Preparation of enantiopure sultams by intramolecular Diels-Alder reaction of furan-containing vinylsulfonamides

Article abstract of DOI:10.1016/S0040-4039(02)00912-7

Enantiomerically pure δ- and γ-sultams have been prepared by intramolecular [4+2] cycloaddition of N-1-phenylethyl substituted vinylsulfonamides with purely thermal activation and under high pressure. An optimized procedure for reductive debenzylation of

Full text of DOI:10.1016/S0040-4039(02)00912-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4753–4756
Preparation of enantiopure sultams by intramolecular
Diels–Alder reaction of furan-containing vinylsulfonamides†
Viktor O. Rogatchov,a Heiko Bernsmann,a Pia Schwab,a,‡ Roland Fro¨hlich,b,‡ Birgit Wibbelingb,‡ and
Peter Metza,*
aInstitut fu¨r Organische Chemie, Technische Universita¨t Dresden, Bergstraße 66, D-01069 Dresden, Germany
bOrganisch-Chemisches Institut, Universita¨t Mu¨nster, Corrensstraße 40, D-48149 Mu¨nster, Germany
Received 3 May 2002; accepted 13 May 2002
Abstract—Enantiomerically pure d- and g-sultams have been prepared by intramolecular [4+2] cycloaddition of N-1-phenylethyl
substituted vinylsulfonamides with purely thermal activation and under high pressure. An optimized procedure for reductive
debenzylation of the resultant d-sultams is also reported. © 2002 Elsevier Science Ltd. All rights reserved.
We recently reported a highly diastereoselective access
to d- and g-sultams by intramolecular Diels–Alder reac-
tion of vinylsulfonamides1,2 bearing furan,1a carbo-
cyclic1c or acyclic1c 1,3-diene moieties (Scheme 1).
Vinylsulfonamide 7 carrying a nitrogen-bound (S)-(−)-
1-phenylethyl unit was easily available by nucleophilic
substitution from mesylate 57 derived from alcohol 4,8
followed by treatment of the resultant amine 6 with
vinylsulfonyl chloride9 (Scheme 2). After refluxing a
solution of 7 in toluene or subjecting a solution of 7 in
dichloromethane to a pressure of 13 kbar at room
temperature,10 sultams 8 and 9 were isolated in high
yield. The diastereomeric ratio11 8:9 was only 1:1 for
the high pressure reaction, while the (S)-(−)-1-
phenylethyl substituent caused a significant, albeit
rather low asymmetric induction under purely thermal
activation.12 Nevertheless, sultams 8 and 9 could be
readily separated by flash chromatography, and their
configuration was unambiguously established by X-ray
diffraction analysis.13
Since sultams3 have proven to be useful heterocycles for
medicinal chemistry2a and asymmetric synthesis,4 we
investigated the enantioselective preparation of six- and
five-membered cyclic sulfonamides via thermal and high
pressure5,6 intramolecular [4+2] cycloadditions. Here we
communicate our studies with furan-containing sub-
strates featuring an external chiral auxiliary attached to
the nitrogen atom.
O
O
O
S
N
O
S
N
O2S
Bn
∆
N
+
:
Vinylsulfonamide 12 incorporating a three atom tether
connecting diene and dienophile was prepared from
aldehyde 10 via the known amine 1114 (Scheme 3). In
this case, the 13 kbar cycloaddition was associated with
a higher asymmetric induction than the reflux/ambient
pressure process.10,11 Again, the two sultam
diastereomers produced were readily separated by flash
chromatography, and their configuration was unequivo-
cally determined by X-ray diffraction analysis of 13.13
Interestingly, exo sultam 13 was favored by (S)-(−)-1-
phenylethyl substitution in vinylsulfonamide 12,
whereas the corresponding maleic monoamide deriva-
tive of 11 preferentially (65:35) led to the opposite
configuration of the newly generated stereogenic centers
at ambient temperature and pressure.14 This is probably
due to the higher steric demand of a tetrahedral sulfon-
O
O
78%
O
Bn
rac-2
94
Bn
rac-1
rac-3
6
Scheme 1.
Keywords: Diels–Alder reactions; pressure; reactions under; sultams;
debenzylation.
* Corresponding author. Tel.: +49-351-463-37006; fax: +49-351-463-
33162; e-mail: peter.metz@chemie.tu-dresden.de
†
Dedicated to Professor Lutz F. Tietze on the occasion of his 60th
birthday.
X-Ray diffraction analysis.
‡
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00912-7

4754
V. O. Rogatcho6 et al. / Tetrahedron Letters 43 (2002) 4753–4756
OR
b
R
O
N
Ph
OR
b
:
rac-15 R = H
a
O
O
:
rac-16 R = Ms
:
:
:
:
4
5
R = H
6
7
R = H
a
c
R = Ms
R = SO2-CH=CH2
R
R
N
Ph
N
Ph
O
O
O
+
O
S
N
O
O
S
7
+
O
O
:
:
18 R = H
17 R = H
N
c
c
:
:
19 R = SO2-CH=CH2
20 R = SO2-CH=CH2
Ph
Ph
8
9
O
O
O
toluene
reflux (10 h)
:
:
62
38
(80%)
(98%)
O
S
N
S
19
+
O
O
13 kbar
CH2Cl2, rt (12 h)
N
50
50
Ph
Ph
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2,
0°C, 45 min, 98%; (b) 3 equiv. (S)-(−)-1-phenylethylamine,
80°C, 12 h, 79%; (c) CH2ꢀCHSO2Cl, Et3N, CH2Cl2, 0°C, 1 h,
96%.
21
22
toluene
reflux (16 h)
:
:
79
21
(87%)
(98%)
13 kbar
CH2Cl2, rt (14 h)
93
7
R
a, b
N
O
O
CHO
10
O
O
O
O
S
N
O
S
N
Ph
11 R = H
20
+
O
O
:
c
:
12 R = SO2-CH=CH2
Ph
Ph
24
23
toluene
reflux (16 h)
O
:
:
54
46
(85%)
(98%)
O
S
O
S
13 kbar
CH2Cl2, rt (14 h)
12
+
O
O
85
15
N
N
Ph
Ph
Scheme 4. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2,
0°C, 45 min, 97%; (b) 3 equiv. (S)-(−)-1-phenylethylamine,
80°C, 12 h, 67%; (c) CH2ꢀCHSO2Cl, Et3N, CH2Cl2, 0°C, 2–3
h, 84% 19, 82% 20.
13
14
toluene
reflux (16 h)
:
:
58
42
(73%)
(94%)
13 kbar
CH2Cl2, rt (14 h)
66
34
vinylsulfonyl chloride delivered the vinylsulfonamides
19 and 20,13 respectively, as pure stereoisomers. As
depicted in Scheme 4, the diastereoselectivities noted
for the high pressure cycloadditions10,11 of 19 and 20
was hardly affected by the (S)-(−)-1-phenylethyl unit
(compare Scheme 2), and equatorial disposition of the
methyl substituent on the d-sultam—and in the corre-
sponding transition state—clearly dominated the stereo-
chemical outcome of these reactions. On the other
Scheme 3. Reagents and conditions: (a) 3 equiv. (S)-(−)-1-
phenylethylamine, MgSO4, ether, 0°C to rt, 15 h, 98%; (b)
LiAlH4, ether, rt, 6 h, 95%; (c) CH2ꢀCHSO2Cl, Et3N,
CH2Cl2, 0°C, 2 h, 98%.
amide as compared to a trigonal carboxylic amide.15 In
contrast to the crystal structures of the N-1-phenylethyl
d-sultams obtained in this study, all of which feature an
sp2 hybridized nitrogen atom, an sp3 hybridization on
nitrogen was unveiled by the crystal structure of g-sul-
tam 13.13
In a third series of experiments, the double stereodiffer-
entiation brought about by the simultaneous presence
of a stereogenic center within the tether (see Scheme 1)
and a chiral auxiliary on nitrogen (see Scheme 2) was
investigated (Scheme 4). To this end, hydroxyalkylfuran
rac-1516 was converted by mesylation and nucleophilic
substitution to give a 1:1 mixture of the diastereomeric
amines 17 and 18, which were separated by flash chro-
matography. Subsequent treatment of 17 and 18 with
Figure 1. Crystal structure of sultam 21.13,17

V. O. Rogatcho6 et al. / Tetrahedron Letters 43 (2002) 4753–4756
21 22
4755
8
9
23
96%
93%
O
96%
95%
O
93%
O
O
O
O
S
N
O
S
O
S
N
O
S
N
O
S
O
O
O
O
O
N
H
N
H
H
H
H
25
ent-25
26
27
ent-26
Scheme 5. Reductive debenzylation of N-1-phenylethyl d-sultams (see text for conditions).
hand, the diastereoselectivities observed for the thermal
process at ambient pressure10,11 were critically depen-
dent on the relative configuration of 19 and 20.
sultam 26 (and ent-26) unveiled an sp3 hybridized nitro-
gen with axial orientation of N–H on a chair d-
sultam.13
In conclusion, a range of enantiopure d- and g-sultams
was readily prepared by intramolecular Diels–Alder
reaction of N-1-phenylethyl substituted vinylsulfon-
amides. Further synthetic elaboration of these heterocy-
cles as well as extension of these studies to non-furan
dienes will be reported in due course.
As is apparent from the result listed in Scheme 2 and
can be extrapolated from the reaction of N-benzyl
vinylsulfonamide rac-1 shown in Scheme 1, formation
of sultam 21 should be favored by virtue of both
stereogenic elements present in 19. However, for sub-
strate 20 a mismatched combination results that causes
a decrease in stereocontrol. While this argument pro-
vides a consistent rationale in a qualitative sense, expla-
nation of the very low ratio 23:24=54:46 has to take
into account that the two inducing elements are not
acting independently of each other. Specifically during
formation of 21 and 23, a non-bonded interaction
between the methyl group on the sultam and the
branched N-1-phenylethyl substituent can hardly be
avoided. Sultams 21 and 22 were readily separated by
flash chromatography, while this was not possible for
the mixture of sultams 23 and 24. Gratifyingly, pure
isomer 23 could be obtained by recrystallization (etha-
nol) of the product mixture from the high pressure
reaction instead. Unambiguous configurational assign-
ment was achieved by X-ray diffraction analysis of
sultams 21, 22 and 23.13
Acknowledgements
Financial support of this work by the Deutsche
Forschungsgemeinschaft, the Russian Foundation for
Basic Research (grant numbers 00-03-32812 and 02-03-
06577) and the Fonds der Chemischen Industrie is
gratefully acknowledged. V.O.R. thanks the DAAD for
a research stipend.
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provided the desired debenzylated d-sultam in high
yield.18,19 Interestingly, X-ray diffraction analysis of

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1
11. Diastereomeric ratios were determined by H NMR inte-
gration of the crude product mixture. Only exo sultams
were formed.
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rated N-1-phenylethyl g-sultam with cyclopentadienes
(no asymmetric induction by the chiral N-substituent
observed), see Ref. 2b.
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structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 183950 (8), CCDC
183128 (9), CCDC 183129 (13), CCDC 183130 (20),
CCDC 183131 (21), CCDC 183132 (22), CCDC 183133
(23), CCDC 183134 (26), CCDC 183135 (ent-26). Copies
of the data can be obtained, free of charge, on applica-
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18. 25: [h]2D0=−10.7 (c 1.0, CH2Cl2); ent-25: [h]2D0=+10.7 (c
1.0, CH2Cl2); 26: [h]D20=+3.2 (c 1.0, CH2Cl2); ent-26:
[h]D20=−3.2 (c 1.0, CH2Cl2); 27: [h]2D0=+17.8 (c 1.0,
CH2Cl2).
19. No intact g-sultam was obtained from N-1-phenylethyl
g-sultams 13 and 14 using this procedure.