Synthesis of antimalarial trioxanes via continuous photo-oxidation with 1O2 in supercritical CO2

Article abstract of DOI:10.1039/c2gc36711d

The oxidation of an allylic alcohol to its hydroperoxides represents a key step in the synthesis of a series of spirobicyclic, antimalarial trioxanes. Herein, we investigate the continuous photo-oxidation of an allylic alcohol with ¹O₂ in scCO₂, as a 'green' alternative to conventional methods, and examine the remaining two steps in the synthesis of antimalarial trioxanes from readily available starting materials.

Full text of DOI:10.1039/c2gc36711d

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Synthesis of antimalarial trioxanes via continuous
photo-oxidation with 1O2 in supercritical CO2†
Cite this: Green Chem., 2013, 15, 177
Jessica F. B. Hall, Richard A. Bourne, Xue Han, James H. Earley, Martyn Poliakoff* and
Michael W. George*
Received 29th October 2012,
Accepted 15th November 2012
The oxidation of an allylic alcohol to its hydroperoxides represents a key step in the synthesis of a series
of spirobicyclic, antimalarial trioxanes. Herein, we investigate the continuous photo-oxidation of an allylic
alcohol with 1O2 in scCO2, as a ‘green’ alternative to conventional methods, and examine the remaining
two steps in the synthesis of antimalarial trioxanes from readily available starting materials.
DOI: 10.1039/c2gc36711d
www.rsc.org/greenchem
Malaria is one of the most devastating infectious diseases in
the world, killing an estimated 655 000 people in 2010 alone.1
Of crucial concern is the fact that the virus Plasmodium falci-
parum, responsible for the most lethal form of malaria,
malaria tropica, is becoming increasingly resistant to former
front-line quinine based antimalarials2 and there is a need for
new antimalarial compounds to be produced.
One example is artemisinin,3,4 a naturally occurring lactone
with a 1,2,4-trioxane core structure.5,6 Synthetic derivatives of
artemisinin also possess excellent antimalarial activity and,
despite concerns that P. falciparum is also showing signs of
resistance to these compounds, artemisinin and its analogues
are still the primary treatments for falciparum malaria.3,7 Arte-
misinin is still commonly extracted from the plant Artemisia
annua because its synthesis is labour-intensive3 and unsuited
to large-scale production.
Scheme 1 Synthetic route to spirobicyclic trioxanes, 4a and 4b, highlighting
the photo-oxidation step. 1: mesityl oxide; 2: 4-methylpent-3-en-2-ol; 3: hydro-
peroxides. Here, n = 1, cyclopentanone, or 2, cyclohexanone to give 8-isoprope-
nyl-9-methyl-6,7,10-trioxa-spiro[4.5]decane (4a) or -isopropenyl-4-methyl-1,2,5-
trioxa-spiro[5.5]undecane (4b) respectively.
A feature common to artemisinin and several other poten-
tial antimalarials is the trioxane moiety, shown in Scheme 1.
Photochemically generated 1O2 offers a convenient way of
introducing such a motif. However, the excitation of ground
remains; like artemisinin, it is usually extracted from A. annua,
although it can now be produced by engineered yeast.9
A number of new antimalarial trioxanes, including 4a and
4b, Scheme 1, have also been synthesised using 1O2 as a key
step. In this work, the photo-oxidation procedure was con-
ducted in a batch reactor using either non-polar solvents or a
solvent-free approach with porphyrin loaded polystyrene
beads.10,11 The addition of spiroadamantane motifs was found
to increase antimalarial activity, however the products were
hardly water soluble, indicating that a diverse approach to a
variety of such compounds is necessary and that more syn-
thetic work is required to evaluate the best antimalarial
compounds.12
3
1
state molecular oxygen, O2 to O2, requires the use of photo-
catalysts. The highly reactive nature of 1O2 can mean that there
are problems with the scale-up of such processes as indust-
rially acceptable solvents must be non-flammable and in-
efficient 1O2 quenchers.
Recent work has resulted in the partial scale-up of the
photo-oxidation of the natural product artemisinic acid to arte-
misinin using CH2Cl2 as the solvent.8 Apart from the nature of
the solvent, the problem of obtaining the artemisinic acid still
We have previously shown that photo-oxidation using 1O2
can be conducted continuously and safely in supercritical
carbon dioxide, scCO2, which provides a non-toxic and non-
flammable reaction medium and which can be used close to
ambient temperature.13–15 The photo-oxidation proceeds
School of Chemistry, University of Nottingham, University Park, Nottingham NG7
2RD, UK. E-mail: martyn.poliakoff@nottingham.ac.uk,
michael.george@nottingham.ac.uk; Tel: +44 (0)115 951 3386
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c2gc36711d
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Scheme 2 The photo-oxidation of 2 to its syn- and anti-hydroperoxides.
Fig. 1 FTIR monitoring of the overall formation of the isomers of 3 via the
ν(C–H) band at 3083 cm−1 during the photo-oxidation of 2 in an unstirred
batch reaction. The cell was irradiated with a single white 1000 lumen LED12 for
60 s and an IR spectrum was recorded before further irradiation until the peak
height of the band at 3083 cm−1 no longer changed. 50 μL of 2 + cyclopenta-
none (1 : 2, mol : mol) was used with a 2 mm path length, 0.78 mL volume, cell.
NMR confirms a ca. 80% yield of 3 for this experiment. Time indicates the
overall irradiation time; the reaction reaches a maximum of 80% yield of 3;
ca. 20% of 2 remained unconverted.
somewhat faster in scCO2 than in many conventional solvents,
probably because gaseous O2 and scCO2 are fully miscible,
allowing for single phase reaction conditions. In addition, O2
Fig. 2 The twin photochemical flow reactor,‡ used to maximise the yield of 3.
CO2 is delivered by a Jasco PU-1580-CO2 pump at 0.3 mL min−1, O2 is added
using a Rheodyne dosage unit. 2 is pumped with the cyclic ketone (2 : 1 ketone :
2, mol : mol) and TPFPP (2 mg mL−1 2) at 0.03 mL min−1 using a Jasco PU-980
HPLC pump. B: ice bath; BPR: back-pressure regulator (Jasco BP-1580-81); F:
round bottomed flask with or without 100 mL CH2Cl2 + 0.2 mL BF3·Et2O; LEDs:
light source (4 × 5 × Citizen Electronics Co. Ltd CL-L233-C13 N on an Al heat
sink); M1 & M2: mixers; R1 & R2: sapphire tube reactors. The total pressure was
18 MPa.
1
has a relatively long lifetime in CO2 (5.1 ms at 14.7 MPa,
314 K, compared to 59 ms for CCl4).16,17 By using a flow
system, the reactor volume is reduced compared to a batch
reactor of similar productivity, giving a higher degree of safety
in these potentially dangerous systems. Recently we also
demonstrated that the photocatalyst could be recycled in a
closed loop whilst maintaining a homogeneous reaction
system18 by incorporating a fluorous biphase into our existing
process.
In this paper, we report the synthesis of the spirobicyclic
trioxanes (4a and 4b), with particular emphasis on the con-
tinuous photo-oxidation of the allylic alcohol (2), to its hydro-
peroxides (3), conducted in scCO2, see Scheme 1.11 The
continuous conversion of mesityl oxide (1) to the allylic
alcohol (2) via heterogeneously catalysed, high temperature
transfer hydrogenation at ca. 20 atm pressure has also been
investigated. In the final step, Lewis acid catalysed conden-
sation of 3 with either cyclopentanone or cyclohexanone yields
4a and 4b respectively. Before scale-up of the photo-oxidation
of 2, we carried out the reaction in the small scale batch
reactor which had been used in our previous work.13 As
before, we used the photosensitiser 5,10,15,20-tetrakis-(penta-
fluorophenyl)porphyrin (TPFPP) to generate 1O2. TPFPP is
insoluble in 2 but, conveniently, we found that the cyclic
ketones, used for the final transformation to 4, could also act
as suitable co-solvents.
determined by FTIR monitoring, Fig. 1. In our scCO2 system,
the reaction ran with quantitative conversion of 2 to 3, in the
presence of either cyclopentanone or cyclohexanone; however
20% of 2 remained unreacted under these conditions. The oxi-
dation of 2, Scheme 2, leads to both the syn and anti isomers
of 3, the ratio of which is solvent dependent.19 With either
cyclopentanone or cyclohexanone, the syn selectivity in scCO2
(d.r. 85 : 15) was found to be higher than in MeOH (d.r. 73 : 27)
but lower than in CCl4 (d.r. 93 : 7), in agreement with the
observation that non-polar solvents favour formation of the syn
isomer and that the hydroxyl group of the allylic alcohol
enhances selectivity.19,20
Following these successful batch experiments, the photo-
oxidation of 2 could be scaled up to a continuous flow process.
Fig. 2 shows a schematic of our continuous 1O2 photo-
reactor with twin irradiation vessels. As the reaction was found
to proceed more slowly than in the examples we have pub-
lished previously,13,14 the total system flow rate had to be
lowered accordingly. In this work, the flow rate of CO2 was
maintained at 0.3 mL min−1 and 2 was pumped with TPFPP
TPFPP, 2 and the cyclic ketone were injected into the cell
prior to pressurisation to 18 MPa, to ensure single phase reac-
tion conditions, at 40 °C with 6% O2 in CO2. A twofold excess
of the cyclic ketone, with respect to 2, was used. The reaction
was found to follow zero-order kinetics with respect to 2, as
‡Safety warning: These reactions involve high pressures and require an appropri-
ately rated apparatus and with due regard to the potentially explosive reaction
between O2 and organic compounds.
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Fig. 3 Summary of results obtained for the high pressure (2 MPa) continuous conversion of 1 to 2 using IPA over an MgO catalyst in the absence of added solvent
with a ratio of IPA : 1 of 10 : 1 unless otherwise stated. (a) Increasing the temperature where a maximum yield of 2 was observed at the highest temperature; (b)
increasing the ratio IPA : 1 where the highest ratio gave the highest yield; (c) increasing the flow rate of the IPA + 1 mixture where the yield reaches a maximum at
0.3 mL min−1 and (d) an extended run at 350 °C demonstrating near stable performance of the catalyst for >24 h. In (a)–(d), the traces are labelled as follows; : 2;
●
○
▲
: 1; : 4-methylpent-4-en-2-ol; X: iso-mesityl oxide.
and the cyclic ketone, again in a twofold excess, at a flow rate reduction of 1, which has previously been investigated over a
of 0.03 mL min−1. In this way, the residence time was variety of metal oxide catalysts.24,25 It has been reported that 1
increased to ca. 40 min with the aim to maximise conversion can be selectively reduced to 2 over basic MgO with a high
of 2. Under these continuous flow conditions, at 18 MPa and surface area, using iso-propanol (IPA) as the H-transfer agent,
with 6% O2 in CO2, we obtained an 86% maximum yield of 3, with yields of 2 of 28%.24 It was suggested that the weak acid–
slightly higher than in batch but with the same selectivity for strong base Mg2+–O2− pair sites of MgO promote a Meerwein–
the syn-isomer of 3 (d.r. 85 : 15), as determined by 1H-NMR.
Ponndorf–Verley mechanism between 1 and IPA.25
With a modification of the equipment, we found that our
We have investigated the continuous reduction of 1 with
perfluorinated photosensitiser18 could be pumped in a fluor- IPA with a view to improving the yield of 2 as an inexpensive
ous solvent, HFE-7500, separately from 2 and could be alternative to LiAlH4 and we synthesised MgO with a BET
recycled. The yield and selectivity for 3 was unaffected by this surface area of ca. 84 m2 g−1. Continuous experiments† were
recycling at the same flow rates and pressure used for the conducted using a high pressure flow rig incorporating a
single pass experiment. This biphasic technique should allow reactor filled with 1 g MgO. The effect of changing the reactor
a wider range of trioxanes to be synthesised because one no parameters was investigated and it was found that, at our
longer requires a ketone which dissolves TPFPP.
optimum conditions, 2 could be obtained in >50% yield
The obvious next step was to investigate the possibility of over a relatively long period, as determined by online GLC,
carrying out each stage of the synthesis continuously. There- see Fig. 3. As the by-product of this reaction, acetone, cannot
fore, we briefly investigated the continuous reduction of 1 to 2 safely be used with peroxides in the planned next step, 2 must
and the Lewis acid catalysed condensation of 3 to yield 4, the be separated from the IPA and acetone prior to photo-
aim being to identify any problems in the development of a oxidation.
‘greener’ route to 4.
The final step, conversion of 3 to 4, requires a Lewis acid
The reduction of 1 to 2 is traditionally conducted21 using catalyst. We approached this conversion in two ways. Initially,
LiAlH4, see ESI† for details. However, LiAlH4 is inconvenient to the product stream from the 1O2 flow experiment, containing 3
handle in continuous processes. Hydrogenation with H2 in plus the cyclic ketone, was collected directly into a round bot-
scCO2 is highly efficient22,23 but is unlikely to have sufficiently tomed flask containing CH2Cl2 (100 mL) and BF3·Et2O
high selectivity towards hydrogenation of the carbonyl group (0.2 mL) so as to quench the peroxide products immediately.
in this system. Therefore, we have focussed on the H-transfer The flask was immersed in an ice bath, the temperature was
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gradually increased to room temperature and the mixture was
stirred for a further 12 h. The product, 4b, was purified by
thick layer column chromatography, see ESI† for details. This
gave an overall yield of 4b of ca. 25%, similar to that reported
previously for this step.11
Since CH2Cl2 is not a particularly ‘green’ solvent, we tried a
solvent-free approach to converting 3 to 4a. A stainless steel
tubular reactor (1/4′′ o.d., 2.5 mL volume) was packed with
silica/BF3 (Aldrich) and the solution of 3 in cyclopentanone
was pumped through at a rate of 0.05 mL min−1. Similar con-
version was achieved as with CH2Cl2, 30% yield of 4a, but BF3
leached into the solution and the conversion dropped off after
20 min.
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We have synthesised two spirobicyclic trioxanes, 4a and 4b, 10 A. G. Griesbeck and A. Bartoschek, Chem. Commun., 2002,
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1594.
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180 | Green Chem., 2013, 15, 177–180
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