A concise synthesis of β-lactam-sulfonamide hybrids

Article abstract of DOI:10.1016/j.tetlet.2004.03.055

Using ring closing metathesis (RCM) as the key operation, a rapid access to β-lactams fused to a sultam moiety of variable ring size was developed from low cost, commercially available starting materials. An efficient RCM of 4-vinyl-azetidin-2-ones to give 1-aza-bicyclo[4.2.0]oct-4-en-8-ones is also reported.

Full text of DOI:10.1016/j.tetlet.2004.03.055

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3589–3592
A concise synthesis of b-lactam–sulfonamide hybrids
Dirk Freitag, Pia Schwab and Peter Metz*
Technische Universit€at Dresden, Institut f€ur Organische Chemie, Bergstraße 66, D-01069 Dresden, Germany
Received 6 February 2004; revised 28 February 2004; accepted 10 March 2004
Dedicated to Professor Achim Mehlhorn on the occasion of his 65th birthday
Abstract—Using ring closing metathesis (RCM) as the key operation, a rapid access to b-lactams fused to a sultam moiety of
variable ring size was developed from low cost, commercially available starting materials. An efficient RCM of 4-vinyl-azetidin-2-
ones to give 1-aza-bicyclo[4.2.0]oct-4-en-8-ones is also reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Seventy-five years after Sir Alexander Fleming’s discovery
of penicillin, b-lactams continue to be one of the most
important classes of antibacterial agents.1 However, many
bacteria have developed effective defense mechanisms
against commonly used b-lactams such as penicillins and
cephalosporins.2 One approach to combat bacterial
resistance is the search for novel bioactive substances
based on the azetidin-2-one core.3 Turos and co-workers
reported a range of nonconventionally fused b-lactams
including the N-sulfonyl compounds 1a,b4a and 2a,b4b by
blending classical b-lactam antibiotic partial structures
from monobactams and carbapenems or clavulanic acids,
respectively (Fig. 1). A sequence involving [2þ2] ketene–
imine cycloaddition, halogen-promoted cyclization of
alkynyl N-methylthio b-lactams and oxidation was used
for the synthesis of these compounds.5
As part of a program initiated to develop novel methods
for the preparation and synthetic elaboration of sultones
and sultams,6 we have devised a complementary access
to the structurally related heterobicyclic compounds 3,
which can be viewed as b-lactam–sulfonamide hybrids
(Scheme 1). Similar to the b-lactam function, the sul-
fonamide functional group stands out as one of the most
important pharmacophores.7 Recently, cyclic sulfona-
mides (sultams) have been shown to be highly useful
heterocycles for medicinal chemistry as well.8;9 Our
approach to hybrids 3 uses [2þ2] olefin–isocyanate
cycloaddition,10 ring closing metathesis (RCM),11;12 and
hydrogenation to rapidly arrive at the designed targets
with variable ring size of the sultam moiety. Moreover,
the presence of the olefin in unsaturated intermediates 4
offers further options for straightforward modification.
b-Lactams 6a,b synthesized by cycloaddition of chloro-
sulfonyl isocyanate (8)13 with 1,3-butadiene (7a) and
I
OAc
H
N
H
N
X
X
I
R
R
Ph
R
S
S
RCM
Ph
O
O
O
O
O
O
N
N
N
n
n
n
S
S
S
O
O
O
1a : X = OMe
1b: X = N-phthalimidyl
2a : X = OMe
2b: X = N-phthalimidyl
O
O
O
O
O
O
3
4
5
Figure 1. Carbapenem–monobactam hybrids 1a,b and clavulanic acid–
monobactam hybrids 2a,b.
R
R
[2+2]
O C N
+
SO2Cl
NH
O
Keywords: Cycloaddition; Ring closing metathesis; b-lactams; Sultams.
* Corresponding author. Tel.: +49-351-463-37006; fax: +49-351-463-
33162; e-mail: peter.metz@chemie.tu-dresden.de
7
8
6
Scheme 1. Synthetic strategy for b-lactam–sulfonamide hybrids 3.
X-Ray diffraction analysis.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.055

3590
D. Freitag et al. / Tetrahedron Letters 45 (2004) 3589–3592
isoprene (7b) according to a published procedure10 were
SO2Cl
(9)
converted to N-sulfonyl derivatives 5 with olefinic sul-
fonyl chlorides 9a–d (Scheme 2, Table 1). Vinylsulfonyl
chloride (9a) can be readily derived from commercially
available 2-chloroethanesulfonyl chloride via dehydro-
halogenation,14 while building blocks 9b–d are easily
secured in two steps from the corresponding olefinic
bromides.15 For preparation of N-vinylsulfonyl imides
5a,b, triethylamine proved to be a suitable base, whereas
for all other RCM substrates 5, deprotonation of 6 with
butyllithium prior to coupling with sulfonyl chlorides
9b–d turned out to give higher yields.
n
R
N
R
(n = 0 - 3)
NH
Et3N, cat. DMAP
CH2Cl2, −40 °C to rt
or
n
S
O
O
O
5
O
6
BuLi, THF, −78 °C to rt
(R = H, Me)
(R = H, Me; n = 0 - 3)
Scheme 2.
Table 1. Preparation of N-sulfonyl b-lactams 5
6
R
9
n
5
Methoda
Yield 5 (%)b
The generation of bicyclic and tricyclic b-lactam arrays by
ring closing metathesis of dienes and enynes has received
considerable attention in recent years.16–20 Since RCM of
4-vinyl-azetidin-2-ones bearing an alkene containing sub-
stituent on nitrogen has met with no success so far,16 we
were not too surprised about the complete failure of a first
attempted RCM of N-sulfonyl b-lactams 5a,b with
Grubbs’ second generation catalyst 10a21 to give the
carbapenem–monobactam hybrids 4a,b (Scheme 3, Table
2). However, much to our delight, subjecting the homologs
5c–h to standard RCM conditions22 resulted in the smooth
a
b
a
b
a
b
a
b
H
a
a
b
b
c
0
0
1
1
2
2
3
3
a
b
c
d
e
f
A
A
B
B
B
B
B
B
64
30
80
46
73
84
68
67
Me
H
Me
H
Me
H
c
d
d
g
h
Me
a Method A: Et3N, 10 mol % DMAP, CH2Cl2, ꢀ40 °C to rt, 2 h.
Method B: 6þBuLi, THF, ꢀ78 °C then 9, ꢀ78 °C to rt, 16 h.
b Isolated yield after flash chromatography.
R
Ru
PCy3
5 mol% 10a
CH2Cl2, reflux
1 bar H2, 30 % Pd/C
EtOAc, rt
R
N
R
N
Cl
Cl
Ph
5
n
n
S
S
O
O
O
O
O
O
Mes
N
N Mes
10a : R =
4
3
(R = H, Me; n = 1 - 3)
(R = H, Me; n = 1 - 3)
10b : R = PCy3
Scheme 3.
Table 2. Synthesis of b-lactam–sulfonamide hybrids 3 by RCM of dienes 5 and subsequent hydrogenation
5
a
b
t (min)a
4
Yield 4 (%)b
3
Yield 3 (%)b
R
60
4a: R ¼ H
0
0
––
––
––
––
N
S
S
60
4b: R ¼ Me
O
O
O
O
R
R
c
30
30
4c: R ¼ H
56
82
3c: R ¼ H
82
N
N
S
O
O
d
4d: R ¼ Me
3d: R ¼ Me
97
O
O
O
O
R
R
e
f
15
15
4e: R ¼ H
98
97
3e: R ¼ H
99
N
O
N
O
S
S
O
4f: R ¼ Me
3f: R ¼ Me
100
O
O
R
R
g
h
90
90
4g: R ¼ H
28
63
3g: R ¼ H
90
92
N
O
N
O
4h: R ¼ Me
3h: R ¼ Me
O
S
O
O
S
O
a Reaction time for the RCM step.
b Isolated yield after flash chromatography.

D. Freitag et al. / Tetrahedron Letters 45 (2004) 3589–3592
3591
In summary, we have established a simple protocol for
the rapid production of potentially pharmacologically
interesting,26 nonconventionally fused b-lactams using a
cycloaddition–RCM strategy. Further functionalization
of the unsaturated sultams 4, as well as investigations on
the pharmacological properties of the novel heterocycles
described in this letter will be reported as results unfold.
Acknowledgements
Figure 2. Crystal structure of unsaturated sultam 4f.23;24
Financial support of this work by the Deutsche For-
schungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged.
formation of the desired heterobicycles 4c–h as crystalline
materials. Unsaturated e-sultam 4f provided suitable
crystals for X-ray diffraction analysis that unequivocally
confirmed its structure, which features an sp2 hybridized
nitrogen atom (sum of angles around N ¼ 359.1°) and a
References and notes
23;24
ꢀ
C(O)–N bond length of 1.393A (Fig. 2).
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amide hybrids 3c–h (Scheme 3, Table 2). A proper
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R
R
N
R
N
R
b
c or d
a
e
6a,b
N
N
O
O
O
O
12a : R = H
11a : R = H
13a : R = H
14a : R = H
12b : R = Me
11b : R = Me
13b : R = Me
14b : R = Me
Scheme 4. Reagents and conditions: (a) aq KOH, cat. Bu4NHSO4, 4-bromo-but-1-ene, cat. NaI, THF, rt, 35% 11a from 6a, 55% 11b from 6b; (b)
5 mol % 10a, CH2Cl2, reflux, 81% 12a from 11a, 100% 12b from 11b; (c) (i) BuLi, THF, ꢀ78 °C, (ii) allyl bromide, ꢀ78 °C to rt, 32% 13a from 6a; (d)
(i) NaH, THF, 0 °C, (ii) allyl bromide, 0 °C to rt, 90% 13b from 6b; (e) 25 mol % 10a, CH2Cl2, reflux.

3592
D. Freitag et al. / Tetrahedron Letters 45 (2004) 3589–3592
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22. Typical procedure for RCM of dienes 5: Under argon
atmosphere, a three-necked flask was charged with a
solution of N-sulfonyl b-lactam 5f (62 mg, 0.27 mmol) in
dichloromethane (27 mL). Grubbs catalyst 10a (11.5 mg,
0.014 mmol, 5 mol %) was added in one portion under
reflux, the mixture was stirred for 30 min at reflux, and the
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(52.7 mg, 97%) as a white solid; IR (neat) 1785 cmꢀ1; H
1
NMR (CDCl3, 300 MHz): d 1.67 (s, 3H), 2.55–2.69 (m,
2H) 3.04 (AB pattern, J ¼ 15:6 Hz, Dd ¼ 19:9 Hz, 2H),
3.29–3.39 (m, 2 H), 5.70–5.80 (m, 2 H); 13C NMR (CDCl3,
75 MHz): d 21.8 (t), 24.9 (q), 52.2 (t), 53.9 (t), 61.6 (s),
125.6 (d), 135.2 (d), 162.5 (s); MS (LC–MS, ESI) m=z: 219
(100) [MþNHþ4 ]. Anal. Calcd for C8H11NO3S: C, 47.75;
H, 5.51; N, 6.96; S, 15.93. Found: C, 47.80; H, 5.71; N,
6.83; S, 15.45.
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with the Cambridge Crystallographic Data Centre as
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Copies of the data can be obtained, free of charge, on
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for 2 h. The resulting mixture was filtered through a short
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;
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53.1 (t), 60.5 (s), 165.3 (s); MS (LC–MS, ESI) m=z: 226 (14)
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N, 6.89; S, 15.78. Found: C, 47.55; H, 6.56; N, 6.55; S,
15.92.
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