Acyl vs Sulfonyl Transfer in N-Acyl β-Sultams and 3-Oxo-β-sultams

Article abstract of DOI:10.1021/ol0361305

(Matrix presented) N-Acylsulfonamides usually react with nucleophiles by acyl transfer and C-N bond fission. However, the hydrolysis of N-acyl β-sultams is a sulfonyl transfer reaction that occurs with S-N fission and opening of the four-membered ring. Similar to other β-sultams, the N-acyl derivatives are at least 10⁶-fold more reactive than N-acyl sulfonamides. 3-Oxo-β-sultams are both β-lactams and β-sultams but also hydrolyze with preferential S-N bond fission.

Full text of DOI:10.1021/ol0361305

ORGANIC
LETTERS
2
004
Vol. 6, No. 2
01-203
Acyl vs Sulfonyl Transfer in N-Acyl
â-Sultams and 3-Oxo-â-sultams
2
Naveed Ahmed, Wing Y. Tsang, and Michael I. Page*
Department of Chemical and Biological Sciences, UniVersity of Huddersfield,
Queensgate, Huddersfield, HD1 3DH, UK
m.i.page@hud.ac.uk
Received October 31, 2003
ABSTRACT
N-Acylsulfonamides usually react with nucleophiles by acyl transfer and C−N bond fission. However, the hydrolysis of N-acyl â-sultams is a
sulfonyl transfer reaction that occurs with S−N fission and opening of the four-membered ring. Similar to other â-sultams, the N-acyl derivatives
6
are at least 10 -fold more reactive than N-acyl sulfonamides. 3-Oxo-â-sultams are both â-lactams and â-sultams but also hydrolyze with
preferential S−N bond fission.
N-Acylsulfonamides 1 are often used to inactivate serine
enzymes, and the mechanism invariably involves acylation
and C-N bond fission with the serine hydroxyl group
sulfonamides, 1, which incorporate both centers in one
1
molecule, nucleophiles preferentially attack the carbonyl
5
group to displace the sulfonamide anion (Scheme 1). Acyl
attacking the carbonyl group to displace the sulfonamide as
the leaving group. In principle, however, nucleophiles could
attack is favored by an electron-deficient carbonyl center and
the strong electron-withdrawing character of the sulfonamide
group, with the sulfonyl group stabilizing the adjacent lone
pair on nitrogen by a polarization effect rather than conjuga-
tive d-p π bonding. This activates the carbonyl group
toward nucleophilic attack, and insofar as sulfonamides are
2
attack the sulfonyl center and expel the amide group, leading
to sulfonylation of the nucleophile. We are interested in the
3
6
role that ring strain plays in controlling reactivity and have
been studying the four-membered ring of â-sultams 2.
(1) Macdonald, S. J. F.; Dowle, M. D.; Harrison, L. A.; Spooner, J. E.;
Shah, P.; Johnson, M. R.; Inglis, G. G. A.; Clarke, G. D. E.; Belton, D. J.;
Smith, R. A.; Molloy, C. R.; Dixon, M.; Murkitt, G.; Godward, R. E.;
Skarzynski, T.; Singh, O. M. P.; Kumar, K. A.; Hodgson, S. T.; McDonald,
E.; Hardy, G. W.; Finch, H. Bioorg. Med. Chem. Lett. 2001, 11, 243-6.
Macdonald, S. J. F.; Dowle, M. D.; Harrison, L. A.; Shah, P.; Johnson, M.
R.; Inglis, G. G. A.; Clarke, G. D. E.; Smith, R. A.; Humphreys, D.; Molloy,
C. R.; Amour, A.; Dixon, M.; Murkitt, G.; Godward, R. E.; Padfield, T.;
Skarzynski, T.; Singh, O. M. P.; Kumar, K. A.; Fleetwood, G.; Hodgson,
S. T.; Hardy, G. W.; Finch, H. Bioorg. Med. Chem. Lett. 2001, 11, 895-8.
(
2) Sykes, N. O.; McDonald, S. J. F.; Page, M. I. J. Med. Chem. 2002,
4
5 2850-2856
(
3) Page, M. I. Chem. Soc. ReV. 1973, 2, 295
(4) King, J. F.; Rathore, R.; Lam, J. Y. L.; Gao, L. E. R.; Klassen, D. F.
J. Am. Chem. Soc. 1992, 114, 3028. Wood, J. M.; Page, M. I. Trends
Heterocycl. Chem. 2002, 8, 19-34.
(
5) Groutas, W. C.; Houser-Archield, N.; Chong, L. S.; Venkateraman,
In general, acyl transfer reactions in acyclic reactants occur
much more readily than analogous sulfonyl transfers. For
example, the rates of alkaline hydrolysis of acyl derivatives
R.; Epp, J. B.; Huang, H.; McClenahan, J. J. J. Med. Chem. 1993, 36, 3178.
Hlasta, D. J.; Bell, M. R.; Boaz, N. W.; Court, J. J.; Desai, R. C.; Franke,
C. A.; Mura, A. J.; Subramanyam, D.; Dunlap, R. P. Bioorg. Med. Chem.
Lett. 1994, 4, 1801.
3
such as acid chlorides and esters are often about 10 -fold
(6) Terrier, F.; Kizilian, E.; Gaumont, R.; Faucher, N.; Wakselman, C.
4
faster than the equivalent sulfonyl derivative. With N-acyl
J. Am. Chem. Soc. 1998, 120, 9496.
1
0.1021/ol0361305 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/25/2003

Scheme 1
Scheme 2
stronger acids than amides by about 5 pK units, sulfonamide
anions are usually better leaving groups than amide anions.
â-Sultams 2 are the sulfonyl analogues of â-lactams and
are potential sulfonylating agents of a variety of nucleophiles
by displacement of the amine leaving group. As sulfona-
mides, albeit in cyclic four-membered rings, â-sultams are
good models for studying the mechanisms of sulfonyl transfer
reactions and are also possible inhibitors of proteolytic
enzymes.
Acyclic sulfonamides are extremely resistant to alkaline
7
and acid hydrolysis. The difficulty of acid-catalyzed hy-
drolysis arises from the low basicity of sulfonamides
compared with carboxamides, and they also differ from the
8
latter by undergoing protonation on nitrogen. The acid and
base-catalyzed hydrolysis of N-alkyl and N-aryl â-sultams
occurs with exclusive S-N fission to give the corresponding
9
â-aminosulfonic acid. â-Sultams show enormously high
reactivity compared with sulfonamides and are estimated to
be at least 10 -fold more reactive. This is in sharp contrast
7
9,10
either acylation or sulfonylation. Herein, we report the results
of our studies of these reactions.
to the almost identical rate of alkaline hydrolysis of â-lactams
1
1
The alkaline hydrolysis in water of the acyclic N-acyl
sulfonamide, 5, occurs by N-acyl fission as a result of
hydroxide ion attack on the carbonyl group followed by
displacement of the sulfonamide anion. This was shown by
compared with that of their acylic amide analogues.
Although sulfonyl transfer reactions of activated sulfonyl
2
4
derivatives usually occur 10 - to 10 -fold slower than the
4
2
corresponding acyl transfer process, â-sultams are 10 to
0 -fold more reactive than corresponding â-lactams, com-
pared with the 10 -fold slower rate of alkaline hydrolysis of
acyclic sulfonamides compared with analogous amides. As
1
3
product analysis using UV and H NMR spectra as well as
1
4
ESIMS showing the benzoate anion produced. The second-
9
order rate constant for the alkaline hydrolysis of 5, kOH, is
3
-1 -1
1
.30 dm mol
s
at 30 °C (Table 1), showing the high
â-sultams are hydrolyzed faster than the corresponding
â-lactams, their hydrolysis appears to be the first example
of the rate of sulfonyl transfer being greater than that of the
corresponding acyl reaction.
The incorporation of an acyl group next to the nitrogen in
â-sultams may be exo- or endocyclic, giving N-acyl â-sul-
tams 3 or 3-oxo-â-sultams 4, respectively. Nucleophilic
attack on N-acyl â-sultams 3 may involve either ring-
opening, arising from sulfonylation as shown in pathway “a”
of Scheme 2, or attack upon the exocyclic acyl amide group
leading to acylation and preservation of the â-sultam ring
as shown in pathway “b”. Nucleophilic attack on 3-oxo-â-
sultams will result in ring opening but again could involve
reactivity of these amide derivatives and the good leaving
group ability of the sulfonamide anion. These activated
5
amides show a 10 greater reactivity than “normal” amides
and are similar to imides in their susceptibility to attack by
1
1
hydroxide ion. By contrast, the alkaline hydrolysis of the
analogous N-benzoyl â-sultam, 3, occurs exclusively by S-N
fission as a result of attack on sulfur and displacement of
1
the carboxamide. This was confirmed by H NMR and
negative ion ESIMS, with the parent ion m/z ) 228
corresponding to the ring-opened â-amidosulfonic acid
product. We believe this is the first example of the hydrolysis
of a N-acylsulfonamide occurring with S-N rather than C-N
fission (Scheme 2).
(
7) Kice, J. L. AdV. Phys. Org. Chem. 1980, 17, 123. Gordon, I. M.;
The pH-rate profile for the hydrolysis of 3 is shown in
Figure 1. It displays a hydroxide-ion catalyzed reaction for
which the second-order rate constant, kOH, for the alkaline
Maskill, H.; Ruasse, M. F. Chem. Soc. ReV. 1989, 18, 123. King, J. F.;
Gill, M. S.; Klassen, D. F. Pure Appl. Chem. 1996, 68, 825. Kice, J. L.
Progr. Inorg. Chem. 1972, 17, 147. Olah, G. A.; Kobayashi, S.; Nishimura,
J. J. Am. Chem. Soc. 1973, 93, 564.
4
3
-1 -1
hydrolysis of the â-sultam 3 is 1.46 × 10 dm mol
Table 1). There is also a pH-independent hydrolysis and,
at low pH, an acid-catalyzed reaction for which the respective
rate constants, k and k , are given in Table 1.
s
(8) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268. Menger, F. M.;
(
Mandell, L. J. Am. Chem. Soc. 1967, 89, 4424. Maarsen, P. K.; Cerfontain,
H. J. Chem. Soc., Perkin Trans. 2 1977, 1003.
(
9) Baxter, N. J.; Laws, A. P.; Rigoreau, L. J. M.; Page, M. I. J. Am.
Chem. Soc. 2000 122, 3375.
10) Baxter, N. J.; Laws, A. P.; Rigoreau, L.; Page, M. I. J. Chem. Soc.,
Perkin Trans. 2 1996, 2245.
11) Page, M. I. AdV. Phys. Org. Chem. 1987, 23, 165. Page, M. I. The
Chemistry of â-Lactams; Page, M. I., Ed.; Blackie: London, 1992; pp 79-
00. Page, M. I. Acc. Chem. Res. 1984, 17, 144-151.
o
H
Although the alkaline hydrolysis of 3 shows an apparent
(
4
rate enhancement of 10 over that for the acyclic analogue
(
5
, it represents a minimum rate difference for S-N fission
1
because the observed rate for the acyclic sulfonamide 5 is
202
Org. Lett., Vol. 6, No. 2, 2004

Table 1. Rate Constants for the Hydrolysis of N-Acyl Sulfonamides and Amides at 30 °C and an Ionic Strength of 1.0 M (KCl)
compound
kOH (dm3 mol-1 s-1
)
ko (s-1
)
kH (dm3 mol-1 s-1
5.84 × 10-5 a
)
4
5
a
-6 a
-5
N-benzoyl â-sultam, 3
1.46 × 10
1.83 × 10
1.30
3.11 × 10
2.53 × 10
N-benzyl 4,4-dimethyl-3-oxo-â-sultam, 4
N-acetyl N-methyl phenylmethyl sulfonamide, 5
N-benzyl saccharin, 6
4.05
11.2
8.77 × 10-
7
3.80 × 10-5
N-benzoyl â-lactam, 7
a
In 5% acetonitrile-water (v/v).
that for the reaction occurring by C-N fission, and thus that
for S-N fission must be at least 100-fold less. A more
accurate rate enhancement for similar bond-breaking pro-
the sulfonyl center and expulsion of a carboxamide leaving
group, as shown by product analysis. Negative ion ESIMS
shows a parent ion m/z ) 256 corresponding to the ring-
6
1
13
cesses is therefore at least 10 . This is similar in magnitude
opened R-amidosulfonic acid (Scheme 2). H, C HMBC
NMR shows a cross-peak between the carbonyl carbon and
the hydrogens of the methylene benzyl substituent, demon-
strating that the benzyl group remains close to the carbonyl
in the product. For comparison N-benzyl saccharin 6, which
is a γ-lactam γ-sultam analogue, undergoes alkaline hy-
drolysis with exclusive C-N fission and a second-order rate
7
to the enhancement of at least 10 previously reported for
9
,10
â-sultams compared with analogous sulfonamides.
The
3
N-acyl â-sultam 3 is also 10 -fold more reactive than the
analogous N-acyl â-lactam 7, similar to the difference
observed for N-alkyl â-sultams and â-lactams.9
The pH-rate profile for the hydrolysis of N-benzyl 4,4-
dimethyl-3-oxo-â-sultam 4 is shown in Figure 1 and displays
a base-catalyzed reaction as well as a pH-independent
pathway. The associated rate constants for these processes
are given in Table 1.
3
-1 -1
4
constant of 4.05 dm mol s , which is about 5 × 10 times
smaller than that for 4.
That hydroxide ion attacks the sulfonyl center in 4 rather
than the â-lactam carbonyl is consistent with the observation
2
3
The 3-oxo-â-sultam 4 is both a â-sultam and a â-lactam
with a second-order rate constant for alkaline hydrolysis kOH
that â-sultams are 10 to 10 times more reactive than
â-lactams toward alkaline hydrolysis. Attack at the acyl
center would expel a better leaving group, the sulfonamide
anion, than attack at the sulfonyl center to expel the amide
anion. However, based on the similar reactivities of imides
and N-acylsulfonamides toward alkaline hydrolysis, the
nature of the leaving group does not have a large effect. For
5
3
-1 -1
of 1.83 × 10 dm mol
s
(Table 1), which is surprisingly
only 10-fold greater than the N-acyl â-sultam 3 with an
exocyclic group. Attack by the hydroxide ion at either
electrophilic center of 4 involves opening the four-membered
ring. However, nucleophilic attack occurs preferentially at
12
example, the kOH for N-methyl phthalimide is actually 5-fold
greater than that for N-benzyl saccharin 6, and that for
1
3
N-methyldiacetamide is very similar to that for the acyclic
N-acyl sulfonamide 5. Although oxygen nucleophiles attack
the sulfonly center of N-acyl â-sultams, amines show no
reaction in competition with alkaline hydrolysis. In contrast,
1
1
amines react readily with â-lactams and so acyl transfer
may become competitive with sulfonyl transfer in the
aminolysis of 4 in aqueous solution.
Although the rate of the pH-independent hydrolysis of the
3
-oxo-â-sultam 4 is also about 10-fold greater than the
â-sultam 3 with the exocyclic acyl group, there is no acid-
catalyzed hydrolysis of 4. This is consistent with the reduced
1
4
basicity of â-lactams compared with amides, so carbonyl
oxygen protonation is more difficult for the â-lactam 4
compared with 3.
Acknowledgment. We thank the University of Hudder-
sfield for financial support.
OL0361305
Figure 1. Dependence of the pseudo-first-order rate constant
against pH for the hydrolysis of N-benzyl 4,4-dimethyl-3-oxo-â-
sultam 4 ([) in 1% acetonitrile-water (v/v) and N-benzoyl â-sultam
(12) Eriksson, S. O.; Jakobsson, M. Acta Pharm. Suecica 1973, 10, 63.
(13) Matsui, S.; Aida, H. J. Chem. Soc., Perkin Trans. 2 1978, 1277.
(14) Proctor, P.; Gensmantel, N. P.; Page, M. I. J. Chem. Soc., Perkin
3
(×) in 5% acetonitrile-water (v/v) at 30 °C and an ionic strength
of 1.0 M.
Trans. 2 1982, 1185. Wan, P.; Modro, T. A.; Yates, K. Can. J. Chem. 1980,
8, 2423. Cox, R. A.; Yates, K. Can. J. Chem. 1981, 59, 2853.
5
Org. Lett., Vol. 6, No. 2, 2004
203