Spiro- and dispiro-1,2-dioxolanes: Contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides

Article abstract of DOI:10.1021/jm0707673

Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid β-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals rather than further reduction of the initially formed Fe(III) complexed oxy radicals.

Full text of DOI:10.1021/jm0707673

5840
J. Med. Chem. 2007, 50, 5840-5847
Spiro- and Dispiro-1,2-dioxolanes: Contribution of Iron(II)-Mediated One-Electron vs
Two-Electron Reduction to the Activity of Antimalarial Peroxides
Xiaofang Wang,† Yuxiang Dong,† Sergio Wittlin,‡ Darren Creek,§ Jacques Chollet,‡ Susan A. Charman,§ Josefina Santo Tomas,‡
Christian Scheurer,‡ Christopher Snyder,‡ and Jonathan L. Vennerstrom*,†
College of Pharmacy, UniVersity of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, Swiss Tropical Institute,
Socinstrasse 57, CH-4002 Basel, Switzerland, and Centre for Drug Candidate Optimisation, Monash UniVersity, 381 Royal Parade,
ParkVille, Victoria 3052, Australia
ReceiVed June 27, 2007
Fourteen spiro- and dispiro-1,2-dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes
in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals
and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperox-
yketals and -acetals derived from ozonolysis of alkenes. The 1,2-dioxolanes were either inactive or orders
of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in
vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-dioxolane
3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane
artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the
latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms
that permits rapid â-scission reactions (or H shifts) to form primary or secondary carbon-centered radicals
rather than further reduction of the initially formed Fe(III) complexed oxy radicals.
Introduction
and evaluated the structurally related 1,2-dioxolanes 3. The
structures of the more chemically stable 1,2-dioxolanes preclude
the Hock-type fragmentation7-9 characteristic of 1,2,4-triox-
olanes (Scheme 1), leading to a prediction that the former should
have better biopharmaceutical properties than the latter.
Without the discovery of quinine from Cinchona trees and
artemisinin from Artemisia annua, it is uncertain how many
antimalarial drugs we would have today.1 Quinine provided the
lead for the discovery of a number of synthetic quinoline
methanols and 4-aminoquinolines, the most notable of which
is chloroquine. A synthetic peroxide antimalarial drug has yet
to be identified, although, as exemplified by artesunate, a
number of semisynthetic artemisinins are now in wide use.2 The
pharmacophoric peroxide bond in the semisynthetic artemisinins
and synthetic peroxides is essential, but not sufficient, for high
antimalarial efficacy.3 Therefore, understanding peroxide bond
reactivity is important in elucidating the chemistry that underlies
the antimalarial action of peroxide antimalarials and in providing
direction in drug design.
Chemistry
1,2-Dioxolanes have been synthesized by a number of
different methods including fragmentation of secondary ozo-
nides10,11 and hydroperoxyacetals and -ketals12,13 with various
Lewis acids in the presence of alkenes. We employed similar
methods to obtain 1,2-dioxolanes 3a-l (Table 1). We used one
Scheme 1. Decomposition of 1,2,4-Trioxolane 1 via a
Hock-Type Fragmentation
Scheme 2. Synthesis of 1,2-Dioxolanes 3 via Peroxycarbenium
Ion Annulations with Alkenes 6
Building on our mechanistic studies of antimalarial 1,2,4-
trioxolanes (secondary ozonides) 1 and 2,4-6 we synthesized
* To whom correspondence should be addressed. Phone: 402.559.5362.
Fax: 402.559.9543. E-mail: jvenners@unmc.edu.
† University of Nebraska Medical Center.
‡ Swiss Tropical Institute.
§ Monash University.
10.1021/jm0707673 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/20/2007

Spiro- and Dispiro-1,2-dioxolanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5841
Table 1. Synthesis of 1,2-Dioxolanes 3a-l
entry
method
peroxycarbenium ion precursor
alkene
1,2-dioxolane product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A
A
A
A
A
B
A
B
A
B
A
A
A
A
B
B
4a
4d
4c
4e
4a
5a
4b
5b
4c
5c
4a
4b
4c
4e
5a
5a
6c
6a
6c
6c
6a
6a
6a
6a
6a
6a
6b
6b
6b
6a
6d
6e
3a
3a
3b
3c
3d
3d
3e
3e
3f
74
35
68
48
86
83
94
94
88
88
90
77
73
56
30
55
3f
3g
3h
3i
3j
3k
3l
of two methods (Scheme 2), both of which proceed by way of
a common peroxycarbenium ion intermediate. The first (method
A) is that of Ramirez and Woerpel14 whereby triethylsilyldiper-
oxyketals and -acetals 4 fragment in the presence of SnCl4 to
form peroxycarbenium ions that undergo annulation with alkenes
6 to form 1,2-dioxolanes 3. The second (method B) is a modified
procedure of Dussault et al.12 that differs from method A14 only
in employing different peroxycarbenium ion precursors: tri-
ethylsilylperoxyketals and -acetals 5.
in similar reactions recorded by Ramirez and Woerpel.14 1,2-
Dioxolane alcohol 3n and carboxylic acid 3m were obtained
by reduction and hydrolysis of ester 3k (Scheme 3).
Scheme 3. Synthesis of 1,2-Dioxolanes 3m and 3n
The two 1,2-dioxolane synthetic methods are complementary.
Advantages of method B compared to method A are the
synthesis of 5 via ozonolysis of alkenes or enol ethers, thereby
avoiding the excess hydrogen peroxide required in the synthesis
of the geminal dihydroperoxide precursors of 4, and the presence
of one vs two peroxide bonds in 5 vs 4. On the other hand,
advantages of method A compared to method B are use of the
more widely available ketones and aldehydes compared to
alkenes, and the unambiguous fragmentation of 4 to form
peroxycarbenium ion intermediates.
Where investigated, both methods provided 1,2-dioxolanes
(3d-f) in identical or nearly identical yields (entries 5-10).
For method B, this implies selective alkoxide complexation of
5 with SnCl4 to effect ionization to the desired peroxycarbenium
ion intermediates. Of course, selectivity is not at stake in the
fragmentation of 4 to form the peroxycarbenium ion intermedi-
ates. The reaction yields for the synthesis of 3 were lower when
acyclic precursors 4 (entries 4 and 14) and 6 (entries 15 and
16) were employed. For 3a (entries 1 and 2), selection of
reaction partners was critical to reaction yield. In entry 2,
competing Bayer-Villiger reaction of 4e to adamantane lactone
was observed, resulting in a lower reaction yield. 1,2-Dioxolanes
3b and 3d-i were obtained as single diastereomers, presumed
to be in cis configurations based on the stereochemical outcome
Antimalarial Activity
As previously described,15 in vitro and in vivo antimalarial
activities were measured using the chloroquine-resistant K1 and
chloroquine-sensitive NF54 strains of P. falciparum and using
P. berghei infected mice (Table 2). Groups of three P. berghei
infected mice were treated 1 day after infection with 100 mg/
kg oral (po) doses of 3a-n dissolved or suspended in a
solubilizing 3% ethanol and 7% Tween-80 vehicle. Antimalarial
activity was measured by percent reduction in parasitemia on
day 3 after infection compared to an untreated control group.
What is immediately evident is that 1,2-dioxolanes 3a-n are
either inactive or orders of magnitude less potent than artemisi-
nin or 1,2,4-trioxolane 1 against P. falciparum. With the
exception of 3f, 3a-n did not have activities against P. berghei
that exceeded 50%. Even 3f, the most active 1,2-dioxolane, is
more than 1000-fold less effective than 1 and 5- to 10-fold less
effective than its 1,2,4-trioxolane isostere (data not shown).
When the sterically bulky spiroadamantane in 3a and 3b was
replaced with a spirocyclohexane (3d, 3f) or spirocyclopentane

5842 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Wang et al.
Table 2. Activity of 1,2-Dioxolanes 3a-n and 1,2,4-Trioxolane
(3g, 3i), potency increased by an order of magnitude. The
opposite trend in antimalarial potencies was observed for 1 and
2,4 the 1,2,4-trioxolane isosteres of 1,2-dioxolanes 3a and 3d.
Consistent with what we have observed before for functionalized
1,2,4-trioxolanes16 and 1,2,4,5-tetraoxanes,15 carboxylic acid 3m
was much less potent than its corresponding ester 3k and alcohol
3n. In summary, these 1,2-dioxolanes were unexpectedly much
less potent than the corresponding 1,2,4-trioxolanes, but their
weak antimalarial activities were similar to the micromolar IC50
values previously recorded for other synthetic17 and natural
product18 1,2-dioxolanes.
Isosteres 1 and 2 against P. falciparum in Vitro and P. berghei in Vivo
compd
IC50, K1/NF54 (ng/mL)a
activity (%)b
3a
3b
3c
3d
3e
3f
770/660
>1000/>1000
120/120
41/110
63/120
41/93
0
0
6
0
30
84
3g
3h
3i
41/62
130/180
38/83
0
45
49
3j
3k
3l
230/360
48/81
440/660
>1000/>1000
50/80
0.97/1.4
100/460
1.6/2.8
0
18
0
0
0
>99.99
0
Interaction of 3a with Iron(II)
3m
The iron activation hypothesis for antimalarial peroxides
proposes that the antimalarial activity is mediated by carbon-
centered free radicals generated following peroxide bond
cleavage by iron within the intraerythrocytic parasite.19 We
investigated the iron(II)-mediated reactivity of 3a, a representa-
tive 1,2-dioxolane and structural analogue of the 1,2,4-trioxolane
1, and found that 3a (0.03 mM) had a pseudo-first-order reaction
rate constant (k) of 0.14 ( 0.004 h-1 with FeSO4 (3 mM) in
MeCN/H2O (1:1) at 37 °C (n ) 3) under Ar. Under the same
conditions, rate constants (k) for 1 and artemisinin were 0.41
( 0.02 and 0.054 ( 0.006 h-1, respectively.6,20 Thus, 3a is
intermediate to 1 and artemisinin with respect to its iron(II)
reactivity. These small differences in reaction rates with iron-
(II), however, cannot explain the very low antimalarial activity
of 3a compared to 1 and artemisinin.
3n
1c
2c
artemisininc
98
a Mean of n ) 2-3 for chloroquine-resistant (K1) and chloroquine-
sensitive (NF54) strains of P. falciparum. Individual measurements generally
differed by less than 50%. b Groups of three P. berghei-infected NMRI mice
were treated (po) 1 day after infection with 1,2-dioxolanes (100 mg/kg)
dissolved or suspended in 3% ethanol and 7% Tween-80. Activity was
measured as percent reduction in parasitemia on day 3 after infection
compared to an untreated control group. Individual measurements generally
differed by less than 10%. c Data from Dong et al.4
Scheme 4. Reaction of 3a with FeBr2 in the Presence of
4-Oxo-TEMPO
In the next experiment, we characterized the reaction products
of 3a with iron(II). Exposure of 3a to FeBr2 (1.5 equiv) in CH2-
Cl2/MeCN (1:1) at 25 °C in the presence of the stable nitroxide
free radical 4-oxo-TEMPO (2 equiv) under Ar afforded a
mixture of diol 7 (64%) and 4-oxo-TEMPO adduct 8 (8%) as
the major reaction products21 (Scheme 4). The formation of only
one 4-oxo-TEMPO adduct (8) resulting from spiroadamantane
â-scission indicates regioselective formation of the Fe(III)
complexed oxy radical resulting from preferential attack of iron-
(II) on the less hindered peroxide bond oxygen atom of 3a.
Under comparable reaction conditions, we observed a similar
regioselective attack of iron(II) on 1, but the corresponding
4-oxo-TEMPO adduct was produced in 56% yield with no
evidence of any two-electron reduction products.5 The low yield
of 4-oxo-TEMPO adduct 8 (8%) from the reaction of 3a with
iron(II) suggested minimal carbon-centered radical formation,
while the predominant reaction product was diol 7, indicating
that the primary reaction course of 3a was a two-electron
Scheme 5. Reaction of Arteflene with FeCl2‚4H2O24,25

Spiro- and Dispiro-1,2-dioxolanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5843
followed by 1 M SnCl4 in CH2Cl2 (2.0 mL, 2.0 mmol). The resulting
mixture was stirred at -78 °C for 30 min and then kept at -30 °C
overnight. The reaction mixture was allowed to warm to -3 °C
and quenched with cold (4 °C) water (30 mL). After separation of
the organic layer, the aqueous layer was extracted with CH2Cl2 (2
× 30 mL). The combined extracts were washed with water (30
mL) and brine (30 mL), dried over MgSO4, filtered, and concen-
trated. Purification by chromatography (silica gel, 0-5% ether in
hexane) followed by crystallization from EtOH/H2O (10:1) afforded
3a (0.09 g, 35%) as a colorless solid.
reduction. Indeed, in a parallel reaction of 3a with 2 equiv of
FeBr2, 8 was not produced, indicating that â-scission is observed
only when less than stoichiometric quantitites of iron(II) are
used. That 7 was completely without antimalarial activity (P.
falciparum, IC50 > 1000 ng/mL) is consistent with the very
weak antimalarial activity of 3a.
As exemplified by arteflene, synthetic 1,2-dioxanes have been
relatively well explored,3 but until this study, very little was
known about the antimalarial properties of synthetic 1,2-
dioxolanes,17 their five-membered ring counterparts. The struc-
ture of arteflene makes an interesting comparison for 1,2-
dioxolanes. First, with an average IC50 of 37 ng/mL against five
P. falciparum isolates,22 arteflene is only slightly more potent
than some of the 1,2-dioxolanes 3 described in this study and
is an order of magnitude less potent than artemisinin. Although
exposure of arteflene to FeCl2‚4H2O produces secondary carbon-
centered radical 923 and enone 10 via â-scission,24 the predomi-
nant reaction product is inactive diol 1125 resulting from two-
electron reduction (Scheme 5). Similarly, for 3a, the iron(II)-
mediated two-electron reduction pathway (Scheme 4) leading
to inactive diol 7 predominates but to an even greater extent,
consistent with the 20-fold lower potency of 3a compared to
arteflene.
We suggest that for optimal antimalarial potency, peroxide
structures such as artemisinin that permit rapid â-scission
reactions (or H shifts) to form primary or secondary carbon-
centered radicals, rather than undergoing further reduction of
the initially formed Fe(III) complexed oxy radicals, are pre-
ferred.26 The key structural element in these active cyclic
peroxides appears to be an oxygen atom attached to one or both
of the peroxide-bearing carbon atoms. Indeed, it is observed5,27
that â-scission reactions arising from oxy radicals at ketal carbon
atoms occur much more quickly than competing â-scission
reactions arising from oxy radicals at nonketal positions. Thus,
1,2,4-trioxanes and 1,2,4,5-tetraoxanes are more active than the
corresponding 1,2-dioxanes,3 and 1,2,4-trioxolanes4 are more
active than the corresponding 1,2-dioxolanes. We predict that
this same trend will also hold true in larger ring cyclic
peroxides.28
Adamantane-2-spiro-3′-8′-phenyl-1′,2′-dioxaspiro[4.5]-
decane (3b). To a solution of 4c (0.50 g, 1.10 mmol) in CH2Cl2
(50 mL) at -78 °C was added 6c (0.49 g, 3.31 mmol) followed by
1 M SnCl4 in CH2Cl2 (2.20 mL, 2.20 mmol). The resulting mixture
was stirred at -78 °C for 30 min and then kept at -30 °C overnight.
The reaction mixture was allowed to warm to -3 °C and quenched
with cold (4 °C) water (30 mL). After separation of the organic
layer, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Purification
by chromatography (silica gel, 0-5% ether in hexane) followed
by crystallization from EtOH/H2O (10:1) afforded 3b (0.25 g, 68%)
1
as a colorless solid: mp 90-92 °C; H NMR δ 1.53-1.88 (m,
16H), 1.95-1.98 (m, 2H), 2.08-2.16 (m, 4H), 2.19 (s, 2H), 2.44-
2.52 (m, 1H), 7.15-7.30 (m, 5H); 13C NMR δ 26.5, 27.1, 30.5,
33.5, 35.7, 35.7, 36.3, 37.3, 43.4, 55.7, 84.0, 88.8, 126.0, 126.8,
128.3, 147.0. Anal. (C23H30O2) C, H.
Adamantane-2-spiro-3′-5′,5′-dipropyl-1′,2′-dioxolane (3c). To
a solution of 4e (0.30 g, 0.76 mmol) in CH2Cl2 (40 mL) at -78 °C
was added 6c (0.34 g, 2.30 mmol) followed by 1 M SnCl4 in CH2-
Cl2 (1.5 mL, 1.5 mmol). The resulting mixture was stirred at
-78 °C for 30 min and then kept at -30 °C overnight. The reaction
mixture was allowed to warm to -3 °C and quenched with cold
(4 °C) water (30 mL). After separation of the organic layer, the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
combined extracts were washed with water (30 mL) and brine (30
mL), dried over MgSO4, filtered, and concentrated. Purification by
chromatography (silica gel, 0-10% ether in hexane) afforded 3c
1
(0.10 g, 48%) as a colorless oil. H NMR δ 0.92 (t, J ) 7.5 Hz,
6H), 1.22-1.94 (m, 20H), 2.07-2.14 (m, 2H), 2.15 (s, 2H); 13C
NMR δ 14.6, 17.7, 26.5, 27.1, 33.5, 35.7, 36.3, 37.3, 38.6, 53.3,
88.2, 88.9. Anal. (C18H30O2) C, H.
14,15-Dioxadispiro[5.1.5.2]pentadecane (3d). Method A. To
a solution of 4a (0.40 g, 1.06 mmol) in CH2Cl2 (46 mL) at -78 °C
was added 6a (0.31 g, 3.23 mmol) followed by 1 M SnCl4 in CH2-
Cl2 (2.12 mL, 2.12 mmol). The resulting mixture was stirred at
-78 °C for 30 min and then kept at -30 °C overnight. The reaction
mixture was allowed to warm to -3 °C and quenched with cold
(4 °C) water (30 mL). After separation of the organic layer, the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
combined extracts were washed with water (30 mL) and brine (30
mL), dried over MgSO4, filtered, and concentrated. Purification by
chromatography (silica gel, 0-10% ether in hexane) followed by
crystallization from EtOH/H2O (5:1) afforded 3d (0.19 g, 86%) as
Experimental Section
General. Melting points are uncorrected. Unless otherwise noted,
1H and 13C NMR spectra were recorded on a 500 MHz spectrometer
using CDCl3 as solvent. All chemical shifts are reported in parts
per million (ppm) and are relative to internal (CH3)4Si (0 ppm) for
1H and CDCl3 (77.0 ppm) for 13C NMR. The alkylidenes 1-tert-
butyl-4-methylenecyclohexane,29 2-methyleneadamantane 6c,30 and
1-methylene-4-phenylcyclohexane31 were prepared according to
literature methods.
Adamantane-2-spiro-3′-1′,2′-dioxaspiro[4.5]decane (3a). Method
A. To a solution of 4a (0.68 g, 1.81 mmol) in CH2Cl2 (80 mL) at
-78 °C was added 6c (0.55 g, 3.72 mmol) followed by 1 M SnCl4
in CH2Cl2 (3.60 mL, 3.60 mmol). The resulting mixture was stirred
at -78 °C for 30 min and then kept at -30 °C overnight. The
reaction mixture was allowed to warm to -3 °C and quenched with
cold (4 °C) water (50 mL). After separation of the organic layer,
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined extracts were washed with water (50 mL) and brine (50
mL), dried over MgSO4, filtered, and concentrated. Purification by
chromatography (silica gel, 0-5% ether in hexane) followed by
crystallization from EtOH/H2O (10:1) afforded 3a (0.35 g, 74%)
1
a colorless solid. mp 50-52 °C; H NMR δ 1.32-1.48 (m, 8H),
1.52-1.78 (m, 12H), 2.04 (s, 2H); 13C NMR δ 23.6, 25.3, 35.8,
55.5, 85.1. Anal. (C13H22O2) C, H.
Method B. To a solution of 5a (0.50 g, 1.92 mmol) in CH2Cl2
(80 mL) at -78 °C was added 6a (0.68 mL, 5.73 mmol) followed
by 1 M SnCl4 in CH2Cl2 (3.80 mL, 3.80 mmol). The resulting
mixture was stirred at -78 °C for 30 min and then kept at -30 °C
overnight. The reaction mixture was allowed to warm to -3 °C
and quenched with cold (4 °C) water (50 mL). After separation of
the organic layer, the aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The combined extracts were washed with water (20
mL) and brine (20 mL), dried over MgSO4, filtered, and concen-
trated. Purification by chromatography (silica gel, 0-10% ether in
hexane) followed by crystallization from EtOH/H2O (5:1) afforded
3d (0.33 g, 83%) as a colorless solid.
1
as a colorless solid: mp 64-65; °C; H NMR δ 1.32-1.48 (m,
4H), 1.52-1.96 (m, 16H), 1.90-1.94 (m, 2H), 2.08-2.14 (m, 2H),
2.14 (s, 2H); 13C NMR δ 23.6, 25.4, 26.5, 27.1, 33.5, 35.7, 35.8,
36.3, 37.3, 54.3, 85.4, 88.9. Anal. (C17H26O2) C, H.
Alternative Method A. To a solution of 4d (0.43 g, 1.00 mmol)
in CH2Cl2 (40 mL) at -78 °C was added 6a (0.36 mL, 3.02 mmol)
3-tert-Butyl-14,15-dioxadispiro[5.1.5.2]pentadecane (3e). Method
A. To a solution of 4b14 (0.30 g, 0.69 mmol) in CH2Cl2 (30 mL)

5844 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Wang et al.
at -78 °C was added 6a (0.30 mL, 2.50 mmol) followed by 1 M
SnCl4 in CH2Cl2 (1.38 mL, 1.38 mmol). The resulting mixture was
stirred at -78 °C for 30 min and then kept at -30 °C overnight.
The reaction mixture was allowed to warm to -3 °C and quenched
with cold (4 °C) water (30 mL). After separation of the organic
layer, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Purification
by chromatography (silica gel, hexane) followed by crystallization
from EtOH/H2O (1:1) afforded 3e (0.17 g, 94%) as a colorless
solid: mp 75-76 °C; 1H NMR δ 0.83 (s, 9H), 0.91-1.00 (m, 1H),
1.22-1.78 (m, 16H), 1.98-2.06 (m, 2H), 2.01 (s, 2H); 13C NMR
δ 23.6, 23.8, 25.38, 27.58, 32.4, 35.8, 36.0, 47.1, 57.0, 84.0, 84.7.
Anal. (C17H30O2) C, H.
-78 °C was added 6b (0.22 mL, 2.07 mmol) followed by 1 M
SnCl4 in CH2Cl2 (1.38 mL, 1.38 mmol). The resulting mixture was
stirred at -78 °C for 30 min and then kept at -30 °C overnight.
The reaction mixture was allowed to warm to -3 °C and quenched
with cold (4 °C) water (30 mL). After separation of the organic
layer, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Purification
by chromatography (silica gel, hexane) followed by crystallization
from EtOH/H2O (3:2) afforded 3h (0.14 g, 77%) as a colorless
solid: mp 68-69 °C; 1H NMR δ 0.84 (s, 9H), 0.91-1.00 (m, 1H),
1.24-1.74 (m, 12H), 1.94-2.06 (m, 4H), 2.24 (s, 2H); 13C NMR
δ 23.8, 24.2, 27.5, 32.4, 36.1, 36.9, 47.1, 56.0, 83.9, 93.5. Anal.
(C16H28O2) C, H.
Method B. To a solution of 5b (0.40 g, 1.27 mmol) in CH2Cl2
(50 mL) at -78 °C was added 6a (0.50 mL, 4.17 mmol) followed
by 1 M SnCl4 in CH2Cl2 (2.60 mL, 2.60 mmol). The resulting
mixture was stirred at -78 °C for 30 min and then kept at -30 °C
overnight. The reaction mixture was allowed to warm to -3 °C
and quenched with cold (4 °C) water (50 mL). After separation of
the organic layer, the aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The combined extracts were washed with water (20
mL) and brine (20 mL), dried over MgSO4, filtered, and concen-
trated. Purification by chromatography (silica gel, 0-10% ether in
hexane) followed by crystallization from EtOH/H2O (1:1) afforded
3e (0.32 g, 94%) as a colorless solid.
10-Phenyl-13,14-dioxadispiro[4.1.5.2]tetradecane (3i). To a
solution of 4c (0.50 g, 1.10 mmol) in CH2Cl2 (50 mL) at -78 °C
was added 6b (0.34 mL, 3.17 mmol) followed by 1 M SnCl4 in
CH2Cl2 (2.20 mL, 2.20 mmol). The resulting mixture was stirred
at -78 °C for 30 min and then kept at -30 °C overnight. The
reaction mixture was allowed to warm to -3 °C and quenched with
cold (4 °C) water (30 mL). After separation of the organic layer,
the aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
combined extracts were washed with water (30 mL) and brine (30
mL), dried over MgSO4, filtered, and concentrated. Purification by
chromatography (silica gel, 0 to 5% ether in hexane) followed by
crystallization from EtOH/H2O (10:1) afforded 3i (0.22 g, 73%)
1
as a colorless solid: mp 101-102 °C; H NMR δ 1.57-1.86 (m,
3-Phenyl-14,15-dioxadispiro[5.1.5.2]pentadecane (3f). Method
A. To a solution of 4c (0.50 g, 1.10 mmol) in CH2Cl2 (50 mL) at
-78 °C was added 6a (0.38 mL, 3.23 mmol) followed by 1 M
SnCl4 in CH2Cl2 (2.20 mL, 2.20 mmol). The resulting mixture was
stirred at -78 °C for 30 min and then kept at -30 °C overnight.
The reaction mixture was allowed to warm to -3 °C and quenched
with cold (4 °C) water (30 mL). After separation of the organic
layer, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Purification
by crystallization from EtOH/H2O (10:1) afforded 3f (0.28 g, 88%)
12H), 1.96-2.06 (m, 2H), 2.08-2.14 (m, 2H), 2.31 (s, 2H), 2.44-
2.52 (m, 1H), 7.15-7.30 (m, 5H); 13C NMR δ 24.3, 30.5, 35.8,
36.9, 43.4, 56.1, 83.5, 93.6, 126.0, 126.9, 128.3, 147.0. Anal.
(C18H24O2) C, H.
3,3-Dipropyl-1,2-dioxaspiro[4.5]decane (3j). To a solution of
4e (0.31 g, 0.79 mmol) in CH2Cl2 (40 mL) at -78 °C was added
6a (0.28 mL, 2.40 mmol) followed by 1 M SnCl4 in CH2Cl2 (1.6
mL, 1.6 mmol). The resulting mixture was stirred at -78 °C for
30 min and then kept at -30 °C overnight. The reaction mixture
was allowed to warm to -3 °C and quenched with cold (4 °C)
water (30 mL). After separation of the organic layer, the aqueous
layer was extracted with CH2Cl2 (2 × 30 mL). The combined
extracts were washed with water (30 mL) and brine (30 mL), dried
over MgSO4, filtered, and concentrated. Purification by chroma-
tography (silica gel, 0-5% ether in hexane) afforded 3j (0.10 g,
56%) as a colorless oil. 1H NMR δ 0.92 (t, J ) 7.5 Hz, 6H), 1.21-
1.80 (m, 18H), 2.05 (s, 2H); 13C NMR δ 14.6, 17.7, 23.7, 25.3,
35.8, 38.6, 54.6, 85.0, 87.9. Anal. (C14H26O2) C, H.
3-[2-(Ethoxycarbonyl)ethyl]-3-methyl-1,2-dioxaspiro[4.5]-
decane (3k). To a solution of 5a (1.1 g, 4.2 mmol) in CH2Cl2 (170
mL) at -78 °C was added 6d (2.0 mL, 12.6 mmol) followed by 1
M SnCl4 in CH2Cl2 (8.0 mL, 8.0 mmol). The resulting mixture
was stirred at -78 °C for 30 min and then kept at -30 °C overnight.
The reaction mixture was allowed to warm to -3 °C and quenched
with cold (4 °C) water (30 mL). After separation of the organic
layer, the aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4, filtered, and concentrated. Purification
by chromatography (silica gel, 0-10% ether in hexane) afforded
3k (0.32 g, 30%) as a colorless oil. 1H NMR δ 1.26 (t, J ) 7.0 Hz,
3H), 1.30 (s, 3H), 1.32-1.80 (m, 10H), 1.82-1.90 (m, 1H), 2.04-
2.18 (m, 3H), 2.32-2.48 (m, 2H), 4.13 (q, J ) 7.0 Hz, 2H); 13C
NMR δ 14.2, 23.5, 23.6, 23.7, 25.2, 29.5, 34.1, 35.5, 35.8, 55.9,
60.4, 84.5, 85.5, 173.5. Anal. (C14H24O4) C, H.
1
as a colorless solid: mp 83-84 °C; H NMR δ 1.32-1.50 (m,
4H), 1.55-1.87 (m, 12H), 2.06-2.16 (m, 2H), 2.08 (s, 2H), 2.44-
2.52 (m, 1H), 7.15-7.30 (m, 5H); 13C NMR δ 23.6, 25.3, 30.5,
35.75, 35.78, 43.4, 57.0, 83.6, 84.9, 126.0, 126.8, 128.3, 147.0.
Anal. Calcd for C19H26O2: C, 79.68; H, 9.15. Found: C, 79.80; H,
8.96.
Method B. To a solution of 5c (0.32 g, 0.95 mmol) in CH2Cl2
(40 mL) at -78 °C was added 6a (0.34 mL, 2.80 mmol) followed
by 1 M SnCl4 in CH2Cl2 (1.90 mL, 1.90 mmol). The resulting
mixture was stirred at -78 °C for 30 min and then kept at -30 °C
overnight. The reaction mixture was allowed to warm to -3 °C
and quenched with cold (4 °C) water (50 mL). After separation of
the organic layer, the aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The combined extracts were washed with water (20
mL) and brine (20 mL), dried over MgSO4, filtered, and concen-
trated. Purification by chromatography (silica gel, 0-10% ether in
hexane) followed by crystallization from EtOH/H2O (10:1) afforded
3f (0.28 g, 88%) as a colorless solid.
13,14-Dioxadispiro[4.1.5.2]tetradecane (3g). To a solution of
4a (0.40 g, 1.06 mmol) in CH2Cl2 (46 mL) at -78 °C was added
6b (0.34 mL, 3.16 mmol) followed by 1 M SnCl4 in CH2Cl2 (2.12
mL, 2.12 mmol). The resulting mixture was stirred at -78 °C for
30 min and then kept at -30 °C overnight. The reaction mixture
was allowed to warm to -3 °C and quenched with cold (4 °C)
water (30 mL). After separation of the organic layer, the aqueous
layer was extracted with CH2Cl2 (2 × 30 mL). The combined
extracts were washed with water (30 mL) and brine (30 mL), dried
over MgSO4, filtered, and concentrated. Purification by chroma-
tography (silica gel, 0-10% ether in hexane) afforded 3g (0.19 g,
90%) as a colorless oil. 1H NMR δ 1.32-1.48 (m, 4H), 1.54-1.76
(m, 12H), 1.94-2.04 (m, 2H), 2.27 (s, 2H); 13C NMR δ 23.7, 24.3,
25.3, 35.8, 37.0, 54.7, 85.0, 93.8. Anal. (C12H20O2) C, H.
10-tert-Butyl-13,14-dioxadispiro[4.1.5.2]tetradecane (3h). To
a solution of 4b14 (0.30 g, 0.69 mmol) in CH2Cl2 (30 mL) at
3-Phenyl-1,2-dioxaspiro[4.5]decane (3l). To a solution of 5a
(0.33 g, 1.3 mmol) in CH2Cl2 (40 mL) at -78 °C was added 6e
(0.50 mL, 4.3 mmol) followed by 1 M SnCl4 in CH2Cl2 (2.6 mL,
2.6 mmol). The resulting mixture was stirred at -78 °C for 30
min and then kept at -30 °C overnight. The reaction mixture was
allowed to warm to -3 °C and quenched with cold (4 °C) water
(30 mL). After separation of the organic layer, the aqueous layer
was extracted with CH2Cl2 (2 × 30 mL). The combined extracts
were washed with water (30 mL) and brine (30 mL), dried over
MgSO4, filtered, and concentrated. Purification by chromatography

Spiro- and Dispiro-1,2-dioxolanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5845
(silica gel, 0-8% ether in hexane) afforded 3l (0.15 g, 55%) as a
washed with water (100 mL), dried over MgSO4, and concentrated.
The residue was purified by chromatography (silica gel, 2% ether
in hexane) to give 4c (3.34 g, 46%) as a colorless oil. H NMR δ
1
colorless oil. H NMR δ 1.36-1.52 (m, 4H), 1.66-1.88 (m, 6H),
1
2.35 (dd, J ) 12.0, 7.5 Hz, 1H), 2.76 (dd, J ) 12.0, 7.5 Hz, 1H),
5.27 (t, J ) 7.5 Hz, 1H), 7.27-7.71 (m, 5H); 13C NMR δ 23.7,
23.8, 25.3, 35.3, 36.1, 53.2, 82.9, 85.9, 126.6, 128.1, 128.6, 138.9.
Anal. (C14H18O2) C, H.
0.72 (q, J ) 8.3 Hz, 6 H), 0.77 (q, J ) 8.3 Hz, 6 H), 1.01 (t, J )
8.3 Hz, 9H), 1.04 (t, J ) 8.3 Hz, 9H), 1.42-1.62 (m, 2H), 1.65-
1.91 (m, 4H), 2.41 (d, J ) 12.7 Hz, 2H), 2.45-2.62 (m, 1H), 7.12-
7.39 (m, 5H); 13C NMR δ 3.92, 3.93, 6.80, 6.83, 30.3, 30.4, 43.8,
108.7, 126.0, 126.8, 128.4, 146.7. Anal. (C24H44O4Si2) C, H.
2,2-Bis[(triethylsilyl)dioxy]adamantane (4d). To a solution of
2-adamantanone (2.43 g, 16.20 mmol) in formic acid (18 mL) at
0 °C was added 50% H2O2 (28.8 mL, 480 mmol). After the mixture
was stirred at 0 °C for 30 min, the resulting precipitate was filtered,
washed with water (50 mL) and hexane (50 mL), and dried at room
temperature to give 2,2-dihydroperoxyadamantane33,34 (2.84 g, 90%
purity) that was used in the next step. To a solution of the above
unpurified 2,2-dihydroperoxyadamantane in DMF (50 mL) at 0 °C
was added 1-methylimidazole (3.30 g, 40 mmol) followed by Et3-
SiOTf (7.0 mL, 30.7 mmol). The mixture was stirred at 0 °C for
30 min and at room temperature overnight before it was quenched
under ice-water cooling with hexane (200 mL) and water (200
mL). After separation of the organic layer, the aqueous layer was
extracted with hexane (2 × 50 mL). The combined organic layers
were washed with water (100 mL), dried over MgSO4, and
concentrated. The residue was purified by chromatography (silica
gel, 1.5% ether in hexane) to give 4d (2.69 g, 39%) as a colorless
3-(2-Carboxyethyl)-3-methyl-1,2-dioxaspiro[4.5]decane (3m).
To a solution of 3k (0.08 g, 0.31 mmol) in EtOH (30 mL) was
added 1 M aqueous NaOH (1 mL). The resulting mixture was stirred
at 50 °C for 6 h. After the solvent was removed, the residue was
diluted with water (10 mL) and acidified with 1 M aqueous HCl
(5 mL). The precipitate was collected by filtration, washed with
cold (4 °C) water, and dried in a vacuum oven at 40 °C to afford
1
3m (0.063 g, 89%) as a colorless solid: mp 58-59 °C; H NMR
δ 1.31 (s, 3H), 1.32-1.80 (m, 10H), 1.82-1.90 (m, 1H), 2.07-
2.18 (m, 3H), 2.40-2.56 (m, 2H); 13C NMR δ 23.4, 23.5, 23.7,
25.2, 28.9, 33.9, 35.5, 35.9, 56.0, 84.4, 85.7, 177.6. Anal. (C12H20O4)
C, H.
3-(3-Hydroxypropyl)-3-methyl-1,2-dioxaspiro[4.5]decane (3n).
To a solution of 3k (0.60 g, 2.3 mmol) in ether (5 mL) and THF
(1 mL) was added dropwise 2 M lithium borohydride in THF (1.2
mL, 2.4 mmol) followed by 1 M lithium triethylborohydride in
THF (0.24 mL, 0.24 mmol). The resulting mixture was stirred at
room temperature overnight, diluted with ether (30 mL), washed
with 1 M aqueous NaOH (2 × 5 mL), water (2 × 5 mL), and
brine (5 mL), dried over MgSO4, filtered, and concentrated.
Purification by chromatography (silica gel, 0-20% ether in hexane)
1
oil. H NMR δ 0.73 (q, J ) 8.3 Hz, 12 H), 1.00 (t, J ) 8.3 Hz,
18H), 1.60 (d, J ) 12.7 Hz, 4H), 1.66 (s, 2H), 1.81 (s, 2H), 1.95
(d, J ) 12.2 Hz, 4H), 2.37 (s, 2H); 13C NMR δ 4.0, 6.9, 27.3,
31.6, 34.0, 37.5, 110.7. Anal. (C22H44O4Si2) C, H.
1
afforded 3n (0.45 g, 90%) as a colorless oil. H NMR δ 1.32 (s,
3H), 1.33-1.83 (m, 14H), 2.09 (d, J ) 11.7 Hz, 1H), 2.15 (d, J )
11.7 Hz, 1H), 3.67 (q, J ) 6.0 Hz, 2H); 13C NMR δ 23.5, 23.6,
23.7, 25.1, 27.6, 35.4, 35.6, 35.7, 55.9, 62.5, 85.4, 85.5. Anal.
(C12H22O3) C, H.
4,4-Bis[(triethylsilyl)dioxy]heptane (4e). To a solution of I2
(0.508 g, 2.0 mmol) and 30% H2O2 (4.5 mL, 40 mmol) in MeCN
(50 mL) was added 4-heptanone (2.8 mL, 20 mmol). After the
reaction mixture was stirred at room temperature for 24 h, the
solvent was removed. The residue was partitioned between CH2-
Cl2 (30 mL) and water (30 mL). The aqueous layer was extracted
with CH2Cl2 (2 × 30 mL). The combined extracts were washed
with water and brine, dried over MgSO4, filtered, and concentrated
to afford 4,4-dihydroperoxyheptane as a colorless oil (3.2 g, 80%
crude yield), which was used immediately in the next step. 1H NMR
δ 0.95 (t, J ) 7.5 Hz, 6H), 1.35-1.47 (m, 4H), 1.63-1.72 (m,
4H), 8.38 (brs, 2H). To a solution of the unpurified 4,4-dihydro-
peroxyheptane (3.2 g) in DMF (100 mL) at 0 °C was added Et3N
(17 mL, 120 mmol) followed by Et3SiOTf (10.2 mL, 48 mmol).
The reaction mixture was stirred at room temperature for 24 h,
cooled to 0 °C, and then diluted with hexane (100 mL) and ice-
water (100 mL). The organic layer was separated, and the aqueous
layer was extracted with hexane (3 × 100 mL). The extracts were
combined, dried over MgSO4, and concentrated. Purification by
chromatography (silica gel, hexane) afforded 4e (2.06 g, 26%) as
a colorless oil. 1H NMR δ 0.70 (q, J ) 8.0 Hz, 12H), 0.90 (t, J )
7.5 Hz, 6H), 0.98 (t, J ) 8.0 Hz, 18H), 1.30-1.40 (m, 4H), 1.65-
1.72 (m, 4H); 13C NMR δ 3.9, 6.8, 14.5, 17.3, 33.1, 112.4.
1-Methoxy-1-[(triethylsilyl)dioxy]cyclohexane (5a). A solution
of 6a (0.96 g, 10.0 mmol) in CH2Cl2 (25.5 mL) and MeOH (4.5
mL) at -78 °C was treated with ozone. After the ozonolysis, the
solution was diluted with CH2Cl2 (30 mL) and washed with cold
(4 °C) water (2 × 10 mL). The organic layer was separated, dried
over MgSO4, and concentrated to afford 1-methoxycyclohexyl
hydroperoxide35 (1.2 g, 82%) as a colorless oil, which was used
immediately in the next step. 1H NMR δ 1.36-1.63 (m, 6H), 1.66-
1.82 (m, 4H), 3.31 (s, 3H), 7.48 (brs, 1H). To a solution of the
unpurified 1-methoxycyclohexyl hydroperoxide (1.2 g, 8.22 mmol)
in DMF (100 mL) at 0 °C was added Et3N (4.5 mL, 32.4 mmol)
followed by Et3SiOTf (2.54 mL, 12 mmol). The reaction mixture
was stirred at room temperature for 24 h, cooled to 0 °C, and then
diluted with hexane (100 mL) and cold (4 °C) water (100 mL).
After the organic layer was separated, the aqueous layer was
extracted with hexane (3 × 100 mL). The extracts were combined,
dried over MgSO4, and concentrated. Purification by chromatog-
raphy (silica gel, 3% ether in hexane) afforded 5a (1.98 g, 93%)
1,1-Bis[(triethylsilyl)dioxy]cyclohexane (4a). To a solution of
cyclohexanone (3.18 g, 32.40 mmol) in formic acid (18 mL) at
0 °C was added 50% H2O2 (30 mL, 521 mmol). After the mixture
was stirred at 0 °C for 15 min, it was diluted with CH2Cl2 (200
mL) and water (200 mL). After separation of the organic layer,
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic layer was washed with brine (200 mL) and
concentrated to give 1,1-dihydroperoxycyclohexane32 (1.56 g, 86%
purity) that was used in the next step. To a solution of the above
unpurified 1,1-dihydroperoxycyclohexane in DMF (40 mL) at
0 °C was added Et3N (3.03 g, 30 mmol) and DMAP (88 mg, 0.72
mmol) followed by Et3SiOTf (8.1 mL, 37.5 mmol). The mixture
was stirred at 0 °C for 30 min and at room temperature overnight
before it was quenched under ice-water cooling with hexane (200
mL) and water (200 mL). After separation of the organic layer,
the aqueous layer was extracted with hexane (2 × 50 mL). The
combined extracts were washed with water (100 mL), dried over
MgSO4, and concentrated. The residue was purified by chroma-
tography (silica gel, 3% ether in hexane) to give 4a (2.20 g, 18%)
1
as a colorless oil. H NMR δ 0.71 (q, J ) 7.8 Hz, 12 H), 0.99 (t,
J ) 7.8 Hz, 18H), 1.35-1.46 (m, 2H), 1.47-1.56 (m, 4H), 1.77
(t, J ) 6.1 Hz, 4H). Anal. (C18H40O4Si2) C, H.
4-Phenyl-1,1-bis[(triethylsilyl)dioxy]cyclohexane (4c). To a
solution of 4-phenylcyclohexanone (2.82 g, 16.20 mmol) in CH2-
Cl2 (24 mL) and formic acid (18 mL) at 0 °C was added 50% H2O2
(28.8 mL, 480 mmol). After the mixture was stirred at 0 °C for 30
min, it was diluted with CH2Cl2 (200 mL) and water (200 mL).
After separation of the organic layer, the aqueous layer was
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers
were washed with brine (200 mL) and concentrated to give 1,1-
dihydroperoxy-4-phenylcyclohexane (3.95 g, 80% purity) that was
used in the next step. To a solution of the above unpurified 1,1-
dihydroperoxy-4-phenylcyclohexane in DMF (50 mL) at 0 °C was
added 1-methylimidazole (3.30 g, 40 mmol) followed by Et3SiOTf
(7.0 mL, 30.7 mmol). The mixture was stirred at 0 °C for 30 min
and at room temperature overnight before it was quenched under
ice-water cooling with hexane (200 mL) and water (200 mL). After
separation of the organic layer, the aqueous layer was extracted
with hexane (2 × 50 mL). The combined organic layers were
1
as a colorless oil. H NMR δ 0.72 (q, J ) 8.0 Hz, 6H), 1.00 (t, J

5846 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Wang et al.
) 8.0 Hz, 9H), 1.36-1.45 (m, 2H), 1.47-1.56 (m, 4H), 1.67-
1.76 (m, 4H), 3.28 (s, 3H); 13C NMR δ 3.8, 6.8, 22.8, 25.6, 31.5,
48.0, 104.8.
unidentified unsaturated alcohol dehydration products of 7 (5 mg,
6%). For 7: mp 128-129 °C; H NMR δ 1.23-1.33 (m, 1H),
1
1.42-1.84 (m, 17H), 1.84-1.92 (m, 4H), 1.89 (s, 2H), 2.17-2.24
(m, 2H), 3.19 (br s, 1H), 3.59 (br s, 1H); 1H NMR (CDCl3 + D2O)
δ 1.23-1.33 (m, 1H), 1.42-1.65 (m, 9H), 1.66-1.84 (m, 8H),
1.84-1.92 (m, 4H), 1.89 (s, 2H), 2.17-2.24 (m, 2H); 13C NMR δ
22.3, 25.6, 26.9, 27.2, 32.8, 34.7, 38.3, 39.0, 39.9, 46.5, 73.6, 77.0;
1H NMR (DMSO-d6) δ 1.18-1.28 (m, 1H), 1.29-1.70 (m, 17H),
1.71-1.79 (m, 2H), 1.74 (s, 2H), 1.80-1.88 (m, 2H), 2.20-2.27
(m, 2H), 5.17 (br s, 1H), 5.35 (br s, 1H); 13C NMR (DMSO-d6) δ
22.1, 25.5, 26.8, 27.0, 32.5, 34.3, 38.2, 38.8, 39.6, 46.2, 72.6, 75.4;
HRMS-FAB for C17H28O2 [M + H]+. For 8: mp 109-110 °C; 1H
NMR δ 1.13 (s, 6H), 1.18-1.74 (m, 16H), 1.29 (s, 6H), 2.00-
2.12 (m, 4H), 2.15-2.32 (m, 4H), 2.46-2.62 (m, 1H), 2.58 (s,
4-tert-Butyl-1-methoxy-1-[(triethylsilyl)dioxy]cyclohexane (5b).
A solution of 1-tert-butyl-4-methylenecyclohexane29 (0.90 g, 5.9
mmol) in CH2Cl2 (25.5 mL) and MeOH (4.5 mL) at -78 °C was
treated with ozone. After the ozonolysis, the solution was diluted
with CH2Cl2 (30 mL) and washed with cold (4 °C) water (2 × 10
mL). The organic layer was separated, dried over MgSO4, and
concentrated to afford 4-tert-butyl-1-methoxycyclohexyl hydrop-
eroxide12,33 (0.98 g, 82%) as a colorless solid (2:1 mixture of
diastereomers), which was used immediately in the next step: mp
1
53-56 °C; H NMR δ 0.87 (s, 9H), 0.96-1.46 (m, 5H), 1.64-
1.74 (m, 2H), 2.06-2.17 (m, 1.33H), 2.18-2.26 (m, 0.67H), 3.29
(s, 2H), 3.32 (s, 1H), 7.47 (s, 0.67H), 7.49 (s, 0.33H). To a solution
of the unpurified 4-tert-butyl-1-methoxycyclohexyl hydroperoxide
(0.98 g, 4.85 mmol) in DMF (50 mL) at 0 °C was added Et3N
(2.10 mL, 14.8 mmol) followed by Et3SiOTf (1.30 mL, 6.10 mmol).
The reaction mixture was stirred at room temperature for 24 h,
cooled to 0 °C, and then diluted with hexane (100 mL) and ice-
water (100 mL). The organic layer was separated, and the aqueous
layer was extracted with hexane (3 × 100 mL). The extracts were
combined, dried over MgSO4, and concentrated. Purification by
chromatography (silica gel, 3% ether in hexane) afforded 5b (0.96
g, 51%) as a colorless oil (5:4 mixture of diastereomers). 1H NMR
δ 0.56-0.78 (m, 6H), 0.86 (s, 9H), 0.94-1.06 (m, 9H), 1.10-
1.40 (m, 5H), 1.60-1.69 (m, 2H), 2.08-2.16 (m, 1.11H), 2.22-
2.30 (m, 0.89H), 3.26 (s, 1.67H), 3.30 (s, 1.33H); 13C NMR δ 3.7,
3.8, 6.8, 23.5, 23.7, 27.6, 27.7, 31.5, 31.8, 32.3, 32.3, 47.3, 47.8,
48.1, 48.3, 104.6, 104.8.
1
4H), 3.89 (s, 1H), 3.98-4.08 (m, 1H); H NMR (CDCl3 + D2O)
δ 1.13 (s, 6H), 1.18-1.74 (m, 16H), 1.29 (s, 6H), 2.00-2.12 (m,
4H), 2.15-2.32 (m, 4H), 2.46-2.62 (m, 1H), 2.58 (s, 4H), 3.98-
4.08 (m, 1H); 13C NMR δ 21.9, 22.7, 25.7, 25.8, 28.3, 28.5, 34.0,
37.7, 39.7, 44.2, 50.8, 53.6, 62.7, 70.7, 75.9, 208.6, 216.7. HRMS-
FAB for C26H43NO4 [M + H]+.
Pseudo-First-Order Reaction Rate Constant of 3a with
Ferrous Sulfate. 1,2-Dioxolane 3a (0.03 mM) was added to a
solution of FeSO4 (3 mM) in MeCN/H2O (1:1, 1.5 mL) and kept
at 37 °C under argon for automated kinetic analysis over 6 h as
previously described.20 1,2-Dioxolane 3a concentrations were
monitored by HPLC/APCI-MS (Waters 2795 HPLC/Waters Mi-
cromass ZQ single quadrupole mass spectrometer, Waters Corp.,
Milford, MA) using the assay previously described for analysis of
neutral 1,2,4-trioxolanes6 with the quasi-molecular ion (m/z 263.3)
monitored at cone voltage 15 V and corona current 15 µA.
Concentrations of 3a were determined from a linear calibration
curve, and pseudo-first-order degradation rate constants were
calculated from three independent reactions. The stability of 3a in
MeCN/H2O (1:1) at 37 °C was also confirmed, with no significant
degradation observed in iron-free controls over the time course of
these reactions.
1-Methoxy-4-phenyl-1-[(triethylsilyl)dioxy]cyclohexane (5c).
A solution of 1-methylene-4-phenylcyclohexane31 (3.1 g, 18.0
mmol) in CH2Cl2 (85 mL) and MeOH (15 mL) was treated with
ozone at -78 °C. After ozonolysis, the solution was diluted with
CH2Cl2 (30 mL) and washed with cold (4 °C) water (2 × 10 mL).
The organic layer was separated, dried over MgSO4, and concen-
trated to afford 1-methoxy-4-phenylcyclohexyl hydroperoxide (4.0
g, 100%) as a colorless solid (5:2 mixture of diastereomers), which
was used immediately in the next step: mp 66-69 °C; 1H NMR δ
1.44-1.96 (m, 6H), 2.18-2.26 (m, 1.43H), 2.26-2.38 (m, 0.57H),
2.52-2.64 (m, 1H), 3.35 (s, 2.14H), 3.37 (s, 0.86H), 7.16-7.36
(m, 5H), 7.49 (brs, 1H). To a solution of the unpurified 1-methoxy-
4-phenylcyclohexyl hydroperoxide (4.0 g, 18.0 mmol) in DMF (100
mL) at 0 °C was added Et3N (7.5 mL, 54 mmol) followed by Et3-
SiOTf (4.7 mL, 22 mmol). The reaction mixture was stirred at room
temperature for 24 h, cooled to 0 °C, and then diluted with ice-
cold hexane (100 mL) and ice-water (100 mL). The organic layer
was separated, and the aqueous layer was extracted with hexane
(3 × 100 mL). The extracts were combined, dried over MgSO4,
and concentrated. Purification by chromatography (silica gel, 3%
ether in hexane) afforded 5c (5.2 g, 86%) as a colorless liquid (5:3
Antimalarial Screens. In vitro and in vivo antimalarial data were
obtained as previously described.15
Acknowledgment. This investigation received financial
support from the Medicines for Malaria Venture (MMV).
Supporting Information Available: Elemental analysis results
and HRMS data for 3a-n, 4a,c,d, 7, and 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
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