Synthesis of spiroannulated and 3-arylated 1,2,4-trioxanes from mesitylol and methyl 4-hydroxytiglate by photooxygenation and peroxyacetalization

  1. Axel G. Griesbeck,
  2. Lars-Oliver Höinck and
  3. Jörg M. Neudörfl

University of Cologne, Department of Chemistry, Organic Chemistry, Greinstr. 4, D-50939 Köln, Germany; Fax: +49(0) 221 470 5057

  1. Corresponding author email

Associate Editor: J. Murphy
Beilstein J. Org. Chem. 2010, 6, No. 61. doi:10.3762/bjoc.6.61
Received 13 Apr 2010, Accepted 18 May 2010, Published 07 Jun 2010

Abstract

Cycloalkanones were utilized in the Lewis acid catalyzed peroxyacetalization of ß-hydroperoxy homoallylic alcohols (prepared by the ene reaction of the allylic alcohols mesitylol and methyl 4-hydroxytiglate, respectively, with singlet oxygen) to give spiroannulated 1,2,4-trioxanes 5a5e and 9a9e, respectively. A second series of 3-arylated trioxanes 10a10h, that are available from the hydroperoxy alcohol 4 and benzaldehyde derivatives, was investigated by X-ray crystallography.

Keywords: ene reaction; peracetalization; peroxides; singlet oxygen; trioxanes

Introduction

The antimalaria-active molecule artemisinin (1) is a naturally occurring sesquiterpene peroxide with remarkable pharmacological properties. Hydrophilic as well as lipophilic derivatives have been prepared from artemisinin and show improved antimalarial properties and better bioavailabilities [1-5]. In recent years, additional medicinal properties of artemisinin and the water soluble artesunates have been discovered such as activities against several cancer cell lines, schistosomiasis and antiviral properties [6,7]. The introduction of substituents into the central peroxide ring system as well as further ring annulation are straightforward approaches for the preparation of other active derivatives which might show promise in overcoming the forthcoming problem of artemisinin resistance [8]. From a synthetic point of view, the preparation of the pharmacophore, the central 1,2,4-trioxane ring system, is possible by a number of strategies [9,10]. We, for example, have previously reported the use of the singlet oxygen ene reaction of allylic alcohols as a route to ß-hydroperoxy alcohols that can be transformed into 1,2,4-trioxanes by reaction with carbonyl compounds in the presence of Lewis acids [11]. This approach leads to simple cyclic peroxides (e.g. 2) which in some cases show similar antimalarial effects as the natural compound (Figure 1) [12]. An apparently useful structural feature is a large 3,3-spirofused hydrophobic group. The adamantane skeleton is a unique motif in other cyclic peroxides with antimalarial activities [13,14] which additionally exhibit other remarkable pharmaceutical properties [15-17]. In this publication we report the use of the alcohols 3 and 6 to explore further the synthetic approach to spirocyclic fused 1,2,4-trioxanes with a series of other spirofused ring structures.

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Figure 1: Antimalaria active natural artemisinin 1 and the spirobicyclic 1,2,4-trioxane derivative 2 show the same in vitro activity.

Results and Discussion

3,3-Spiroannulated 1,2,4-trioxanes

The photooxygenation reactions via sensitization of triplet oxygen with meso-tetraphenylporphyrin (TPP) were performed in polystyrene beads under solvent-free conditions (Scheme 1) [18,19]. Numerous applications of the hydroperoxides 4 and 7, that result from the singlet oxygen ene reactions, have already been reported [20,21]. In context with our work on bis-peroxide synthesis from bifunctional ketones [22], we have also studied the peroxyacetalization of the allylic hydroperoxide 7 with the bifunctional cyclohexane-1,4-dione (CHD, Scheme 2). In this case, one equivalent of the diketone gave the monoadduct 9c in 20% yield.

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Scheme 1: Singlet oxygen ene reaction of methyl 4-hydroxytiglate (3) and mesitylol (6) under solid-phase conditions.

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Scheme 2: 1,2,4-trioxane 9c and bis-trioxane 8a,b formation from the bifunctional cyclohexa-1,4-dione.

The products from the reaction of monofunctional ketones with ß-hydroperoxy alcohols 4 and 7 are collected in Table 1. All trioxanes 5ae derived from 4 were crystalline and could be analyzed by X-ray structure analysis (Figure 2). The bond lengths of the crucial O-O bond were similar in all cases with the exception of the adamantane derivative 5d which has a remarkably shorter O-O bond distance.

Table 1: 3,3-Spiroannulated 1,2,4-trioxanes by photooxygenation and peroxyacetalization.a

tiglate-derived trioxanes Yield [%]b
O-O [Å]c
mesitylol-derived trioxanes Yield [%]b
O-O [Å]c
[Graphic 1] 5a 86
1.465d
[Graphic 6] 9a 73e
[Graphic 2] 5b 12
1.480
[Graphic 7] 9b 14
[Graphic 3] 5c 20
1.466
[Graphic 8] 9c 20
[Graphic 4] 5d 30
1.427d
[Graphic 9] 9d 40
1.482f
[Graphic 5] 5e 5
1.480
[Graphic 10] 9e 19
1.464

aStandard reaction conditions: substrate (2 mmol, 4 × 10−2 M), CCl4 (50 mL), meso-tetraphenylporphyrin (0.01 mmol, 2 × 10−4 M), r.t., 10 h; then addition of a solution of the carbonyl compound (2.5 mmol) in CH2Cl2 (10 mL), 0 °C, 3 h. bYields of per-oxyacetalization. cFrom X-ray analysis, CCDC deposited [23]. d[19]. e[20]. f[12].

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Figure 2: Structure of the spirobicyclic trioxane 5c in the crystal.

4-Arylated 1,2,4-trioxanes

The 1,2,4-trioxanes 10 were formed in moderate to good yields, with the Hock-type cleavage product from the ß-hydroperdiol as the only side-product, from 4 and substituted benzaldehydes under BF3-catalysis in CH2Cl2 solution (Scheme 3). In all cases the trans products were formed in high (>98:2) diastereoselectivities. All compounds could be crystallized from acetone or from the neat liquid. In the crystal the central 1,2,4-trioxane ring is almost undistorted in a cyclohexane chair conformation with the acrylate and the aryl substituents in equatorial positions (Figure 3). In the crystal lattice the compounds, especially the 4-halophenyl-substituted trioxanes, tend to form π-stacked stabilized chain structures with channels that are filled with water molecules (Figure 4). In the elementary cell of the 4-chloro derivative 10c, an average of 320 Å3 of channel space corresponds to one water molecules per trioxane molecule. By contrast, the 4-trifluormethyl derivative 10f crystallized in a compact chain-like package of anti-parallel arranged pairs of trioxanes.

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Scheme 3: BF3-catalyzed acetalization of hydroperoxide 4 with benzaldehyde derivatives.

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Figure 3: Structure of the 3-arylated trioxane 10b in the crystal.

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Figure 4: Structure of the p-bromophenyl derivative 10d in the crystal lattice (disordered water molecules in the cannels are not shown) viewed along the a axis.

The orientation of the aryl groups relative to the 1,2,4-trioxane equator depends largely on the nature of the para-substituent: in the phenyl-substituted trioxane 10a and in the para-halogenated analogs 10b10d, the aryl group is nearly coplanar with the C(3)-H bond, whereas in the 4-nitro-, 4-trifluoromethyl-, and 4-cyano compounds 10e10f coplanarity of the aryl substituent with the O(4)-C(3) bond of the trioxane chair was observed (Table 2 and for numbering Figure 5).

Table 2: Structural features of the 1,2,4-trioxanes 10ah.a

10 R = Θ4-3-C(ar/q)-C(ar) (°) Θ2-3-C(ar/q)-C(ar) (°) ΘH(C3)-3-C(ar/q)-C(ar) (°)
10a H 127 115 3
10b F 142 100 19
10c Cl 141 101 18
10d Br 140 100 18
10e NO2 179 59 59
10f CF3 154 90 26
10g CN 153 89 29
10h OMe 139 103 17

aSee [24] for CCDC submission.

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Figure 5: Numbering of 3-aryl-1,2,4-trioxanes 10 and relevant bonds; structure of artemether (AM).

In the artemisinin-derived arthemether (AM), the central trioxane ring has a twist-boat conformation resulting from the additional propylene bridge connecting C-3 and C-6. In Table 3 the yields of the peroxyacetalization reactions, the characteristic 13C NMR shifts of the peracetal carbon C-3 and two significant bond lengths are listed. It is clear that the electronic nature of the substituent on the aryl group does not significantly change the bond length of the central peroxide bond (mean value: 1.479 Å). The mean value of the characteristic 13C NMR shift of the peroxyacetal carbon C-3 is 103.4 ppm. The bond length of the central oxygen-oxygen bond in arthemether as determined by an independent structure analysis is 1.472(1) Å.

Table 3: Yields, structural and 13C-NMR properties of 1,2,4-trioxanes 10ah, and arthemether (AM).

10 R = yield (%)a δ(C-3) (ppm)b O1-O2 (Å) O2-C3 (Å)
10ac H 61 104.2 1.485(7) 1.451(8)
10b F 40 103.5 1.472(3) 1.432(3)
10c Cl 35 103.4 1.474(3) 1.425(4)
10d Br 29 103.4 1.469(9) 1.415(11)
10ec NO2 31 102.6 1.471(9) 1.398(11)
10f CF3 44 103.1 1.474(2) 1.432(2)
10g CN 38 102.7 1.4823(14) 1.436(2)
10h OMe 23 104.0 1.4806(19) 1.438(2)
AM 102.9 1.472(1) 1.416(3)

aIsolated yield after purification by column chromatography. bIn ppm, 75 MHz in CDCl3. cMedium quality crystals, data not deposited.

More pronounced bond lengths effects were observed for the O2-C3 ring bonds that range from 1.39 to 1.45 Å. Analysis of the Cambridge crystallographic data file revealed that the mean oxygen-oxygen (O1-O2) bond distance for 1,2,4-trioxanes (108 compounds) is 1.472 Å with a narrow distribution ranging from the extremes 1.460 (3 compounds) to 1.482 (4 compounds). All compounds 10ah investigated by us fall into this range, 10a,g,h showing the longest O1-O2 bond distances. With regards to antimalarial activity, all 4-arylated 1,2,4-trioxanes exhibited low in vitro activities (EC50/plasmodium falciparum > 50 μM) with the nitro-substituted compound 10e as the most active derivative (EC50 = 48 μM) [25]. Thus, the peroxide bond lengths do not correlate with biological activity, cf. the highly active AM and the fluoro compound 10b.

Conclusion

In summary, we have reported the synthesis of a series of six-membered ring 3,3-spiroannulated 1,2,4-trioxanes from methyl 4-hydroxytiglate and from mesitylol, respectively, by the singlet oxygen ene reaction and subsequent peroxyacetalization. A series of 4-arylated 1,2,4-trioxanes from methyl 4-hydroxytiglate was obtained by the same protocol. These compounds were fully characterized by spectroscopic methods and by X-ray structure determination.

Experimental

Synthesis of the 4-fluorophenyl derivative 10b: A solution of 290 mg (2.0 mmol) of the hydroperoxide 4 (prepared from methyl 4-hydroxytiglate (3) by the method described in [10]) and 220 mg (2.0 mmol) of 4-fluorobenzaldehyde in 40 ml of dichloromethane was treated at 0 °C with 0.2 ml of boron trifluoride in diethyl ether. After stirring overnight at room temperature, the solution was diluted to 100 ml with dichloromethane, washed successively with 20 ml of saturated aqueous sodium bicarbonate solution, brine and water. The organic phase was separated and dried. After evaporation and column chromatography (silica, EtOAc), 200 mg (40%) of 10b was obrained as a colorless viscous oil that crystallized as thin plates on standing: C13H15FO6 (corresponds to C13H13FO5 × H2O: colorless thin needles from aqueous acetone), M = 286.25, a = 6.1264(3), b = 16.8514(9), c = 26.2519(14), α, β, γ = 90°, orthorhombic, space group Pnaa, Mo-Kα, 15276 reflections measured, 2948 reflections with I > 2σ(I), R1 (all data) = 0.0573, wR2 = 0.1811.

Acknowledgements

We thank the DFG for project funding and the University of Cologne for a start-up grant. Biological testing was performed in South-Korea. AGG is recipient of the 2009 Honda-Fujishima award (Asian Photochemistry Association) for the antimalarial trioxane research.

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