Stereoselective synthesis of γ- and δ-sultams by intramolecular diels-alder reaction of vinylsulfonamides possessing an acyclic or carbocyclic 1,3-diene moiety

Article abstract of DOI:10.3987/COM-05-S(T)80

A range of novel γ- and enantiopure δ-sultams was prepared by intramolecular [4+2] cycloaddition of vinylsulfonamides with purely thermal activation and under high pressure.

Full text of DOI:10.3987/COM-05-S(T)80

HETEROCYCLES, Vol. 67, No. 2, 2006
589
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 589 - 595. © The Japan Institute of Heterocyclic Chemistry
Received, 8th September, 2005, Accepted, 19th October, 2005, Published online, 21st October, 2005. COM-05-S(T)80
STEREOSELECTIVE SYNTHESIS OF γ- AND δ-SULTAMS BY
INTRAMOLECULAR DIELS-ALDER REACTION OF
VINYLSULFONAMIDES POSSESSING AN ACYCLIC OR
CARBOCYCLIC 1,3-DIENE MOIETY
Victor O. Rogachev,a Victor D. Filimonov,b Roland Fröhlich,c,d Olga
Kataeva,a,d and Peter Metza,*
a Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66,
D-01069
Dresden,
Germany,
Fax:
(+49)-351-463-33162,
e-mail:
peter.metz@chemie.tu-dresden.de
b
Department of Organic Chemistry, Tomsk Polytechnic University, pr. Lenina
Tomsk, 634050, Russia, Fax: (+7)-3822-563637, e-mail:
filim@org.chtd.tpu.edu.ru
c Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, D-48149
Münster, Germany, Fax: (+49)-251-833-9772, e-mail:
frohlic@nwz.uni-muenster.de
d Authors responsible for the X-ray diffraction analyses
30,
Abstract – A range of novel γ- and enantiopure δ-sultams was prepared by
intramolecular [4+2] cycloaddition of vinylsulfonamides with purely thermal
activation and under high pressure.
INTRODUCTION
Sultams1 are useful heterocycles for asymmetric synthesis2 and medicinal chemistry.3 Recently developed
powerful methodologies for the generation of these cyclic sulfonamides include the intramolecular
Diels-Alder reaction,4 sulfonamide dianion alkylation,5 radical cyclization,6 ring closing metathesis,7 and
intramolecular Heck cyclization.8 In a previous communication,4a we reported the preparation of five- and
six-membered sultams via thermal and high pressure intramolecular [4+2] cycloadditions of
furan-containing vinylsulfonamides. Here we communicate an extension of these studies to the synthesis
of γ- and enantiomerically pure δ-sultams by intramolecular Diels-Alder reaction of vinylsulfonamides
possessing an acyclic or carbocyclic 1,3-diene moiety.

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HETEROCYCLES, Vol. 67, No. 2, 2006
RESULTS AND DISCUSSION
Vinylsulfonamides (4-6) incorporating a three atom tether connecting diene and dienophile were readily
available by treatment of N-benzyldienylamines (1-3)9 with vinylsulfonyl chloride10 (Scheme 1). Upon
refluxing a solution of 4-6 in toluene,11 γ-sultams (rac-7), (rac-8), and (rac-9) were formed in good yields
as single diastereomers, respectively. Subjecting a solution of 4-6 in dichloromethane to a pressure of 13
kbar at room temperature11 proved to be even more efficient. The relative configuration of the γ-sultams
was elucidated by 2D NOESY experiments and additionally by X-Ray diffraction analysis in case of
sultam (rac-9).12
SiMe3
R
R
R
N
N
N
Bn
Bn
Bn
:
:
:
3 R = H
1 R = H
2 R = H
a
a
a
:
:
:
4 R = SO2-CH=CH2
5 R = SO2-CH=CH2
6 R = SO2-CH=CH2
b or c
b or c
b or c
H
H
H
H
SO2
H
SO2
N
SO2
H
Me3Si
N
N
Bn
Bn
Bn
rac-7
rac-8
rac-9
Reagents and conditions: (a) CH2=CHSO2Cl, Et3N, CH2Cl2, 0°C, 1-2 h, 92% 4, 95% 5, 96% 6; (b)
toluene, reflux, 1 bar, 70% rac-7 (22 h), 79% rac-8 (8 h), 71% rac-9 (16 h); (c) CH2Cl2, rt, 13 kbar, 71%
rac-7 (29 h), 93% rac-8 (10 h), 90% rac-9 (12 h).
Scheme 1.
An earlier investigation revealed a high diastereoselectivity in the cyclization of vinylsulfonamide
(rac-10) featuring a 1,3-cyclohexadienyl unit to give the endo δ-sultams (rac-11) and (rac-12) under
purely thermal activation or high pressure conditions (Scheme 2).4c Following our studies on
furan-containing substrates bearing an external chiral auxiliary attached to the nitrogen atom,4a we
examined a similar approach toward enantiopure δ-sultams derived from a carbocyclic 1,3-diene moiety.

HETEROCYCLES, Vol. 67, No. 2, 2006
591
see ref. 4c
O2S
NBn
+
S
S
O
NBn
O
BnN
O
O
rac-10
rac-11
90
rac-12
10
toluene, reflux, 1 bar (3 h)
CH2Cl2, rt, 13 kbar (12 h)
:
:
(77%)
(93%)
97
3
Scheme 2.
Primary alcohol (17) was synthesized from sulfone (13) according to a known methodology13,14 (Scheme
3). Nucleophilic substitution of mesylate (18) derived from 17 with (S)-(–)-1-phenylethylamine and
subsequent treatment of the resultant amine (19)15 with vinylsulfonyl chloride gave rise to
vinylsulfonamide (20)15 carrying a nitrogen-bound (S)-(–)-1-phenylethyl unit. Both the thermal and the
high pressure cycloaddition11 led to a roughly 1:1 ratio of endo product diastereomers.16,17 Nevertheless,
δ-sultams (21) and (22) could be readily isolated in pure form after separation by flash chromatography
followed by recrystallization (methanol), and their configuration was unambiguously established by
X-Ray diffraction analysis of 22.12,15
a
c
f
R
N
PhO2S
OR
SO2Ph
OR
14 R = H
13
Ph
:
16 R = THP
:
d
e
b
:
17 R = H
:
19 R = H
:
15 R = THP
g
:
18 R = Ms
:
20 R = SO2-CH=CH2
h or i
20
+
S
S
O
N
O
N
O
O
Ph
Ph
21
53
45
22
47
55
h:
i:
:
:
Reagents and conditions: (a) BuLi, THF, –30°C, 1.5 h, then ethylene oxide, –30°C (1 h) to rt, 98%; (b)
3,4-dihydro-2H-pyrane, PPTS, CH2Cl2, 0°C, 24 h, 100%; (c) t-BuOK, t-BuOH, reflux, 1.5 h, 57%; (d)
EtOH, PPTS, 60°C, 24 h, 63%; (e) MsCl, Et3N, CH2Cl2, 0°C, 1 h, 93%; (f) (S)-(–)-1-phenylethylamine,
80°C, 12 h, 79%; (g) CH2=CHSO2Cl, Et3N, CH2Cl2, 0°C, 1 h, 77%; (h) toluene, reflux, 1 bar, 17 h, 60%;
(i) CH2Cl2, rt, 13 kbar, 23 h, 75%.
Scheme 3.

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HETEROCYCLES, Vol. 67, No. 2, 2006
In a further series of experiments, the double stereodifferentiation brought about by the simultaneous
presence of a stereogenic center within the tether (see Scheme 2) and a chiral auxiliary on nitrogen (see
Scheme 3) was investigated (Scheme 4).
b
+
R
N
R
N
OR
Ph
Ph
:
:
:
26 R = H
:
28 R = SO2-CH=CH2
rac-23 R = H
25 R = H
a
c
c
:
:
rac-24 R = Ms
27 R = SO2-CH=CH2
d or e
27
+
S
S
O
N
O
N
O
O
Ph
Ph
29
30
30
6
d:
e:
70
94
:
:
d or e
28
+
S
O
N
S
O
N
O
O
Ph
Ph
31
73
96
32
27
4
d:
e:
:
:
Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0°C, 1 h, 96%; (b) (S)-(–)-1-phenylethylamine, 80°C,
12 h, 31% 25 + 26; (c) CH2=CHSO2Cl, Et3N, CH2Cl2, 0°C, 3 h, 76% 27, 79% 28; (d) toluene, reflux, 1
bar, 24 h, 44% 29 + 30, 36% 31 + 32; (e) CH2Cl2, rt, 13 kbar, 82 h, 68% 29 + 30, 66% 31 + 32.
Scheme 4.
To this end, alcohol (rac-23)13 was converted by mesylation and nucleophilic substitution with
(S)-(–)-1-phenylethylamine to give a 1:1 mixture of the diastereomeric amines (25) and (26),15 which
were separated by flash chromatography. N-Sulfonation of 25 and 26 with vinylsulfonyl chloride
delivered the vinylsulfonamides (27) and (28),15 respectively, as pure stereoisomers. Due to the additional
methyl substituent present in 27 and 28 as compared to 20 or rac-10, a considerably lower reactivity for
cycloaddition was noted for these sterically more encumbered substrates. As listed in Scheme 4, the 13

HETEROCYCLES, Vol. 67, No. 2, 2006
593
kbar activation was associated with a significantly higher asymmetric induction than the reflux/ambient
pressure process for both 27 and 28.11,16 Clearly, a preferential equatorial orientation of the methyl
substituent on a chair-like folded tether controlled the stereochemical outcome of these reactions.
Interestingly, and in contrast to the situation with furan substrates,4a the diastereoselectivities noted for the
thermal reactions of 27 and 28 at ambient pressure were likewise not affected to a great extent by the
(S)-(–)-1-phenylethyl unit. Separation of the two resulting sultam mixtures (29/30) and (31/32),
respectively, by flash chromatography was not possible. However, pure isomers (29) and (31) could be
obtained by recrystallization (methanol) of the product mixtures from the high pressure reactions instead,
and their configuration was unequivocally determined by X-Ray diffraction analysis.12,15
Application of our optimized conditions for reductive debenzylation of N-1-phenylethyl-δ-sultams4a,18
smoothly effected cleavage of the chiral auxiliary from the sultams (21), (29), (22), and (31) in nearly
quantitative yield (Scheme 5). Similar to the furan cases studied before,4a X-Ray diffraction analysis of
the debenzylated sultams (33), (34) [and (ent-34)] unveiled an sp3 hybridized nitrogen atom (sum of
angles around N = 333.8° - 335.9°) with axial orientation of N-H on a chair δ-sultam,12,15 whereas the
crystal structures of N-1-phenylethyl-δ-sultams (22) and (31) feature an sp2 hybridized nitrogen atom
(sum of angles around N = 355.0° for 22 and 355.2° for 31), and the N-1-phenylethyl substituent in 29
(sum of angles around N = 340.8°) is oriented nearly equatorially on a chair δ-sultam in the solid state.12
HCO2H, rt, 1.5 h
S
O
N
S
O
O
HN
O
Ph
R
R
:
:
33 R = H
:
34 R = Me
21 R = H
98%
97%
:
29 R = Me
HCO2H, rt, 1.5 h
S
O
N
O
S
O
NH
O
R
R
Ph
:
:
ent-33 R = H
:
ent-34 R = Me
22 R = H
98%
97%
:
31 R = Me
Scheme 5.
In conclusion, a range of novel γ- and enantiomerically pure δ-sultams was efficiently prepared by
intramolecular Diels-Alder reaction of vinylsulfonamides possessing an acyclic or carbocyclic 1,3-diene
moiety. Further synthetic elaboration of these heterocycles will be reported in due course.

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HETEROCYCLES, Vol. 67, No. 2, 2006
ACKNOWLEDGEMENTS
This paper is dedicated with our best wishes to Professor Barry M. Trost on the occasion of his 65th
birthday. Financial support of this work by the Deutsche Forschungsgemeinschaft (grants ME 776/15-2
and 436 RUS 17/90/04), the Ministry of Science and Education of Russia (grants 15134 and 399), and the
Bundesministerium für Bildung und Forschung (grant RUS 02/044) is gratefully acknowledged. We
thank Prof. Dr. H. Mayr, Ludwig-Maximilians-Universität München, for samples of dienylamines (2) and
(3).
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15. 19: [α]20D = −50.4° (c 1.0, CH2Cl2); 20: [α]20D = −14.2° (c 1.0, CH2Cl2); 21: [α]20D = −39.0° (c 1.0,
CH2Cl2); 22: [α]20 = −29.0° (c 1.0, CH2Cl2); 25: [α]20 = −94.5° (c 1.0, CH2Cl2); 26: [α]20
=
D
D
D
−35.4° (c 1.0, CH2Cl2); 27: [α]20D = +29.4° (c 1.0, CH2Cl2); 28: [α]20D = −10.0° (c 1.0, CH2Cl2); 29:
[α]20 = +0.4° (c 1.0, CH2Cl2); 31: [α]20 = −2.3° (c 1.0, CH2Cl2); 33: [α]20 = +10.4° (c 1.0,
D
D
D
CH2Cl2); ent-33: [α]20D = −10.4° (c 1.0, CH2Cl2); 34: [α]20D = +10.1° (c 1.0, CH2Cl2); ent-34: [α]20
D
= −10.1° (c 1.0, CH2Cl2).
16. Diastereomeric ratios were determined by 1H NMR spectral integration of the crude product mixture.
Only endo sultams were formed.
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intermolecular Diels-Alder reactions, see references 4a and 4c and: (a) F.-G. Klärner and F. Wurche,
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Eur. J., 1999, 5, 297.
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W. Y. Wong, W. H. Chan, and A. W. M. Lee, Tetrahedron Lett., 2001, 42, 3121. (b) W. H. Chan, A.
W. M. Lee, L. S. Jiang, and T. C. W. Mak, Tetrahedron: Asymmetry, 1997, 8, 2501.