Side-chain Modifications of Highly Functionalized 3(2H)-Furanones

A series of 3(2H)-furanones, based on side-chain modifications of a parent 3(2H)-furanone, was synthesized in good yield. The parent compound was prepared by hydrogenolysis, and subsequent acid hydrolysis, of isoxazole derivatives. The isoxazole was prepared by a [3+2] 1,3-dipolar cycloaddition reaction between 3-butyn-2-ol and nitrile oxide.


Introduction
As a prominent structural feature, 3(2H)-furanone seems to be relevant in many classes of biologically active natural products, such as the examples collected in Figure 1 [1][2][3][4]. Sesquiterpene lactones encompass a large class of natural products showing a large diversity of molecular structures and a variety of biological activities. For a long time, much attention has been given to the α-methylenelactone unit, as can be seen in the structure of goyazensolide, because this group is considered to be responsible for activities such as cytotoxicity [5,6], through a mechanism involving a Michael addition of a cysteine sulfhydryl group [7]. Later, it was shown that many sesquiterpene lactones lacking the α-methylene group in the lactone unit, such as the eremantholides, present the same sort of activity. It seems reasonable that the 3(2H)-furanone unit could be the electrophilic center responsible for the activity of eremantholides [5,6]. A large number of biological active natural OPEN ACCESS compounds possessing the 3(2H)-furanone unit have been isolated. Geiparvarin and jatrophone, for example, have antitumor activity [8,9]. In recent years, several synthetic methods have been applied to build these skeletons [10,11]. Chimichi and co-wokers [8,9] reported the preparation of 3(2H)-furanones through hydrogenolysis and subsequent acid hydrolysis of isoxazole derivatives. This approach is very interesting because it allows the preparation of series of 3(2H)-furanones possessing different side chains, which may also contain reactive functional groups. Such compounds are useful for studies related to biological activities of furanones and as starting material for the synthesis of sesquiterpene lactones such as furanoheliangolides.
Since we are interested both in the preparation of libraries of compounds for biological testing and in the development of synthetic methodology for the preparation of natural products, we disclose herein our exploration of Chimichi's method for the preparation of a series of structurally modified 3(2H)-furanones.

Results and Discussion
Following Chimichi's procedure, isoxazole 2 was prepared by a [3+2] 1,3-dipolar cycloaddition reaction between 3-butyn-2-ol and nitrile oxide, prepared in situ from nitropropane (Scheme 1) [8]. PCC oxidation of compound 2 furnished the keto-isoxazole 3 in good yield. In the original paper the authors prepared ketone 3 by an alternate route, by MnO 2 oxidation of the isoxazoline obtained from nitrile oxide and methyl vinyl ketone.
Ketone 3 is a key intermediate to introduce a suitable side chain into the future furanone ring. For the intended series of compounds, we choose to treat compound 3 with the Grignard reagent 4, which contains a protected aldehyde as a reactive functional group for future use. The reagent 4 was prepared from commercially available 2-(2-bromoethyl)-1,3-dioxane in THF [12], affording 5 in 95% yield (Scheme 2). Hydrogenolysis of isoxazoles followed by acid hydrolysis leads to furanones [8]. Thus, compound 5 was exposed to a hydrogen atmosphere in the presence of platinum supported on carbon leading to the β-aminoenone 6 in 91% yield. It is interesting to note that β-aminoenones can usually occur as two isomers 6 and 6a, which can be distinguished from each other by typical H(N) chemical shifts (E-isomer: δ H 4.0-8.0; Z-isomer: δ H 9.0-13.0) [13]. In our case, we have obtained only one isomer; structure 6 was assigned to this isomer based both on the H(N) chemical shift (δ H 9.6) and on the observation of a nOe effect between H2 and H5 (Scheme 3). Compound 6 is the precursor of the planned series of 3(2H)-furanones. We report here the preparation of the compounds depicted in Figure 2. This series can be easily expanded since the side chain is suitably functionalized. The parent compound of the series, 7, was prepared in 85% yield from 6 by treatment with hydrochloric acid. Under mild acidic conditions, the enol-imine tautomeric form of 6 provides a favorable 5-exo-trig arrangement for the cyclization in accordance with Baldwin's rules (Scheme 4) [14].  The second furanone in the series, 8, was obtained in 60% yield by treatment of 7 with more concentrated hydrochloric acid (2 M). Later, compound 8 was obtained in 80% yield directly from 6 using a "one pot" procedure, starting with the treatment of compound 6 with 0.1 M HCl and three subsequent additions of 1 M HCl in one-hour intervals to speed up the cyclization of β-aminoenone 6, and then, 2 M HCl was added to hydrolyze the acetal (Scheme 5). At this point, we elongated the side chain of compound 8 with allylmagnesium bromide [15] (Scheme 6) obtaining compound 9 in 52% yield. The product seems to be homogenous either by TLC and column chromatography, however the 13 C-NMR spectrum shows duplicates for seven out of the expected 14 signals, suggesting the formation of two diastereoisomers. In the 1 H-NMR spectrum, only the signal of the coupled methyl group appears as a duplicated triplet, and all other signals of both diastereoisomers remained unresolved. All attempts to separate the two diastereoisomers by TLC were unsuccessful. The relative intensities of the two triplets mentioned above indicate that the diastereoselectivity of the addition of the allylmagnesium bromide to the aldehyde 8 was very poor, leading to almost equivalent amounts of both isomers. An alkylation reaction is all that is needed to prepare compound 10 from compound 9. Treatment of 9 with NaH in THF should lead to an equilibrium mixture of the alkoxide and the enolate of the unsaturated ketone. The addition of CH 3 I to this mixture, however, resulted only in the C-alkylation product, thus transforming the ethyl into an isopropyl substituent, giving rise to 10 with 60% yield (Scheme 7). Finally, the ethyl group of compound 9 was easily transformed into an isopropylidene group through an adaptation of the Danishefsky's method [16,17], originally developed to insert a methylene group in the α position of a lactone, affording the last compound in Figure 2, furanone 11 (Scheme 8). As occurred with compound 9, all attempts to separate the diastereoisomers of 10 and 11 were unsuccessful.

General
Melting points were determined on a Kofler hot plate with an uncalibrated thermometer, installed on a Bristoline microscope. The purification of reaction products was performed by column chromatography using silica gel (70-230 mesh). Analytical thin-layer chromatography was performed on silica gel 60 F 254 aluminum sheets. Visualization was accomplished with UV light and vanillin solution followed by heating. The infrared spectra were obtained in a Perkin-Elmer Spectrum RX IFTIR System. The wavelengths of maximum absorbance (max) are quoted in wavenumbers (cm −1 ). 1 H and proton-decoupled 13 C-NMR spectra were taken in C 6 D 6 or CDCl 3 on a Bruker DPX-300

5-Ethyl-2-(3-hydroxyhex-5-en-1-yl)-2-methylfuran-3(2H)-one (9): Preparation of the Grignard reagent:
A solution of allyl bromide (0.46 g, 0.33 mL, 3.8 mmol) in diethyl ether (2 mL) was added slowly to magnesium turnings (0.28 g, 11.4 mmol) activated with iodine and diethyl ether (1.2 mL), at 0 °C under an atmosphere of nitrogen, keeping the stirring for an additional hour. A portion of this solution (1.6 mL) was added dropwise, at room temperature, into a flask containing a solution of compound 8 (173.6 mg, 0.95 mmol) in THF (30 mL). Immediately there was formation of a white solid. After 1 h a saturated solution of ammonium chloride (15 mL) was added to dissolve the precipitate and the mixture was extracted with dichloromethane (4 × 15 mL) and ethyl acetate (4 × 15 mL). The combined organic extract was dried with anhydrous magnesium sulfate, filtered and the solvent removed at reduced pressure.  (10): Under nitrogen atmosphere and 0 °C, sodium hydride (31.8 mg, 79.4 mmol, 60% in mineral oil) was dissolved in dimethylformamide (2 mL). Then, the compound 9 (137 mg, 0.61 mmol) in dimethylformamide (7 mL) was added and maintained for 30 minutes under these conditions. Then methyl iodide was added (0.43 g, 0.19 mL, 3.05 mmol) at 0 °C and the reaction was maintained under these conditions for 3 h and then another 1 h at room temperature. The compound 10 was obtained after column chromatographic purification on silica gel using hexane-ethyl acetate-methanol

Conclusions
We have prepared a short series of 3(2H)-furanones through a very efficient method that uses an isoxazole as intermediate. An initial functionalized side chain introduced in the isoxazole can be modified later, leading easily to a large number of compounds having a common core structure, the furanone ring, that makes the method suitable for the preparation of libraries of compounds for biological activity studies. The presence of double bonds and/or functional groups in the side-chains also makes the compounds useful as starting materials for the synthesis of natural products.