In recent years, natural substances have attracted growing interest in several industrial fields [1,2,3], including the cosmetic, pharmaceutical, and food industries. In addition, valorization of active ingredients of natural origin represents high added value from the economic point of view. In this context, modern pharmaceutical industry still relies heavily on the diversity of plant secondary metabolites in order to find new molecules with interesting biological properties [4].

With regard to its special geographical position, Morocco possesses varied vegetation and is considered among the top five floristically richest countries across the Mediterranean basin [5]. These natural resources include Cedrus atlantica essential oil, which is considered as a valuable starting material for the perfume industry. This oil is primarily made up of sesquiterpenic bicyclic hydrocarbons (75%), in which β-himachalene represents the major component [6, 7]. The reactivity of this sesquiterpene and its derivatives has been studied extensively in order to prepare new products having enhanced biological activities [8,9,10].

Previous studies have shown that the acid-catalyzed rearrangement of two enantiomerically pure epoxides 2α,3α-epoxy-cis-himachal-7(13)-ene and 6α,7α-epoxyhimachal-2-ene derived from α-cis and β-himachalene, respectively, gave several new polycyclic compounds with different selectivities depending upon the catalysts used and the reaction conditions [11, 12].

In addition, the rearrangement of epoxides to carbonyl compounds represents a useful synthetic transformation and hence several products could be obtained according to the nature of the epoxide, catalysts, and reaction conditions [13]. A large number of catalyst types have been used in the literature for this purpose, including a variety of Lewis acids [14, 15].

Within the framework of a research project based on valorization of Moroccan plant resources [16,17,18,19,20], we herein report the synthesis of a new epoxide himachalenes skeleton starting from β-himachalene [21, 22] isolated from Cedrus atlantica essential oil using chromatography on a silica gel column impregnated with silver nitrate (10%) and a mixture of hexane–ethyl acetate (99:1) as eluent. We decided to explore the chemistry of gem-dihalogenocyclopropane oxides 3a, 4a, 6a, and 7a (Scheme 1). The rearrangements of these epoxides to the corresponding carbonyl compounds were studied with different Lewis and Bronsted acids.

Scheme 1.
scheme 1

General pathway for the synthesis of gem-dihalogenocyclopropane oxides 3a, 4a, 6a, and 7a.

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We investigated the rearrangement of the epoxides derived from β-himachalene. The epoxides were synthesized as described in the literature [23, 24]. Firstly, the β-himachalene was transformed to the corresponding epoxides using m-CPBA (1 eq) in dichloromethane. The products 3 and 4 were obtained with yields of 63 and 83%, respectively, as two diastereoisomers (Scheme 1) from β-epoxyhimachalene by the action of chloroform or bromoform (1.5 eq) in the presence of potassium tert-butylate (t-BuOK) as a base in hexane.

Using the same strategy, we prepared other epoxides from β-himachalene. Indeed, β-himachalene was converted to the corresponding dihalogenocyclopropanes under the same conditions previously described but using only 1 eq of chloroform (or bromoform). The reaction allowed us to obtain products 5a and 5b with yield of 10 and 55%, respectively, after 15 h of stirring at room temperature. In both cases, the reaction gave regio- and stereospecifically one enantiomer [23, 25]. Then the epoxidation of the products 5a and 5b was carried out and led to the products 6 and 7 with yields of 63 and 83% as two diastereoisomers with a–b ratios of 80:20 and 75:25, respectively (Scheme 1). In all cases the majority of epoxides were isolated and purified using chromatography on a silica gel column and a mixture of hexane–ethyl acetate (99:1) as eluent. The structures of all obtained products were established by 1H and 13C NMR. The stereochemistry of the asymmetric carbons was confirmed by single-crystal X-ray diffraction [26, 27].

We have shown previously that Lewis acids are efficient catalysts for epoxide opening-mediated rearrangement [11, 12]. Our study began with the epoxides 3a and 4a, which were treated using BF3–Et2O (0.1%) in dichloromethane. This led predominantly to the formation of two tricyclic ketones (8a, 8b) and (9a, 9b), respectively (Scheme 2).

Scheme 2.
scheme 2

Rearrangement of products 3a and 4a.

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A full conversion was obtained after 0.5 h and led to the formation of ketones 8a and 8b as major products. The structures of the newly prepared products were characterized by their spectral data (NMR). Then we investigated the effect of different Lewis and Bronsted acids on the conversion and selectivity of the reaction. The results obtained are summarized in Table 1.

Table 1. Rearrangement of Epoxides 3a and 4a Catalyzed with 0.1% of Acids
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In all cases (E1-E7), complete conversion was obtained, and the selectivity depended on the nature of the acid. The rearrangement products were obtained with high selectivity to total carbonylated products ranging from 50 (E6) to 96% (E1).

Comparison of the various tests showed the remarkable effect of the Lewis acid on the rate and selectivity of the reaction. With BF3–OEt2, Bi(OTf)3, and Sn(OTf)2, a complete and rapid conversion of epoxide was observed (E1, E3, and E5), while the reaction time must be increased to 2 or 4 h to obtain a complete conversion of the substrate with InCl3, FeCl3, and AlCl3 (E2, E6, and E7). Indeed, BF3–OEt2 catalyst gave the best selectivity to carbonylated products with excellent chemoselectivity (96%) and a selectivity of 8a and 9a (E1) of 88% and 8%, respectively. However a middle chemoselectivity was obtained using Sn(OTf)2, FeCl3–6H2O or AlCl3.

Bronsted acids have been used as catalysts in order to compare their activities and selectivities to those of Lewis acids. The reaction was studied under the same conditions with methanesulfonic acid (MSA) and p-toluenesulfonic acid (PTSA). In both cases no traces of ketones or alcohols were observed, and only side products due to dehydration and isomerization of the double bonds formed were detected by gas chromatography. We were able to get the product 10a with a selectivity of 92% using PTSA (E8) and 90% with MSA (E9).

Following the encouraging results obtained with epoxide 3a and Lewis acid in terms of selectivity, we decided to extend this reaction to other epoxides. The chlorinated analogous 4a gave similar results as those obtained previously in terms of conversion, with total chemoselectivity to the ketone 8b (87–91%) (E10–E12), since no trace of the ketone 9b was detected. We also noticed a slight improvement in the chemoselectivity for carbonyl products with the catalysts tested (BF3–OEt2, Bi(OTf)3, and InCl3). A selectivity of 91% was recorded with BF3–OEt2 (E10).

To that end, the ring-opening reaction of epoxides 6a and 7a was investigated under the same catalytic conditions (Scheme 3). The results obtained are summarized in Table 1.

Scheme 3.
scheme 3

Ring opening reaction of 6a and 7a.

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The reaction led predominantly to the formation of the corresponding ketones with good yields ranging from 88% to 93% (E13–E18), and BF3–OEt2 proved to be the best catalyst for the opening of these epoxides 93% (E13). The gas chromatography of the reaction mixture revealed the presence of other easily identifiable products in very small quantities up to 12%.

The structures of the newly prepared ketones were established by 1H and 13C NMR after purification on a silica gel column. In addition, all products were crystallized using slow diffusion in pentane at room temperature. The molecular structures and relative stereochemistry of compounds 8a, 8b, 9a, 9b, 11a, and 11b were elucidaed unambiguously by single-crystsl X-ray diffraction [28,29,30,31,32].

In order to explain the formation of these compounds, we proposed the mechanism presented in Scheme 4, based on previous work reported by Meinwald and co-workers [15]. The formation of the products can be explained by the transfer of the free electron pair from the epoxide oxygen to the orbital empty catalyst, which promoted the formation of two carbocations A and A′. The product 8 was obtained by the rearrangement of carbocation A via the opening of the C2–C3 bond and migration of C3 to C1. Moreover, the rearrangement of the carbocation A′ was carried out by the migration of C12 to C2 and led to the formation of product 9 (Scheme 4).

Scheme 4.
scheme 4

Proposed mechanism of epoxide-opening rearrangement using Lewis acid catalysts.

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In this work, we have described an efficient opening of epoxides 3a, 4a, 6a, and 7a semisynthesized from β-himachalene, the main component of Cedrus atlantica essential oil, using Lewis acid catalysts, into enantiomerically pure corresponding ketones in good yields and high selectivities.

The high catalytic activities and chemoselectivities in favor of carbonyl compounds can be achieved using Lewis acids, more particularly with BF3–OEt2, which gave the best result with different epoxides. However, using Bronsted acids led selectively to the formation of dehydration products. Further studies, including the biological activities of the ketones obtained, are currently in progress.

In summary, the epoxy himachalene scaffolds 3a, 4a, 6a, and 7a appear to be an interesting source of new chiral polycyclic structures, which can be valuable intermediates in the agrochemical and pharmaceutical industries.

EXPERIMENTAL

General. All operations were carried out in an inert atmosphere of nitrogen gas using technical standard check. Column chromatography was performed using 70–230 mesh silica gel. All reagents and solvents were obtained from commercial suppliers and used without further purification. All compounds were characterized by 1H and 13C NMR. All NMR spectral data were recorded at 25°C on DPX300 spectrometers with TMS as internal for 1H and 13C. Spectral assignments were made by means of routine one- and two-dimensional NMR experiments where appropriate. Melting points were taken on a Buchi 510 capillary apparatus. Mass spectra (MS) were recorded on GC/TOF using chemical ionization by desorption in methane.

General Procedure of Epoxidation. To a solution of compound 5a (500 mg, 1.33 mmol) in CH2Cl2 (20 mL) was added m-CPBA (241 mg, 2 mmol) portion wise at 0°C. The mixture was stirred at room temperature for 2 h. Then it was diluted with CH2Cl2 (20 mL) and washed twice with a solution of 10% NaHCO3 (20 mL). The organic phase was combined and washed twice with 20 mL of distilled water, dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by silica gel CC using n-hexane–EtOAc (98:2) as eluent.

For the gem-dihalogenocyclopropanation reaction procedure, see [9 and 23].

(1S,3R,8R,9S,10R)-2,2-Dibromo-9,10-epoxy-3,7,7,10-tetramethyltricyclo[6.4.0.01,3]dodecane (6a), white powder, mp 126–127°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.88, 0.89 (each 3H, s, H-15, 16), 1.04 (3H, s, H-14), 1.05–1.70 (10H, m, H-4, 5, 6, 11, 12), 1.14 (1H, d, J = 3.3, H-8), 1.20 (3H, s, H-13), 3.04 (1H, d, J = 3.3, H-9). 13C NMR (75 MHz, CDCl3, δ, ppm): 39.2 (C-1), 47.3 (C-2), 33.1 (C-3), 35.6 (C-4), 19.5 (C-5), 41.1 (C-6), 27.3 (C-7), 42.5 (C-8), 70.5 (C-9), 62.3 (C-10), 24.6 (C-11), 24.8 (C-12), 23.5 (C-13), 18.2 (C-14), 27.4 (C-15), 27.6 (C-16). MS m/z 391.8 [M]+.

(1S,3R,8R,9S,10R)-2,2-Dichloro-9,10-epoxy-3,7,7,10-tetramethyltricyclo[6.4.0.01,3]dodecane (7a), white powder, mp 136–137°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 1.05–1.71 (10H, m, H-4, 5, 6, 11, 12), 3.01 (1H, d, J = 3.3, H-9), 1.12 (1H, d, J = 3.3, H-8), 1.22 (3H, s, H-14), 1.35 (3H, s, H-13), 1.04, 1.09 (each 3H, s, H-15, H-16). 13C NMR (75 MHz, CDCl3, δ, ppm): 39.1 (C-1), 76.15 (C-2), 33.4 (C-3), 35.8 (C-4), 19.3 (C-5), 41.4 (C-6), 27.1 (C-7), 42.3 (C-8), 54.8 (C-9), 60.9 (C-10), 24.3 (C-11), 24.7 (C-12), 23.3 (C-13), 18.1 (C-14), 27.3 (C-15), 27.7 (C-16). MS m/z 303 [M]+.

General Procedure for the Rearrangement Reaction of Epoxide Derivatives. Epoxide (5 mmol) was dissolved in CH2Cl2 (10 mL) and stirred at room temperature under argon. Then 1% mmol of Lewis acid (or Bonsted acid) was added to the solution, and the reaction mixture was stirred and monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 10 mL of CH2Cl2 and washed using saturated aqueous solutions of NaHCO3 (10 mL). The organic layer was dried with sodium sulfate (Na2SO4), and the solvent was removed on a rotary evaporator. The reaction mixture was analyzed by gas chromatography and then purified using flash column chromatography.

Ring Opening of Epoxide with BF3–OEt2. BF3–OEt2 (0.2 mL) was added dropwise to a solution of epoxide (0.66 mol) in CH2Cl2 (20 ml) at –78°C under N2. The reaction mixture was stirred for 90 min at constant temperature and then left at room temperature for 24 h. Water (20 mL) was added in order to separate the two phases, and the organic phase was dried and concentrated. Silica-gel chromatography of the crude gave the ketone in a yield of 60%. Crystallization was carried out at room temperature from a hexane solution.

1-[(1S,6R,7S,9R)-8,8-Dibromo-5,5,9-trimethyltricyclo[5.4.0.07,9]undecan-1-yl]ethanone (8a), white powder, mp 74–76°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.85, 0.98 (each 3H, s, H-14, 15), 1.31–2.02 (10H, m, H-2, 3, 4, 10, 11), 1.44 (3H, s, H-16), 1.88 (1H, d, J = 3, H-6), 1.98 (1H, d, J = 3, H-7), 2.13 (3H, s, H-13). 13C NMR (75 MHz, CDCl3, δ, ppm): 52.8 (C-1), 35.5 (C-2), 16.5 (C-3), 44.7 (C-4), 29.4 (C-5), 62.2 (C-6), 36.7 (C-7), 49.0 (C-8), 35.1 (C-9), 29.4 (C-10), 25.5 (C-11), 212.7 (C-12), 25.0 (C-13), 18.1 (C-14), 19.2 (C-15), 17.0 (C-16). MS m/z 392 [M]+.

1-[(1S,6R,7S,9R)-8,8-Dichloro-5,5,9-trimethyltricyclo[5.4.0.07,9]undecan-1-yl]ethanone (8b), white powder, mp 54–56°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.85, 0.98 (each 3H, s, H-14, 15), 1.31–2.02 (10H, m, H-2, 3, 4, 10, 11), 1.40 (3H, s, H-16), 1.85 (1H, d, J = 3, H-6), 1.97 (1H, d, J = 3, H-7), 2.12 (3H, s, H-13). 13C NMR (75 MHz, CDCl3, δ, ppm): 49.0 (C-1), 35.1 (C-2), 18.5 (C-3), 44.7 (C-4), 29.4 (C-5), 52.8 (C-6), 36.7 (C-7), 72.3 (C-8), 35.5 (C-9), 29.4 (C-10), 25.7 (C-11), 212.7 (C-12), 25.0 (C-13), 18.2 (C-14), 19.1 (C-15), 17.4 (C-16). MS m/z 302 [M]+.

(1R,4R,6S,7R)-5,5-Dibromo-1,4,8,8-tetramethyltricyclo[5.4.11,7.04,6]dodecan-12-one (9a), white powder, mp 79–80°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.90, 1.1 (each 3H, s, H-15, 16), 1.23–1.81 (10H, m, H-2, 3, 9, 10, 11), 1.38 (3H, s, H-14), 1.44 (3H, s, H-13), 1.80 (1H, d, J = 13, H-6), 2.10 (1H, d, J = 13, H-7). 13C NMR (75 MHz, CDCl3, δ, ppm): 46.9 (C-1), 26.2 (C-2), 37.3 (C-3), 30.1 (C-4), 43.9 (C-5), 35.4 (C-6), 51.8 (C-7), 30.0 (C-8), 48.1 (C-9), 20.2 (C-10), 36.2 (C-11), 219.1 (C-12), 19.0 (C-13), 17.5 (C-14), 22.3 (C-15), 21.9 (C-16). MS m/z 392 [M]+.

(1R,4R,6S,7R)-5,5-Dichloro-1,4,8,8-tetramethyltricyclo[5.4.11,7.04,6]dodecan-12-one(9b), white powder, mp 61–62°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.91, 1.12 (each 3H, s, H-15, 16), 1.14 (3H, s, H-14), 1.21–1.83 (10H, m, H-2, 3, 9, 10, 11), 1.42 (3H, s, H-13), 1.7 (1H, d, J = 13, H-6), 2.20 (1H, d, J = 13, H-7). 13C NMR (75 MHz, CDCl3, δ, ppm): 46.7 (C-1), 26.3 (C-2), 37.1 (C-3), 30.3 (C-4), 43.7 (C-5), 35.1 (C-6), 51.6 (C-7), 29.8 (C-8), 48.3 (C-9), 20.4 (C-10), 36.1 (C-11), 215.5 (C-12), 19.2 (C-13), 17.3 (C-14), 22.1 (C-15), 21.8 (C-16). MS m/z 303.25 [M]+.

(7R,8S,10R)-9,9-Dibromo-2,6,6,10-tetramethyltricyclo[5.5.0.02,4]dodeca-1,2-diene (10a), white powder, mp 121–122°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.82, 1.05 (each 3H, s, H-14, 15), 0.97–1.36 (6H, m, H-4, 5, 11), 1.04 (3H, s, H-13), 1.05 (1H, d, J = 3, H-8), 1.91 (1H, d, J = 3, H-7), 2.01 (3H, s, H-16), 5.5 (2H, m, H-3, 12). 13C NMR (75 MHz, CDCl3, δ, ppm): 137.06 (C-1), 137.3 (C-2), 124.62 (C-3), 45.55 (C-4), 29.61 (C-5), 42.7 (C-6), 50.5 (C-7), 36.52 (C-8), 60.05 (C-9), 45.55 (C-10), 35.01 (C-11), 127.38 (C-12), 27.86 (C-13), 28.46 (C-14), 23.52 (C-15), 24.47 (C-16). MS m/z 374 [M]+.

(7R,8S,10R)-9,9-Dichloro-2,6,6,10-tetramethyltricyclo[5.5.0.02,4]dodeca-1,2-diene (10b), white powder, mp 101–103°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.82, 1.06 (each 3H, s, H-14, 15), 0.96–1.37 (6H, m, H-4, 5, 11), 1.04 (1H, d, J = 3, H-8), 1.05 (3H, s, H-13), 1.90 (1H, d, J = 3, H-7), 2.01 (3H, s, H-16), 5.40 (2H, m, H-3, 12). 13C NMR (75 MHz, CDCl3, δ, ppm): 135.07 (C-1), 136.8 (C-2), 124.64 (C-3), 45.55 (C-4), 29.42 (C-5), 42.70 (C-6), 50.06 (C-7), 35.01 (C-8), 73.5 (C-9), 45.57 (C-10), 36.52 (C-11), 126.9 (C-12), 27.86 (C-13), 28.32 (C-14), 23.52 (C-15), 24.47 (C-16). MS m/z 284 [M]+.

(1S,3R,8R,10R)-2,2-Dibromo-3,7,7,10-tetramethyltricyclo[6.4.0.01,3]dodecan-9-one (11a), white powder, mp 91–93°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 0.92 (3H, d, J = 3, H-16), 1.09 (6H, s, H-14, 15), 1.10 (3H, d, J = 12, H-13), 1.22–2.10 (10H, m, H-4, 5, 6, 11, 12), 2.30–2.40 (1H, m, H-10), 2.40 (1H, s, H-8). 13C NMR (75 MHz, CDCl3, δ, ppm): 45.88 (C-1), 59.06 (C-2), 34.95 (C-3), 35.98 (C-4), 16.16 (C-5), 45.93 (C-6), 31.68 (C-7), 75.86 (C-8), 209.11 (C-9), 46.50 (C-10), 29.93 (C-11), 33.01 (C-12), 20.74 (C-13, 14), 21.40 (C-14, 15), 27.01 (C-15), 15.95 (C-16, 13). MS m/z 392 [M]+.

(1S,3R,8R,10R)-2,2-Dichloro-3,7,7,10-tetramethyltricyclo[6.4.0.01,3]dodecan-9-one (11b), white powder, mp 89–90°C. 1H NMR (300 MHz, CDCl3, δ, ppm, J/Hz): 1.09 (3H, d, J = 3, H-16), 1.10 (3H, d, J = 12, H-13), 1.22 (6H, s, H-14, 15), 1.56–2.20 (10H, m, H-4, 5, 6, 11, 12), 2.45 (1H, m, H-10), 2.65 (1H, s, H-8). 13C NMR (75 MHz, CDCl3, δ, ppm): 34.8 (C-1), 76.9 (C-2), 32.1 (C-3), 31.0 (C-4), 25.2 (C-5), 43.8 (C-6), 28.8 (C-7), 45.0 (C-8), 213.0 (C-9), 38.3 (C-10), 27.2 (C-11), 25.2 (C-12), 15.4 (C-13), 26.4 (C-14), 26.2 (C-15), 20.5 (C-16). MS m/z 302 [M]+.