Synthesis and anti-fungal properties of some simple cyclopentenones and derivatives

Article abstract of DOI:10.1016/S0040-4039(00)02110-9

1-Methylsulphenyl-2-phenylsulphenylethyne has been shown to be a precursor for either α-sulphenyl ketone or α-methylene ketone moieties in cyclopentenoids produced via [3+2] cycloaddition of an allyl cation. One of these ketones, the α-sulphenyl cyclopentenone 5, has been found to display potency against a range of fungi in vitro but its close analogues are largely inactive.

Full text of DOI:10.1016/S0040-4039(00)02110-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 955–959
Synthesis and anti-fungal properties of some simple
cyclopentenones and derivatives
J. Allen Miller,* Ashley W. Pugh, G. Mustafa Ullah and G. Malcolm Welsh
Department of Medicinal Chemistry, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, UK
Received 17 October 2000; revised 9 November 2000; accepted 15 November 2000
Abstract—1-Methylsulphenyl-2-phenylsulphenylethyne has been shown to be a precursor for either a-sulphenyl ketone or
a-methylene ketone moieties in cyclopentenoids produced via [3+2] cycloaddition of an allyl cation. One of these ketones, the
a-sulphenyl cyclopentenone 5, has been found to display potency against a range of fungi in vitro but its close analogues are
largely inactive. © 2001 Elsevier Science Ltd. All rights reserved.
More than a decade ago, one of us reported1 the
synthesis of 4-chlorocyclopentenes via the [3+2]
cycloaddition of alkynes to allyl cations, generated
from allylic chlorides under Lewis acidic conditions.
Subsequently, this reaction was applied to 1-sulpheny-
lalkynes bearing either an MeS- or PhS- group, and
incorporation of these sulphenyl ligands was observed
to result in regiochemical control and in higher yielding
cycloadditions.2,3 Given the facility with which these
cycloadducts can be transformed into sulphenylated
cyclopentadienes,4 there was a good prospect that the
use of bis-sulphenylethynes in the cycloaddition would
allow entry to a range of simple sulphenylcyclopent-
enones via the cycloadducts 1 and 2, followed by
hydrolysis of the dienyl sulphide intermediates 3 and 4,
as outlined in Scheme 1. We report here that this
projected chemistry has been achieved and represents a
novel, short and flexible route to cyclopentenones, such
as 5 and 6, bearing organosulphur ligands.5
The reason for this structural focus lay in the range of
biological and potentially medicinal properties exhib-
ited by cyclopentenones and their analogues. Some of
these are natural products like methylenomycin B, an
anti-bacterial,6 and
a range of cyclopent-2-enone
prostanoids such as the punaglandins and clavulones,7
which were originally of interest for their anti-tumour
properties, but which are now under scrutiny as poten-
tial anti-viral agents and cytoprotectives.8 The patent
literature9 also describes natural cyclopentenones and
Scheme 1. Reagents: (i) ZnCl2, CH2Cl2; (ii) chromatographic separation; (iii) KOtBu, THF; (iv) HgCl2, aq. acetone, D.
Keywords: [3+2] cycloaddition; allyl cations; sulphenyl cyclopentenones; anti-fungal activity.
* Corresponding author. Present address: Protherics plc, Beechfield House, Lyme Green Business Park, Macclesfield, Cheshire SK11 0JL, UK.
Tel.: +0044 (0)1625 500555; fax: +0044 (0)1625 500666; e-mail: allen.miller@protherics.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02110-9

956
J. A. Miller et al. / Tetrahedron Letters 42 (2001) 955–959
surprise,10 although it contrasts sharply with the com-
plete lack of regioselection in the previous [3+2]
cycloaddition step. As shown in Scheme 2, ketone 5
was then elaborated into further derivatives 7–13 using
methods that were standard, apart from the use of
palladium mediated reduction of 5 with diphenylsi-
lane,11 to give 9—conditions that were novel at the
time. The dienone 13, which is a structural isomer of
methylenomycin B, and also contains the same dienone
‘pharmacophore’ as the clavulones, was formed sponta-
neously from the diastereomeric sulphoxides derived
from 12.
For some of our targets, 5 was not a sensible starting
point. Thus we prepared12 4,4-dimethylcyclopent-2-
enone 14 and from this the ketones 15–17 were made,
as shown in Scheme 3. The benzylation and methane-
sulphonylation of the lithium dienolate of 14 proceeded
normally, but sulphenylation was more problematic.
Phenylsulphenylation, to provide 5 by a route different
from [3+2] cycloaddition, worked well using diphenyl-
disulphide, but the corresponding reaction with di-
methyldisulphide gave polysulphenylated products.
This difficulty was overcome by using methyl methan-
thiol-sulphonate13 as a sulphenylating agent.
Scheme 2. Reagents: (i) LAH, Et2O; (ii) NaBH4, EtOH; (iii)
ZnCl2, Ph2SiH2, Pd(PPh3)4, CHCl3; (iv) m-CPBA, CH2Cl2
(−40°C); (v) m-CPBA, CH2Cl2 (22°C); (vi) LDA, MeI; (vii)
m-CPBA.
synthetic 2-substituted variants for which a range of
claims are made with respect to anti-tumour activity
and inhibition of osteoporosis. Here we also describe
the in vitro anti-fungal properties of 5, along with the
subsequent synthesis and anti-fungal testing of a series
of its simple analogues.
It was also deemed desirable to have at least one
lipophilic and relatively bulky group at the 4-position
of analogues of 5. This was achieved from 1-methylcy-
clopenten-3-one using the methodology of Horiguchi et
1-Chloro-3-methylbut-2-ene was used as the allyl cation
precursor in our cycloaddition experiments, which were
run under the same conditions as those reported ear-
lier.1–3 Cycloaddition to 1-methylsulphenyl-2-phenyl-
sulphenylethyne occurred in good yield, but,
interestingly, the product was a 50:50 mixture of the
regioisomeric adducts 1 and 2. Fortunately, these
adducts were readily separated by careful column chro-
matography, and each was then transformed individu-
ally into the corresponding dienes, 3 and 4, respectively,
using potassium t-butoxide.4 Subsequent mercuric chlo-
ride catalysed hydrolyses of 3 and 4 (1 and 2 were both
inert to hydrolysis) each gave only the products result-
ing from hydrolysis of the methylsulphenyl group, i.e.
enones 5 and 6, respectively. The highly selective
hydrolysis of the methyl vinyl sulphide function was no
al.14 to add an n-butyl group in a copper mediated
Michael addition. This chemistry is outlined in Scheme
4 and yielded compounds 18–20 as diastereomeric
mixtures.
When the ketones and derivatives 5–21 were submitted
to a range of microbiological screens, the anti-fungal
properties of 5 stood out. Using miconazole as an
internal standard, 5 was found to be more active
against some strains, particularly the dermatophytes.
The only other compound to display any significant
activity was the methylated homologue 12. From these
data, it was clear that 5 had the makings of an anti-fun-
gal lead, and that the structural features required for
activity were rather tight, as shown by the data in the
Table 1,15 which records all compounds with any hint
Scheme 3. Reagents: (i) PhCH2Br; (ii) MeSO2Cl; (iii) MeS-SO2Me.

J. A. Miller et al. / Tetrahedron Letters 42 (2001) 955–959
957
Scheme 4. Reagents: (i) BuMgBr, THF, HMPA–CuBr·SMe2; (ii) Me3SiCl; (iii) PhSCl, CH2Cl2; (iv) m-CPBA, −78–20°C, CH2Cl2.
of activity. Compounds 7–9, 14, 16 and 18–21 were
completely inactive. In particular, the data show that in
5 the double bond, the keto group, and the phenyl-
sulphenyl group (especially striking is the lack of activ-
ity in the MeS, PhCH2-, PhS(O)- and PhS(O)2-
analogues) are all critical to activity. Even the cyclohex-
enyl homologue 21 is inactive. We are not aware of any
other reports of anti-fungal activity in sulphenyl
cyclopentenones, although arylcyclopentanes, such as
the herbertols16 and arylated heterocyclics, such as the
2H,5H-furan-2-ones,17 are known to have anti-fungal
properties.
various measures of metabolic performance in isolated
rat liver cells.
Details of experimental procedures for the preparation
of 1-methylsulphenyl-2-phenylsulphenyl-ethyne, for its
[3+2] cycloaddition, and for the preparation of 5,
appear below.
Preparation of 1-methylsulphenyl-2-phenylsulphenyl-
ethyne
Phenylsulphenylethyne (2.4 g, 17.9 mmol) was dissolved
in dry THF (20 ml) in a flame-dried flask under dry
nitrogen and the stirred solution was cooled to −78°C.
n-Butyllithium (1.6 M in hexane, 12.2 ml, 19.6 mmol)
was then added gradually by syringe and the mixture
stirred at −78°C for a further hour. Dimethyldisulphide
(1.61 ml, 17.9 mmol) in dry THF (5 ml) was added
dropwise at −20°C and the mixture stirred for three
hours at −20°C, before allowing the temperature to rise
to 20°C. Then water (25 ml) was added and the shaken
mixture separated into two phases. The aqueous phase
was washed with ether (3×10 ml) and the ether wash-
ings combined with the original THF phase. The com-
Given the interest in ketone 5, it was subjected to a
number of other bioassays. However, it showed little or
no activity against a series of commercially important
yeasts, and was not active in an in vivo model—Can-
dida albicans nephritis in mouse. Moreover, it was not
active against a range of Gram negative or Gram
positive bacteria. Against flu-A and flu-B, 5 had IC50s
of 6 and 5 mM, respectively, but further studies sug-
gested that these properties were the result of toxicity
against the host MDCK cells in the culture. In contrast,
no such indications of toxicity came from other cell
culture media, or from studies of the effects of 5 on
Table 1. Anti-fungal activitya of cyclopentanoids and miconazole
Organism
Miconazole
Compound number in text
5
6
10
11
12
100
>100
>100
100
100
100
25
25
25
25
25
15
17
Candida albicans P712
Candida tropicalis P501
6.2
6.2
1.6
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
6.2
25
25
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Nil
Nil
Nil
Nil
Nil
Nil
100
100
100
100
100
100
100
100
100
100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Cryptococcuus neoformans S9027
Saccharomyces cerevisiae S7449
Aspergillus fumigatus S7448
Fusarium solani P420
Microsporum canis S8029
Microsporum canis P351
Microsporum gypseum P352
Microsporum gypseum CN344
Trichophyton equinum S6571
Trichophyton mentagrophyt S8354
Trichophyton mentagrophyt P354
Trichophyton rubrum S6572
Trichophyton rubrum P356
Epidermophyton floccosum S8362
Sporothrix schenckii S7445
Sporothrix schenckii S8380
Exophiala jeanselmei S8370
Exophiala werneckii S8366
>100
25
25
25
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
6.2
6.2
6.2
6.2
25
25
25
25
25
100
100
100
100
a Data are reported as MIC (mg/ml), i.e. the minimum concentration of drug required to inhibit growth of the fungus on an appropriate in vitro
medium.

958
J. A. Miller et al. / Tetrahedron Letters 42 (2001) 955–959
bined organic phases were dried (MgSO4) and the solvent
was evaporated. The crude product was purified by
fractioned distillation, and 1-methylsulphenyl-2-phenyl-
sulphenylethyne (1.70 g, 53%) was obtained as a pure,
colourless oil, bp 94–98°C/0.05 mmHg. The IR spectrum
2. Gray, B. D.; McMillan, C. M.; Miller, J. A.; Ullah, G.
M. Tetrahedron Lett. 1987, 28, 689–692.
3. Gray B. D.; Miller, J. A. J. Chem. Soc., Chem. Commun.
1987, 1136–1137.
4. Miller J. A.; Ullah, G. M. J. Chem. Res. (S) 1988, 350; J.
Chem. Res. (M) 1988, 2737–2746.
1
showed a weak C–C stretch at 2060 cm−1 and the H
NMR showed l 2.40 (s, 3H, SMe) and 7.2 (bs, 5H, SPh)
5. Recent examples of the synthesis of such cyclopentenes
and cyclopentenones include (a) non-[3+2] routes, for
example: Yakura, T.; Ueki, A.; Morioka, Y.; Kurata, T.;
Tanaka, K.; Ikeda, M. Chem. Pharm. Bull. 1998, 46,
1182–1183; Padwa, A.; Filipkowski, M. A.; Meske, M.;
Murphree, S. S.; Watterson, S. H.; Ni, Z. J. Org. Chem.
1994, 59, 588–596; Mathew, J.; Alink, B. J. Chem. Soc.,
Chem. Commun. 1990, 684–686; Asokan, C. V.; Ila, H.;
Junjappa, H. Tetrahedron Lett. 1985, 26, 1087–1090; (b)
[3+2] routes, such as Magnus, P.; Quagliato, D. J. Org.
Chem. 1985, 50, 1621–1626; Trost, B. M.; Seoane, P.;
Mignani, S.; Acemoglu, M. J. Am. Chem. Soc. 1989, 111,
7487–7500; Trost, B. M. Angew. Chem., Int. Ed. Engl.
1986, 25, 1–20; Tius, M. A.; Astrab, D. P. Tetrahedron
Lett. 1984, 25, 1539–1542; Takeda, K.; Nakajima, A.;
Yoshii, E. Synlett 1997, 255–256. None of the (b) group
uses chemistry related to that described in this paper.
6. (a) Haneishi, T.; Kitahara, N.; Takiguchi, Y.; Arai, M.;
Sugawara, S. J. Antibiot. 1974, 27, 386–392; (b) Haneishi,
T.; Terahara, A.; Arai, M.; Hata, T.; Tamura, C. J.
Antibiot. 1974, 27, 393–399.
7. (a) Punaglandins: Baker, B. J.; Scheuer, P. J. J. Nat.
Prod. 1994, 57, 1346–1353; (b) clavulones and related
series: Grechkin, A. N. J. Lipid Mediators Cell Signal.
1995, 11, 205–218.
8. (a) Santoro, M. G. Trends Microbiol. 1997, 5, 276–281;
(b) Santoro, M. G.; Roberts, S. M. Drug News Perspect.
1999, 12, 395–400; (c) Rossi, A.; Kapahi, P.; Natoli, G.;
Takahashi, T.; Chen, Y.; Karin, M.; Santoro, M. G.
Nature 2000, 403, 103–108.
ppm.
Cycloaddition of 1-chloro-3-methylbut-2-ene to
1-methylsulphenyl-2-phenylsulphenylethyne
Compounds
1 and 2: 1-Methylsulphenyl-2-phenyl-
sulphenylethyne (2.20 g, 12.20 mmol) and reagent grade
zinc chloride (3.00 g, 22.05 mmol) were added sequen-
tially to stirred, dry, dichloromethane (25 ml) under dry
nitrogen in a flame-dried, three-necked flask. 1-Chloro-
3-methylbut-2-ene (1.50 g, 14.66 mmol) in dry di-
chloromethane (10 ml) was then added dropwise over 10
min, and the mixture stirred at room temperature for a
further 4 h. The reaction was then quenched by the
cautious addition of a 33% ammonia solution and the
dichloromethane phase was separated. The aqueous
ammonia phase was then washed with chloroform (2×20
ml) and the combined dichloromethane and chloroform
phases were dried over anhydrous magnesium sulphate.
Filtration of the solution and evaporation of the solvents
yielded 3.80 g of a slightly yellow oil, the TLC (1% ether
in 40–60°C petrol) of which revealed two major close
running, high Rf spots. These were then separated by
careful dry column chromatography on silica using
40–60°C petrol to give compounds 2 (1.31 g, 38%) and
1 (1.28 g, 37%)18 in sequence, as colourless oils.
Hydrolysis of 1-phenylsulphenyl-2-methylsulphenyl-
5,5-dimethylcyclopenta-1,3-diene (3)
9. EP 131 441 A/1985; EP 338 796 A/1989; JP 05310685
A/1994; JP 06211728 A/1994; JP 07089929 A/1995.
10. McClelland, R. A. Can. J. Chem. 1977, 55, 548–551. This
reports that hydrolysis of methyl vinyl sulphide is forty
times faster than that of phenyl vinyl sulphide under the
same conditions.
11. Keinan, E.; Greenspoon, N. J. Am. Chem. Soc. 1986,
108, 7314–7325.
12. Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10,
273–278.
Compound 5: Cyclopentadiene 3 (496 mg, 2.0 mmol) and
mercuric chloride (2.7 g, 10 mmol) were dissolved in 20%
aqueous acetone (20 ml) and the stirred mixture was
refluxed for 6 days. The mixture was then filtered and the
residue washed with acetone, and the original filtrate and
the washings were then combined and the solvent evap-
orated to yield a yellowish oil (495 mg). Dry column
chromatography with ether:40–60°C petrol (1:1) then
gave pure 4,4-dimethyl-5-phenylsulphenylcyclopent-2-
enone (5)20 as a thick, colourless syrup (401 mg, 92%).
13. Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem.
Soc. 1976, 98, 4887–4902.
14. Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima,
I. Tetrahedron Lett. 1986, 27, 4025–4028.
15. All compounds were characterised by appropriate analyt-
ical and spectroscopic data.
16. Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc.,
Perkin Trans. 1 1986, 701–710.
Acknowledgements
The authors acknowledge the anti-fungal data provided
by Dr. David Knowles (Wellcome Research, Becken-
ham, UK) and Chris Richman (Burroughs Wellcome Co,
North Carolina, USA) and their colleagues.
17. Pour, M.; Spulak, M.; Balsanek, V.; Kunes, J.; Buchta,
V.; Waisser, K. Bioorg. Med. Chem. Lett. 2000, 10,
1893–1895.
18. Compound 2: 1H NMR (CDCl3) l 1.08 (s, 3H, CH3),
1.15 (s, 3H, CH3), 2.33 (s, 3H, SCH3), 2.48 (m, 2H, CH2),
3.93 (dd, J=9 Hz and 7.5 Hz, 1H, CHCl) and 7.27 (bs,
5H, PhS) ppm. IR (neat) 2940, 2900, 2840, 1570, 1540,
References
1. Miller, J. A.; Moore, M. Tetrahedron Lett. 1980, 21,
577–580.

J. A. Miller et al. / Tetrahedron Letters 42 (2001) 955–959
959
1465, 1450, 1425, 1270, 1250, 1010, 847 (str),19 730, 690
and 675 cm−1. MS (m/z) 284.0459 (C14H17S2Cl requires:
284.0462). Compound 1: 1H NMR (CDCl3) l 1.03 (s, 3H,
CH3), 1.06 (s, 3H, CH3), 2.25 (s, 3H, SCH3), 2.90 (m, 2H,
CH2), 4.10 (dd, appears as t, J=7 Hz, 1H, CHCl), 7.13
(bs, 5H, Ph) ppm, MS (m/z) 284.0460 (C14H17S2Cl
requires: 284.0462).
enes produced in this and other [3+2] cycloadditions to
allyl cations, as described in References 1–3.
1
20. Compound 5: H NMR (CDCl3) l 1.23 (s, 6H, 2×CH3),
3.57 (s, 1H, CHSPh), 6.1 (d, J=6 Hz, 1H, ꢀCHꢁCꢀO),
7.2–7.5 (m, 6H, Ph and HCꢀCꢁCꢀO). IR (neat) 1670(s),
1470, 1450, 1425, 1350, 1325, 1240, 1130, 830, 800, 730
and 680 cm−1. MS (m/z) 218.0773 (C13H14OS requires:
218.0765).
19. This absorption is consistent in the 4-chlorocyclopent-1-
.
.