Design of 1,2-dioxines with anti-Candida activity: aromatic substituted 1,2-dioxines

Article abstract of DOI:10.1016/j.tet.2007.11.071

In an ongoing effort to rationally design new antimicrobials, 47 new 1,2-dioxines have been synthesised. Broad antifungal structure-activity relationships governing aromatically substituted epoxy-1,2-dioxines 2 and 3 and their parent 1,2-dioxines 1 were a

Full text of DOI:10.1016/j.tet.2007.11.071

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1225e1232
www.elsevier.com/locate/tet
Design of 1,2-dioxines with anti-Candida activity:
aromatic substituted 1,2-dioxines
a
a
b
Ian G. Macreadie b, , Thomas D. Avery , Tony V. Robinson , Peter Macreadie ,
*
Miles Barraclough b, Dennis K. Taylor a, , Edward R.T. Tiekink
*
c
a Department of Chemistry, The University of Adelaide, 5005 South Australia, Australia
b CSIRO, Molecular and Health Technologies, Parkville, 3052 Victoria, Australia
c Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX 78248-0698, USA
Received 7 September 2007; received in revised form 5 November 2007; accepted 22 November 2007
Available online 23 November 2007
Abstract
In an ongoing effort to rationally design new antimicrobials, 47 new 1,2-dioxines have been synthesised. Broad antifungal structureeactivity
relationships governing aromatically substituted epoxy-1,2-dioxines 2 and 3 and their parent 1,2-dioxines 1 were assessed primarily against the
pathogenic yeast, Candida albicans, with haemolytic activity of selected examples also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Antifungal; 1,2-Dioxine; Candida; Epoxy-1,2-dioxine; Haemolytic activity
1. Introduction
O O
O O
New effective antifungal agents are urgently required, due
to evolving resistance of fungal pathogens to existing drugs.
These resistant pathogens are ‘selected’ through increased im-
mune deficiency within our population, a result of our ageing
population and the increased numbers of surgical procedures
(including transplantations) or chemotherapies, requiring
immune suppression. There is further need for effective anti-
fungals with reduced toxicity to humans.
Previously we have screened a wide range of 1,2-dioxines
and epoxy-1,2-dioxines with aliphatic (cyclic and acyclic)
substituents in combination with hydroxyl and ester functional
groups about the dioxine ring.1a,b These prior studies have
yielded promising lead compounds and generated a wealth
of structureeactivity data for monocyclic 1,2-dioxines and ep-
oxy-1,2-dioxines. During this process we tested the antifungal
activity of the bis aromatically substituted 1,2-dioxine and its
corresponding epoxy-1,2-dioxine, Figure 1.
O
IC50 31-63 µM
IC50 500-1000 µM
Figure 1. Previously tested bis aromatic 1,2-dioxine and epoxy-1,2-dioxine.
This simple aromatically substituted 1,2-dioxine gave an
IC50 value of 31e63 mM.1a In order to elaborate upon this
promising result we embarked on synthesising and testing a
series of aromatic substituted 1,2-dioxines. Due to synthetic
difficulties and solubility problems we chose to investigate pri-
marily mono-substituted aromatic 1,2-dioxines, whose parent
1,3-butadienes were simple to construct through the reaction
of a chosen benzaldehyde and allyltriphenylphosphonium
bromide.
2. Results and discussion
1,2-Dioxines 1aeq were synthesised from the appropriate
1,3-butadiene through the photosensitised cycloaddition of
singlet oxygen.2 Epoxidation is achieved through the treatment
* Corresponding authors.
E-mail addresses: ian.macreadie@csiro.au (I.G. Macreadie), dennis.
taylor@adelaide.edu.au (D.K. Taylor).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.071

1226
I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
of 1,2-dioxines with m-chloroperbenzoic acid (m-CPBA) in
good yield,3 generating isomers 2 and 3, Scheme 1.
combination of size and/or electro-negativity from the substit-
uents studied. It is interesting to note that for the para
substituted compounds, there was no change in activity with
the change of substituent (all had IC50¼31e63 mM).
O O
O O
R1
O O
R1
R1
R2
R2
The addition of an aliphatic (cyclic 1q or acyclic 1p) sub-
stituent at R2 had no effect on antifungal activity of 1,2-diox-
ine or epoxy-1,2-dioxine over the hydrogen substituted series
(1c, 2c, 3c). Similarly, addition of an aromatic group at R1 had
little effect on antifungal activity.
R2
a
+
O
O
R
R
R
1a: R = 2-OMe, R1 = R2 = H
1b: R = 3-OMe, R1 = R2 = H
1c: R = R1 = R2 = H
2a-m,o-q
3a-m,q
1d: R = 2-F, R1 = R2 = H
1e: R = 3-F, R1 = R2 = H
1f: R = 4-F, R1 = R2 = H
1g: R = 2-Cl, R1 = R2 = H
1h: R = 3-Cl, R1 = R2 = H
1i: R = 4-Cl, R1 = R2 = H
1j: R = 2-Br, R1 = R2 = H
1k: R = 3-Br, R1 = R2 = H
1l: R = 4-Br, R1 = R2 = H
1m: R= 3,5-Br, R1 = R2 = H
1n: R = 3-I, R1 = R2 = H
1o: R = H, R1 = Ph, R2 = H
1p: R = R1 = H, R2 = Me
1q: R = R1 = H, R2 = c-C6H11
The greatest activity observed was for compound 1k, the
meta-bromophenyl 1,2-dioxine with an IC50 of 5e10 mM.
Unexpectedly, the activity of compound 1m, the 3,5-dibromo-
phenyl 1,2-dioxine, was slightly decreased (16e31 mM) from
1k. Having this 3,5-substitution was expected to slightly
increase activity due to the conformational locking of bromine.
The antifungal activity of 1k is the best of all compounds
screened in this study and our previous two studies.1a,b Com-
pound 1k was therefore further screened against Candida krusei
and Candida tropicalis. The results are presented in Table 2.
Scheme 1. Reagents: (a) m-CPBA.
Table 2
A comparison of growth inhibition of Candida strains exposed to 1,2-dioxine
1k compared with some commercial compounds
From the data presented in Table 1, some general trends can
be observed about the antifungal activities of the 1,2-dioxines
1 and the corresponding trans (2) and cis (3) epoxy-1,2-diox-
ine structures against Candida albicans. It is apparent that the
parent 1,2-dioxines 1 are more active than the corresponding
epoxidesdwithout exception. Also there appears to be a mar-
ginal increase in activity moving from trans epoxy-1,2-dioxine
to the cis isomer, however, generally the activities are similar.
For the 1,2-dioxines 1, the position and type of aromatic
substituent (R) appear important. The ortho substituted 1,2-
dioxines were generally the least active followed by meta,
with para being the most active except in the R¼Br series.
For both the ortho and meta substituted compounds the follow-
ing substituent trend was established: H, F<Cl, OMe<Br>I
(meta only), with R¼Br appearing to have the optimum
Compound
IC50 against C.
albicans (mM)
IC50 against C.
tropicalis (mM)
IC50 against C.
krusei (mM)
Amphotericin B
Ketoconazole
Nystatin
0.5
0.1e0.4
11.8e47
100e200
1.6
0.2e0.4
100e200
100e200
209
250e500
250e500
0.8
Fluconazole
1k
5e10
31e63
4e8
The results show that the activity of 1k is far superior to
nystatin and ketoconazole against C. albicans, however, it is
still 10-fold less active than amphotericin B. Compound 1k
appears active against all of the strains tested; most impor-
tantly it is very active against C. krusei compared to flucon-
azole, to which the strain is relatively insensitive.
To determine the potential of the compounds as orally
administered agents, an erythrocyte lysis assay on a selection
of 1,2-dioxines and ‘trans’ epoxy-1,2-dioxines was conducted
with an upper concentration limit of the IC50 assay (1 mM)
(Table 3). This is a measure of whether or not the compounds
will cause red blood cells to rupture.
Table 1
Growth inhibition of C. albicans exposed to 1,2-dioxine compounds
Endoperoxide IC50 (mM) trans
Epoxide
IC50 (mM) cis
Epoxide
IC50 (mM)
1a
1b
1c
1d
1e
1f
63e125
63e125
250e500
250e500
250e500
31e63
2a
>1000
250e500
250e500
3a
d
d
2b
2c
2d
2e
2f
3b
3c
Table 3
The % haemolysis of erythrocytes at 1 mM of 1,2-dioxine or epoxy-1,2-dioxine
500e1000
500e1000
500e1000
500e1000
500e1000
250e500
250e500
250e500
250e500
250e500
250e500
d
500e1000 3d
500e1000 3e
500e1000 3f
Endoperoxide
% Haemolysis
trans Epoxide
% Haemolysis
1b
1c
1k
1l
8
58
2b
2c
2k
2l
1
1
3
2
1g
1h
1i
125e250
63e125
31e63
2g
2h
2i
250e500
3g
500e1000 3h
500e1000 3i
500e1000 3j
100
81
1j
63e125
5e10
31e63
16e31
31e63
2j
1k
1l
2k
2l
250e500
125e250
125e250
d
3k
3l
1m
1n
1o
1p
1q
2m
d
2o
2p
2q
3m
d
d
3p
It is apparent from the results above that parent 1,2-
dioxines tended to be quite haemolytic except for the OMe
substituted 1b. The epoxidation of the 1,2-dioxines leads to
a significant decrease in the haemolytic activity of the com-
pounds. This observation is consistent with their much reduced
125e250
250e500
250e500
500e1000
>1000
d
d
500e1000 3q
>1000
2a, 3a, 2b and 3b were analysed as a 4:1 mixture.

I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
1227
antifungal activity. Given that the IC50s of the compounds
tested in the haemolysis assays are much lower than the upper
limit of 1 mM at which the assay was carried out, the potential
of compounds such as 1k as an oral antifungal should not be
ruled out. Further testing would be required to assess the hae-
molytic activity of 1k at lower concentrations. The haemolysis
results may not be important if the compounds are to be
applied as topical antifungal agents only.
microplate was incubated in a microplate shaker at 35 ꢀC,
and the A595 was measured at the time of compound addition
and 2 h later using a microplate reader (Labsystem Multiscan
Ascent). Each sample was assayed in triplicate. Absorbance
values were averaged and plotted against the drug and com-
pound concentration, and the concentration required to inhibit
50% growth (IC50) was calculated.
4.2. General synthetic methods
3. Conclusion
Solvents were dried by appropriate methods wherever
needed. Thin-layer chromatography (TLC) used aluminium
sheets coated with silica gel 60 F254 (40ꢂ80 mm) from Merck,
visualised under 254 nm light or developed in vanillin or
permanganate dip. Flash chromatography was conducted using
Merck silica gel 60 of particle size 0.040e0.063 mm. Melting
points were taken on a Reichert Thermovar Kofler apparatus
and are uncorrected. Infrared spectra were recorded on an ATI
Mattson Genesis series FTIR spectrophotometer. 1H NMR
and 13C NMR spectra were recorded in CDCl3 solution on a Var-
ian Gemini 2000 (200 MHz), Varian Gemini 2000 (300 MHz)
or Varian INOVA (600 MHz) instrument, using TMS (0 ppm)
and CDCl3 (77.0 ppm) as internal standards. Electron impact
mass spectra (EIMS) were recorded at 70 eV. Crystal structures
were determined on a Bruker AXS SMART CCD. All yields
reported refer to isolated material judged to be homogeneous
by TLC and NMR spectrometry.
A series of novel substituted aromatic 1,2-dioxines and
their epoxide derivatives have been successfully synthesised
and antifungal activity assessed against C. albicans. Broad
structureeactivity relationships were determined with epoxide
derivatives in all cases showing reduced activity when com-
pared to their parent 1,2-dioxines. Lead compound 1k was
then assessed against C. tropicalis and C. krusei showing
good activity against C. krusei which is insensitive to flucon-
azole. We feel that compound 1k and possibility derivatives
thereof may be good candidates for further evaluation, espe-
cially given 1k’s apparent broad spectrum activity. Moreover
other compounds tested may represent good candidates for
topical applications as haemolytic activity is not necessarily
detrimental to being a good candidate.
4. Experimental
4.1. General biological methods
4.3. General procedure for the synthesis of 1,2-dioxines
1aeq2
Yeast strains were maintained on solidified YEPD (1%
yeast extract, 2% peptone, 2% glucose, 1.5% agar) and stored
at 4 ꢀC. Cells were prepared as fresh inoculations in liquid
YEPD at 35 ꢀC, 24 h prior to their utilisation. Candida strains
employed in this study were the clinical isolates, C. albicans
JRW #5, C. krusei WM 03,204, and the American Type
Culture Collection strain C. tropicalis 750.
A solution of the appropriate parent 1,3-butadiene in
CH2Cl2 (30 mL/g) was photolysed with 3ꢂ500 W halogen
lamps in the presence of Rose Bengal bis(triethylammonium)
salt (100 mg) and oxygen for 6e9 h. The reaction was per-
formed in a Pyrex flask fitted with an external cooling jacket.
The solution was concentrated in vacuo and the resulting
residue purified by flash chromatography. In all cases starting
diene was reclaimed from the photolysis reactions as the other
major product. The following 1,2-dioxines are known: 1c,2 1i,4
1o,4 1p,2 1q.5 The following 1,2-dioxines were prepared.
1,2-Dioxine compounds were prepared as 100 mM ethanolic
stock solutions. Dimethylsulfoxide was used to aid the solubili-
sation of amphotericin B (Sigma, St. Louis, MO, USA) and flu-
conazole (Pfizer Pharmaceuticals, New York, NY, USA).
Ketoconazole (Sigma, St. Louis, MO, USA) was solubilised
in methanol. Nystatin suspension (Sigma, St. Louis, MO,
USA) and amphotericin B stocks were stored at ꢁ80 ꢀC. Other
stocks were stored at 4 ꢀC until required. DMSO, ethanol and
methanol comprised <1% of the total test volume. Growth
curves were determined using concentrations of DMSO,
ethanol and methanol equal to those present in test solutions
to verify that they did not inhibit the growth of Candida.
Yeast was grown to log phase and diluted in YEPD to
achieve a starting optical density at A595 of 0.2e0.4 in order
to examine growth inhibition immediately after addition of
compounds. The yeast inocula (100 mL) were then added to
each well of a 96-well microplate (Nunc, Wiesbaden, Ger-
many). Drugs and endoperoxide compounds were then added
as twofold serial dilutions down from 1 mM concentrations. A
growth control was included in the same microplate. The
4.3.1. ꢃ3-(2-Methoxyphenyl)-3,6-dihydro-1,2-dioxine (1a)
Yield: 360 mg, 6%; colourless oil; Rf 0.39 (1:19 ethyl acetate/
1
hexane); H NMR (200 MHz, CDCl3): d 7.40e7.28 (m, 2H),
6.98e6.88 (m, 2H), 6.19e6.05 (m, 3H), 4.74e4.58 (m, 2H),
3.85 (s, 3H); 13C NMR (50 MHz, CDCl3): d 157.4, 129.8,
129.0, 127.1, 125.7, 124.4, 120.4, 110.7, 74.5, 69.9, 55.6; IR
(neat): 1601, 1589, 1493, 1464, 1248, 1050, 1030 cmꢁ1; MS
m/z (EIþ): 192 (Mþ, 60), 174 (43), 160 (100), 145 (19), 135
(77), 91 (16); HRMS (EIþ) (M)þ found 192.0789; (M)þ calcd
for C11H12O3 192.0786.
4.3.2. ꢃ3-(3-Methoxyphenyl)-3,6-dihydro-1,2-dioxine (1b)
Yield: 960 mg, 17%; colourless oil; Rf 0.37 (1:9 ethyl ace-
1
tate/hexane); H NMR (200 MHz, CDCl3): d 7.33e7.24 (m,
1H), 6.99e6.85 (m, 3H), 6.18 (dddd, J¼10.3, 2.2, 2.2,

1228
I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
2.2 Hz, 1H), 6.09 (dddd, J¼10.3, 2.2, 2.2, 2.2 Hz, 1H), 5.59
(dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.76 (dddd, J¼16.3, 2.2,
2.2, 2.2 Hz, 1H), 4.58 (dddd, J¼16.3, 2.2, 2.2, 2.2 Hz, 1H),
3.81 (s, 3H); 13C NMR (50 MHz, CDCl3): d 159.7, 138.7,
129.5, 126.8, 124.8, 120.7, 114.5, 113.9, 80.5, 69.9, 55.2; IR
(neat): 1602, 1588, 1489, 1455, 1284, 1047, 760 cmꢁ1; MS
m/z (EIþ): 192 (Mþ, 44), 174 (50), 160 (100), 145 (22), 135
(39), 92 (17); HRMS (EIþ) (M)þ found 192.0782; (M)þ calcd
for C11H12O3 192.0786.
2.2, 2.2, 1.6 Hz, 1H), 6.11 (dddd, J¼10.2, 2.2, 2.0, 1.6 Hz,
1H), 6.04 (dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.69e4.66
(m, 2H); 13C NMR (50 MHz, CDCl3): d 135.1, 133.9, 129.8,
129.7, 129.6, 126.8, 125.8, 125.2, 76.9, 69.8; IR (neat): 1593,
1573, 1474, 1440, 1253, 1035, 757 cmꢁ1; MS m/z (EIþ): 198
(Mþ, 37Cl, 1), 196 (Mþ, 35Cl, 4), 178 (6), 164 (68), 139 (25),
129 (100), 111 (13); HRMS (EIþ) (M)þ found 196.0292; (M)þ
calcd for C10H9O235Cl 196.0291.
4.3.7. ꢃ3-(3-Chlorophenyl)-3,6-dihydro-1,2-dioxine (1h)
Yield: 1.12 g, 19%; colourless oil; Rf 0.26 (2:3 CH2Cl2/hex-
ane); 1H NMR (600 MHz, CDCl3): d 7.38e7.37 (m, 1H),
7.32e7.25 (m, 3H), 6.18 (dddd, J¼10.5, 2.4, 2.4, 2.4 Hz, 1H),
6.08 (dddd, J¼10.5, 2.4, 2.4, 2.4 Hz, 1H), 5.53 (dddd, J¼2.4,
2.4, 2.4, 2.4 Hz, 1H), 4.68 (dddd, J¼16.8, 2.4, 2.4, 2.4 Hz,
1H), 4.61 (dddd, J¼16.8, 2.4, 2.4, 2.4 Hz, 1H); 13C NMR
(50 MHz, CDCl3): d 139.4, 134.3, 129.7, 128.8, 128.4,
126.5, 126.0, 125.2, 79.7, 69.8; IR (neat): 1598, 1575, 1477,
1430, 1248, 1035, 785 cmꢁ1; MS m/z (EIþ): 198 (Mþ, 37Cl,
6), 196 (Mþ, 35Cl, 17), 178 (28), 164 (68), 139 (27), 129
(100), 111 (20); HRMS (EIþ) (M)þ found 196.0291; (M)þ
calcd for C10H9O235Cl 196.0291.
4.3.3. ꢃ3-(2-Fluorophenyl)-3,6-dihydro-1,2-dioxine (1d)
Yield: 720 mg, 12%; colourless oil; Rf 0.34 (2:3 CH2Cl2/
1
hexane); H NMR (200 MHz, CDCl3): d 7.48e7.24 (m, 2H),
7.17e7.01 (m, 2H), 6.19 (dddd, J¼10.3, 2.6, 2.6, 2.0 Hz, 1H),
6.08 (dddd, J¼10.3, 2.0, 2.0, 1.6 Hz, 1H), 5.92 (dddd, J¼2.0,
2.0, 2.0, 2.0 Hz, 1H), 4.68e4.64 (m, 2H); 13C NMR (50 MHz,
CDCl3): d 160.8 (d, J¼247.4 Hz), 130.3 (d, J¼8.4 Hz), 129.7
(d, J¼3.4 Hz), 125.8, 125.2, 124.7 (d, J¼13.7 Hz), 124.0 (d,
J¼3.8 Hz), 115.5 (d, J¼21.7 Hz), 79.9 (d, J¼3.5 Hz), 69.8; IR
(neat): 1616, 1588, 1489, 1457, 1231, 1035, 996 cmꢁ1; MS m/
z (EIþ): 180 (Mþ, 10), 162 (98), 148 (100), 133 (20), 123 (25),
95 (15); HRMS (ESI) (MþNa)þ found 203.0482; (MþNa)þ
calcd for C10H9O2FNa 203.0484.
4.3.8. ꢃ3-(2-Bromophenyl)-3,6-dihydro-1,2-dioxine (1j)
Yield: 320 mg, 6%; colourless oil; Rf 0.48 (1:9 ethyl acetate/
hexane); 1H NMR (300 MHz, CDCl3): d 7.59 (dd, J¼7.8,
1.5 Hz, 1H), 7.48 (dd, J¼7.8, 1.2 Hz, 1H), 7.30 (ddd, J¼7.8,
7.5, 1.2 Hz, 1H), 7.19 (ddd, J¼7.8, 7.5, 1.5 Hz, 1H), 6.21
(dddd, J¼10.4, 3.0, 3.0, 2.4 Hz, 1H), 6.11 (dddd, J¼10.4, 2.4,
2.0, 2.0 Hz, 1H), 6.01 (dddd, J¼2.4, 2.4, 2.4, 2.4 Hz, 1H),
4.69e4.66 (m, 2H); 13C NMR (75 MHz, CDCl3): d 136.7,
133.1, 130.1, 129.9, 127.4, 125.9, 125.2, 124.2, 79.2, 69.9; IR
(neat): 1591, 1571, 1467, 1441, 1186, 1025, 999 cmꢁ1; MS m/z
(EIþ): 242 (Mþ, 81Br, 6), 240 (Mþ, 79Br, 6), 210 (40), 208 (41),
155 (6), 129 (100); HRMS (EIþ) (M)þ found 239.97889; (M)þ
calcd for C10H9O279Br 239.97895.
4.3.4. ꢃ3-(3-Fluorophenyl)-3,6-dihydro-1,2-dioxine (1e)
Yield: 1.12 g, 23%; colourless oil; Rf 0.31 (2:3 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.39e7.26 (m, 1H), 7.20e
6.96 (m, 3H), 6.18 (dddd, J¼10.3, 2.2, 2.2, 1.6 Hz, 1H), 6.08
(dddd, J¼10.3, 2.2, 2.2, 1.6 Hz, 1H), 5.56 (dddd, J¼2.2, 2.2,
2.2, 2.2 Hz, 1H), 4.70 (dddd, J¼16.8, 2.2, 2.2, 1.6 Hz, 1H),
4.60 (dddd, J¼16.8, 2.2, 2.2, 1.6 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 162.8 (d, J¼245.1 Hz), 139.9 (d, J¼6.9 Hz), 130.0
(d, J¼8.0 Hz), 126.2, 125.2, 124.0 (d, J¼3.05 Hz), 115.6 (d,
J¼20.9 Hz), 115.2 (d, J¼21.7 Hz), 79.8 (d, J¼1.9 Hz), 69.8;
IR (neat): 1616, 1592, 1488, 1449, 1265, 1140, 1035 cmꢁ1
;
MS m/z (EIþ): 180 (Mþ, 24), 162 (36), 148 (100), 133 (15),
123 (13), 95 (15); HRMS (ESI) (MþNa)þ found 203.0483;
(MþNa)þ calcd for C10H9O2FNa 203.0484.
4.3.9. ꢃ3-(3-Bromophenyl)-3,6-dihydro-1,2-dioxine (1k)
Yield: 760 mg, 14%; colourless oil; Rf 0.42 (1:9 ethyl
1
acetate/hexane); H NMR (200 MHz, CDCl3): d 7.58e7.44
4.3.5. ꢃ3-(4-Fluorophenyl)-3,6-dihydro-1,2-dioxine (1f)
Yield: 2.25 g, 31%; colourless planks; mp 30e31 ꢀC; Rf 0.30
(m, 2H), 7.36e7.19 (m, 2H), 6.21 (dddd, J¼10.3, 2.2, 2.2,
2.2 Hz, 1H), 6.08 (dddd, J¼10.3, 2.2, 2.2, 2.2 Hz, 1H), 5.54
(dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.72 (dddd, J¼16.6, 2.2,
2.2, 2.2 Hz, 1H), 4.63 (dddd, J¼16.6, 2.2, 2.2, 2.2 Hz, 1H);
13C NMR (50 MHz, CDCl3): d 139.7, 131.9, 131.4, 130.1,
127.1, 126.1, 125.4, 122.6, 79.8, 69.9; IR (neat): 1596, 1569,
1474, 1427, 1190, 1060, 998 cmꢁ1; MS m/z (EIþ): 242 (Mþ,
81Br, 11), 240 (Mþ, 79Br, 11), 210 (84), 208 (89), 183 (27),
155 (12), 129 (100); HRMS (EIþ) (M)þ found 239.97892;
(M)þ calcd for C10H9O279Br 239.97859.
1
(2:3 CH2Cl2/hexane); H NMR (200 MHz, CDCl3): d 7.41e
7.31 (m, 2H), 7.11e6.98 (m, 2H), 6.18 (dddd, J¼10.2, 2.2,
2.2, 2.2 Hz, 1H), 6.07 (dddd, J¼10.2, 2.2, 2.2, 2.2 Hz, 1H),
5.58 (dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.72 (dddd, J¼16.6,
2.2, 2.2, 2.2 Hz, 1H), 4.57 (dddd, J¼16.6, 2.2, 2.2, 2.2 Hz,
1H); 13C NMR (50 MHz, CDCl3): d 163.0 (d, J¼246.2 Hz),
133.0 (d, J¼3.1 Hz), 130.4 (d, J¼8.4 Hz), 126.6, 125.1, 115.4
(d, J¼21.7 Hz), 79.8, 69.8; IR (Nujol): 1604, 1509, 1225,
1158, 1060, 996, 839 cmꢁ1; MS m/z (EIþ): 180 (Mþ, 10), 162
(4), 148 (100), 133 (9), 123 (14), 95 (8). Anal. Calcd for
C10H9O2F: C, 66.66; H, 5.03. Found: C, 66.78; H, 4.81.
4.3.10. ꢃ3-(4-Bromophenyl)-3,6-dihydro-1,2-dioxine (1l)
Yield: 1.24 g, 27%; colourless flakes; mp 75e76 ꢀC; Rf
1
0.36 (1:9 ethyl acetate/hexane); H NMR (200 MHz, CDCl3):
4.3.6. ꢃ3-(2-Chlorophenyl)-3,6-dihydro-1,2-dioxine (1g)
Yield: 540 mg, 9%; colourless oil; Rf 0.29 (2:3 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.52e7.45 (m, 1H),
7.43e7.35 (m, 1H), 7.31e7.21 (m, 2H), 6.21 (dddd, J¼10.2,
d 7.53e7.46 (m, 2H), 7.31e7.23 (m, 2H), 6.20 (dddd, J¼10.3,
2.2, 2.2, 2.2 Hz, 1H), 6.07 (dddd, J¼10.3, 2.2, 2.2, 2.2 Hz,
1H), 5.55 (dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.72 (dddd,

I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
1229
J¼16.7, 2.2, 2.2, 2.2 Hz, 1H), 4.61 (dddd, J¼16.7, 2.2, 2.2,
2.2 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 136.4, 131.7,
130.1, 126.3, 125.2, 123.0, 79.8, 69.9; IR (Nujol): 1587, 1570,
1410, 1256, 1057, 994 cmꢁ1; MS m/z (EIþ): 242 (Mþ, 81Br,
28), 240 (Mþ, 79Br, 29), 210 (50), 208 (51), 185 (100), 183
(98), 129 (88). Anal. Calcd for C10H9O2Br: C, 49.82; H,
3.76. Found: C, 49.91; H, 3.68.
1.6 Hz, 1H), 4.40 (dd, J¼13.8, 0.6 Hz, 1H), 3.86 (s, 3H),
3.58 (ddd, J¼4.4, 0.9, 0.6 Hz, 1H), 3.47 (dd, J¼4.4, 1.6 Hz,
1H); 13C NMR (75 MHz, CDCl3): d 157.0, 130.3, 128.9,
127.9, 120.6, 110.9, 76.9, 69.3, 55.5, 53.8, 48.7; IR (neat):
1603, 1590, 1495, 1464, 1250, 1036, 785 cmꢁ1; MS m/z
(EIþ): 208 (Mþ, 39), 176 (3), 147 (9), 135 (100), 131 (26),
119 (21), 107 (19); HRMS (EIþ) (M)þ found 208.0738;
(M)þ calcd for C11H12O4 208.0736.
4.3.11. ꢃ3-(3,5-Dibromophenyl)-3,6-dihydro-1,2-dioxine
(1m)
4.4.2. ꢃ(1aR,2R,5aR)-2-(2-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3a)
Yield: 710 mg, 27%; colourless oil; Rf 0.42 (2:3 CH2Cl2/hex-
1
ane); H NMR (200 MHz, CDCl3): d 7.64 (dd, J¼1.8, 1.8 Hz,
Yield: 107 mg, 19%; colourless oil; Rf 0.34 (1:3 ethyl acetate/
1
hexane); H NMR (300 MHz, CDCl3): d 7.57e7.53 (m, 1H),
1H), 7.47 (dd, J¼1.8, 0.5 Hz, 2H), 6.22 (dddd, J¼10.3, 2.8,
2.2, 2.2 Hz, 1H), 6.07 (dddd, J¼10.3, 28, 2.2, 2.2 Hz, 1H),
5.43 (ddddd, J¼2.2, 2.2, 2.2, 2.2, 0.5 Hz, 1H), 4.71 (dddd,
J¼16.6, 2.8, 2.2, 2.2 Hz, 1H), 4.62 (dddd, J¼16.6, 2.8, 2.2,
2.2 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 141.5, 134.2,
130.1, 125.9, 125.2, 123.0, 78.9, 69.9; IR (neat): 1585, 1557,
1424, 1191, 1060, 1035, 858 cmꢁ1; MS m/z (EIþ): 322 (Mþ,
81Br81Br, 13), 320 (Mþ, 81Br79Br, 27), 318 (Mþ, 79Br79Br,
15), 288 (30), 128 (100), 75 (25); HRMS (ESI) (MþNa)þ found
340.8785; (MþNa)þ calcd for C10H8O279Br2Na 340.8789.
7.36e7.30 (m, 1H), 7.01e6.89 (m, 2H), 5.83 (br s, 1H), 4.58
(ddd, J¼13.9, 1.1, 0.6 Hz, 1H), 4.39 (dd, J¼13.9, 3.9 Hz, 1H),
3.87 (s, 3H), 3.61 (ddd, J¼4.5, 3.9, 1.1 Hz, 1H), 3.58 (ddd, J¼
4.5, 1.4, 0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 156.8,
129.9, 128.9, 124.1, 120.8, 110.4, 73.6, 70.1, 55.5, 50.9, 50.6;
IR (neat): 1602, 1589, 1494, 1464, 1291, 1026, 757 cmꢁ1; MS
m/z (EIþ): 208 (Mþ, 81), 176 (1), 147 (13), 135 (100), 131
(39), 119 (36), 107 (35); HRMS (EIþ) (M)þ found 208.0731;
(M)þ calcd for C11H12O4 208.0736.
4.3.12. ꢃ3-(3-Iodophenyl)-3,6-dihydro-1,2-dioxine (1n)
Yield: 340 mg, 28%; colourless oil; Rf 0.29 (2:3 CH2Cl2/
hexane); 1H NMR (200 MHz, CDCl3): d 7.73 (dd, J¼1.7,
1.7 Hz, 1H), 7.68 (ddd, J¼7.8, 1.7, 1.2 Hz, 1H), 7.36 (ddd, J¼
7.8, 1.7, 1.2 Hz, 1H), 7.10 (dd, J¼7.8, 7.8 Hz, 1H), 6.20 (dddd,
J¼10.3, 2.2, 2.2, 1.8 Hz, 1H), 6.08 (dddd, J¼10.3, 2.2, 2.2,
1.8 Hz, 1H), 5.51 (dddd, J¼2.2, 2.2, 2.2, 2.2 Hz, 1H), 4.72
(dddd, J¼16.6, 2.2, 2.2, 1.8 Hz, 1H), 4.62 (dddd, J¼16.6, 2.2,
2.2, 1.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 139.6, 137.8,
137.3, 130.2, 127.7, 126.1, 125.3, 94.3, 79.7, 69.9; IR (neat):
1590, 1566, 1471, 1422, 1059, 997, 781 cmꢁ1; MS m/z (EIþ):
288 (Mþ, 7), 272 (45), 271 (100), 257 (53), 256 (16), 145 (32),
130 (54). Anal. Calcd for C10H9O2I: C, 41.69; H, 3.15. Found:
C, 41.93; H, 3.13.
4.4.3. ꢃ(1aS,2R,5aS )-2-(3-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2b)
Yield: 387 mg, 74%; colourless oil; Rf 0.38 (1:3 ethyl ace-
1
tate/hexane); H NMR (200 MHz, CDCl3): d 7.37e7.25 (m,
1H), 7.01e6.88 (m, 3H), 5.35 (br s, 1H), 4.57 (ddd, J¼13.7,
1.5, 0.4 Hz, 1H), 4.41 (ddd, J¼13.7, 0.9, 0.4 Hz, 1H), 3.82
(s, 3H), 3.58 (ddd, J¼4.4, 1.0, 0.4 Hz, 1H), 3.50 (dddd, J¼
4.4, 1.5, 0.9, 0.4 Hz, 1H); 13C NMR (50 MHz, CDCl3): d
160.1, 137.2, 130.1, 120.2, 114.8, 113.7, 81.4, 69.5, 55.5, 53.7,
48.9; IR (neat): 1603, 1587, 1493, 1456, 1287, 1157,
1037 cmꢁ1; MS m/z (EIþ): 208 (Mþ, 100), 176 (3), 161 (11),
147 (13), 135 (64), 121 (10), 109 (13); HRMS (EIþ) (M)þ
found 208.0740; (M)þ calcd for C11H12O4 208.0736.
4.4.4. ꢃ(1aR,2R,5aR)-2-(3-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3b)
Yield: 97 mg, 19%; colourless oil; Rf 0.32 (1:3 ethyl acetate/
4.4. General procedure for the synthesis of epoxy-1,2-
dioxines 2aem,oeq and 3aem,q3
1
hexane); H NMR (200 MHz, CDCl3): d 7.37e7.27 (m, 1H),
To a solution of 1,2-dioxine 1 (1 equiv) in CH2Cl2 (20 mL/
g) was added 70% m-chloroperbenzoic acid (2 equiv), and the
reaction was stirred at ambient temperature until complete by
TLC. Dichloromethane was then added and the solution ex-
tracted with satd Na2S2O3 followed by NaHCO3. The organic
layer was dried over MgSO4, filtered and the volatiles removed
in vacuo. The crude epoxides were purified by column chro-
matography. The following epoxy-1,2-dioxines are known:
2c,3 3c,3 2o,6 2p,3 3p,3 2q,5 3q.5 The following epoxy-1,2-di-
oxines were prepared.
7.14e7.06 (m, 2H), 7.02e6.89 (m, 1H), 5.36 (br s, 1H), 4.61
(ddd, J¼14.0, 1.3, 0.8 Hz, 1H), 4.39 (dd, J¼14.0, 4.2 Hz, 1H),
3.82 (s, 3H), 3.66 (ddd, J¼4.4, 4.2, 1.3 Hz, 1H), 3.53 (ddd,
J¼4.4, 1.1, 0.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 159.8,
136.3, 129.6, 120.8, 115.2, 113.8, 79.7, 70.1, 55.3, 51.1, 50.6;
IR (neat): 1601, 1585, 1494, 1462, 1265, 1158, 1064 cmꢁ1
;
MS m/z (EIþ): 208 (Mþ, 56), 176 (5), 161 (15), 136 (28), 135
(100), 121 (13), 109 (21); HRMS (EIþ) (M)þ found 208.0739;
(M)þ calcd for C11H12O4 208.0736.
4.4.5. ꢃ(1aS,2R,5aS )-2-(4-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2c)
4.4.1. ꢃ(1aS,2R,5aS )-2-(2-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2a)
Yield: 402 mg, 74%; colourless oil; Rf 0.43 (1:3 ethyl ace-
tate/hexane); H NMR (300 MHz, CDCl3): d 7.38e7.31 (m,
2H), 6.99e6.91 (m, 2H), 5.70 (br s, 1H), 4.56 (dd, J¼13.7,
Yield: 415 mg, 75%; colourless solid; mp 93e94 ꢀC; Rf 0.38
(1:3 ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d 7.35e7.30 (m, 2H), 6.94e6.90 (m, 2H), 5.32 (br s, 1H), 4.56
(dd, J¼13.4, 1.5 Hz, 1H), 4.39 (ddd, J¼13.4, 0.6, 0.6 Hz, 1H),
1

1230
I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
3.81 (s, 3H), 3.58 (ddd, J¼4.3, 0.9, 0.6 Hz, 1H), 3.51 (ddd,
J¼4.3, 1.5, 0.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 160.3,
129.5, 127.6, 114.2, 81.0, 69.1, 55.3, 53.6, 48.7; IR (Nujol):
1610, 1583, 1515, 1249, 1180, 1028, 800 cmꢁ1; MS m/z
(EIþ): 208 (Mþ, 39), 176 (19), 149 (18), 135 (89), 73 (88), 57
(64), 43 (100). Anal. Calcd for C11H12O4: C, 63.46; H, 5.81.
Found: C, 63.36; H, 5.86.
J¼13.8, 1.6, 0.4 Hz, 1H), 4.42 (ddd, J¼13.8, 0.8, 0.4 Hz, 1H),
3.57e3.49 (m, 2H); 13C NMR (50 MHz, CDCl3): d 162.8 (d,
J¼245.8 Hz), 137.9 (d, J¼7.2 Hz), 130.4 (d, J¼8.0 Hz), 123.4
(d, J¼3.5 Hz), 116.1 (d, J¼20.9 Hz), 114.7 (d, J¼22 Hz), 80.4
(d, J¼1.9 Hz), 69.3, 52.9, 48.7; IR (Nujol): 1618, 1593, 1491,
1449, 1273, 1022, 989 cmꢁ1; MS m/z (EIþ): 196 (Mþ, 6), 164
(3), 138 (13), 124 (29), 123 (100), 109 (28), 95 (78). Anal. Calcd
for C10H9O3F: C, 61.22; H, 4.62. Found: C, 61.31; H, 4.49.
4.4.6. ꢃ(1aR,2R,5aR)-2-(4-Methoxyphenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3c)
4.4.10. ꢃ(1aR,2R,5aR)-2-(3-Fluorophenyl)perhydro-
Yield: 110 mg, 20%; colourless oil; Rf 0.30 (1:3 ethyl acetate/
oxireno[2,3-d][1,2]dioxine (3e)
1
hexane); H NMR (300 MHz, CDCl3): d 7.51e7.45 (m, 2H),
Yield: 116 mg, 20%; colourless oil; Rf 0.19 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.42e7.33 (m, 1H), 7.31e
7.22 (m, 2H), 7.13e7.01 (m, 1H), 5.35 (br d, J¼1.2 Hz, 1H),
4.57 (ddd, J¼13.9, 1.3, 0.6 Hz, 1H), 4.38 (dd, J¼13.9, 4.1 Hz,
1H), 3.65 (ddd, J¼4.4, 4.1, 1.3 Hz, 1H), 3.53 (ddd, J¼4.4, 1.2,
0.6 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 162.5 (d, J¼
245.1 Hz), 137.0 (d, J¼7.2 Hz), 129.8 (d, J¼8.0 Hz), 123.8 (d,
J¼3.0 Hz), 115.9 (d, J¼20.9 Hz), 115.2 (d, J¼22.4 Hz), 78.8 (d,
J¼1.9 Hz), 69.8, 50.8, 50.2; IR (Nujol): 1617, 1592, 1491, 1449,
1272, 1143, 992 cmꢁ1; MS m/z (EIþ): 196 (Mþ, 100), 164 (20),
135 (23), 125 (32), 123 (72), 109 (35), 95 (46). Anal. Calcd for
C10H9O3F: C, 61.22; H, 4.62. Found: C, 61.33; H, 4.56.
6.94e6.89 (m, 2H), 5.31 (br s, 1H), 4.59 (ddd, J¼13.9, 1.2,
0.9 Hz, 1H), 4.37 (dd, J¼13.9, 4.5 Hz, 1H), 3.81 (s, 3H), 3.65
(ddd, J¼4.5, 4.2, 1.2 Hz, 1H), 3.49 (ddd, J¼4.2, 0.9, 0.9 Hz,
1H); 13C NMR (75 MHz, CDCl3): d 160.4, 130.4, 126.9,
114.0, 79.4, 70.1, 55.3, 51.1, 50.6; IR (neat): 1607, 1581, 1497,
1236, 1174, 1056, 821 cmꢁ1; MS m/z (EIþ): 208 (Mþ, 23), 176
(16), 147 (14), 136 (36), 135 (81), 77 (100); HRMS (EIþ) (M)þ
found 208.0739; (M)þ calcd for C11H12O4 208.0736.
4.4.7. ꢃ(1aS,2R,5aS )-2-(2-Fluorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2d)
Yield: 384 mg, 72%; colourless oil; Rf 0.18 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.49e7.32 (m, 2H), 7.22e
7.05 (m, 2H), 5.59 (br s, 1H), 4.56 (dd, J¼13.7, 1.8 Hz, 1H), 4.42
(ddd, J¼13.7, 0.6, 0.4 Hz, 1H), 3.6 (ddd, J¼4.3, 0.6, 0.4 Hz,
1H), 3.53 (ddd, J¼4.3, 1.8, 0.6 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 160.6 (d, J¼248.2 Hz), 131.1 (d, J¼8.4 Hz), 130.1
(d, J¼3.8 Hz), 124.4 (d, J¼3.4 Hz), 122.7 (d, J¼13.7 Hz),
115.9 (d, J¼21.6 Hz), 76.6 (d, J¼1.6 Hz), 69.4, 52.8 (d, J¼
3.1 Hz), 48.7; IR (neat): 1618, 1589, 1494, 1456, 1233, 1037,
930 cmꢁ1; MS m/z (EIþ): 196 (Mþ, 60), 164 (48), 138 (27),
135 (29), 123 (100), 109 (59), 95 (35); HRMS (ESI) (MþNa)þ
found 219.0431; (MþNa)þ calcd for C10H9O3FNa 219.0433.
4.4.11. ꢃ(1aS,2R,5aS )-2-(4-Fluorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2f)
Yield: 406 mg, 74%; colourless solid; mp 69.5e70.5 ꢀC; Rf
0.14 (1:1 CH2Cl2/hexane); 1H NMR (200 MHz, CDCl3):
d 7.45e7.34 (m, 2H), 7.16e7.04 (m, 2H), 5.36 (br s, 1H), 4.57
(dd, J¼13.6, 1.4 Hz, 1H), 4.42 (ddd, J¼13.6, 0.6, 0.6 Hz, 1H),
3.56 (ddd, J¼4.3, 1, 0.6 Hz, 1H), 3.54e3.50 (m, 1H); 13C
NMR (50 MHz, CDCl3): d 163.2 (d, J¼247.4 Hz), 131.5 (d,
J¼3.0 Hz), 129.9 (d, J¼8.4 Hz), 115.9 (d, J¼21.7 Hz), 80.7,
69.3, 53.3, 48.7; IR (Nujol): 1608, 1515, 1423, 1226, 1022,
987 cmꢁ1; MS m/z (EIþ): 196 (Mþ, 5), 164 (2), 149 (21), 138
(11), 123 (100), 109 (27), 95 (52). Anal. Calcd for C10H9O3F:
C, 61.22; H, 4.62. Found: C, 61.47; H, 4.67.
4.4.8. ꢃ(1aR,2R,5aR)-2-(2-Fluorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3d)
Yield: 108 mg, 20%; colourless oil; Rf 0.29 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.68e7.58 (m, 1H), 7.42e
7.28 (m, 1H), 7.22e7.03 (m, 1H), 5.74 (br d, J¼1.2 Hz, 1H),
4.57 (ddd, J¼13.8, 1.3, 0.8 Hz, 1H), 4.41 (dd, J¼13.8, 3.8 Hz,
1H), 3.64 (ddd, J¼4.3, 3.8, 1.3 Hz, 1H), 3.58 (ddd, J¼4.3, 1.2,
0.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 160.2 (d,
J¼246.6 Hz), 130.6 (d, J¼8.4 Hz), 129.6 (d, J¼3.1 Hz), 124.4
(d, J¼3.4 Hz), 122.7 (d, J¼13.7 Hz), 115.2 (d, J¼21.3 Hz),
72.9 (d, J¼3.8 Hz), 70.0, 50.9, 50.5 (d, J¼1.5 Hz); IR (Nujol):
1618, 1589, 1494, 1456, 1234, 1035, 990 cmꢁ1; MS m/z
(EIþ): 196 (Mþ, 100), 164 (47), 138 (13), 135 (14), 123 (85),
109 (35), 95 (24); HRMS (ESI) (MþNa)þ found 219.0432;
(MþNa)þ calcd for C10H9O3FNa 219.0433.
4.4.12. ꢃ(1aR,2R,5aR)-2-(4-Fluorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3f)
Yield: 108 mg, 20%; colourless flakes; mp 89.5e90.5 ꢀC; Rf
0.18 (1:1 CH2Cl2/hexane); 1H NMR (200 MHz, CDCl3):
d 7.58e7.47 (m, 2H), 7.13e7.00 (m, 2H), 5.33 (br s, 1H), 4.57
(ddd, J¼13.9, 1.3, 0.8 Hz, 1H), 4.37 (dd, J¼13.9, 4.2 Hz, 1H),
3.65 (ddd, J¼4.4, 4.2, 1.2 Hz, 1H), 3.49 (ddd, J¼4.4, 1.0,
0.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 163.3 (d, J¼
247.0 Hz), 130.8 (d, J¼3.2 Hz), 130.6 (d, J¼8.4 Hz), 115.5
(d, J¼21.3 Hz), 79.0, 70.0, 51.1, 50.5; IR (Nujol): 1603, 1510,
1417, 1226, 1034, 987 cmꢁ1; MS m/z (EIþ): 196 (Mþ, 38),
164 (2), 138 (8), 125 (64), 123 (100), 109 (33), 95 (91). Anal.
Calcd for C10H9O3F: C, 61.22; H, 4.62. Found: C, 61.43; H,
4.64.
4.4.9. ꢃ(1aS,2R,5aS )-2-(3-Fluorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2e)
4.4.13. ꢃ(1aS,2R,5aS )-2-(2-Chlorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2g)
Yield: 346 mg, 74%; colourless oil; Rf 0.16 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.50e7.40 (m, 2H), 7.37e
Yield: 413 mg, 72%; colourless solid; mp 54e55 ꢀC; Rf 0.14
1
(1:1 CH2Cl2/hexane); H NMR (200 MHz, CDCl3): d 7.44e
7.32 (m, 1H), 7.22e7.02 (m, 3H), 5.36 (br s, 1H), 4.55 (ddd,

I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
1231
7.25 (m, 2H), 5.75 (br s, 1H), 4.59 (dd, J¼13.8, 1.4 Hz, 1H), 4.42
(ddd, J¼13.8, 0.4, 0.4 Hz, 1H), 3.57 (ddd, J¼4.3, 0.4, 0.4 Hz,
1H), 3.52 (m, 1H); 13C NMR (50 MHz, CDCl3): d 133.4,
133.2, 130.2, 130.0, 129.1, 127.0, 78.4, 69.4, 53.1, 48.7; IR
(neat): 1595, 1574, 1476, 1441, 1244, 1038, 928 cmꢁ1; MS
m/z (EIþ): 214 (Mþ, 37Cl, 24), 212 (Mþ, 35Cl, 79), 180 (44),
141 (68), 139 (100), 131 (51), 77 (70); HRMS (ESI) (MþNa)þ
found 235.0134; (MþNa)þ calcd for C10H9O335ClNa 235.0138.
(br s, 1H), 4.56 (dd, J¼13.9, 1.3 Hz, 1H), 4.42 (ddd, J¼13.9,
0.8, 0.6 Hz, 1H), 3.56e3.5 (m, 2H); 13C NMR (50 MHz,
CDCl3): d 135.2, 134.1, 129.2, 129.1, 80.5, 69.3, 53.0, 48.7; IR
(neat): 1598, 1494, 1423, 1410, 1091, 1016, 929 cmꢁ1; MS m/z
(EIþ): 214 (Mþ, 37Cl, 23), 212 (Mþ, 35Cl, 69), 180 (31), 141
(64), 139 (100), 131 (15), 77 (43). Anal. Calcd for
C10H9O3Cl: C, 56.49; H, 4.27. Found: C, 56.75; H, 4.20.
4.4.18. ꢃ(1aR,2R,5aR)-2-(4-Chlorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3i)
4.4.14. ꢃ(1aR,2R,5aR)-2-(2-Chlorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3g)
Yield: 113 mg, 19%; colourless solid; mp 81e82 ꢀC; Rf 0.26
1
(1:1 CH2Cl2/hexane); H NMR (200 MHz, CDCl3): d 7.51e
Yield: 86 mg, 18%; colourless oil; Rf 0.21 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.68e7.58 (m, 1H), 7.43e
7.35 (m, 1H), 7.33e7.25 (m, 2H), 5.84 (br d, J¼0.8 Hz, 1H),
4.59 (ddd, J¼14.0, 1.2, 1.2 Hz, 1H), 4.39 (dd, J¼14.0, 4.2 Hz,
1H), 3.65 (ddd, J¼4.4, 4.2, 1.2 Hz, 1H), 3.62 (ddd, J¼4.4, 1.2,
0.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 133.2, 132.9,
130.0, 129.6, 129.4, 127.1, 75.9, 70.0, 51.2, 49.9; IR (neat):
1595, 1574, 1475, 1442, 1280, 1034, 917 cmꢁ1; MS m/z
(EIþ): 214 (Mþ, 37Cl, 31), 212 (Mþ, 35Cl, 97), 180 (44), 141
(65), 139 (100), 131 (24), 77 (67); HRMS (ESI) (MþNa)þ found
235.0134; (MþNa)þ calcd for C10H9O335ClNa 235.0138.
7.43 (m, 2H), 7.41e7.33 (m, 2H), 5.33 (br d, J¼1.1 Hz, 1H),
4.57 (ddd, J¼14.0, 1.3, 0.6 Hz, 1H), 4.38 (dd, J¼14.0, 4.2 Hz,
1H), 3.66 (ddd, J¼4.4, 4.2, 1.3 Hz, 1H), 3.50 (ddd, J¼4.4, 1.1,
0.6 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 135.3, 133.5,
129.9, 128.8, 79.0, 70.0, 51.1, 50.4; IR (Nujol): 1596, 1493,
1411, 1096, 1016, 909 cmꢁ1; MS m/z (EIþ): 214 (Mþ, 37Cl,
23), 212 (Mþ, 35Cl, 87), 180 (31), 141 (91), 139 (100), 131
(43), 77 (61). Anal. Calcd for C10H9O3Cl: C, 56.49; H, 4.27.
Found: C, 56.66; H, 4.13.
4.4.19. ꢃ(1aS,2R,5aS )-2-(2-Bromophenyl)perhydro-
4.4.15. ꢃ(1aS,2R,5aS )-2-(3-Chlorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2h)
oxireno[2,3-d][1,2]dioxine (2j)
Yield: 235 mg, 69%; colourless solid; mp 67.5e68.5 ꢀC; Rf
0.21 (1:1 CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3):
d 7.63 (dd, J¼7.8, 1.5 Hz, 1H), 7.43 (dd, J¼7.8, 1.2 Hz, 1H),
7.34 (ddd, J¼7.8, 7.5, 1.2 Hz, 1H), 7.24 (ddd, J¼7.8, 7.5,
1.5 Hz, 1H), 5.74 (br s, 1H), 4.59 (dd, J¼13.7, 1.5 Hz, 1H),
4.42 (br d, J¼13.7 Hz, 1H), 3.56 (ddd, J¼4.5, 0.6, 0.6 Hz,
1H), 3.50 (ddd, J¼4.5, 1.5, 0.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 134.7, 132.7, 130.3, 129.9, 127.7, 123.0, 78.2, 70.0,
51.3, 49.9; IR (Nujol): 1590, 1570, 1441, 1243, 1023, 975,
836 cmꢁ1; MS m/z (EIþ): 258 (Mþ, 81Br, 23), 256 (Mþ, 79Br,
24), 224 (9), 183 (29), 117 (44), 77 (83), 44 (100). Anal. Calcd
for C10H9O3Br: C, 46.72; H, 3.52. Found: C, 46.62; 3.48.
Yield: 403 mg, 74%; colourless oil; Rf 0.23 (1:1 CH2Cl2/hex-
ane); 1H NMR (600 MHz, CDCl3): d 7.42e7.32 (m, 3H), 7.31e
7.28 (m, 1H), 5.34 (br s, 1H), 4.55 (dd, J¼13.8, 1.8 Hz, 1H), 4.43
(ddd, J¼13.8, 0.6, 0.6 Hz, 1H), 3.54 (ddd, J¼4.2, 0.6, 0.6 Hz,
1H), 3.52 (ddd, J¼4.2, 1.8, 0.6 Hz, 1H); 13C NMR (150 MHz,
CDCl3): d 137.5, 134.7, 130.1, 129.3, 127.9, 126.0, 80.5, 69.3,
52.9, 48.7; IR (neat): 1599, 1575, 1479, 1433, 1195, 1036,
843 cmꢁ1; MS m/z (EIþ): 214 (Mþ, 37Cl, 30), 212 (Mþ, 35Cl,
90), 180 (34), 141 (55), 139 (100), 131 (22), 111 (56); HRMS
(ESI) (MþNa)þ found 235.0133; (MþNa)þ calcd for
C10H9O335ClNa 235.0138.
4.4.16. ꢃ(1aR,2R,5aR)-2-(3-Chlorophenyl)perhydro-
4.4.20. ꢃ(1aR,2R,5aR)-2-(2-Bromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3j)
oxireno[2,3-d][1,2]dioxine (3h)
Yield: 107 mg, 20%; colourless oil; Rf 0.28 (1:1 CH2Cl2/
hexane); 1H NMR (600 MHz, CDCl3): d 7.53 (dd, J¼1.2,
1.2 Hz, 1H), 7.40 (ddd, J¼7.8, 1.2, 1.2 Hz, 1H), 7.35 (ddd,
J¼7.8, 1.2, 1.2 Hz, 1H), 7.32 (dd, J¼7.8, 7.8 Hz, 1H), 5.33
(br d, J¼1.2 Hz, 1H), 4.57 (ddd, J¼13.8, 1.2, 1.2 Hz, 1H),
4.39 (dd, J¼13.8, 4.2 Hz, 1H), 3.66 (ddd, J¼4.2, 4.2,
1.2 Hz, 1H), 3.53 (ddd, J¼4.2, 1.2, 1.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3): d 136.9, 134.5, 129.8, 129.3, 128.6,
126.5, 79.0, 70.0, 51.0, 50.4; IR (neat): 1600, 1575, 1478,
1424, 1195, 1035, 843 cmꢁ1; MS m/z (EIþ): 214 (Mþ, 37Cl,
21), 212 (Mþ, 35Cl, 64), 180 (19), 141 (69), 139 (91), 111
(59), 77 (100); HRMS (ESI) (MþNa)þ found 235.0134;
(MþNa)þ calcd for C10H9O335ClNa 235.0138.
Yield: 78 mg, 23%; colourless oil; Rf 0.27 (1:1 CH2Cl2/hex-
ane); 1H NMR (300 MHz, CDCl3): d 7.63 (dd, J¼7.8, 1.4 Hz,
1H), 7.58 (dd, J¼7.8, 1.2 Hz, 1H), 7.37 (ddd, J¼7.8, 7.4,
1.2 Hz, 1H), 7.23 (ddd, J¼7.8, 7.4, 1.4 Hz, 1H), 5.82 (br s,
1H), 4.61 (br d, J¼13.7 Hz, 1H), 4.40 (dd, J¼13.7, 3.9 Hz,
1H), 3.68e3.63 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 135.1, 133.3, 130.4, 129.1, 127.6, 123.0, 80.3, 69.4, 53.2,
48.7; IR (neat): 1593, 1568, 1473, 1439, 1278, 1024,
990 cmꢁ1; MS m/z (EIþ): 258 (Mþ, 81Br, 38), 256 (Mþ, 79Br,
39), 224 (15), 185 (82), 131 (100), 117 (37), 77 (57); HRMS
(EIþ) (M)þ found 255.9744; (M)þ calcd for C10H9O379Br
255.9735.
4.4.21. ꢃ(1aS,2R,5aS )-2-(3-Bromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2k)
Yield: 395 mg, 74%; colourless oil; Rf 0.19 (1:1 CH2Cl2/
4.4.17. ꢃ(1aS,2R,5aS )-2-(4-Chlorophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2i)
Yield: 451 mg, 76%; colourless oil; Rf 0.18 (1:1 CH2Cl2/hex-
ane); 1H NMR (200 MHz, CDCl3): d 7.42e7.30 (m, 4H), 5.35
1
hexane); H NMR (200 MHz, CDCl3): d 7.59e7.49 (m, 2H),
7.38e7.23 (m, 2H), 5.33 (br s, 1H), 4.57 (dd, J¼13.4,

1232
I.G. Macreadie et al. / Tetrahedron 64 (2008) 1225e1232
1.2 Hz, 1H), 4.43 (dd, J¼13.4, 0.6 Hz, 1H), 3.57e3.50 (m,
2H); 13C NMR (50 MHz, CDCl3): d 137.8, 132.3, 130.8,
130.4, 126.5, 122.9, 80.4, 69.4, 52.9, 48.7; IR (neat): 1596,
1569, 1477, 1428, 1192, 1074, 841 cmꢁ1; MS m/z (EIþ): 258
(Mþ, 81Br, 83), 256 (Mþ, 79Br, 85), 224 (23), 185 (100), 183
(89), 157 (44), 131 (33); HRMS (EIþ) (M)þ found 255.97396;
(M)þ calcd for C10H9O379Br 255.97351.
0.8 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 139.3, 134.8,
129.5, 123.4, 79.6, 69.5, 52.4, 48.8; IR (neat): 1588, 1557,
1424, 1194, 1036, 860 cmꢁ1; MS m/z (EIþ): 338 (Mþ,
81Br81Br, 48), 336 (Mþ, 81Br79Br, 100), 334 (Mþ, 79Br79Br,
49), 304 (18), 263 (98), 211 (37), 209 (37), 156 (25), 102
(31); HRMS (ESI) (MþNa)þ found 356.8739; (MþNa)þ
calcd for C10H8O379Br2Na 356.8738.
4.4.22. ꢃ(1aR,2R,5aR)-2-(3-Bromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3k)
4.4.26. ꢃ(1aR,2R,5aR)-2-(3,5-Dibromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3m)
Yield: 111 mg, 21%; colourless oil; Rf 0.26 (1:1 CH2Cl2/
Yield: 93 mg, 17%; colourless solid; mp 108.5e110.5 ꢀC;
1
hexane); H NMR (200 MHz, CDCl3): d 7.70e7.66 (m, 1H),
1
Rf 0.29 (1:1 CH2Cl2/hexane); H NMR (200 MHz, CDCl3):
7.55e7.40 (m, 2H), 7.30e7.21 (m, 1H), 5.33 (br s, 1H), 4.58
(br d, J¼14.0 Hz, 1H), 4.39 (dd, J¼14.0, 4.0 Hz, 1H), 3.66
(dd, J¼4.2, 4.0 Hz, 1H), 3.53 (dd, J¼4.2, 1.2 Hz, 1H); 13C
NMR (50 MHz, CDCl3): d 137.2, 132.3, 131.5, 130.1, 127.0,
122.6, 79.0, 70.0, 51.1, 50.4; IR (neat): 1596, 1569, 1476,
1425, 1191, 1034, 990 cmꢁ1; MS m/z (EIþ): 258 (Mþþ2,
47), 256 (Mþ, 48), 224 (13), 185 (72), 183 (49), 131 (60),
77 (100); HRMS (EIþ) (M)þ found 255.9742; (M)þ calcd
for C10H9O379Br 255.9735.
d 7.68 (dd, J¼1.8 Hz, 1H), 7.61 (dd, J¼1.8, 0.6 Hz, 2H), 5.29
(br d, J¼1.4 Hz, 1H), 4.55 (ddd, J¼13.9, 1.2, 0.4 Hz, 1H),
4.40 (dd, J¼13.9, 3.7 Hz, 1H), 3.66 (ddd, J¼4.3, 3.7, 1.2 Hz,
1H), 3.54 (ddd, J¼4.3, 1.4, 0.4 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 138.7, 134.8, 130.0, 123.1, 78.3, 69.9, 51.0, 50.2;
IR (Nujol): 1588, 1557, 1423, 1187, 1037, 862 cmꢁ1; MS
m/z (þEI): 338 (Mþ, 81Br81Br, 39), 336 (Mþ, 81Br79Br, 86),
334 (Mþ, 79Br79Br, 42), 304 (9), 263 (100), 211 (65), 209 (66),
156 (29), 102 (53); HRMS (ESI) (MþNa)þ found 356.8739;
(MþNa)þ calcd for C10H8O379Br2Na 356.8738.
4.4.23. ꢃ(1aS,2R,5aS )-2-(4-Bromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2l)
Acknowledgements
Yield: 410 mg, 73%; colourless solid; mp 70e71 ꢀC; Rf 0.20
1
(1:1 CH2Cl2/hexane); H NMR (300 MHz, CDCl3): d 7.58e
We thank the University of Adelaide and CSIRP through
the granting of a Brailsford Robertson Award for financial
support. We thank Pfizer for the gift of fluconazole.
7.51 (m, 2H), 7.32e7.25 (m, 2H), 5.34 (br s, 1H), 4.56 (dd,
J¼13.7, 1.4 Hz, 1H), 4.43 (ddd, J¼13.7, 0.8, 0.6 Hz, 1H),
3.56e3.49 (m, 2H); 13C NMR (75 MHz, CDCl3): d 134.5,
132.0, 129.5, 123.3, 80.5, 69.3, 52.9, 48.6; IR (Nujol): 1591,
1575, 1408, 1242, 1073, 1013, 987 cmꢁ1; MS m/z (EIþ): 258
(Mþþ2, 19), 256 (Mþ, 20), 224 (3), 185 (100), 183 (86), 131
(65), 77 (33). Anal. Calcd for C10H9O3Br: C, 46.72; H, 3.53.
Found: C, 46.97; H, 3.33.
Supplementary data
Experimental details for diene precursors to 1,2-dioxines
4m,n and 5m,n and 1H or 13C NMR spectra for 1e3d, 1e3h,
1e3l, 1e3m and 1n. Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 648695 (1l), 648694 (2l) and 648693
(3l). Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.11.071.
4.4.24. ꢃ(1aR,2R,5aR)-2-(4-Bromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (3l)
Yield: 109 mg, 19%; colourless solid; mp 92.5e94.5 ꢀC; Rf
0.27 (1:1 CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3):
d 7.56e7.49 (m, 2H), 7.44e7.36 (m, 2H), 5.32 (br d,
J¼1.2 Hz, 1H), 4.58 (ddd, J¼13.9, 1.3, 0.8 Hz, 1H), 4.39 (dd,
J¼13.9, 4.2 Hz, 1H), 3.66 (ddd, J¼4.4, 4.2, 1.3 Hz, 1H), 3.51
(ddd, J¼4.4, 1.2, 0.8 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 134.0, 13.8, 30.2, 123.5, 79.1, 70.0, 51.1, 50.4; IR (Nujol):
1592, 1491, 1403, 1243, 1071, 1012, 996 cmꢁ1; MS m/z
(EIþ): 258 (Mþþ2, 28), 256 (Mþ, 29), 224 (2), 185 (63), 183
(43), 131 (100), 77 (44). Anal. Calcd for C10H9O3Br: C,
46.72; H, 3.53. Found: C, 47.00; H, 3.57.
References and notes
1. (a) Avery, T. D.; Macreadie, P. I.; Greatrex, B. W.; Robinson, T. V.; Taylor,
D. K.; Macreadie, I. G. Bioorg. Med. Chem. 2007, 15, 36e42; (b) Macreadie,
P. I.; Avery, T. D.; Greatrex, B. W.; Taylor, D. K.; Macreadie, I. G. Bioorg.
Med. Chem. Lett. 2006, 16, 920e922.
2. Matsumoto, M.; Dobasshi, S.; Kuroda, K.; Kondo, K. Tetrahedron 1985,
41, 2147e2154.
4.4.25. ꢃ(1aS,2R,5aS )-2-(3,5-Dibromophenyl)perhydro-
oxireno[2,3-d][1,2]dioxine (2m)
3. Greatrex, B. W.; Jenkins, N.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem.
2003, 68, 5205e5210.
4. Takahashi, Y.; Wakamatsu, K.; Morishima, S.; Miyashi, T. J. Chem. Soc.,
Perkin Trans. 2 1993, 243e253.
5. Taylor, D. K.; Avery, T. D.; Greatrex, B. W.; Tiekink, E. R. T.; Macreadie,
I. G.; Macreadie, P. I.; Humphries, A. D.; Kalkanidis, M.; Fox, E. N.;
Klonis, N.; Tilley, L. J. Med. Chem. 2004, 47, 1833e1839.
6. Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2004, 69, 2577e2579.
Yield: 332 mg, 62%; colourless oil; Rf 0.21 (1:1 CH2Cl2/
hexane); 1H NMR (200 MHz, CDCl3): d 7.69 (dd, J¼1.8,
1.8 Hz, 1H), 7.50 (dd, J¼1.8, 0.5 Hz, 2H), 5.29 (br s, 1H), 4.56
(dd, J¼13.8, 1.8 Hz, 1H), 4.45 (ddd, J¼13.8, 0.8, 0.6 Hz, 1H),
3.55 (ddd, J¼4.2, 0.8, 0.6 Hz, 1H), 3.50 (ddd, J¼4.3, 1.8,