Piperidine dispiro-1,2,4-trioxane analogues

Article abstract of DOI:10.1016/j.bmcl.2008.09.052

Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)₂ catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting β-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.

Full text of DOI:10.1016/j.bmcl.2008.09.052

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5804–5808
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Piperidine dispiro-1,2,4-trioxane analogues
a
b
b
c
a
c
Sunil Sabbani , Paul A. Stocks , Gemma L. Ellis , Jill Davies , Erik Hedenstrom , Stephen A. Ward ,
b,
*
Paul M. O’Neill
Chemistry, Department of Natural Sciences, Mid Sweden University, SE-85170 Sundsvall, Sweden
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2008
Revised 11 September 2008
Accepted 12 September 2008
Available online 17 September 2008
Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac) catalysed perhydrolysis of N-Boc
spirooxirane followed by condensation of the resulting b-hydroperoxy alcohol 10 with 2-adamantanone.
2
N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subse-
quently used to prepare derivatives (4–7). Several of these novel 1,2,4-trioxanes had nanomolar antima-
larial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile
derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogen peroxide
1
,2,4-Trioxane
Endoperoxide
Antimalarial
Mechanism of action
Currently, semi-synthetic derivatives of artemisinin1 are the
,2
In the synthesis of trioxanes 2–7 the key intermediate was the
b-hydroperoxy alcohol. Initially we started the synthesis of 5 with
the hydrochloride salt of 4-piperidone to obtain N-phenylsulfonyl-
piperidinone which was subjected to Corey–Chaykovsky epoxida-
3
drugs of choice to treat multi-drug resistant malaria. However,
the commercial availability of artemisinin 1a1 (and hence its
semi-synthetic derivatives) is somewhat limited since it is a natu-
ral product isolated from the herb Artemisia annua. As a result,
extensive research into synthetic endoperoxide antimalarial drugs
has been carried out in the last 15 years4 to produce molecules
that are structurally simpler and synthetically accessible with a
projected low cost of goods4 (Fig. 1).
,2
1
0
tion
to obtain N-phenylsulfonylpiperidinone spiroepoxide
(Scheme 1). The resulting epoxide was used to synthesise N-phen-
ylsulfonylpiperidine b-hydroperoxy alcohol (Scheme 1) following
–6
1
1
the procedure described by Vennerstrom et al. Several attempts
,7
failed to obtain N-phenylsulfonylpiperidine b-hydroperoxy alcohol
Fully synthetic cyclic endoperoxides examined in the literature
include 1,2-dioxanes, 1,2,4-trioxolanes, 1,2,4-trioxanes and 1,2,4,5-
tetraoxanes, all of which retain the critical endoperoxide bond.
4 2 2
by treating the spiroepoxide with MgSO and dried H O in pres-
ence of molybdenyl acetylacetonate (Scheme 1). Later, we used
commercially available N-Boc-4-piperidone 8 as the starting mate-
rial to first obtain the N-Boc spiroepoxide 9 followed by perhydro-
lysis to get b-hydroperoxy alcohol 10 in good yield. The
spiroepoxide 9 was obtained via Corey–Chaykovsky reaction in a
Padmanilayam et al. recently synthesised a series of piperidine
8
1
,2,4-trioxolanes and reported impressive antimalarial activities.
Inspired by this work, we were interested in exploring the antima-
larial activities of dispiro-1,2,4-trioxanes with a fused piperidine
ring. The advantage of incorporating a nitrogen within the C ring
of a 1,2,4-trioxane lies in the fact that the resulting endoperoxide
is achiral in contrast to 1,2,4-trioxanes such as 1b and hybrid mol-
ecules such as the 1,2,4-trioxaquines,9 for example, 1c and this
may be an advantage in terms of avoiding expensive asymmetric
synthesis or having to perform resolution of racemic drug
substance.
1
2
yield of 82%. When the epoxide 9 was subjected to molybdenyl
acetylacetonate catalysed perhydrolysis in presence of H , the
2 2
O
b-hydroperoxy alcohol 10 was obtained almost quantitatively
(Scheme 2).
The b-hydroperoxy alcohol 10 was used without any further
purification as TLC, MS and NMR indicated the presence of only
one product. Hydrogen peroxide (50%) used in the perhydrolysis
reaction was dissolved in anhydrous ether and dried twice with
In this paper we report on the first synthesis of piperidine 1,2,4-
trioxanes 2–7 and the isomeric 1,2,4- trioxane 12.
4
anhydrous MgSO . It is interesting to note that b-hydroperoxy
alcohol 10 was obtained almost quantitatively from 9 (Scheme 2)
while N-phenylsulfonylpiperidine b-hydroperoxy alcohol was not
accessible from N-phenylsulfonylpiperidine spiro epoxide (Scheme
1). Following a previously published procedure, b-hydroperoxy
*
Corresponding author.
E-mail address: P.M.oneill01@liv.ac.uk (P.M. O’Neill).
0
960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.052

S. Sabbani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5804–5808
5805
O
O
O
H
O
O
O
O
N R
O
A
B
C
R
O
O
2: R = Boc
3: R = H.HCl
H
H
1b
4
5
7
: R = H
5a: R = SO Ph
2
O
b: R = SO Et 6: CH CO
2
3
: R = Fmoc
O O
O
NH NH
N
O
O
1a
N
SO Ph
2
O
2
1c
Cl
1
Figure 1. Artemisinin (1a) and synthetic piperidine dispiro-1,2,4-trioxanes (2–7).
OH OH
O
O
O
O
N
CH S(O)I,
H O ,
2 2
N
S O
3
N
S O
N
S O
K CO , CHCl
DMSO, NaH
MoO (acac)
2 2
2
3
3
O
O
O
H
O, PhSO
2
Cl
reflux, 25 ºC
Et O
2
2
H
.
HCl
Scheme 1. Attempted synthesis of N-phenylsulfonylpiperidine b-hydroperoxy alcohol.
OH OH
O
2
-
O
N
O
N
O
O
O
O
CH S(O)I,
adamantanone,
CH Cl ,
3
H O , MoO (acac)
2
(
CH OCH )
2
2
2
3
2 2
2
2
t-BuOK,
reflux 18 h,
Et O, 22h,
2
quantitative yield
N
TsOH, 92 %
82 %
N
O
O
O
O
O
O
O
8
9
10
2
Scheme 2. Synthesis of N-Boc-1,2,4-trioxane (2).
alcohol 10 was allowed to react with 2-adamantanone in presence
of catalytic amount of p-toluenesulfonic acid monohydrate to ob-
tain the N-Boc trioxane 2.11 We chose 2-adamantanone as the
reacting ketone since it is widely reported that spiro 1,2,4-triox-
anes with an adamantane ring have better activities than spiro
similar reaction trioxane hydrochloride salt 3 was reacted with 9-
fluorenylmethyl chloroformate to obtain N-Fmoc trioxane 7 (82%)
(Scheme 3). The amide 6 was prepared by acylation with acetyl
chloride using two equivalents of triethylamine as base to provide
6 in 85% yield. (Scheme 4).
For the purposes of comparison of antimalarial activity, the syn-
thesis of regioisomer phenylsulfonyl 1,2,4-trioxane 12 was carried
out using similar methods to that depicted in Schemes 2 and 3.
Thus the epoxide 11 derived from adamant-2-one was allowed to
react with hydrogen peroxide and the resultant peroxy alcohol
was coupled with the phenylsulfonyl piperidinone derivative to
produce 12 in moderate yield (39%).
1
3
1
,2,4-trioxanes with cyclopentane or cyclohexane rings. The N-
Boc trioxane 2 was isolated in a yield of 92%. Once we had access
to the trioxane 2 we decided to deprotect the BOC group of 2
and convert it into a trioxane hydrochloride salt 3.
The deprotection of the BOC group of 2 was not straight for-
ward; attempted removal of the BOC group using 1.0 M ethereal
hydrochloric acid solution failed as the deprotection was incom-
plete and the yield was very low. We then used 2.0 M ethereal
hydrochloric acid solution to successfully remove the BOC group
The trioxane series was tested against the 3D7 strain of Plasmo-
dium falciparum and 1,2,4,5-tetraoxane 16 and 1,2,4-trioxolane 17
1
4
16
to obtain the trioxane hydrochloride salt 3 in a yield of 62%. With
trioxane 3 to hand it was easy to manipulate the substituents on
the N-atom of the spiro trioxane to obtain different derivatives
and the free base amine trioxane 4 was prepared by extracting
an alkaline aqueous solution of hydrochloride 3 with dichloro-
methane and diethyl ether. In a biphasic reaction in presence of
potassium carbonate, the amine hydrochloride 3 was treated either
with benzenesulfonyl chloride or ethanesulfonyl chloride to obtain
were included for comparison. All of the 1,2,4-trioxanes tested
demonstrated nanomolar antimalarial activity with amine hydro-
chloride having the highest potency with an IC50 of 120 nM. The
phenylsulfonyl derivative 5a had moderate activity of 710 nM;
interestingly the regioisomer 12 was not active up to a concentra-
tion of 1000 nM. The difference in antimalarial activity between
isomeric spiro 1,2,4-trioxanes has been attributed to the types of
radicals that can be produced following homolytic cleavage of
1
5
17
the sulfonamide trioxanes 5a (92%) and 5b (78%) (Scheme 3). In a
the endoperoxide-bridge. In the case of the active adamantylid-

5
806
S. Sabbani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5804–5808
O
S
O
O
K CO , CHCl ,
2
3
3
N
HCl / Et O (2M)
O O
O
2
H O, PhSO Cl
O O
2
2
NH
5
a, 92%
2
HCl
O
S
O
O
3, 62%
Aq. NaOH
K CO
2
, CHCl
3
3
,
N
O O
H O, EtSO Cl
2
2
5
b, 78%
O O
O
NH
O
O
2
eq. Et N
3
H C
3
N
Free base
4
O O
CH COCl
3
6
, 85%
K CO , CHCl ,
2
3
3
O
O
O
N
H O, FmocCl
2
O O
7, 82%
Scheme 3. Synthesis of N-substituted dispiro-1,2,4-trioxanes (3–7).
O
N
5
0 % H O ,
2 2
SO Ph
MoO (acac) ,
2
O
O
Camphor
sulfonic-acid
O
2
2
NaH, CH S(O)I
O
3
Et
2
O
O
OH
OH
65%
25%
3
9%
O
N
1
1
SO Ph
2
12
Scheme 4. Synthesis of regioisomeric 1,2,4-trioxane (12).
Fe(III)
A
B
O O
Fe(II)
O
O
O
β-scission
2
FeBr /THF
N
R
N
R
5
a
13
O
FeBr /
2
TEMPO
THF
5a, R = SO Ph
2
N
O
O HO
Fe(III)
Br
O
O
HO
O
N
R
N
R
N SO Ph
2
O
O
O
1
3
14, R = SO
Ph, 47%
2
15, 42%
1
2
C
Fe(III)
D
1
2
FeBr /THF
Fe(II) to O
Fe(III)
2
Fe(II) to O1
2
O O
β-scission
O O
TEMPO
N
R
N
R
O
FeBr
THF
2
/
O O
O
N
R
1
2, R = SO
2
Ph
O
20
Fe(III)
β-
scission
Fe(III)
-
Fe(III)
OH O
O
O
O
N
R
N R
O
O
O
O
Br
+
N
R
18
1
9, 14% + 2-adamantanone , 48%
O
21
45%
Scheme 5. (A) Generation of a secondary C-radical 13 via Fe(II) (FeBr
Adduct 15. (C and D) Reactivity of 1,2,4-trioxane 5b in the presence of FeBr
2
) mediated degradation of 1,2,4-trioxane 5a. (B) Interception of intermediate 13 with TEMPO to give
2
.

S. Sabbani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5804–5808
5807
Table 1
new achiral 1,2,4-trioxanes with improved potency can be pre-
pared using this synthetic methodology including analogues of chi-
ral trioxaquines such as 1c.
a
In vitro antimalarial activity versus the 3D7 strain of Plasmodium falciparum
References and notes
O
O
O
O
O
O
O
1
2
3
.
.
.
Haynes, R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73.
Klayman, D. L. Science 1985, 228, 1049.
WHO,
TreatmentGuidelines2006.pdf.
4. Jefford, C. W. Drug Discovery Today 2007, 12, 487.
O’Neill, P. M.; Posner, G. H. J. Med. Chem. 2004, 47, 2945.
6. Biagini, G. A.; O’Neill, P. M.; Nzila, A.; Ward, S. A.; Bray, P. G. Trends Parasitol.
003, 19, 479.
Vangapandu, S.; Jain, M.; Kaur, K.; Patil, P.; Patel, S. R.; Jain, R. Med. Res. Rev.
007, 27, 65.
2006.
Available
from:
http://www.who.int/malaria/docs/
N
N
5.
SO Ph
SO Ph
2
2
2
1
6
17
7
.
.
2
8
(a) Dong, Y. X.; Chollet, J.; Matile, H.; Charman, S. A.; Chiu, F. C. K.; Charman, W.
N.; Scorneaux, B.; Urwyler, H.; Tomas, J. S.; Scheurer, C.; Snyder, C.; Dorn, A.;
Wang, X. F.; Karle, J. M.; Tang, Y. Q.; Wittlin, S.; Brun, R.; Vennerstrom, J. L. J.
Med. Chem. 2005, 48, 4953; (b) Padmanilayam, M.; Scorneaux, B.; Dong, Y. X.;
Chollet, J.; Matile, H.; Charman, S. A.; Creek, D. J.; Charman, W. N.; Tomas, J. S.;
Scheurer, C.; Wittlin, S.; Brun, R.; Vennerstrom, J. L. Bioorg. Med. Chem. Lett.
Endoperoxide
IC50 (nM)
St. Dev.
Artemether
Artemisinin
2
3
1.26
9.54
0.11
1.10
197.86
121.33
710.23
179.62
183.45
174.23
>1000
10.72
6.22
21.96
29.70
19.93
19.95
32.78
23.29
23.29
2.35
2
006, 16, 5542.
Dechy-Cabaret, O.; Benoit-Vical, F.; Robert, A.; Meunier, B. Chembiochem 2000,
, 281.
5
5
6
7
1
1
1
a
b
9
.
1
1
1
0. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
1. Tang, Y. Q.; Dong, Y. X.; Wang, X. F.; Sriraghavan, K.; Wood, J. K.; Vennerstrom,
J. L. J. Org. Chem. 2005, 70, 5103.
2
6
7
12. Olah, G. A.; Wu, A. H. Synthesis 1990, 887.
13. Tang, Y. Q.; Dong, Y. X.; Vennerstrom, J. L. Med. Res. Rev. 2004, 24, 425.
2.12
1
1
1
4. Cali, P.; Begtrup, M. Synthesis 2002, 63.
5. Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444.
6. (a) t-Butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9). A mixture of 1-Boc-4-
a
Parasites were maintained in continuous culture according to the method of
18
Trager and Jensen. IC50 values were measured according to the methods described
by Desjardins et al.19
3
piperidone (3.05 g, 15.3 mmol), Me S(O)I (97% pure, 3.4 g, 15.3 mmol) and t-
BuOK (95% pure, 1.973 g, 15.3 mmol) in 1,2-dimethoxyethane (80 ml) was
refluxed for 18 h, cooled to room temperature and then quenched with water.
The organic layer was separated and the aqueous layer was extracted with
ene fused endoperoxides such as 2–7 it appeared likely, by analogy
with previous work by Vennerstrom, that scission to produce an
Et
2
O (3 Â 50 ml) and CH
2
Cl
2
(2 Â 50 ml) followed by general work up to give
crude N-Boc spiro epoxide which was purified by flash chromatography (SiO
2
,
6
5
0% EtOAc in n-Hexane) to give pure N-Boc spiro epoxide 9 (2.70 g, 82%). Mp
0–52 °C; H NMR (400 MHz, CDCl
adamantane secondary carbon centred radical would occur on
1
3 a
) d 3.69–3.74 (2H , ddd, J = 4.74 Hz), 3.40–
exposure to reducing Fe(II) (Scheme 5A).1
1,17
To confirm this pro-
3.46 (2H
b
, ddd, J = 9.49 Hz), 2.68 (2H, s), 1.76–1.83 (2H, ddd, J = 9.49 Hz), 1.47
13
(
9H, s), 1.43–1.46 (2H, ddd, J = 4.74 Hz); C NMR (100 MHz, CDCl
3
) d 155.01,
posal we carried out iron mediated degradation of sulfonamide
a using ferrous bromide in THF. The major product was the bromo
À1
79.84, 57.35, 53.94, 42.81, 33.28, 28.73; IR (neat, cm ) 2972, 2925, 2864,
5
1
682, 1421, 1363, 1317, 1238, 1161, 1122, 989, 912; m/z (CI, +ve, NH
3
), 214
requires
4-hydroperoxy-4-(hydroxymethyl)piperidine-1-
carboxylate (10). The N-Boc spiro epoxide 9 (2.21 g, 10.36 mmol), MgSO
dried –Et (150 ml, see note below) and bis(acetylacetonato)-
+
+
alcohol 14 (47% yield) indicating that 13 had been produced as an
intermediate. In a separate experiment, definitive confirmation
that the secondary C-radical was obtained by using TEMPO as
([M+H] , 16%); HRMS: Found [M+H] , 214.14487,
14.14430. (b) t-Butyl
11 3
C H20NO
2
4
H
2
O
2
2
O
the spin-trapping agent; exposure of 5a to FeBr
of TEMPO led to formation of an adduct 15 in 42% yield (Scheme
B). In contrast, isomeric 1,2,4-trioxane 12 produced only a 14%
yield of bromoalkane 19, a product indicating the formation of
the primary C-radical 18 as an intermediate. Attempts to trap
intermediate 18 with TEMPO led to a low yield (<10%) of the
spin-trapped adduct (not shown). The major product from the
2
in the presence
dioxomolybdenum(VI) were stirred together in a reaction flask at room
temperature for 22 h after which the reaction mixture was washed with water
(
1 Â 100 ml) and brine (1 Â 100 ml). The combined aqueous layers were
5
extracted with CH Cl
2
2
(2 Â 75 ml). General workup of the combined organic
layers resulted in the Boc-protected hydropeoxy product 10 (2.5 g, 98%) which
was used in the next step without any further purification as the TLC indicated
the presence of only one product and was also confirmed by NMR and mass
spectra. 1H NMR (400 MHz, CDCl
3
) d 9.41 (1H, br s), 8.64 (1H, br s), 3.69–3.89
(2H, m), 3.64 (2H, s), 3.11–3.17 (2H, m), 1.89–1.92 (2H, m), 1.47–1.50 (2H, m),
1.46 (9 H, s); 13C NMR (100 MHz, CDCl
) d 155.67, 81.66, 80.59, 66.4, 53.85,
29.51, 28.86; m/z (ES, +ve, CH OH), 270 ([M+Na] , 100%); HRMS: Found
Na requires 270.13170. Note: Method to dry
(42 ml, 50 wt% in H O) and anhydrous Et
(395 ml) under constant stirring, anhydrous MgSO was added until a thick
white slurry settled at the bottom of the flask. Then the supernatant was
decanted and once again dried with anhydrous MgSO and filtered. One
hundred and fifty milliliters of the dried H –Et O solution was used in the
reaction above (Scheme 2) to obtain the Boc-protected hydroperoxy product
0. (c) Synthesis of N-Boc trioxane 2. To a mixture of b-Hydroperoxy alcohol 10
2.5 g, 10.12 mmol) and 2-admantanone (2.42 g, 16.11 mmol) in anhydrous
CH Cl (135 ml) was added p-toluenesulfonic acid monohydrate (217 mg,
1.14 mmol) and the reaction mixture was stirred at room temperature for 5 h
and then washed with aqueous saturated NaHCO (80 ml), water (80 ml) and
brine (80 ml). The combined aqueous phases were extracted with CH Cl
reaction was 2-adamantanone indicating that in this system, as
3
+
in the previously studied 1,2,4-trioxolanes,8 steric shielding of
3
+
[
M+Na] , 270.13320, C11
H21NO
5
the endoperoxide bridge by the adamantly group leads to a prefer-
H
2
O
2
2
–Et O: To a mixture of H
2
O
2
2
2
O
ence for association of Fe(II) with O
2
of the endoperoxide bridge. As
4
reported in a previous study,11 no products supporting b-scission
4
of 20 to the ketone secondary carbon centred radical 21 were ob-
tained. The fact that 5b generates minor amounts of a carbon cen-
tred radical coupled with a preference to produce inert ketone
degradation products might explain the poor antimalarial activity
observed with this analogue. (Table 1).
In summary, N-Boc b-hydroperoxy alcohol 10 was successfully
obtained from its precursor in good yield. The deprotection of
the N-Boc-protected trioxane 2 needs further optimisation to im-
prove the yields but the current method does allow access to the
hydrochloride salt of the trioxane 3. Compound 3 and the small
number of analogues prepared here have moderate activity com-
2
O
2
2
1
(
2
2
3
2
2
(
3 Â 50 ml). After general work up of combined organic layers the crude
product was purified by flash chromatography (SiO , 30% EtOAc in n-Hexane)
to give pure N-Boc trioxane 2 (3.55 g, 92.4%). Mp 74–76 °C; H NMR (400 MHz,
2
1
CDCl ) d 3.65–3.86 (4H, m), 3.09–3.42 (2H, m), 1.49–2.14 (18H, m), 1.44–1.48
3
13
(
3
9H, s); C NMR (100 MHz, CDCl ) d 155.16, 105.00, 79.94, 76.07, 65.65, 47.39,
39.67, 37.57, 36.73, 35.27, 33.77, 28.85, 27.88, 27.54; IR (neat, cmÀ1) 2912,
2854, 1689, 1450, 1414, 1363, 1244, 1155, 1107, 1086, 1065, 1009; m/z (ES,
pared with the semi-synthetic artemisinin derivatives, synthetic
+
+
tetraoxanes (e.g., 16) or ozonides (e.g., 17);20 however it is likely
+ve, CH
33NO
trioxane 3. Anhydrous HCl–Et
Boc trioxane 2 (1.05 g, 2.76 mmol) in anhydrous Et
2
3
OH), 402 ([M+Na] , 100%); HRMS: Found [M+Na] , 402.22470,
Na requires 402.22560. (d) Synthesis of hydrochloride salt of
O (2.0 M, 25 ml) was added to a solution of N-
O (5 ml) and the reaction
C
21
H
5
that by simple derivitisation of 3 by the chemistry employed here
2
(
and by simple reductive amination depicted in Scheme 3) many

5
808
S. Sabbani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5804–5808
mixture was stirred at room temperature under an atmosphere of N
4 h a white solid precipitated out which was then washed with anhydrous
Et O to give the desired hydrochloride salt of the trioxane 3 as a white solid
538 mg, 62%). C NMR (100MHz, CDCl
7.74, 36.86, 34.93, 34.89, 33.42, 32.68, 27.12; m/z (ES, +ve, CH
2
. After
reduced pressure. The crude product was then purified by flash
chromatography using gradient elution with increasing polarity (SiO , EtOAc/
n-Hexane) to give the desired sulfonamide trioxane 5 (244 mg, 92%) as a white
2
2
2
13
1
(
3
3
) d 107.13, 74.79, 64.57, 42.06, 39.85,
solid. Mp 168–170 °C;
aromatic), 3.24–3.92 (4H, m, –CH
3
1.52–1.96 (18H, 2H2a, 2H2b and 14 adamantane, m). C NMR (100 MHz, CDCl )
H
NMR (400 MHz, CDCl
3
) d 7.50–7.80 (5H, m,
+
3
OH), 280 ([M]
26NO requires
80.19130. (e) Synthesis of amine trioxane 4. Trioxane hydrochloride salt 3 was
dissolved in aqueous NaOH solution and then extracted three times with
CH Cl followed by general work up of the organic layer to give the amine
trioxane 4. H NMR (400 MHz, CDCl
m), 2.70–2.88 (2H , m), 2.17 (1H, s), 1.88–2.13 (4H, m), 1.86–1.79 (2H, m),
2
–O, and 2H1a), 2.53–3.00 (2H, m, 2H1b),
+
13
cation, 100%); HRMS: Found [M] cation, 280.19020, C16
H
3
2
d 136.86, 133.16, 129.50, 128.02, 105.19, 74.99, 65.65, 43.79, 38.41, 37.49,
À1
36.11, 35.15, 33.69, 27.48, 27.45; IR (neat, cm ) 2910, 2856, 1448, 1348, 1325,
+
2
2
1186, 1161, 1086, 1045, 931, 735, 687; m/z (ES, +ve, CH
3
OH), 442 ([M+Na] ,
1
+
3
) d 3.39–3.83 (2H, br s), 2.90–3.10 (2H
a
,
100%); HRMS: Found [M+Na] , 442.16540, C22
Elemental analysis (C22 29NO S), found C: 62.39%, H: 6.80%, N: 3.00 (requires
C: 62.98%, H: 6.97%, N: 3.34).
5
H29NO SNa requires 442.16640;
b
H
5
1
3
1
7
3
1
2
5
.38–1.77 (10H, m), 1.15–1.35 (2H, m); C NMR (100 MHz, CDCl
3
) d 104.83,
À1
6.36, 65.82, 53.78, 37.61, 33.78, 31.26, 30.07, 27.59, 27.57; IR (neat, cm
)
17. For a comprehensive study of iron mediated degradation studies on 1,2,4-
trioxanes, see (a) Posner, G. H.; Wang, D.; Cumming, J. N.; Oh, C. H.; French, A.
N.; Bodley, A. L.; Shapiro, T. A. J. Med. Chem. 1995, 38, 2273–2275; (b) Posner, G.
H.; Oh, C. H. J. Am. Chem. Soc. 1992, 114, 8328–8329.
18. Trager, W.; Jensen, J. B. Science 1976, 193, 673–675.
19. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents
Chemother. 1979, 16, 710–718.
20. Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.;
Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.;
Lozanom, S.; Jesus, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. J. Med. Chem.
2008, 51, 2170–2177.
367, 2914, 2854, 1718, 1624, 1541, 1446, 1425, 1286, 1267, 1107, 1084, 1066,
+
+
043, 995; m/z (CI, +ve, NH
80.19166, C16 26NO requires 280.19125. (f) Synthesis of sulfonamide trioxane
a: (General procedure). To a reaction flask containing the hydrochloride salt of
(7.0 ml), water (7.0 ml) and K CO
224 mg, 1.62 mmol), benezenesulfonyl chloride (0.13 ml, 1.02 mmol) was
added. After stirring the reaction mixture for 24 h the reaction was quenched
by the addition of aq saturated NaHCO . The organic layer was separated and
the aqueous layer was extracted with CH Cl
(3 Â 25 ml). The combined
organic layers were dried with anhydrous MgSO and concentrated under
3
), 280 ([M+H] , 100%); HRMS: Found [M+H] ,
H
3
trioxane 3 (200 mg, 0.63 mmol), CHCl
(
3
2
3
3
2
2
4