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Abstract

Three efficient, general approaches were investigated for the total synthesis of cis-(3,3-dimethylcyclopropane-1,2-diyl)dimethanol (cis-DMCP) (6) from the readily available natural product (+)-3-carene (1). (−)-3-Carene-2,5-dione(2), a strategic intermediate for accessing cis-DMCP, was first afforded via selective allylic oxidation of this starting material with aluminium oxide-supported cobalt phthalocyanine (CoPc/Al₂O₃) as a catalyst. This protocol provides synthetic routes to dimethylcyclopropane derivatives.

Keywords

(+)-3-carene (−)-3-carene-2,5-dione dimethylcyclopropane

Introduction

Dimethylcyclopropane is an important and interesting organic moiety that has unexpectedly been found in many natural and non-natural bioactive molecules and exhibits robust biological activity.¹ 3-Carene, a natural bicyclic monoterpene, occurs coniferous oleoresins and aromatic essential oils.^2,3 This starting material has been reported to have pluripotent biological effects, notably as an antimicrobial,^4–6 antioxidant,^5–8 anticancer,^9,10 semiochemical,^11,12 and fumigant properties.^13,14

(+)-3-Carene is particularly interesting because of reactivity originates from two electron-rich sites: the olefinic C=C linkage and the strained gem-dimethylcyclopropane scaffold. Therefore, (+)-3-Carene has been used a dimethylcyclopropane source for the synthesis of many drugs,^15–18 such as (+)-ingenol,¹⁹ 2,2-dimethyl-1,3-disubstitutedcyclopropane,²⁰ Δ-9-tetrahydrocannabinol,²¹ a 5-lipoxygenase-activating protein (FLAP) modulator,²² the first seco-casbane diterpene (EBC-329) (Figure 1),²³ boceprevir (Figure 2),²⁴ the sex pheromone of the Madeira mealybug (Figure 3),²⁵ and tefluthrin (Figure 4).²⁶ Therefore, in this work, we develop the synthesis of cis-DMCP(6), a pivotal intermediate in the preparation of the target molecules, potentially providing a new avenue for studies on the synthesis of dimethylcyclopropane derivatives.

Figure 1.

Structure of EBC-329.

Figure 2.

Structure of boceprevir.

Figure 3.

Structure of the madeira mealybug sex pheromone.

Figure 4.

The structure of tefluthrin.

Results and discussion

In this study, three efficient, general approaches were investigated for the total synthesis of cis-DMCP (6) (Scheme 1) from the readily available natural product (+)-3-carene (1). The crucial step in the synthetic strategy is the functionalization at C9/C10 of (+)-3-carene (1) with the new catalyst aluminium ioxide-supported cobalt phthalocyanine (CoPc/Al₂O₃) under O₂ atmosphere with tert-butyl hydroperoxide (TBHP) to yield compound 2, although the synthesis of this compound with CuCl₂/activated carbon (CuCl₂/AC) as a catalyst has been previously reported.²⁷ Single-factor exploratory analysis (Figures 5 –8) was applied to determine the optimal parameters, which are as follows: mass ratios of CoPc/Al₂O₃, TBHP, and dichloroethane (DCE) and (+)3-carene of 7.5:1.5: 5% and a reaction temperature of 65°C. Under above conditions, the yield of compound 2 reached 64%.

Figure 5.

Influence of the reaction temperature.

Figure 6.

Influence of reaction time.

Figure 7.

Catalyst loading-dependent reaction yield.

Figure 8.

Influence of the amount of TBHP product yield.

The synthesis of compound 3 was attempted by the direct oxidation of compound 2 using silica-supported potassium permanganate (KMnO₄/SiO₂) or unsupported KMnO₄ as the catalyst. As shown in Table 1, we observed that unsupported KMnO₄ is suitable for use as an oxidant because it produces the desired product in higher yield under intense conditions, with high purity. The optimal conditions are: molar ratio of KMnO₄ to compound 2, reaction temperature of 50°C, and acetic acid-to-water volume ratio of 20:1. Under efficient conditions, the conversion of compound 2 reached 80%.

Table 1.

Influence of KMnO₄ and KMnO₄/SiO_2..

No.	Oxidant	Yield (%)
1	KMnO₄/SiO₂	35
2	KMnO₄	80

In this study, three approaches to synthesize the target product 6 from compound 3 are reported.

In the synthetic route, cis-3,3-dimethylcyclopropane-1,2-dicarboxylic acid (3) is converted into cis-3,3-dimethylcyclopropane-1,2-diethyl ester (4) by esterification and then reduced to cis-DMCP (6) (Scheme 2).

Scheme 1.

Synthesis of (3,3-dimethylcyclopropane-1,2-diyl) dimethanol.

Scheme 2.

Synthesis of cis-DMCP.

In this synthetic route, compound 4 is first synthesized from compound 3 in ethanol using ferric chloride (FeCl₃) as a catalyst and cyclohexane as an azeotropic water carrying agent. Then, lithium aluminium hydride (LiAlH₄) reduction of compound 4 produced diol 6 in 95% yield. In the first step, ferric chloride is better than general acid catalysts for the synthesis of shorter fatty acid esters with commercially available raw materials owing to its high esterification reactivity, convenient operation, mild reaction conditions, and reduced erosion. In addition, we used cyclohexane instead of the toxic reagents benzene. For the second step, single-factor exploratory analysis identified the optimal molar ratio of compound 4 to LiAlH₄ was 1:6. If this ratio is higher or lower, then the yield decreases.

In the second synthetic route: cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (5) was synthesized from compound 3 by dehydration with acetic anhydride and then reduction to cis-DMCP 6 (Scheme 3).

Scheme 3.

Synthesis of cis-DMCP.

We used acetic anhydride as the dehydrating agent and compound 3 as the raw material to prepare compound 5 in 80% yield. Then, LiAlH₄ reduction of compound 5 produced diol 6 in 80% yield. Single-factor exploratory analysis revealed that the optimal molar ratio of compound 5 to LiAlH₄ was 0.45:1, and increasing or decreasing this ratio led to decreased yields.

In the synthetic route, compound 3 was directly reduced with LiAlH₄ to produce target compound 6 in 40% yield (Scheme 4).

Scheme 4.

Synthesis of cis- DMCP.

The direct reduction of diacid 3 to diol 6 has not yet been reported. In addition, this reaction proceeded under strict anhydrous conditions. However, this reaction can be further optimized.

Experimental section

Unless explicitly purified, commercial starting materials and commercial reagents were employed without further purification. Powdered activated carbon (AR), (+)-3-carene (1) (RG), tetrahydrofuran (THF), and diethyl ether (Et₂O) were performed via Na/benzophenone. Flash chromatography used 200–300 mesh silica gel (FCC (SiO₂, 200–300 mesh). The 1H and 13C nuclear magnetic resonance (NMR) spectra were acquired on a Bruker Avance 500 MHz spectrometer. NMR data (δ, multiplicity): s, d, t, q, m. FT-IR spectra were acquired on an Shimadzu Japan Affinity-1 spectrometer. High-resolution mass spectra (HRMS) were acquired spectrometer (Bruker solari X 70 FT-MS) using ESI ionization.

CoPc/Al₂O₃ was prepared according to previous methods.²⁸ CoCl₂·6H₂O (7.14 g, 0.03 mol) was delivered to a stirred suspension of Al₂O₃ (50 g, 0.49 mol) in ethanol. The mixture was macerated for 24 h at room temperature (rt), filtered and dried before being placed in a muffle furnace at 300°C for 4 h and then cooled to rt. Maceration was then repeated as described above CoCl₂·6H₂O, o-phthalic anhydride, and urea were mixed at a molar ratio of 0.25:1:25, with a final mass percentage of ammonium molybdate of 1%. The samples were then ground, mixed well and melted to yield a thick, purple–black, which was placed in a high-temperature muffle furnace set to 240°C for 4 h. The crude CoPc/Al₂O₃ was washed repeatedly with water, ethanol, and acetone.

Synthesis of compound 2

CoPc/Al₂O₃ (0.15 g) and TBTP (3.00 g) were added to (+)-3-carene (1) (2.00 g, 15.00 mmol) solubilized in DCE (10 mL). The reaction mixture was heated at 60°C under oxygen flow rate of 20~30 mL/min with stirring for 24 h. After full conversion, the residual solid catalyst was removed from the solution by filtering, and the filtrate was dehydrated using anhydrous Na₂SO₄, followed by solvent evaporation under vacuum. Purification by FCC(SiO₂, EtOAc/pet. ether = 1: 20) afforded (−)-3-carene-2,5-dione (2) as pale yellow needle-like crystals (1.54 g, 9.50 mmol, 64%). [α]²³_{D ^-1} = −9.4 (c= 0.31, EtOH); Mp 101–102°C; IR (KBr): v 3037 (=CH), 1670 (C=O) cm; ¹HNMR (CDCl₃, 500 MHz): δ 6.50 (s, 1H, =CH), 2.32-2.35 (m, 2H, >CH-CH<), 1.97 (s, 3H, CH₃), 1.33 (s, 3H, CH₃), 1.32 (s, 3H, CH₃); ¹³CNMR (125 MHz, CDCl₃): δ 194.4, 194.3, 150.0, 137.6, 39.8, 39.0 (CH), 33.4(CH₃), 29.1 (CH₃), 16.14 (C), 15.40 (CH₃); HRMS (ESI) for C₁₀H₁₂O₂Na [M+Na] calcd 187.0737; found: 187.0730.

Synthesis of compound 3

(−)-3-Carene-2,5-dione (2) (2.00 g, 12.18 mmol) was introduced to a mixture of acetic acid (60 mL) and water (3 mL). Then KMnO₄ (9.64 g, 61.01 mmol) was introduced to the mixture in portions over 0.5 h at 50°C and stirring was maintained for 3 h. After full conversion, saturated aqueous sodium carbonate solution (Na₂CO₃) (400 mL) was infused dropwise until the pH of the solution was reached 8–9. The manganese salts were removed by filtration, and the filtrate was subsequently washed three times with EtOAc (3 × 300 mL). The aqueous phase was acidified with 6 N HCl (100 mL) until pH was lowered to 2–3, and then the aqueous phase was extracted three times with EtOAc (3 × 300 mL). The organic phase was dried over MgSO₄, followed by solvent evaporation under vacuum to provide the crude product compound 3 as a white solid (1.54 g, 9.74 mmol, 80%). Mp 167–173°C, IR (KBr) v: 3188 (O-H), 1720(C=O) cm^-1; ¹HNMR (DMSO, 500 MHz): δ 12.13 (br, s, 2H), 1.83 (s, 2H), 1.29 (s, 3H), 1.12 (s, 3H); ¹³CNMR (125 MHz, DMSO): δ 171.0, 31.9 (CH), 27.8 (C), 25.3(CH₃), 16.0 (CH₃); HRMS (ESI) for C₇H₁₀O₄Na [M+Na] calcd 181.0777; found: 181.0470.

Synthesis of compound 4

Ferric chloride (0.12 g, 0.70 mmol) and ethanol (1.00 g, 21.71 mmol) were charged to a solution of compound 3 (1.00 g, 6.32 mmol) in cyclohexane(CYH) (30 mL) and the suspension was heated to reflux at 65 °C for 2.5 h. Then the solution was washed successively with water (10 mL), 15 wt% aqueous sodium hydrogen carbonate (NaHCO₃) (15 mL) and sodium chloride brine (10 mL). The organic phase was then dried over anhydrous Na₂SO₄, followed by solvent evaporation under vacuum to afford a faint-yellow mobile oil (0.95 g, 4.43 mmol, 70%), which was pure enough to be used in the next step. IR (KBr): v 1739 (C=O), 1159(C-O-C) cm-1; 1HNMR (500 MHz, CDCl₃): δ 4.12 (q, 4H, J=7.0), 1.84 (s, 2H), 1.40 (s, 3H), 1.23 (t, 6H, J=7.0), 1.20 (s, 3H, CH₃); ¹³CNMR (125 MHz, CDCl₃): δ 169.00, 60.4, 32.0, 28.0, 25.7, 15.4, 14.1; HRMS (ESI) for C₁₁H₁₈O₄Na [M+Na] calcd 237.1103; found: 237.1099.

Synthesis of compound 5

In a 50 mL reaction vessel assembled with a reflux apparatus and desiccant tube, compound 3 (0.50 g, 3.16 mmol) and redistilled acetic anhydride (0.53 g, 5.19 mmol) were added. The mixture was mixed gently in an oil bath with a magnetic stirrer until a clear solution was obtained, after which the reaction was refluxed at 140 °C for 3 h. The complete assembly was removed from the oil bath, followed by solvent evaporation under vacuum, giving the compound 5 as white crystals (0.35 g, 2.53 mmol, 80%). Mp 53–59°C; IR (KBr): v 1847 (C=O), 1775 (C-O-C) cm^-1; ¹HNMR (500 MHz, CDCl₃): δ 2.66 (s, 2H); 1.43 (s, 3H); 1.33 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 167.2, 34.9, 32.7, 25.4, 16.8.

Synthesis of compound 6 (一)

Compound 4 (0.50 g, 2.33 mmol) dissolved in anhydrous ether (10 mL) was dripped slowly into an ice-cold stirred suspension of LiAlH₄ (0.53 g, 13.99 mmol) in anhydrous ether (20 mL) under N₂. The reaction liquid was heated to reflux at 35°C for 3 h. With the reaction complete, the reaction mixture was cooled to 0°C, quenched dropwise with water (1 × 0.53 mL) and 15 wt% aqueous NaOH (3 × 0.53 mL) after which water (1 × 0.53 mL) was added to minimize exotherm. The gelatinous precipitate was filtered off, and washed with dichloromethane (DCM) (50 mL). The filtrate was dehydrated with anhydrous Na₂SO₄, followed by solvent evaporation under vacuum to obtain the compound 6. Purification by FCC(SiO₂, EtOAc/pet. ether = 4: 1) afforded compound 6 (0.29 g, 2.21 mmol, 95%).

Synthesis of compound 6 (二)

Compound 5 (1.00 g, 7.12 mml) dissolved in anhydrous THF (20 mL) was dripped slowly into a ice-cold vigorously stirred LiAlH₄ (0.60 g, 15.70 mmol) suspension in anhydrous THF (20 mL) under N₂. The reaction liquid was warmed to rt and agitated for 30 min. When the reaction had finished, the liquid was cooled to 0°C and cautiously quenched dropwise with water(1 × 0.6 mL) and 15 wt% aqueous NaOH (3 × 0.6 mL), after which water (1 × 0.6 mL) was introduced cautiously. The gelatinous precipitate was filtered off, and washed with DCM (20 mL). Water adsorption by anhydrous Na₂SO₄, followed by solvent evaporation under vacuum to provide the crude product. Purification by FCC(SiO₂, EtOAc/pet. ether = 4: 1) afforded compound 6 (0.74 g, 7.14 mmol, 80%).

Synthesis of compound 6 (三)

Compound 3 (2.00 g, 12.64 mmol) dissolved in anhydrous THF (30 mL) was dripped slowly to a ice-cold s vigorously stirred LiAlH₄ (2.80 g, 73.77 mmol) suspension in anhydrous THF (30 mL) over 4 h under N₂. The mixture was maintained at reflux (68°C) for 4 h. After full conversion, the reaction was cooled to 0°C and cautiously quenched dropwise of water (1 × 2.8 mL), 15% aqueous NaOH (3 × 2.8 mL) and then a single aliquot of water (1 × 2.8 mL) was carefully introduced. Gelatinous precipitate was filtered off, and DCM-washed (40 mL). The filtrate was desiccated over anhydrous Na₂SO₄, and followed by solvent evaporation Purification by FCC(SiO₂, EtOAc/pet.ether=4:1) afforded compound 6 as a colourless oil (0.66 g, 5.05 mmol, 40%). IR (KBr): v 3345 (OH), 1008 (C-O) cm^-1; ¹HNMR (500 MHz, CDCl₃): δ 3.91-3.94 (m, 2H), 3.68 (br, s, 2H), 3.40–3.50 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 1.02–1.05 (m, 2H); ¹³CNMR (125 MHz, CDCl₃): δ 59.1, 28.9, 28.8, 19.7, 15.2. MS m/z, (%): 82 (100), 81 (85.07), 43 (47.59), 67 (43.96), 79 (38.89), 41(38.59), 71 (36.64), 55 (34.19); HRMS (ESI) for C₁₄H₂₈O₄Na [2M+Na] calcd 283.1886; found: 283.1886.

Conclusion

In summary, we presented efficient synthetic route for the synthesis of cis-(3,3-dimethylcyclopropane-1,2-diyl)dimethanol from 3-carene. The key synthetic step is the selective allylic oxidation of (+)-3-carene using CoPc/Al₂O₃ as the catalyst. In addition, three approaches to synthesize target product 6 from compound 3 have been reported. This strategy could be further extended to the synthesis of dimethylcyclopropane derivatives.

Footnotes

ORCID iD

Xiaonian Ji

Ethical considerations

This study required no ethical approval as it involved neither human participants nor animal subjects.

Consent to participate

This study did not involve human or animal subjects, and no consent to participate was required.

Consent for publication

All participants provided consent for the publication of their data in this journal.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data used to support the findings of this study are included within the article.

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