(1R,2R,6S)-2(4-(4-Isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol

Alexandra V. Podturkina; Nikolai S. Li-Zhulanov; Konstantin P. Volcho; Nariman F. Salakhutdinov

doi:10.3390/M1546

,

and

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Avenue 9, 630090 Novosibirsk, Russia

^*

Author to whom correspondence should be addressed.

Molbank2023, 2023(1), M1546;https://doi.org/10.3390/M1546

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly characterized by movement dysfunction. Earlier, it was found that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremin) demonstrated antiparkinsonian activity in vivo on different animal models of PD. The paper presents synthesis of new Prottremin derivative, (1R,2R,6S)-2(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol. The derivative was obtained by epoxide ring opening reaction with 1-(4-isopropylbenzyl)piperazine. The product yield was 48% after purification.

Keywords:

monoterpene; epoxide cycle opening; tertiary amine

1. Introduction

Parkinson’s disease (PD) is one of the most common age-related movement disorders characterized by progressive death of nigrostriatal dopamine neurons, which leads to classical symptoms of PD including tremors, rigidity, and bradykinesia. [1]. Currently, therapy against PD is aimed at relieving symptoms for a long time. Levodopa, a direct metabolic precursor of dopamine, is the gold standard of PD treatment. Unfortunately, the drug is most effective only in the first few years of administration. Additionally, the “on-off” syndrome has been found in patients with PD taking Levodopa. During the “off” period the symptoms of PD return [2].

Earlier, it was demonstrated that Prottremin ((1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol) possessed potent antiparkinsonian activity in vivo on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), rotenone, 6-hydroxydopamine (6-OHDA), and haloperidol models of PD on mice and rats at a dose of 20 mg/kg [3,4]. Further investigations showed that change in Prottremin configuration or removal of one of its functional groups (double bonds or alcohol groups) diminishes or decreases activity [3,5]. However, the addition of thiopropyl and butyl fragment to the Prottremin molecule at position 9 allows one to obtain compounds 2 and 3 with high antiparkinsonian activity [6]. In addition, epoxydiol 4, an active metabolite of Prottremin, was synthesized. It was shown that epoxydiol 4 protected cultured dopamine neurons [7]. Recently, it was found that Prottremin derivative PA96 alleviated symptoms of haloperidol-induced PD model at dose 1 mg/kg (active dose of Prottremin is 20 mg/kg) and protected cultured dopamine neurons against spontaneous and toxin-induced death of dopamine neurons [8]. Thus, the synthesis of new derivatives and analogues of Prottremin is an important task. Here, the synthesis of new derivative of Prottremin, (1R,2R,6S)-2-(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-en-1-ol 1, is presented (Figure 1).

Figure 1. Prottremin and its derivatives.

2. Results and Discussion

The synthesis of (1R,2R,6S)-2-(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-en-1-ol 1 began with the preparation of Prottremin according to the method [3] from (−)-verbenone. The total yield of Prottremin over three stages was 23%. Thereafter, the reaction of Prottremin with acetic anhydride gave diacetate 5 [9]. After purification, diacetate 5 was refluxed with sodium tert-butoxide in toluene for 2 h affording the epoxide 6 at a 78% yield [8] (Scheme 1).

Scheme 1. Synthesis of (1S,5S,6R)-2-methyl-5-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]hept-2-ene 6.

1-(4-Isopropylbenzyl)piperazine 9 was used for the modification of Prottremin and prepared according to [10]. This molecule contains fragments of monoterpene p-cymene demonstrating various pharmacological properties [11]. Piperazine is a versatile linker and pharmacophore for the construction of biologically active compounds [12]. At the first stage, 4-isopropylbenzaldehyde 8 reacted with tert-butyl piperazine-1-carboxylate 7 and 30 min sodium triacetoxyborohydride was added. After the work up of the reaction mixture, organic residue was involved in the reaction with trifluoroacetic acid for Boc-deprotection. The yield of product 9 was 98% (Scheme 2).

Scheme 2. Synthesis of 1-(4-isopropylbenzyl)piperazine 9.

Reaction of epoxide 6 with 1-(4-isopropylbenzyl)piperazine 9 in the presence of potassium carbonate was carried out in ethanol. The reaction mixture was refluxed for 8 h. After purification by column chromatography on SiO₂, compound 1 was isolated with 48% yield (Scheme 3).

Scheme 3. Synthesis of (1R,2R,6S)-2-(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-en-1-ol 1.

3. Materials and Methods

3.1. General

All reagents and solvents are commercially available and used as supplied. Spectral and analytical measurements were obtained at the Multi-Access Chemical Research Center SB RAS (Novosibirsk, Russia). Column chromatography (CC): silica gel (SiO₂; 60–200 μ; Macherey-Nagel); hexane/EtOAc 100:0 → 0:100 and MeOH/CH₂Cl₂ (1:1). GC/MS (purity control and products analysis): Agilent 7890A (Agilent Technologies, Santa Clara, CA, USA) with a quadrupole mass spectrometer Agilent 5975C as a detector, HP-5MS quartz column, 30,000 × 0.25 mm, He (1 atm) as carrier gas. Optical rotation: polAAr 3005 spectrometer (Optical Activity LTD, Huntingdon, UK), CHCl₃ soln. HR-MS: DFS-Thermo-Scientific spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) in a full scan mode (15–500 m/z, 70 eV electron-impact ionization, direct sample introduction) and Agilent 7200 Accurate Mass Q-TOF GC/MS (Agilent Technologies, Santa Clara, CA, USA) (70 eV, electron-impact ionization).¹H- and ¹³C-NMR: Bruker Avance-III 600 (Bruker Corporation, Karlsruhe, Germany) apparatus at 600.30 MHz (¹H) and 150.95 MHz (¹³C) and Bruker Avance 400 (Bruker Corporation, Karlsruhe, Germany) apparatus 400.13 MHz (¹H) and 100.61 MHz (¹³C) in CDCl₃; chemical shifts δ in ppm rel. to residual CHCl₃ (δ (H) 7.24, δ (C) 76.90 ppm), J in Hz. Structure determinations: by analyzing the ¹H NMR spectra, including ¹H-¹H 2D homonuclear correlation (COSY); J-modulated ¹³C NMR spectra (JMOD), and ¹³C-¹H 2D heteronuclear correlation with one-bond and long-range spin-spin coupling constants (C-H COSY, ¹J(C,H) = 135 Hz; HSQC, ¹J(C,H) = 145 Hz; HMBC, ^2,3J(C,H) = 7 Hz). All the target compounds reported in this paper have a purity of at least 95%. Prottremin was synthesized according to [3] from (−)-verbenone (Aldrich).

(1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diacetate 5 was synthesized according to [9]. (1S,5S,6R)-2-Methyl-5-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]hept-2-ene 6 was synthesized from diacetate 5 according to [8].

3.2. Synthesis of 1-(4-Isopropylbenzyl)piperazine 9

4-Isopropylbenzaldehyde 8 (1.0 g, 6.75 mmol, 1 eq.) was added to the solution of tert-butyl piperazine-1-carboxylate 7 (1.26 g, 6.75 mmol, 1 eq.) in CH₂Cl₂ (50 mL). The reaction mixture was stirred for 30 min, and NaBH(AcO)₃ (2.0 g, 9.45 mmol) was added in small portions. After 1 h the reaction mixture was washed with a saturated solution of NaHCO₃ (3 × 20 mL). The organic layer was dried over Na₂SO₄. The desiccant was filtered off, the solvent was distilled off, the residue was dissolved in CH₂Cl₂ (10 mL), and TFA (3 mL) was added dropwise. The reaction mixture was stirred for 2 h, then washed with a saturated solution of K₂CO₃ (3 × 20 mL). The organic layer was dried over Na₂SO₄. The desiccant was filtered off, and the solvent was distilled off. The residue was purified by column chromatography on SiO₂ with CH₂Cl₂/MeOH (50%) as eluent, and the product (1.4 g, 98%) was obtained as slightly yellow oil. ¹H and ¹³C spectra are consistent with the previous results [10]. HR-MS: 218.1777 ([M⁺], C₁₄H₂₂N₂; calcd 218.1778).

3.3. Synthesis of (1R,2R,6S)-2-(4-(4-Isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-en-1-ol 1

Et₃N (125 mg, 1.24 mmol, 1 eq.) was added to the solution of epoxide 6 (186 mg, 1.24 mmol, 1 eq.) and 1-(4-isopropylbenzyl)piperazine 9 (297 mg, 1.36 mmol, 1.1 eq.) in EtOH (10 mL). The reaction mixture was refluxed for 8 h, and then the solvent was evaporated, and the residue was diluted with EtOAc (10 mL) and washed with brine (3 × 10 mL). The organic layer was dried over Na₂SO₄. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by column chromatography on SiO₂ with EtOAc/hexane gradient (0–100%). The compound 1 (222 mg, 48%) was obtained as a slightly yellow oil.

{[α]}_{D}^{26}

= −27.7 (c 0.39, CHCl₃). ¹H-NMR (CDCl₃, δ_H, ppm, J, Hz): 1.22 (s, 3H, H-23 or H-24), 1.23 (s, 3H, H-23 or H-24), 1.53–1.62 (m, 1H, OH), 1.72 (s, 3H, H-10), 1.82 (s, 3H, H-9), 1.91 (ddm, J = 16.7, 4.6, 1H, H_e-5), 2.10–2.21 (m, 1H, H_a-5), 2.25 (dd, J = 11.3, 4.4, H-6), 2.41 (br. s, 4H, H-12, H-14), 2.53–2.63 (m, 2H, H-11 or H-13), 2.71–2.80 (m, 2H, H-11 or H-13), 2.87 (sept, 1H, H-22), 2.96 (br. s, 1H, H-2), 3.45 (s, 2H, H-15), 4.08 (br. s, 1H, H-1), 4.80 (br. s, 1H, H-8), 4.94 (br. s, 1H, H-8), 5.63–5.68 (m, 1H, H-4), 7.15 (d, J = 8.0, 2H, H-18, H-20), 7.21 (d, J = 8.0, 2H, H-17, H-21). ¹³C-NMR (CDCl₃, δ_C, ppm): 147.42 (s; C-16), 145.99 (s; C-7), 135.23 (s; C-19), 131.15 (s; C-3), 129.11 (d; C-17, C-21), 126.04 (d; C-18, C-20), 124.78 (d; C-4), 110.97 (t; C-9), 67.85 (d; C-2), 64.97 (d; C-1), 62.86 (t; C-15), 54.03 (t; C-12, C-14), 49.10 (t; C-11, C-13), 42.62 (s; C-6), 33.60 (d; C-22), 23.88 (t; C-5), 23.88 (q; C-23, C-24), 22.85 (q; C-8), 21.85 (q; C-10). HR-MS: 368.2826 ([M⁺], C₂₄H₃₆N₂O; calcd 368.2822).

¹H-NMR, ¹³C-NMR, 2D correlation spectra ¹H-¹H (COSY), ¹H-¹³C (HSQC, HMBC), and mass spectra of compound 1 are presented in Supplementary Materials.

4. Conclusions

The method for preparation of Prottremin derivative with aryl-piperazine substituent at C-2 position was developed. According to this method, (1R,2R,6S)-2-(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-en-1-ol 1 was synthesized in 48% yield. Its structure was determined by 1D and 2D NMR experiments (HSQC, HMBC, COSY) and HRMS.

Supplementary Materials

The following supporting information can be downloaded online: Figure S1: ¹H NMR spectra of compound 1 (CDCl₃, 400 MHz); Figure S2. ¹³C NMR spectrum of compound 1 (CDCl₃, 100 MHz); Figure S3. ¹³C NMR spectrum (JMOD) of compound 1 (CDCl₃, 100 MHz); Figure S4. HSQC spectrum of compound 1 (CDCl₃, ¹H(400 MHz), ¹³C(100 MHz)); Figure S5. An expanded view of HSQC spectrum of compound 1 (CDCl₃, ¹H(400 MHz), ¹³C(100 MHz)); Figure S6. COSY spectrum of compound 1 (CDCl₃, 400 MHz); Figure S7. HMBC spectrum of compound 1 (CDCl₃, ¹H(400 MHz), ¹³C(100 MHz)); Figure S8. Mass-spectrum of compound 1; Figure S9. ¹H NMR spectra of compound 6 (CDCl₃, 600 MHz). (*-residual solvent); Figure S10. ¹³C NMR spectrum (JMOD) of compound 6 (CDCl₃, 150 MHz). (*-residual solvent) Figure S11. HSQC spectrum of compound 6 (CDCl₃, ¹H(600 MHz), ¹³C(150 MHz)); Figure S12. HMBS spectrum of compound 6 (CDCl₃, ¹H(600 MHz), ¹³C(150 MHz)); Figure S13. COSY spectrum of compound 6 (CDCl₃, 600 MHz); Figure S14. Mass-spectrum of compound 6.

Author Contributions

Conceptualization: A.V.P., N.S.L.-Z., K.P.V. and N.F.S.; investigation: A.V.P. and N.S.L.-Z.; writing—original draft preparation: A.V.P. and N.S.L.-Z.; writing—review and editing: K.P.V. and N.F.S. All authors have read and agreed to the published version of the manuscript.

Funding

Russian state-funded project for NIOCh SB RAS (number 1021051703312-0-1.4.1).

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

The authors would like to acknowledge the Multi-Access Chemical Service Centre SB RAS for spectral and analytical measurements.

Conflicts of Interest

The authors declare no conflict of interest.

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