Epoxy lactones by photooxidative rearrangement of 6β-acetoxyvouacapane

Tetrahedron Letters 58 (2017) 2901–2903

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Epoxy lactones by photooxidative rearrangement of 6b-acetoxyvouacapane Armando Talavera-Alemán a,b, Mario A. Gómez-Hurtado a, Rosa E. del Río a,⇑, Jérôme Marrot b, Christine Thomassigny b,⇑, Christine Greck b a b

Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia, Michoacán 58030, Mexico Université de Versailles Saint-Quentin-en-Yvelines, ILV, UMR CNRS 8180, 45, Avenue des Etats-Unis, 78035 Versailles, France

a r t i c l e

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Article history: Received 11 April 2017 Revised 6 June 2017 Accepted 12 June 2017 Available online 12 June 2017 Keywords: Vouacapane diterpene Photooxidation reaction Epoxy lactone Spirolactone

a b s t r a c t The first study of photooxidation reaction of 6b-acetoxyvouacapane isolated from Caesalpinia platyloba is reported. The reaction yielded four new epoxy lactones, 6b-acetoxy-15,16a-epoxy-13-spirocassa-12,16olide, 6b-acetoxy-15,16b-epoxy-13-spirocassa-12,16-olide, 6b-acetoxy-12,13b-epoxycassa-16,12-olide and 6b-acetoxy-12,13a-epoxycassa-16,12-olide. All the structures were supported by 1D and 2D NMR spectroscopy as well as mass spectrometry. The stereochemistry was established on the base of single crystal X-ray diffraction. Ó 2017 Elsevier Ltd. All rights reserved.

Introduction Photosensitized oxidation reactions in furans are known for being of relevant importance in modifications and synthesis of bioactive natural products1,2 or precursors3 in organic chemistry. These reactions have been described to occur by 2,5-endoperoxide formation,4 which can be rearranged in different ways to generate esters, epoxides, and hydroperoxides, depending on the solvent and temperature used in the reaction.5 Vouacapane diterpenes are natural tetracyclic cassanes found in the Fabaceae family and having a disubstituted furan ring or a butanolide at C-12/C-13.6,7 As examples we can cite the echinalide A (1) or the hydroxybutenolide 2 which are metabolites from Caesalpinia echinata (Fig. 1).8 Some of these diterpenes exhibit cytotoxic,9 analgesic,10 antimalarial,11 antioxidant,12 or antiviral bioactivities.13 Chemical modifications in the vouacapane furan ring can led to structures with chemical and biological interest. In particular, oxidation reactions have been carried out in the way to label a biosynthetical route,14 to establish stereochemical structure15–17 or to obtain new derivatives with potential biological activities.18 Most of the methods of oxidation used strong conditions (NaIO4/KMnO4, mCPBA/HCl), leading to a complete degradation of the furan ring.14,16,17 Softer conditions (mCPBA, ⇑ Corresponding authors. E-mail addresses: [email protected] (Rosa E. del Río), [email protected] (C. Thomassigny). http://dx.doi.org/10.1016/j.tetlet.2017.06.030 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

K2Cr2O7/H2O/H2SO4) gave interesting patterns such as spirofuranones or 5-hydroxyfuranones.15,16,18 We aimed to enlarge the collection of such structures by oxidation of the furan ring in vouacapane diterpenes. In a previous work, we reported the isolation and determination of the absolute configuration by vibrational circular dichroism of 6b-acetoxyvouacapane (3) from the leaves of Caesalpinia platyloba.19 In the present paper we report the first vouacapane photooxidation reaction employing 3 as raw material, to get four new diterpene cassanes derivatives. Results and discussion Furans A are known to react with singlet oxygen via a concerted [4+2] cycloaddition across the 2,5-positions of the furan, leading to the corresponding endoperoxide B (Scheme 1),20 which can decompose by homolytic cleavage of the O–O bond when the reaction is run in non-polar aprotic solvents, giving C. This bis-alkoxy radical can undergo several derivatives such as dimerization, epoxylactonization D or bis-epoxidation E depending on the reaction conditions. Recently, Gryko and coworkers described a photoorganocatalytic a-oxyamination of carbonyl with TEMPO radical in the presence of organo- and photoredox catalysts.21 As we aimed to make a similar reaction with the C-6 ketonic derivative of the 6b-acetoxyvouacapane (3) for the oxidation at C-7, we then firstly studied the reactivity of the furan ring of 3 under similar conditions. The

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Fig. 1. Vouacapane diterpenes isolated from C. echinata. Fig. 2. X-ray diffraction of compounds 4 and 7.

Scheme 1. Reactivity of furans with singlet oxygen.

first assays of irradiation of 3 with white light in the presence of TEMPO radical led to no one or very few reaction. We then studied the effect of air or oxygen as oxidant under photooxidation conditions, and which is the subject of the present article (Scheme 2). Natural photoredox catalysts, namely eosin and methylene blue, have been tested first. In all cases, four new lactones were obtained, respectively 4 and 5 having a spiro skeleton at C-13 and an epoxide in position C-15, C-16, and 6 and 7 with an epoxide in position C-12, C-13. The full assignment of compound 4 has been firstly based on NMR, COSY, HMQC and HMBC experiments. The 1H NMR spectrum showed in particular two doublets at 3.61 and 5.55 ppm, attributed to the epoxide protons H-15 and H-16 (J = 2.3 Hz). The 13C NMR spectrum exhibited two signals (178.2 and 170.3 ppm) corresponding to the carbonyls (lactone and acetate) and three supplementary quaternary carbons atoms especially the signal at 54.6 ppm assigned to the spiro carbon C-13. In assumption that the chiral centers on the rings A and B remain intact in the reaction process, the absolute stereochemistry of this compound was easily established by single X-ray diffraction analyses (Fig. 2), confirming the a-orientations of both the lactone carbonyl (C-12) and the epoxide oxygen. The NMR data of spirolactone 5 were very similar in comparison with those of compound 4. The relative stereochemistry was performed by NOESY, in which H-15 correlated with the secondary methyl signal (CH3-17), indicating the C13–C15 bond was a-orientated; a correlation between H-15 and one proton of the CH2-11

indicated a b-orientation of the epoxide oxygen. Compounds 4 and 5 are presenting a spiro cassane skeleton: similar patterns have been reported previously in natural products like spirocaesalmin,13 and Caesalminaxin B and C,22 isolated from Caesalpinia minax, and Echinalide T by Caesalpinia echinata,15 and by vouacapane oxidation with mCPBA.16 Their obtaining could be explained by formation of bis-radical C (following the Scheme 1), that could give in one part the epoxide at C-16/C-17, and in another part a concerted lactonization/1,2-alkyl shift leading to the spirolactonic derivative. The 1H NMR of compounds 6 and 7 exhibited two doublets with J = 18.9 Hz each (respectively at 2.90 and 2.78 ppm for 6 and at 3.04 and 2.69 ppm for 7), corresponding to the AB system of the geminal protons of methylene CH2-15. The complete NMR analyses indicated that 6 and 7 were diastereomeric lactones with an epoxide in position C-12, C-13. The absolute stereochemistry of 7 was determined by X-ray diffraction (Fig. 2) in which was observed the a-orientation of the epoxide oxygen. We then deduced the stereochemistry of 6 to be the b-epoxy orientated. The structures and configuration of 6 and 7 are in agreement with the mechanism proposed in the literature for similar structures, concerning a rearrangement of the endoperoxide.23 The photooxidation of 3 led to the four compounds 4–7 with different proportions, depending on the reaction conditions. The results are presented in the Table 1. The epoxy spirolactones 4 and 5 were always predominant (20–34% yield) compared to the epoxy lactones 6 and 7 (12–22% yield), and these last ones were constantly obtained with a proportion very near to 1/1, showing no stereospecificity during the addition of O2 during their formation. The first assays have been run in the presence of eosin as photocatalyst, acetonitrile as solvent and oxygen from the atmospheric air or from an O2 (solvent degazed then charged with O2) atmosphere (Table 1, entries 1 and 2). After two hours TLC showed the complete disappearance of 3, confirmed by 1H NMR of the crude, and showing the formation of compounds 4, 5, 6 and 7. The analysis of the 1H NMR spectrum of the experiment under air atmosphere gave a proportion (4+5):(6+7) of 57:43, with a ratio

Scheme 2. Photooxidation of 6b-acetoxyvouacapane (3).

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A. Talavera-Alemán et al. / Tetrahedron Letters 58 (2017) 2901–2903 Table 1 Photooxidation of 3. Entry

Conditions

Yielda (%) (4+5):(6+7)

Ratiob (4+5):(6+7)

Ratiob 4:5

1 2 3 4 5 6 7 8 9 10

Air, Eosin, CH3CN, 2 h O2, Eosin, CH3CN, 2 h Air, Methylene blue, CH3CN, 2 h O2, Methylene blue, CH3CN, 2 h Air, Ru(bpy)3(PF6)2, CH3CN, 2 h O2, Ru(bpy)3(PF6)2, CH3CN, 1 h O2, Ru(bpy)3(PF6)2, CH2Cl2, 18 h O2, Ru(bpy)3(PF6)2, Acetone, 2 h Air, Ru(bpy)3(PF6)2, Toluene, 18 h Air, Ru(bpy)3(PF6)2, THF, 18 h

20:12 32:17 33:17 30:13 34:22 32:22 n.d. n.d. – –

57:43 55:45 56:44 60:40 60:40 59:41 56:44 50:50 – –

1:1.3 1:1.2 1:1.8 1:2 1:1.7 1:1.8 1:1.1 1:1.4

Reaction conditions: 6b-acetoxyvouacapane (3), solvent (25 g/L) and catalyst (3 mol%) were irradiated with white light under oxygen or air atmosphere. n.d.: not determined (low yield). a Isolated yield after purification by silica gel chromatography column; b Determined by NMR in the crude reaction.

of the two spiro lactones 4:5 of 1:1.3. Different O2 source induced no notable modification of the ratios but an interesting increase of yield in favor of the spiro derivatives 4 and 5 (air: 20%; O2: 32% after purification by flash chromatography). In the presence of methylene blue (entries 3 and 4), both ratios (4+5):(6+7) and 4:5 increased respectively up to 60/40 to 1:2 when the reaction was run under an O2 atmosphere. Using Ru(bpy)3(PF6)2 as catalyst allowed comparable ratios of (4+5):(6+7) and 4:5 in the time of only 1 h when using oxygen atmosphere (entry 6). We can notice an improvement of the yield of compounds 6 and 7 to 22%. The change of solvent to CH2Cl2 or acetone did not allow an increase of the conversion rate, even with longer reaction time (entries 7 and 8), whereas the reaction did not occur in toluene or THF (entries 9 and 10). In the absence of catalyst, the reaction provided a very complex mixture of products, in which no one of the compounds 4–7 was observed. In conclusion, we developed the photooxidation reaction of 6bacetoxyvouacapane (3) furan ring, to obtain four new compounds: the epoxy spirolactones 4 and 5 obtained by 1,2-alkyl shift and the epoxy lactones 6 and 7. In particular, the use of methylene blue under O2 atmosphere allowed the obtaining of the spiro lactones in the proportion 1:2. Acknowledgments We thank CIC-UMSNH for financial assistance, and to CONACYT-Mexico for scholarship 398462. A. Supplementary data Supplementary data (detailed description of the experimental procedure, a listing of 1D and 2D NMR, IR spectral data for com-

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