Synthesis, Fe(II)-induced degradation, and antimalarial activities of 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonanes: Direct evidence for nucleophilic O-1,2-aryl shifts

Article abstract of DOI:10.1016/S0040-4039(02)00166-1

1,5-Diaryl-6,7-dioxabicyclo[3.2.2]nonanes 1a-d (1a: Ar=p-FC₆H₄, 1b: Ar=Ph, 1c: Ar=p-MeC₆H₄, 1d: Ar=p-MeOC₆H₄) were prepared by a modified method of photo-electron transfer oxygenation, and the reactions of 1 with FeBr₂ were investigated under various conditions. The Fe(II)-induced degradation of 1 afforded various rearrangement products and fragmentation products through competitive single electron transfer (SET) and Lewis acid pathways. Direct evidence for the O-1,2-aryl shift was obtained by the isolation of rearrangement products, 1-aryloxy-5-aryl-8-oxabicyclo[3.2.1]octanes 8. The degradation mechanism was proposed and the in vitro antimalarial activities were also evaluated.

Full text of DOI:10.1016/S0040-4039(02)00166-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2063–2067
Synthesis, Fe(II)-induced degradation, and antimalarial activities
of 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonanes: direct evidence for
nucleophilic O-1,2-aryl shifts
Masaki Kamata,a,* Motoko Ohta,a Ken-ichi Komatsu,a Hye-Sook Kimb and Yusuke Watayab
aDepartment of Chemistry, Faculty of Education and Human Science, Niigata University, Ikarashi, Niigata 950-2181, Japan
bFaculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan
Received 21 December 2001; revised 16 January 2002; accepted 18 January 2002
Abstract—1,5-Diaryl-6,7-dioxabicyclo[3.2.2]nonanes 1a–d (1a: Ar=p-FC6H4, 1b: Ar=Ph, 1c: Ar=p-MeC6H4, 1d: Ar=p-
MeOC6H4) were prepared by a modified method of photo-electron transfer oxygenation, and the reactions of 1 with FeBr2 were
investigated under various conditions. The Fe(II)-induced degradation of 1 afforded various rearrangement products and
fragmentation products through competitive single electron transfer (SET) and Lewis acid pathways. Direct evidence for the
O-1,2-aryl shift was obtained by the isolation of rearrangement products, 1-aryloxy-5-aryl-8-oxabicyclo[3.2.1]octanes 8. The
degradation mechanism was proposed and the in vitro antimalarial activities were also evaluated. © 2002 Elsevier Science Ltd.
All rights reserved.
The discovery of non-alkaloidal antimalarial endoper-
oxides such as artemisinin and related compounds has
stimulated synthetic and mechanistic studies on anti-
malarial cyclic peroxides.1–14 In particular, considerable
efforts have been devoted to mechanistic studies for the
Fe(II)-induced degradation of cyclic peroxides to clarify
potent antimalarial intermediates.15–17 Posner reported
that structurally simple and easily prepared 1,5-diaryl-
6,7-dioxabicyclo[3.2.2]nonanes 1b (Ar=Ph) and 1d
(Ar=p-MeOC6H4) are potent antimalarials.6,7 They
also demonstrated that the reaction of 1,5-diphenyl-
substituted cyclic peroxide 1b with FeBr2 afforded vari-
ous fragmentation products (3b, 6b, and 7b) and
rearrangement products (4b and 5b) (Scheme 1).6,7
However, they later reported that the structural assign-
ment of 1b was incorrect.7 These results have prompted
us to investigate the synthesis of variously substituted
1a–d, the reactions with FeBr2, and the antimalarial
activities since we have been studying the effects of
aromatic substituents on the reactivities of the oxyl
radical species generated from arylated cyclic perox-
ides.18–20 Herein we wish to report our preliminary but
novel results for the improved synthesis of 1a–d, Fe(II)-
induced degradation of 1a–d involving direct evidence
for nucleophilic O-1,2-aryl shifts,20 and their antimalar-
ial activities.
As for the synthesis of 1b–d, Takahashi reported that
9,10-dicyanoanthracene (DCA)-sensitized photo-elec-
tron transfer (PET) oxygenation of the corresponding
HO
Ph
+
Ph
Ph
Ph
FeBr2
THF
O
O
O
+
Ph
Ph
Ph
Ph
Ph
O
OH
O
HO
4b
O
3b
5b
1b
Ph
Ph
+
+
Ph
O
O
7b
6b
Scheme 1.
Keywords: 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonanes; cyclic peroxides; FeBr2; rearrangement; fragmentation; O-1,2-aryl shift; reaction mechanism;
antimalarial activity.
* Corresponding author. Tel./fax: +81-25-262-7150; e-mail: kamata@ed.niigata-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00166-1

2064
M. Kamata et al. / Tetrahedron Letters 43 (2002) 2063–2067
2,6-diaryl-1,6-heptadienes 2b–d afforded 1b–d in 0%
(11%: in the presence of Mg(ClO4)2), 37, 98% yields,
respectively.21,22 In order to improve the isolation proce-
dures and the yields of 1a–c, we modified the above
method by using 2,4,6-triphenylpyrylium tetra-
fluoroborate (TPPBF4) as a sensitizer since TPPBF4 has
a stronger oxidizing power than DCA and can be easily
separated from the reaction mixtures by column or TLC
separation. As summarized in Scheme 2 and Table 1,
TPPBF4-sensitized PET oxygenation of 2a–c afforded the
corresponding 1a–c in reasonable yields (33–58%).† While
the DCA-sensitized PET oxygenation of 2d produced 1d
in good yield (87%) as reported in the literature,21,22 the
TPPBF4-sensitized PET oxygenation of 2d resulted in the
decomposition of 1d. These results indicate that the choice
of a suitable sensitizer is essential for the PET oxygenation
of 2. Thus, TPPBF4 is suitable for the less electron-donat-
ing substrates such as 2a–c whereas DCA is suitable for
the more electron-donating substrate such as 2d.
Inordertoclarifythereactivitiesoftheoxylradicalspecies
generated from 1a–d, the reactions of 1a–d with FeBr2
were performed (Scheme 3). When 1,5-di(p-fluoro-
phenyl)-substituted cyclic peroxide 1a (0.2 mmol) was
treated with 1 equiv. of FeBr2 in dry THF (10 ml) under
nitrogen (4 h), 2-hydroxy-1,5-di(p-fluorophenyl)-8-
oxabicyclo[3.2.1]octane 4a (15%), 1-(p-fluorophenyl)-3-
(2-(p-fluorophenyl)tetrahydrofuran-2-yl)propan-1-one
5a (22%), 1,5-di(p-fluorophenyl)-pentan-1,5-dione 6a
Ar
Ar
hν/sens./O2
O
O
Ar
Ar
CH3CN
2
1
a : Ar = p-FC6H4
b: Ar = C6H5
c : Ar = p-MeC6H4
d : Ar = p-MeOC6H4
(12%),
and
1,5-di(p-fluorophenyl)-8-oxabicyclo-
Scheme 2.
[3.2.1]octane 7a (33%) were obtained (run 1 in Table 2).‡
HO
Ar
Ar
+
Ar
Ar
FeBr2
solvent/4 hrs
O
O
+
Ar
O
Ar
Ar
Ar
Ar
Ar
O
O
OH
HO
3
5
1
4
a : Ar = p-FC6H4
b: Ar = C6H5
c : Ar = p-MeC6H4
d : Ar = p-MeOC6H4
Ar
Ar
O
O
Ar
+
+
OAr
+
O
O
6
8
7
+
+
Ar
O + Ar
O
Ar-OH
11
9
10
Scheme 3.
† A typical experimental procedure is as follows: An oxygen-purged acetonitrile (50 ml) solution of 2 (0.50 mmol) and sensitizer (TPPBF4: 0.05
mmol; DCA: 0.0125 mmol) was selectively irradiated (u>360 nm) with a 2 kW Xe lamp. The resulting reaction mixture was concentrated and
the residue was separated by TLC (CH2Cl2–n-hexane) to afford products. The cyclic peroxides 1a–d were characterized by their spectral data
and also confirmed by the comparison with reported spectral data.21,22
Selected data for 1d: mp 185–186°C (CH3CN); IR (KBr, cm−1) 3080, 3040, 3020, 2990, 2960, 2940, 2880, 1615, 1587, 1518; 1H NMR (200 MHz,
CDCl3) l 1.78–2.50 (m, 10H), 3.79 (s, 6H), 6.82–6.92 (m, 4H), 7.30–7.42 (m, 4H); 13C NMR (50 MHz, CDCl3) l 21.28 (t, 1C), 29.36 (t, 2C),
40.44 (t, 2C), 55.25 (q, 2C), 82.48 (s, 2C), 113.53 (d, 4C), 125.75 (d, 4C), 138.54 (s, 2C), 158.56 (s, 2C). Anal. calcd C, 74.19; H, 7.25; requires
C, 74.09; H, 7.11; MS (EI) 340 (M+, 12%), 135 (100%).
‡ A typical experimental procedure is as follows: To a solution of 1 (0.2 mmol) in dry THF or dry CH2Cl2 (10 ml) was added FeBr2 (0.2 mmol).
The mixture was stirred at 23–25°C under a nitrogen atmosphere for 4 h. The mixture was passed through silica gel short column and eluted
with CH2Cl2 to remove inorganic iron compounds. The eluent was concentrated and the residue was separated by TLC (CH2Cl2–n-hexane) to
afford products. All products were characterized by their spectral data.
Selected data for 4c: colorless oil; IR (CHCl3, cm−1) 3600–3300 (OꢀH), 3075, 3020, 2975, 2945, 2900, 1518, 1475, 1450, 1385, 1360, 1300, 1260;
1H NMR (200 MHz, CDCl3) l 1.76–2.42 (m, 9H), 2.35 (s, 3H), 2.36 (s, 3H), 3.80–3.91 (m, 1H), 7.14–7.24 (m, 4H), 7.35–7.47 (m, 4H); 13C NMR
(50 MHz, CDCl3) l 21.09 (q, 2C), 25.96 (t, 1C), 33.25 (t, 1C), 35.67 (t, 1C), 36.39 (t, 1C), 70.35 (d, 1C), 84.59 (s, 1C), 86.36 (s, 1C), 124.36 (d,
2C), 124.77 (d, 2C), 128.81 (d, 2C), 128.99 (d, 2C), 136.31 (s, 1C), 136.52 (s, 1C), 140.68 (s, 1C), 143.48 (s, 1C).
1
Selected data for 5d: colorless oil; IR (CHCl3, cm−1) 3050, 3020, 2970, 2950, 2930, 2890, 2850, 1675 (CꢁO), 1603, 1580, 1512; H NMR (200 MHz,
CDCl3) l 1.70–2.36 (m, 6H), 2.47–2.67 (m, 1H), 2.95–3.14 (m, 1H), 3.80 (s, 3H), 3.83 (s, 3H), 3.89–4.01 (m, 2H), 6.82–6.92 (m, 4H), 7.26–7.35
(m, 2H), 7.78–7.88 (m, 2H); 13C NMR (50 MHz, CDCl3) l 25.56 (t, 1C), 33.61 (t, 1C), 36.38 (t, 1C), 39.36 (t, 1C), 55.18 (q, 1C), 55.36 (q, 1C),
67.60 (t, 1C), 85.84 (s, 1C), 113.41 (d, 2C), 113.45 (d, 2C), 126.29 (d, 2C), 129.99 (s, 1C), 130.20 (d, 2C), 138.06 (s, 1C), 158.09 (s, 1C), 163.14
(s, 1C), 199.03 (s, 1C).
Selected data for 7d: mp 126–127.5°C (CH3OH); IR (KBr, cm−1) 3080, 3050, 2960, 2930, 2880, 2850, 1618, 1587, 1513; 1H NMR (200 MHz,
CDCl3) l 1.62–2.12 (m, 8H), 2.25–2.40 (m, 2H), 3.80 (s, 6H), 6.84–6.93 (m, 4H), 7.37–7.47 (m, 4H); 13C NMR (50 MHz, CDCl3) l 19.34 (t, 1C),
37.20 (t, 2C), 37.71 (t, 2C), 55.24 (q, 2C), 83.83 (s, 2C), 113.34 (d, 4C), 125.66 (d, 4C), 139.79 (s, 2C), 158.10 (s, 2C). Anal. calcd C, 77.48; H,
7.67; requires C, 77.75; H, 7.46; MS (EI) 324 (M+, 13%), 135 (100%).
Selected data for 8d: mp 109–110°C (CH3OH); IR (KBr, cm−1) 3050, 3020, 2980, 2960, 2930, 2890, 2860, 1618, 1590, 1521, 1510; 1H NMR (200
MHz, CDCl3) l 1.52–2.28 (m, 10H), 3.76 (s, 3H), 3.80 (s, 3H), 6.75–6.92 (m, 4H), 7.13–7.24 (m, 2H), 7.28–7.38 (m, 2H); 13C NMR (50 MHz,
CDCl3) l 19.60 (t, 1C), 32.44 (t, 1C), 34.07 (t, 1C), 34.90 (t, 1C), 37.53 (t, 1C), 55.22 (q, 1C), 55.46 (q, 1C), 84.19 (s, 1C), 109.51 (s, 1C), 113.40
(d, 2C), 113.92 (d, 2C), 123.31 (d, 2C), 125.37 (d, 2C), 138.96 (s, 1C), 147.95 (s, 1C), 155.64 (s, 1C), 158.21 (s, 1C). Anal. calcd C, 74.02; H, 7.12;
requires C, 74.09; H, 7.11; MS (EI) 340 (M+, 21%), 217 (100%).
1
Selected data for the mixture of 9d and 10d: pale yellow oil; IR (neat, cm−1) 3050, 2960, 2950, 2920, 2850, 1702 (CꢁO), 1608, 1573, 1512; H NMR
(200 MHz, CDCl3) for 9d: l 2.02–2.20 (m, 2H), 2.60–2.85 (m, 4H), 3.32 (d, 2H, J=6.3 Hz), 3.81 (s, 3H), 5.79 (t, 1H, J=6.3 Hz), 6.82–6.92 (m,
2H), 7.22–7.33 (m, 2H); 1H NMR (200 MHz, CDCl3) for 10d: l 2.43–2.56 (m, 2H), 2.60–2.85 (m, 6H), 3.81 (s, 3H), 6.03 (t, 1H, J=5.8 Hz),
6.82–6.92 (m, 2H), 7.22–7.33 (m, 2H).

M. Kamata et al. / Tetrahedron Letters 43 (2002) 2063–2067
Table 1. PET oxygenation of 2,6-diaryl-1,6-heptadienes 2a
2065
and CH2Cl2, the mono-oxyl radical intermediate A is
generated by single electron transfer (SET) from Fe(II)
to 1.6,7,20,23 Four different pathways are plausible for
the product formation from A. The first and the second
pathways are the formation of 5 (path a-1: C1ꢀC2
cleavage) and 6 (path a-2: C1ꢀC8 cleavage) through
CꢀC bond cleavage. The third is the formation of the
intermediate B through a 1,5-hydrogen shift followed
by direct epoxidation to afford the intermediate C (path
b), which finally rearranges to 4 through an intramolec-
ular nucleophilic cyclization. The fourth is the forma-
tion of deoxygenated product 7 through an electrophilic
oxyl radical 1,5-substitution accompanied with elimina-
tion of the Fe(IV)ꢁO species (path c).20 In CH2Cl2,
Fe(II) also acts as a Lewis acid that generates the
complex of 1 with Fe(II) (1-Fe(II)). 1-Fe(II) undergoes
a nucleophilic O-1,2-aryl shift to generate the interme-
diate D (path d),20 which is promoted by electron-
donating substituents (p-An>p-Tol>Ph=p-FC6H4:
runs 5–9). The intermediate D undergoes cyclization to
afford the rearrangement product 8 which is direct
evidence for the nucleophilic O-1,2-aryl shift. In the
presence of the Fe(II) species (Lewis acid), 8d easily
undergoes fragmentation to afford 9d, 10d, and 11d.
Thus, the products 4–7 are produced through the SET
pathway while 8–11 are produced through the Lewis
acid pathway. THF and TMB are considered to act as
a weak Lewis base, interfering with the Lewis acid
pathway and/or promoting the SET pathway.
Run Substrate
Sensitizerb
Irradiation
time (min)
Yield of 1
(%)c
1
2
3
4
2a
2b
2c
2d
TPPBF4
TPPBF4
TPPBF4
DCA
50
65
20
15
33
44
58
87
a 2=0.5 mmol; CH3CN=50 ml; irradiated by a 2 kW Xe lamp
(l>360 nm).
b TPPBF4=0.05 mmol; DCA=0.0125 mmol.
c Isolated yield by silica gel TLC.
No diol 3a was obtained.6 When 1b and 1c were treated
with FeBr2, similar product distributions were observed
(runs 2 and 3). Interestingly, a new type of product,
1-(p-methoxyphenyl)oxy-5-(p-methoxyphenyl)-8-oxabi-
cyclo[3.2.1]octane 8d (11%) was obtained besides 4d–7d
when 1,5-di(p-methoxyphenyl)-substituted 1d was
treated with FeBr2 (run 4). On the other hand, 8a–c
(11%, 8%, 86%) were produced from 1a–c, respectively
in the reactions of 1a–c with FeBr2 in dry CH2Cl2 (runs
5–7). On the contrary, 4-(p-methoxyphenyl)cyclohept-
3-en-1-one 9d and 4-(p-methoxyphenyl)cyclohept-4-en-
1-one 10d (9d+10d=74%) were newly produced
accompanied with p-methoxyphenol 11d (65%) when 1d
was treated with FeBr2 in dry CH2Cl2 (run 8). Interest-
ingly, a catalytic amount of FeBr2 (0.5 equiv.) also
promoted the OꢀO bond cleavage reactions of 1b and
1d (runs 9 and 10). A control experiment in CH2Cl2
demonstrated that 8d was decomposed by a catalytic
amount of FeBr2 to afford 9d, 10d, and 11d quantita-
tively (Lewis acid-catalyzed fragmentation).20 Addition
of an electron-donating compound such as 1,2,4,5-tet-
ramethoxybenzene (TMB) slightly suppressed the frag-
mentation of 8d (run 11).
The in vitro antimalarial activities of 1a–d against P.
falciparum and cytotoxicities against FM-3A cells were
tested to clarify the relationship between the antimalar-
ial activities and the effects of the aromatic substituents
of 1 (Table 3).12 The EC50 values of 1a–d against P.
falciparum were in the range from 2.5×10−7 to 9.0×10−8
M and the selectivities were fairly high (60–300),
regardless of their aromatic substituents. In particular,
1b–d can be promising lead compounds for the synthe-
sis of new antimalarial drugs. Notably, fluoro-substi-
On the basis of the above results, we propose a plausi-
ble mechanism as shown in Scheme 4. Both in THF
a
Table 2. Reactions of 1,5-diaryl-6,7-dioxabicyclo[3.2.2]nonanes 1 with FeBr2
Run
Substrate
Solvent
Additive
Yields (%)b
3
4
5
6
7
8
9+10 (9:10)c
11
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1b
1c
1d
1b
1d
1d
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
None
None
None
None
None
None
None
None
Noned
Noned
TMBe
0
0
0
0
0
0
0
0
0
0
0
15
14
19
12
11
9
0
0
9
0
22
24
27
22
29
29
8
0
28
0
12
13
28
17
30
29
6
0
27
0
33
42
34
31
10
2
0
0
1
0
0
0
0
11
11
8
86
0
13
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
65
0
78
77
74 (44:56)
0
84 (54:46)
72 (54:46)
9
10
11
0
0
0
3
10
a 1=0.2 mmol, FeBr2=0.2 mmol, solvent=10 ml, at 23–25°C.
b Isolated yield by silica gel TLC.
c Determined by 1H NMR.
d FeBr2=0.1 mmol.
e In the presence of 1,2,4,5-tetramethoxybenzene (0.2 mmol).

2066
M. Kamata et al. / Tetrahedron Letters 43 (2002) 2063–2067
Scheme 4.
Table 3. In vitro antimalarial activities of 1 against P.
falciparum (FCR-3 strain) and cytotoxicities against
FM3A cellsa
In conclusion, we have improved the synthesis of 1a–c
by using the TPPBF4-induced PET oxygenation. We
have found the direct evidence (isolation of 8) for the
nucleophilic O-1,2-aryl shifts in the Fe(II)-induced
degradation of 1. Furthermore, we have disclosed that
Fe(II) acts not only as a SET donor but also as a Lewis
acid in the Fe(II)-induced OꢀO bond cleavage of cyclic
peroxides. We are conducting further studies on the
Fe(II)-induced degradation of arylated cyclic peroxides
to substantiate the generality of the reaction and the
relationship between the reaction intermediates and the
antimalarial activities.
Substrate
EC50 (M)
Selectivityb
P. falciparum
FM3A
1a
1b
2.5×10−7
9.0×10−8
1.5×10−5
2.7×10−5
(59%)d
60
\300
(8.9×10−8 c
1.6×10−7
)
1c
1d
1.6×10−5
(59%)d
\100
\100
1.6×10−7
1.6×10−5
(83%)d
(6.2×10−8 c
)
We are grateful to Professor Eietsu Hasegawa (Faculty
of Science, Niigata University), Professor Tsutomu
Miyashi and Dr. Hiroshi Ikeda (Faculty of Science,
Tohoku University), Professor Yasutake Takahashi
(Faculty of Engineering, Mie University), and Professor
Akinori Kon-no (Faculty of Engineering, Shizuoka
University) for their helpful comments and assistance.
Artemisinin
Chloroquine
7.8×10−9
1.8×10−8
1.0×10−5
3.2×10−5
1280
1780
a Ref. 12.
b Selectivity=cytotoxicity/antimalarial activity.
c IC50 values against P. falciparum (NF54 strain), Ref. 6.
d Growth percent at the concentration indicated.
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