A novel heterocyclic scaffold formed by ring expansion of a cyclic sulfone to sulfonamides

Article abstract of DOI:10.1021/ol9023024

"Chemical Equation Presented" A novel heterocyclic scaffold with a peptidomimetlc backbone structure has been synthesized. The scaffold is formed by insertion of primary amines into a cyclic sulfone to give the corresponding ring-expanded sulfonamides. By

Full text of DOI:10.1021/ol9023024

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5470-5472
A Novel Heterocyclic Scaffold Formed
by Ring Expansion of a Cyclic Sulfone
to Sulfonamides
Magnus Sellstedt and Fredrik Almqvist*
Department of Chemistry, Umeå UniVersity, SE-901 87 Umeå, Sweden
fredrik.almqVist@chem.umu.se
Received October 5, 2009
ABSTRACT
A novel heterocyclic scaffold with a peptidomimetic backbone structure has been synthesized. The scaffold is formed by insertion of primary
amines into a cyclic sulfone to give the corresponding ring-expanded sulfonamides. By varying the amine component, a series of potentially
biologically interesting compounds has been synthesized.
Biologically relevant molecules with ring-fused 2-pyridones
as central fragments are found both in nature1 and as peptide
backbone mimetics.2 We have previously described the
synthesis of compound 1 (Figure 1) that inhibits aggregation
of an Alzheimer’s peptide (Aꢀ1-40) into amyloids.3 The same
compound also inhibits formation of curli, a functional
amyloid that is a virulence factor in Gram-negative bacteria.4
The central bicyclic 2-pyridone core of 1 has two substi-
tiuents that can be indepentently varied,5 and the scaffold
Figure 1
formation.
. A known inhibitor of both curli and Alzheimer’s amyloid
(1) (a) Liu, J. S.; Zhu, Y. L.; Yu, C. M.; Zhou, Y. Z.; Han, Y. Y.; Wu,
F. W.; Qi, B. F. Can. J. Chem. 1986, 64, 837–839. (b) Misra, R.; Pandey,
R. C.; Silverton, J. V. J. Am. Chem. Soc. 1982, 104, 4478–4479. (c) Wall,
M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim,
G. A. J. Am. Chem. Soc. 1966, 88, 3888–3890.
can also be further reacted to form ring-fused pyrazoles,
giving a rigid tricyclic structure with a peptidomimetic
backbone.6
Now we report the synthesis of a novel scaffold with
potential peptidomimetic properties by modification of
compound 1. This scaffold holds an additional substituent
introduced through a ring-expanding transformation, convert-
ing a cyclic sulfone to sulfonamides.
(2) (a) Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Brown,
E. L.; Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.;
Matthews, D. A.; Hou, X.; Meador, J. W.; Ferre, R. A.; Worland, S. T.
Bioorg. Med. Chem. Lett. 2002, 12, 733–738. (b) Svensson, A.; Larsson,
A.; Emtena¨s, H.; Hedenstro¨m, M.; Fex, T.; Hultgren, S. J.; Pinkner, J. S.;
Almqvist, F.; Kihlberg, J. ChemBioChem 2001, 12, 915–918. (c) Zhang,
X. J.; Schmitt, A. C.; Decicco, C. P. Tetrahedron Lett. 2002, 43, 9663–
9666. (d) Åberg, V.; Sellstedt, M.; Hedenstro¨m, M.; Pinkner, J. S.; Hultgren,
S. J.; Almqvist, F. Bioorg. Med. Chem. 2006, 14, 7563–7581.
(3) Åberg, V.; Norman, F.; Chorell, E.; Westermark, A.; Olofsson, A.;
Sauer-Eriksson, A. E.; Almqvist, F. Org. Biomol. Chem. 2005, 3, 2817–
2823.
In the work with analogues of 1, the corresponding sulfone
4 was prepared (Scheme 1).
10.1021/ol9023024 CCC: $40.75
Published on Web 11/05/2009
 2009 American Chemical Society

Scheme 1
.
Oxidation of 1
Table 1. Ring Expansion of Compound 3 To Form
Sulfonamides
entry
R2
product
yield (%)
1
2
3
4
5
Bn
Me
iPr
CH2CH2OH
PMB
6a
6b
6c
6d
6e
74
65
42
61
71
It was curiously noticed that, unlike 2, the stereocenter of
3 was completely epimerized during basic hydrolysis of the
methyl ester. This could suggest reversible elimination of
the sulfone under basic conditions, and indeed, in the
presence of benzyl amine with sodium methoxide as base,
the conjugate addition product 5 was formed (Figure 2).
amine. To the best of our knowledge this is a transformation
not earlier described. It was beneficial to use methanol as
solvent in the first step, as significant decomposition occurred
in nonprotic solvents. However, a change of solvent in the
next step was necessary to avoid oxidation of the sulfinate
to the corresponding sulfate. A variety of primary alkyl
amines reacted well, while anilines and ammonia did not
give any of the expected product and instead decomposition
of 3 was observed. The unsubstituted sulfonamide could
though conveniently be obtained by acidic cleavage of the
PMB group in compound 6e under microwave conditions.
(Scheme 2).
Figure 2. Proposed intermediates formed from compound 3 under
basic conditions in presence of benzyl amine.
Although somewhat unstable, with loss of sulfur dioxide as
primary decomposition product, the conjugate acid of 5 could
be isolated in 53% yield.
Scheme 2. Cleavage of the PMB Group in 6e
Sulfonamides are common structural features in drugs,7
and compound 5 was immediately recognized as a potential
precursor to a cyclic sulfonamide. Oxidative coupling of
sulfinic acids and amines using potassium ferrricyanide has
been reported.8 However, 5 was unaffected by these condi-
tions. Sodium sulfinates form sulfonbromides when reacted
with bromine,9 and when 5 was treated with bromine and
pyridine, ring closure to a novel heterocyclic scaffold
occurred (Table 1).
Effectively this two-step one-pot reaction expands a cyclic
sulfone to its sulfonamide analogue by insertion of a primary
With the unsubstituted sulfonamide 6f in hand, coupling
to form an N-arylated species was attempted. Copper(I)-
catalyzed coupling of sulfonamides with aryl halides has
proven successful.10 However, attempted reaction of 6f with
iodobenzene did not produce any coupling product. The
attention was then turned to Chan-Lam couplings.11 Although
(4) Cegelski, L.; Pinkner J. S.; Hammer N.; Cusumano C. K.; Hung
C. S.; Chorell E. ; Åberg V.; Garofalo C.; Walker J. N.; Seed P. C.; Almqvist
F.; Chapman M. R.; Hultgren S. J. Nat. Chem. Biol. 2009, DOI:10.1038/
nchembio.242.
(5) Emtenas, H.; Alderin, L.; Almqvist, F. J. Org. Chem. 2001, 66, 6756–
6761.
(6) Sellstedt, M.; Almqvist, F. Org. Lett. 2008, 10, 4005–4007.
(7) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr.
Med. Chem. 2003, 10, 925–953.
(10) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q. X. Tetrahedron
Lett. 2005, 46, 7295–7298.
(11) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Vincent, G.;
Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–
3418.
(8) Farrar, W. V. J. Chem. Soc. 1965, 856–858.
(9) Cristol, S. J.; Harrington, J. K.; Singer, M. S. J. Am. Chem. Soc.
1966, 88, 1529–1532.
Org. Lett., Vol. 11, No. 23, 2009
5471

electron-deficient aryls reacted poorly, we were pleased to
find that both electron-rich and electron-neutral aryls could
be coupled (Table 2).
Table 3. Hydrolysis of Methyl Esters 6a-h
Table 2. Chan-Lam N-Arylations
entry
R2
product
yield (%)
1
2
3
4
5
6
7
8
Bn
Me
iPr
CH2CH2OH
PMB
H
Ph
pMeOPh
7a
7b
7c
7d
7e
7f
96
96
91
88
89
84
88
96
entry
Ar
product
yield (%)
1
2
3
Ph
6g
6h
6i
53
37
trace
pMeOPh
mNO2Ph
7g
7h
Finally, the methyl esters 6a-h were hydrolyzed to their
corresponding carboxylic acids, revealing a scaffold with a
C-terminal peptidomimetic backbone (Table 3).
ously prepared compounds this scaffold holds an additional
easily variable substitiuent, allowing access to diverse
molecular libraries.
The obtained compounds will initially be biologically
tested as racemates. However, resolution using chiral chro-
matography appears quite straightforward as indicated by
analytical separation of the enatiomers of 7a and 7b. Further,
enantio-enrichment by co-precipitation of 7a with (S)-1-
phenylethylamine was possible, giving an enantiomeric
excess of about 60% of each enantiomer in the mother liquor
and precipitate, respectively (see Supporting Information).
In conclusion, we report a novel heterocyclic scaffold with
structural peptidomimetic properties. The scaffold is prepared
by a two-step one-pot ring-expanding reaction between a
cyclic sulfone and primary amines. Compared to our previ-
Acknowledgment. We thank the Swedish Natural Re-
search Council, the Knut and Alice Wallenberg Foundation,
and JC Kempe Foundation (SJCKMS) for financial support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new compounds and
chromatograms of chiral chromatography of coumpounds 7a
and 7b. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9023024
5472
Org. Lett., Vol. 11, No. 23, 2009