Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; Synthetic antimalarials with superior activity to artemisinin

Article abstract of DOI:10.1039/b613565j

The design and synthesis of dispiro- and spirotetraoxanes through acid-catalyzed cyclocondensation of bis(hydroperoxides) with ketones were investigated. Various modular synthetic methods were used to enable many different analogues to be prepared from common achiral synthetic intermediates and some of the key reactions employed include reductive amination and mixed anhydride amide coupling reactions. The synthesis of 1,2,4,5-tetraoxanes was also dependent on several factors, including the structure of the ketone or aldehyde, temperature, solvent, pH, and the equilibria between the ketone and the precursors of cyclic peroxides. The required 1,2,4,5-tetraoxane was formed by crosscondensation of the bis(hydroperoxide) and the 1,4-cyclohexanedione was obtained in low temperature. Reductive amination of the ketone with various amino compounds also produced compounds in moderate to good quantities.

Full text of DOI:10.1039/b613565j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic
antimalarials with superior activity to artemisinin†‡
Richard Amewu,a Andrew V. Stachulski,a Stephen A. Ward,b Neil G. Berry,a Patrick G. Bray,b Jill Davies,b
Gael Labat,a Livia Vivasc and Paul M. O’Neill*a
Received 18th September 2006, Accepted 26th October 2006
First published as an Advance Article on the web 3rd November 2006
DOI: 10.1039/b613565j
Unsymmetrical dispiro- and spirotetraoxanes have been de-
signed and synthesized via acid-catalyzed cyclocondensation
of bis(hydroperoxides) with ketones. Incorporation of water-
soluble and polar functionalities, via reductive amination and
amide bond formation, produces several analogues with low
nanomolar in vitro antimalarial activity. Several analogues
display an unprecedented level of oral antimalarial activity
for this class of endoperoxide drug.
The discovery of artemisinin1,2 and the establishment that the
endoperoxide bridge is crucial for antimalarial activity3,4 has led
to many attempts by chemists to synthesise simple but effective
synthetic endoperoxides.5,6 Artemisinin (1) is a naturally occur-
ring endoperoxide sesquiterpene lactone compound of Artemisia
annua, a herbal remedy used in Chinese medicine. Although
artemisinin derivatives are extensively used against malaria, cost,
Fig. 1 Naturally occurring endoperoxides artemisinin (1), Yingzhaosu A
(2) and synthetic tetraoxanes (3) and (4).
supply and high recrudescent rates remain issues with this
class of drug.7,8 Other known cyclic peroxides with antimalarial
potency include Yingzhaosu A (2) and the 1,2,4,5-tetraoxanes
WR1489999(3) and steroid amide (4) (Fig. 1).10
Tetraoxanes are cyclic peroxides that have received considerable
that first pass metabolism plays a role in reducing effective
drug absorption.8,30 Therefore, our aim was to prepare more
stable unsymmetrical 1,2,4,5-tetraoxanes functionalised by polar
water-solubilising functionalities. The synthetic routes described
in this paper have been designed to be modular to enable
many different analogues to be prepared from common achiral
synthetic intermediates. Key reactions employed include reductive
amination and mixed anhydride amide coupling reactions.
The synthesis of 1,2,4,5-tetraoxanes is dependent on several
factors such as the structure of the ketone or aldehyde, temper-
ature, solvent, pH, the catalyst, concentration of the substrate
as well as the equilibria between the ketone and the precursors
of cyclic peroxides.31 All of these factors result in variable yields
being achieved from selected carbonyl starting materials. Having
surveyed the literature, our initial target molecule was prepared
by the method reported by Iskra et al.32 (Scheme 1) in which
cyclohexanone 5 and 1,4-cyclohexanedione 6 are allowed to react
in a two-step sequence.
attention in the literature. Initially, these systems were used
industrially for the production of macrocyclic hydrocarbons and
lactones.11,12 Subsequent pioneering work by the Vennerstrom
group in the early 1990s demonstrated that symmetrical dispiro
1,2,4,5-tetraoxanes such as (3) possess impressive in vitro anti-
malarial activity.9 It has been proposed that these compounds
share a similar antimalarial mode of action to the naturally
occurring peroxides such as artemisinin.13–15
Surprisingly, in spite of the development of a variety of synthetic
methodologies for the synthesis of the tetraoxane heterocycle,16–29
there has been little success in the discovery of molecules with
high stability and good oral bioavailability in rodent models of
malaria. One notable exception is the steroidal-based 1,2,4,5-
tetraoxanes, such as 4.10 Many of the first generation tetraoxane
derivatives are highly lipophilic, suggesting that poor absorption
is the key factor affecting bioavailability, but it is also apparent
The required 1,2,4,5-tetraoxane 7a, formed by cross-
condensation of the bis(hydroperoxide) 5a and the 1,4-cyclo-
hexanedione 6, was obtained in rather low yield. A significant
amount of the symmetrical 1,2,4,5-tetraoxane 7b, resulting from
competitive homo-cyclocondensation of bis(hydroperoxide), also
was recovered, with a small amount of trimeric cyclic peroxide
by-product 7c. It was earlier reported,33 that the presence of excess
hydrogen peroxide after the formation of the bis(hydroperoxide)
leads to the formation of this trimeric cyclic by-product. As a
result, we decided to remove any excess hydrogen peroxide by
aDepartment of Chemistry, University of Liverpool, PO Box 147, Liverpool,
UK L69 3BX. E-mail: P.M.oneill01@liv.ac.uk; Fax: (+44) 151 794 3588;
Tel: (+44) 151 794 3553
bLiverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK L3
5QA
cDepartment of Infectious and Tropical Diseases, London School of Hygiene
and Tropical Medicine, London, UK WC1E 7HT
† The HTML version of this article has been enhanced with colour images.
‡ Electronic supplementary information (ESI) available: Experimental
procedures and characterization details. See DOI: 10.1039/b613565j
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Reductive amination35 of the ketone 7a with various amino
compounds afforded compounds 9–14 in moderate to good yields
(20–85%) (Scheme 2). Next, we examined the reaction between 5a
and ethyl-4-oxocyclohexane carboxylate (the acetal deprotected
product of 15) and also the reaction between 16 and cyclohex-
anone. The latter gave a significant reduction in the trimeric
by-product. Intermediate 16 was formed either by hydrolysing
the ketal 15, followed by formic acid catalysed formation of the
bis(hydroperoxide) and subsequent acid catalyzed condensation
with cyclohexanone or via tungstic acid catalysed25 formation
directly from the ketal (Scheme 3).
Scheme 1 Reagents and conditions: (i) 30% H2O2 (2 equiv.), methyltrioxo-
rhenium (MTO) (0.1 equiv.)–TFE (0.5 M); (ii) 6 (2 equiv.), EtOAc, HBF4
(1 equiv.), 28%.
carrying out a two-step synthesis of the tetraoxanes; first, by
preparing the bis(hydroperoxide) and removing any unreacted
hydrogen peroxide, then followed by the tetraoxane formation
reaction (Scheme 2). The yield of the required tetraoxane was
improved slightly. We then investigated various methodologies
available for the formation of the bis(hydroperoxide) and examined
the method reported by Ledaal.34 Performing the reaction in
acetonitrile led to the elimination of the formation of a solid
mass in the flask, leading to quantitative conversion of the ketone
to the bis(hydroperoxide). While some methodologies led to an
exclusive formation of the symmetrical tetraoxanes, others led to
the formation of compound 8 (Fig. 2). Several attempts to form the
cyclic product according to existing literature34 procedures failed.
Scheme 3 Reagents and conditions: (i) 20% H2SO4, ethanol; (ii) 30% H2O2
(4 equiv.), HCOOH (4 equiv.), CH3CN, 0 ◦C, 63% or (i,ii) H2WO4 (2 equiv.),
THF, 30% H2O2, 0 ◦C, 48 h; (iii) cyclohexanone (2 equiv.), EtOAc, HBF4
(1 equiv.), 35%; (iv) KOH (5.5 equiv.), CH3OH, 70 ◦C, 1 h, 85%; (v)
NEt3 (1 equiv.), ClCO2C2H5 (1.3 equiv.), CH2Cl2, 0 ◦C, 1 h; (vi) R1R2NH
(2 equiv.), 0 ◦C–rt.
The ester was hydrolysed to the corresponding acid (Scheme 3)
by a procedure reported by Opsenica et al.10 The resulting
acid was coupled with a selection of amino compounds via a
mixed anhydride intermediate to give the corresponding amides
(Scheme 3).
Scheme 2 Reagents and conditions: (i) 30% H2O2(2 equiv.), CH3CN, 0 ◦C,
4 min, 76%; (ii) 1,4-cyclohexanedione 6 (2 equiv.), EtOAc, HBF4 (1 equiv.),
38%; (iii) R1R2NH (1.3 equiv.), NaBH(OAc)3 (1.3 equiv.), CH2Cl2, 18 h.
Considering the relatively high cost of15, wepreparedthe higher
homologue via an alternative route, by first carrying out a Wittig
reaction between 1,4-cyclohexanedione monoethylketal and ethyl
(triphenylphosphoranylidene)acetate (Scheme 4). Hydrogenation
in the presence of palladium on carbon afforded the required start-
ing material 25. The bis(hydroperoxide) formed was condensed
with various ketones to afford the corresponding tetraoxanes 27a,
28a and 29a. Hydrolysis, followed by amide coupling reactions led
to various water-soluble analogues listed in Table 1.
For analogues 27h and 29h crystals were grown by slowly evapo-
rating a dichloromethane–hexane mixture and the single crystal
X-ray structures were solved for these two tetraoxanes (Fig. 3).§
Fig. 2 Open chain dimeric peroxide.
4432 | Org. Biomol. Chem., 2006, 4, 4431–4436
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In addition to the synthesis of dispiro derivatives we also decided
to investigate the synthesis of some simple spiro derivatives. How-
ever, in the reaction of bis(hydroperoxide) 5a and ethyl levulinate,
only the trimeric cyclic product 31 (Scheme 5) was produced.
Incorporation of amino functionalities into 31 was carried out to
see if this class of cyclic endoperoxide had antimalarial properties;
hydrolysis of the ester function of 31 to the carboxylic acid,
followed by amide coupling gave analogues 32–34.
Table 1 Yields for amide synthesis
By reversing this route, by preparing the bis(hydroperoxide)
from ethyl levulinate and condensing with cyclohexanone
(Scheme 6) the required tetraoxane was made in low yield; we
attribute this low yield to the instability of the bis(hydroperoxide)
30a.
Acid
Amide product
Yield (%)
27b
27b
27b
27b
27b
27b
28b
28b
28b
28b
28b
28b
29b
29b
29b
29b
29b
29b
27c, R3 = CH(CH2)2, R4 = H
85
78
81
76
58
84
88
81
82
78
74
90
83
80
78
77
66
81
27d, R3 = CH2CH2N(CH2)4, R4 = H
27e, R3 = CH2CH2N(CH2)5, R4 = H
27f, R3 = CH2CH2N(CH2)4O, R4 = H
27g, R3 = CH2CH2N(C2H5)2, R4 = H
27h, R3, R4 = (CH2)4O
The ester handle was converted into the corresponding amides
37–40 as shown in Scheme 6.
A selection of the 1,2,4,5-tetraoxanes was tested against the
3D7 strain of the Plasmodium falciparum and the results are
summarized in Table 2 below. Most of the analogues have
comparable antimalarial IC50 values to the naturally occurring
endoperoxide artemisinin. The incorporation of a methylene
spacer into 19–22 generally improves activity. The adamantane
analogues of the tetraoxanes and their corresponding amide have
a better activity than their cyclohexanone and cyclododecanone
counterparts. Notably, the spiro-amides 37–40 have much lower
potency than members of the dispiro series.
28c, R3 = CH(CH2)2, R4 = H
28d, R3 = CH2CH2N(CH2)4, R4 = H
28e, R3 = CH2CH2N(CH2)5, R4 = H
28f, R3 = CH2CH2N(CH2)4O, R4 = H
28g, R3 = CH2CH2N(C2H5)2, R4 = H
28h, R3, R4 = (CH2)4O
29c, R3 = CH(CH2)2, R4 = H
29d, R3 = CH2CH2N(CH2)4, R4 = H
29e, R3 = CH2CH2N(CH2)5, R4 = H
29f, R3 = CH2CH2N(CH2)4O, R4 = H
29g, R3 = CH2CH2N(C2H5)2, R4 = H
29h, R3, R4 = (CH2)4O
A 4-day Peter’s suppressive test was performed on a selection
of the compounds and the results are summarized in Table 3. The
=
Scheme 4 Reagents and conditions: (i) Ph3P CHCO2Et (1.1 equiv.), benzene–toluene, reflux, 24 h, 90%; (ii) Pd/C, H2, EtOAc, 95%; (iii) H2WO4
(2 equiv.), THF, 30% H2O2(2 equiv.), 0 ◦C, 48 h, 88%; (iv) cyclohexanone/cyclododecanone/adamantanone (2 equiv.), EtOAc, HBF4 (1 equiv.); (v) KOH
(5.5 equiv.), CH3OH, 70 ◦C, 1 h; (vi) Et3N (1 equiv.), ClCO2C2H5 (1.3 equiv.), 0 ◦C, 1 h; (vii) R3R4NH (2 equiv.), 0 ◦C–rt.
Fig. 3 Single crystal X-ray structures of compounds 27h and 28h.¶
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Table 2 in vitro antimalarial activity of 1,2,4,5-tetraoxanes versus 3D7
strain of Plasmodium falciparum
Compound
Mean IC50a/nM
Compound
Mean IC50a/nM
Artemether
Chloroquine
Artemisinin
7a
9
12
14
17
19
20
21
22
27a
3.4
8.5
9.5
27c
27d
27e
27f
27g
27h
28c
28h
29c
29h
37
19.9
19.1
19.2
19.1
5.15
22.2
18.7
15.5
2.3
6.0
20.0
28.1
29.4
59.7
26.1
1.5
21.3
23.6
24.2
5.2
469.2
473.7
40
a The mean IC50 was calculated from triplicate results. Antimalarial
activities were assessed by a previously published protocol.38
Table 3 Peter’s suppressive test results versus Plasmodium berghei ANKA
strain in mice.39a
Scheme 5 Reagents and conditions: (i) ethyl levulinate (2 equiv.), EtOAc,
HBF4(1 equiv.), 68%; (ii) KOH (5.5 equiv.), CH3O◦H, 70 ◦C, 1 h; (iii) Et3N
(1 equiv.), ClCO2C2H5 (1.3 equiv.), CH2Cl2, 0 C, 1 h; (iv) R1R2NH
(2 equiv.), 0 ◦C–rt.
Percentage of
inhibition at
Compound
R1 and R2
R3 and R4
30 mg kg−1 (pob)
27c
(CH2)5
(CH2)5
(CH2)11
(CH2)11
Adamantylidine
Adamantylidine
—
H and CH(CH2)2
(CH2)4O
H and CH(CH2)2
(CH2)4O
H and CH(CH2)2
(CH2)4O
—
24.8
33.0
50
99.6
100
100
100
100
27h
28c
28h
29c
29h
Artesunate
Artemether
—
—
a Compounds were administered orally in a standard suspending vehicle
(SSV). The aqueous formulation used contained medium-viscosity (CMC)
(0.5%), ‘4-day’ test benzyl alcohol (0.5%), Tween 80 (0.4%) and NaCl
(0.9%). b po = oral route of administration.
respectively, rendered using DS Visualizer.42 The polar surface
area (PSA) was calculated for each conformation, and the
Boltzmann weighted average calculated for the two compounds.
Interestingly, the calculations revealed that the two molecules have
very similar Boltzmann weighted polar surface areas, but very
different logP values. Calculations demonstrate that compound
29h is significantly more hydrophobic than 28h.43
Scheme 6 Reagents and conditions: (i) 30% H2O2 (2 equiv.), CH3CN,
0
◦C, 4 min, (ii) cyclohexanone (2 equiv.), EtOAc, HBF4 (1 equiv.), 18%;
(iii) KOH (5.5 equiv.), CH3OH, 70 ◦C, 1 h, 86%; (iv) Et3N (1 equiv.),
ClCO2C2H5 (1.3 equiv.), CH2Cl2, 0 ◦C, 1 h; (v) R1R2NH (2 equiv.), 0 ◦C–rt.
2-adamantanone derived analogues 29c and 29h showed 100%
inhibition by oral administration at a dose of 30 mg kg−1; in
addition, the cyclododecylidene analogue 28h displayed potent
activity at this dosing level. Based on these exciting results,
analogues 29c and 29h were assessed in the 4-day Peter’s test to
determine oral in vivo ED50 and ED90 values versus Plasmodium
berghei (ANKA). Compound 29h demonstrates outstanding oral
activity and is superior to the semi-synthetic control artemether
(Table 4). Compound 29c was less potent in these tests.
In summary, we have prepared a small array of tetraoxane
derivatives that have remarkable antimalarial activities in vitro.
Preliminary in vivo evaluation demonstrates that adamantylidene
and cyclododecylidene derivatives have very promising oral ac-
tivities; it is clear from this study that the cyclododecyl27 and
adamantyl functional groups are unique in imparting extra levels
of antiparasitic activity. The latter observation follows on from
studies with 1,2,4-trioxolanes (ozonides)40 and 1,2,4-trioxanes,44,45
where only systems containing this functional group had oral
activities in mouse models of malaria. The 1,2,4,5-tetraoxanes
described here have significant advantages over the racemic
synthetic endoperoxides that have been prepared to date5,6 since
A conformational search using a Monte-Carlo method with
the MMFF94 force field was performed on molecules 28h and
29h.41 Fig. 4 displays low energy conformations of 28h and 29h
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Table 4 Oral activities of 29c and 29h versus Plasmodium berghei ANKA39a
Compound
R1 and R2
R3 and R4
ED50/mg kg−1
ED90/mg kg−1
29c
Adamantylidine
Adamantylidine
—
H and CH(CH2)2
(CH2)4O
—
10.27
3.18
5.88
20.33
3.88
10.57
29h
Artemether
a Compounds were administered orally in a standard suspending vehicle (SSV). The aqueous formulation used contained medium-viscosity CMC (0.5%),
‘4-day’ test benzyl alcohol (0.5%), Tween 80 (0.4%) and NaCl (0.9%).
Fig. 4 Low energy conformations of tetraoxanes 28h and 29h.
they have equivalent activity to the natural product artemisinin,
are achiral and can be synthesized in good yields from simple
starting materials. Further studies will establish whether these
1,2,4,5-tetroxane derivatives are viable alternatives to the 1,2,4-
trioxolane class of antimalarial recently described by Vennerstrom
and co-workers.40
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Acknowledgements
The authors thank the BBSRC (SAW, PON grants BB/C006321/1
and 26/B13581) and Romark (NB, RA) for generous funding of
this work. We also thank the EU (Antimal. FP6 Malaria Drugs
Initiative) for funding the in vivo evaluation of 27c, 27h, 29c and
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˚
§ Crystal data◦for 27h: C18H29NO6; space group◦P1, a = 5.9604(12) A,
˚
˚
a = 92.596(4) , b = 8.5899(17) A, b = 95.039(4) , c = 17.360(3) A, c =
99.803(4)◦; crystal size 0.5 × 0.4 × 0.1 mm; crystal system: triclinic; V =
870.8(3) A ; Z = 2; density (calculated) = 1.356 g cm−3; reflections =
3
˚
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goodness-of-fit on F2: 1.014; final R indices [I > 2r(I)]: R1 = 0.0761,
wR2 = 0.1793; R indices (all data): R1 = 0.0948, wR2 = 0.1924. CCDC
616879. For crystallographic data in CIF or other electronic format see
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´
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◦
˚
˚
90 , b = 37.479(3) A, b = 90.841(2) , c = 8.6291(8) A, c = 90 ; crystal
3
˚
size 0.4 × 0.3 × 0.2 mm; crystal system: monoclinic; V = 2024.7(3) A ;
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