; Scheidt, K.
A.; McKerrow, J. H.; Hansell, E. J. Am. Chem. Soc.
1998, 120, 10994–10995.
8. Plietker, B.; Seng, D.; Fro¨hlich, R.; Metz, P. Tetrahedron
2000, 56, 873–879.
1
9. Prop-1-ene 1,3-sultam 4: mp 82–83°C; H NMR (CDCl3,
270 MHz): l 4.15 (t, 2H, J=2.43 Hz), 4.88 (s, 1H), 6.73
(dt, 1H, J=6.48, 2.43), 6.87 (dt, 1H, J=6.48, 2.43 Hz).
13C NMR (CDCl3, 67.8 MHz): l 47.6, 127.49, 137.40. IR
(KBr) w (cm−1): 3241, 3100, 1604, 1388, 1276, 1155.

3124
K. F. Ho et al. / Tetrahedron Letters 42 (2001) 3121–3124
10. Lee, A. W. M.; Chan, W. H.; Yuen, W. H.; Xia, P. F.;
Wong, W. Y. Tetrahedron: Asymmetry 1999, 10, 1421–
1424.
11. Jiang, L. S.; Chan, W. H.; Lee, A. W. M. Tetrahedron
1999, 55, 2245–2262.
12. Crystal data for 11a: C18H19Cl4NO4S, M=487.20,
orthorhombic, P212121 (no. 19), a=9.4717(7), b=
3
,
,
14.561(1), c=15.116(1) A, V=2084.8 (3) A , Z=4, T=
293 K, v(Mo-Ka)=6.93 cm−1
,
12115 reflections
measured, 4660 unique, (Rint=0.0241), final R1=0.0284,
wR2=0.0757 (based on F2) for 4660 [I>2|(I)] observed
reflections.
.
.