Curzerene

One-Step Synthesis of Furan Rings from α‑Isopropylidene Ketones Mediated by Iodine/DMSO: An Approach to Potent Bioactive Terpenes

■ INTRODUCTION

Terpene furans encompass a number of structures ranging from monoterpenes to tri- or tetraterpenes (carotenes) possessing an interesting variety of biological activities.1inflammatory and antinociceptive effects of Atractylodes japonica.6 It also shows antiallergic,6b antitumor,6c antiviral,6d and insecticidal properties.6e Its isomer, isoatractylon (4), was isolated from the Antarctic gorgonian Dasystenella acanthine and was reported to exhibit ichthyotoXicity against the

Among them, menthofuran (mintfuran) 1 is an aromatic compound present in the essential oil of different peppermint varieties, including Mentha piperita and pennyroyal (Mentha pulegium).2 Recently, menthofuran has been found in red wines, where it is considered the precursor of p-menthane lactones, which are an important group of aromatizers.3 This substance possesses, among other activities, antifungal and hepatotoXic properties.4 Curzerene 2 was originally isolated from the “curcuma rhizomes”, a plant used in traditional Chinese medicine.5 It was also found in wild celery (Smyrnium olusatrum) and other Smyrnium species.5b This was reported to contribute to the antioXidant properties5c of the essential oils of curcuma and to exhibit cytotoXic and antitumor mosquito fish Gambusia affinis.7 Linderazulene (5) is a purple pigment isolated from Paramuricea chamaeleon8a and other gorgonians8b−d This compound was reported to be a neoplasm inhibitor, immunomodulator, and fungicide.8e

The synthesis of menthofuran (1) has been previously reported,9 including a cyclization from pulegone using an aqueous solution of Ba(OH)2 in the presence of a solution of I2/KI in MeOH.9b However, few synthetic efforts reporting the synthesis of 2−4 were described10 despite the wide range of biological activities displayed by these compounds.

Molecular iodine is a versatile reagent in organic chemistry11 mediating a great number of synthetic transformations, including some dehydration and dehydrogenative processes. Additionally, the combined use with dimethyl sulfoXide (DMSO) not only has increased the range of transformations promoted by I2 but also made possible its use in catalytic activity.5b,d Atractylon 3 is an eudesmane derivative isolated from the rhizomes of species of Atractylodes.6a This furan sesquiterpene presents a wide range of biological activities. Thus, atractylon is the major factor responsible of the anti-intermediates III or V would evolve, likewise, via an iodoetherification reaction to give the iododihydrofuranes IV or VI. Finally, an easy HI elimination from intermediates IV or VI would generate the more stable aromatized structure, VIII. Alternatively, intermediate V could also produce the α-iodo-described an I2/DMSO-mediated synthesis of furans from α- isopropylidene cyclohexanones (I), a structural moiety present in different natural products and easily accessible by synthetic means (Scheme 1).

It has been reported that in some living organisms terpene furans co-occur with the corresponding derivatives possessing a α-isopropylidene ketone. This moiety was postulated as a biogenetic precursor of the furan ring through cytochrome P450-mediated oXidations.13 Bearing all this in mind, we The process would imply the addition of the iodine reagent to enol II to produce the cyclic iodonium ions III or V. Since in the intermediate II the two double bonds should be twisted, there should not exist much conjugation between the isopropylidene group and the enol moiety, which would render the intermediate V more likely to be formed. Then, β,γ-unsaturated ketone VII before evolving to aromatic VIII.14

Finally, it should be noted that according to the proposed mechanism, the process of regeneration of I2 by DMSO generates DMS. This sulfide, in the presence of I2, could generate iododimethylsulfonium iodide,15 which in turn may contribute to the furan ring synthesis.

RESULTS AND DISCUSSION

To test the feasibility of this approach to synthesizing furans and explore its applicability to the synthesis of natural bioactive (MTBE) for 6 h,12b menthofuran (1) was obtained in 15% yield together with minor proportions of dehydromintlactone (7) (Table 1, entry 1). The latter product was formed from 1 via an iodination-Kornblum oXidation tandem process. This result proved the feasibility of our approach to the synthesis of furans via the cascade of transformations depicted in Scheme 1. If under the same experimental conditions, the reaction time was prolonged to 25 h, only a 2% yield of 1 was obtained, but the production of 7 increased up to 35% (Table 1, entry 2).
When solvents of medium−low polarity, such as THF, DCM, or CCl4, were tested (Table 1, entries 3−5), mainly degradation of the starting material was obtained when performing the reaction with THF or DCM. However, when CCl4 was used, notable proportions of lactone 7 and ketofuran 8 were obtained. The use of benzene or toluene as solvent (Table 1, entries 6−9) also led to the formation of dehydromintlactone (7) as the major reaction product, which implies that the conditions were too harsh to stop the process at the furan level. When hexane was used as solvent, the transformation proceeded more smoothly (Table 1, entries 10−13), and the best yield of 1 (68%) was obtained when the quantity of iodine was reduced to substoichiometric proportions of I2, that is, 0.2 mmol. Notably, the use of an excess of I2 led to a 55% yield of dehydromintlactone 7 (Table 1, entry 13). Gratifyingly, the combined use of I2 (0.2 mmol) and DMSO as solvent led to a 75% yield of furan 1 (Table 1, entry 14). Additionally, different reactions were achieved using NIS as source of I+ (Table 1, entries 15 and 16).

Thus, the reaction of 0.2 mmol of NIS with pulegone in DMSO at 50 °C 916 as the main reaction product, with only traces of 1 being obtained. The formation of 9 implies a retro-Aldol condensation of 1 yielding acetone, which couples with an appropriate furan intermediate.16

It should be noted that compounds 7 and 8, found in some of the above-mentioned tests, were also natural products. Thus, dehydromintlactone 7 is claimed to be responsible for the coumarinic odor, indicating high quality in the corresponding peppermint oils.17 Compound 8 is a minor constituent of Mentha piperita.18

Once we proved that menthofuran (1) can be efficiently synthesized from the corresponding α-isopropylidene cyclo- hexanone, i.e., pulegone (6), we focused our efforts on checking if this methodology is useful to other bioactive furan terpenes, such as natural compounds 2−5. All of these compounds were planned to be synthesized using germacrone (11) as common starting material. Germacrone is a sustainable natural product, available in multigram scale from cultivated Geranium macrorrhizum.19

The synthesis of curzerene (2) was anticipated to proceed in only two steps from germacrone (Scheme 2). The first step involved the Pd(II)-mediated Cope rearrangement of germacrone to produce elemenone (12) in 98% yield.20

When elemenone was treated with 0.2 mmol of I2 in DMSO (the best experimental conditions obtained for menthofuran synthesis), curzerene (2) was produced in an excellent (83%) yield. The high chemoselectivity of this transformation warrants mention, since elemenone (12) presents two additional double bonds also susceptible of reacting with positive iodine ions (I+). It should also be noted that when the reaction was performed in refluXing toluene and using 1 mmol of I2, variable quantities (up to 21%) of the natural elemenolactone curzerenone (14) were produced together with minor proportions of the ketocurzerene derivative 13. Both compounds were previously described from natural sources. Thus, ketone 13 was found in the essential oil of Asarum caulescens,21 whereas lactone 14 was isolated from Commiphora molmol (Burseraceae) “Myrrha” and Curcuma wenyujin (Zingiberaceae). Compound 14 shows an important cytotoXic activity and anti-inflammatory action comparable to that of hydrocortisone.22

Three different synthetic routes to atractylon (3) and its isomer 4 were planned (Scheme 3). The first one supposed the initial reaction of germacrone with catalytic Bi(OTf)3 to yield (70%) a miXture of eudesmanes 15−17 in a 1:1:0.4 ratio.23 From this miXture, the exo isomer 16 was isolated and tested reaction with the system of I2/DMSO in different solvents and conditions. Up to 80% yield of atractylon was obtained after refluXing 16 in MTBE for 6 h. The reaction of 17 under the same experimental conditions afforded 82% yield of isoatractylon (4).

In the second route to atractylon, the eudesmane skeleton was generated via electrophilic bromination of germacrone to give the bromoderivatives 18 and 19 in 19 and 53% yields, respectively. The reductive bromination of 18 and 19 proceeded with yields higher than 95% to produce eudesmanes 16 and 17, which were converted into 3 and 4 following our iodine-mediated protocol for the synthesis of furans.
For the third route, we anticipated that the I2/DMSO system could provoke in only one step the iodocarbocycliza- tion of germacrone to produce iodoeudesmanes that would evolve in the same reaction media to the corresponding iodofurans 20 and 21. A reductive deiodination in a subsequent step would lead to atractylon (3) and its isomer 4. Thus, when germacrone (11) was made to react with the I2/ DMSO system under different experimental conditions, it was found that a 74% of the miXture of iodofurans 20 and 21 (5:1 ratio) were produced if 1 mmol of I2 and 5 mmol of DMSO were employed, and the reaction was let to evolve for 48 h at rt in hexane. The radical-promoted hydrodeiodination of 20 using the system nBu3SnH-AIBN afforded a 54% of atractylon (3). The same transformation produced 56% of furan 4 from iododerivative 21.

■ CONCLUSIONS

In conclusion, an I2/DMSO-mediated biomimetic protocol for the synthesis of furan rings from α-isopropylidene ketones was developed. The utility of the method was demonstrated by the the capability of the I2/DMSO system of opening epoXides and carrying out carbocyclizations efficiently. Compound 26 is described for the first time, whereas 23−25 are active principles of different Curcuma species.25 With the ultimate idea of improving the efficiency in the generation of linderazulene, we found that the miXture of guaianes 23−25 could be converted in 5 with a 46% yield after treatment with 0.5 mmol I2 and 5 mmol DMSO in refluXing toluene for 3 min.

EXPERIMENTAL SECTION

General Remarks. Silica gel SDS 60 (35−70 μm) was used for flash column chromatography. NMR spectra were acquired with Varian Direct-Drive 600 (1H 600 MHz/13C 150 MHz), Varian Direct- Drive 500 (1H 500 MHz/13C 125 MHz), Varian Direct-Drive 400 (1H 400 MHz/13C 100 MHz), and Varian Inova Unity 300 (1H 300 MHz/13C 75 MHz) spectrometers. Accurate mass determinations were achieved with a SYNAPT G2-Si Quadrupole time-of-flight mass spectrometer (Waters, Milford, MA) equipped with high-efficiency T- Wave ion mobility, and an orthogonal Z−spray electrospray ionization (ESI) source was used for mass analyses. MassLynx v.4.1 software was used for HRMS instrument control, peak detection, and integration. The reactions were monitored by TLC, which were performed on 0.25 mm E. Merck silica gel plates (60F-254) and involved the use of UV light for visualization and solutions of phosphomolybdic acid in EtOH and heat as the developing agents. HPLC with UV light and RI detection was also used. Semipreparative HPLC separations were conducted on a silica column (5 μm, 10 × 250 mm) at a flow rate of 2.0 mL/min using an Agilent Series 1100 instrument. The reagents were purchased at the highest quality that was commercially available and were used without further purification.

General Procedure for the I2/DMSO-Mediated Generation of Furan Rings from α-Isopropylidene Ketones. To a solution of the corresponding starting material (1 mmol) in the organic solvent (0.1 M) heated under refluX were added iodine (0.2−3 mmol) and DMSO (5 mmol). The solution was stirred at refluX and monitored by thin-layer chromatography. Upon consumption of the starting material, the reaction was diluted in tert-butyl methyl ether (MTBE) (100 mL) and washed with a saturated solution of sodium thiosulfate (1 × 100 mL) and brine (1 × 100 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo. Purification was performed by silica gel chromatography to yield chromatographically and spectroscopically pure product.

Ixodicidal Bioassay. Engorged females of the tick Hyalomma lusitanicum Koch 1844 (IXodoidea: IXodida) were collected from their host (deer) in central Spain (Finca La Garganta. Ciudad Real) and maintained at 22−24 °C and 70% RH until oviposition and larval hatching. Larvae (4−6 weeks old) were used for the bioassay, as described by Ruiz-Vaśquez et al.28 The larvicidal activity data are 1H), 5.44 (bs, 1H), 2.65 (dd, J = 15.5, 4.2 Hz, 1H), 2.65 (dd, J = 15.5,4.2 Hz, 1H), 2.37 (bd, J = 17.4 Hz, 1H), 2.32 (dd, J = 15.7, 1.0 Hz,1H), 2.21−2.11 (m, 2H), 2.03−1.95 (m, 2H), 1.94 (bs, 3H), 1.73 (s,3H), 1.62−1.50 (m, 2H), 0.83 (s, 3H); 13C{1H} NMR (125 MHz, CD3COCD3): δ 149.8, 137.1, 134.3, 121.6, 119.3, 117.0, 43.7, 38.4, 36.8, 32.9, 22.5, 21.0, 20.6, 15.9, 7.2. The spectroscopic data found for this compound were consistent with those reported in the literature.7 Reaction of Eudesmanes 16 and 17 with the System I2/ DMSO: Synthesis of Atractylone (3) and Isoatractylone (4). The standard procedure was followed in both cases using 0.5 mmol (107 mg) 16 or 17, 0.1 mmol (25 mg) iodine, and MTBE as solvent, with a reaction time of 6 h. The crude product was purified by column chromatography over silica gel using H/MTBE (97:3) to obtain atractylone (3) (86 mg, 80%) from 16, and isoatractylone (4) (89 mg,82%) from 17.