5-(6-Hydroxy-6-methyl-5-oxoheptan-2-yl)-2-methyl Phenyl Acetate

Abstract

We synthesized a novel compound, 5-(6-hydroxy-6-methyl-5-oxoheptan-2-yl)-2-methylphenyl acetate, in a good yield by oxidation of 1-O-acetyl-xanthorrizol using potassium permanganate in acidic condition. The structure was elucidated by Fourier Transform Infrared (FTIR), ¹H-Nuclear Magnetic Resonance (NMR) and ¹³C-NMR, two-dimensional (2D)-HSQC, Distortionless Enhancement by Polarization Transfer (DEPT), 2D-Heteronuclear Multiple Bond Correlation (HMBC), and High-Resolution Mass Spectra (HRMS) spectral data.

1. Introduction

Xanthorrhizol, 2-methyl-5-[(2R)-6-methylhept-5-en-2-yl]phenol, is a major component extracted from Curcuma xanthorrhiza Roxb (Java turmeric) rhizomes. It has been established to have a variety of biological activities such as anticancer, anti-inflammatory, anticandidal, anti-hyperglycaemic, antibacterial, antioxidant, and anti-hypertensive [1,2,3,4,5,6,7,8,9]. Several xanthorrizol derivatives have been synthesized such as by esterification of the hydroxyl group, bromination of the phenyl ring, and epoxidation, asymmetric dihydroxylation, or hydrogenation of the carbon-carbon double bond of the compound [10,11]. Permanganate is a well-known and versatile oxidizing agent used to oxidize the carbon-carbon double bonds in organic chemistry [12]. However, there is no report of the use of this reagent for oxidation of xanthorrizol or its derivatives. Herein, we reported the oxidation of 1-O-acetyl-xanthorrizol using permanganate to acquire a new xanthorrizol derivative, 5-(6-hydroxy-6-methyl-5-oxoheptan-2-yl)-2-methylphenyl acetate.

2. Results and Discussion

The title compound, 5-(6-hydroxy-6-methyl-5-oxoheptan-2-yl)-2-methylphenyl acetate, was synthesized via a method summarize in Scheme 1. The starting material, 1-O-acetyl-xanthorrhizol (1), was a known compound prepared by acetylation of xanthorrizol according to phenol acetylation method reported earlier [10,11,13]. Compound 1 was oxidized by potassium permanganate at 0–5 °C in a mixture of glacial acetic acid, acetone, and distilled water and produced a moderate yield (51.9%) of the title compound (2).

The Fourier Transform Infrared (FTIR) spectrum of the compound 2 exhibited the appearance of hydroxyl, carbonyl ester, and carbonyl ketone bands at 3482, 1762, and 1710 cm⁻¹. In the ¹H-NMR spectrum, the appearance of a singlet peak at δ 3.71 ppm confirmed the formation of the hydroxyl group, while the presence of two singlet peaks at δ 1.26 and 1.27 ppm indicated that the two methyl group bound to quaternary carbon. In the ¹³C-NMR spectrum, the appearance of peaks at δ 214.6 and 76.3 ppm confirmed the formation of ketone (C=O) and C-O aliphatic groups [14,15]. Furthermore, in Distortionless Enhancement by Polarization Transfer (DEPT) spectrum showed that carbon peak at δ 76.3 ppm was a quaternary carbon. The structure was supported by a two-dimensional (2D) Heteronuclear Multiple Bond Correlation (HMBC) spectrum displaying correlations between proton on a hydroxyl group at δ 3.71 ppm with thecarbon at δ 76.3, 26.6, and 26.5 ppm; protons on two methyl groups at δ 1.26 and 1.27 ppm with the carbon at δ 76.3 ppm; and other proton-carbon correlations due to two-bonds—four-bond couplings [14] (Figure 1 and Table 1), and a High-Resolution Electrospray Ionization Mass Spectometry (HRESIMS), which showed a molecular ion peak at m/z 315.1563 ([M + Na]⁺). All data obtained are in entire agreement with the structure of the title compound.

Based on the above result, the oxidation of the carbon-carbon double bond of the side chain of xanthorrizol by permanganate ion (one equimolar) in acidic condition produced an α-hydroxy ketone compound as the main product (51.9% yield). However, the side products of the reaction have not been identified yet. The result reported earlier showed that the oxidation of carbon-carbon double bond in acidic condition afforded the cleavage products as the main product [12], for example, the oxidation of carbon-carbon double bond of the side chain of eugenol by permanganate ion (five equimolar) in acidic condition produced 3,4-dimethoxybenzyl carboxylic acid [16]. The difference of the amount of permanganate ion used may cause different results in the oxidation reaction.

3. Materials and Methods

3.1. General

Xanthorrhizol was supplied by Java Plant, Karanganyar, Indonesia. Potassium permanganate, hydrogen peroxide (Merck, Darmstadt, Germany), and solvents used were obtained commercially. A purity test was performed using thin layer chromatographic (TLC) method on silica gel 60 F254 plates (Merck). The infrared (IR) spectrum was recorded on a FTIR Spectrophotometer (Nicolet iS10, Thermo Fisher Scientific, Waltham, MA, USA); Nuclear Magnetic Resonance (NMR) spectra were measured on an NMR spectrometer (Agilent, Santa Clara, CA, USA) at 500 MHz for proton and 125 MHz for carbon using in CDCl₃ as solvent and tetramethylsilane (TMS) as internal standard. High-resolution Mass spectra (HRMS) was recorded on an LCT Premier XE-TOF Mass Spectrometer (Waters Corp., Milford, MA, USA) in positive electrospray ionization (ESI) mode.

3.2. Synthesis of the Title Compound 2

1-O-Acetyl-xanthorrhizol (1) was prepared by acetylation of xanthorrizol using phenol acetylation method reported earlier [10,11,13] with little modification. Furthermore, to a solution of the compound 1 (2.44 mmol, 635.3 mg) in a mixture of glacial acetic acid (5.45 mL), acetone (11 mL), and distilled water (4.3 mL), potassium permanganate crystal (2.7 mmol, 428 mg) was added slowly for 6 h while stirring in an ice bath (0–5 °C), then followed by additional stirring for 1 h. The reaction was monitored using TLC. Upon completion, the reaction solution was poured onto 12 mL of distilled water, and then, 2–3 drops of hydrogen peroxide solution were added to decolorize the reaction. The main product was extracted with dichloromethane and purified by column chromatography using a mixture of hexane and ethyl acetate (5:2) as the mobile phase to provide 2 as a yellow liquid in 51.9% yield and Rf = 0.5 (hexane-ethyl acetate = 5:2).

FTIR (KBr) υmax cm⁻¹: 3482 (O-H), 2932, 2971 (CH aliphatic), 1762 (C=O ester), 1710 (C=O ketone), 1217 (C-O ester) [14]. ¹H-NMR and 2D-HSQC (500 Hz, CDCl₃), δ, ppm: 7.14 (1H, d, J = 8, H-4_Ar), 6.95 (1H, d, J = 8, H-3_Ar), 6.79 (1H, s, H-6_Ar), 3.71 (1H, s, HO), 2.67 (1H, m, H-2, C-HC-Ar), 2.41 (2H, m, H-4, C-H₂C-C=O), 2.31 (3H, s, H-1”, H₃C-_acetate), 2.14 (3H, s, H2’, H₃C-Ar), 1.82 and 1.91 (2 peak: 1H, m and 1H, m, H-3, C-CH₂-C), 1.26 and 1.27 (6H, 2 s, H-6’ and 7, 2 CH₃-C), 1.25 (3H, d, J = 7, H-1, CH₃-CH). ¹³C-NMR and HSQC (500 MHz, CDCl₃), δ, ppm: 214.6 (1C, C-5, C=O_ketone), 169.4 (1C, C-1’, C=O_acetate), 149.5 (1C, C-1_Ar), 145.4 (1C, C-5_Ar), 131.3 (1C, C-3_Ar), 127.9 (1C, C-2_Ar), 124.7 (1C, C-4_Ar), 120.6 (1C, C-6_Ar), 76.3 (1C, C-6, C-O), 38.9 (1C, C-2), 33.6 (1C, C-4), 31.8 (1C, C-3), 26.6 and 26.5 (2 peak 1C and 1C, C-6’ and 7), 22.7 (1C, C-1), 21.0 (1C, C-1”, CH₃-_acetate), 15.9 (1C, C-2’, CH₃-Ar). DEPT: Quaternary carbon, δ (ppm): 214.6 (C-5, C=O_ketone), 169.4 (C-1’, C=O_acetate), 149.5 (C-1_Ar), 145.4 (C-5_Ar), 127.9 (C-2_Ar), and 76.3 (C-6, C-OH). Secondary carbons, δ, ppm: 33.6 (C-4) and 31.8 (C-3). HRESIMS (m/z) found 315.1563 ([M + Na]⁺), calculated masses for C₁₇H₂₄O₄Na: 315.1572 (error −2.9 ppm).

Supplementary Materials

The following are available online, Figure S1: FTIR of the title compound 2, Figure S2: ¹H-NMR of the title compound 2, Figure S3: ¹³C-NMR of the title compound 2, Figure S4: 2D-HSQC of the title compound 2, Figure S5: DEPT of the title compound 2, Figure S6: HRESI-MS of the title compound 2.

Author Contributions

H.H. and S.K. conceived and designed the experiments; M.D.R. performed the experiments; H.H. and M.D.R. analyzed the data; S.K. and H.H. contributed reagents/materials; H.H. and M.D.R. wrote the paper.

Funding

This research was funded by Programme of International Indexed Publication Grants for Student Final Assignments (PITTA Grant) Fiscal Year 2018, Universitas Indonesia, grant number 1768/UN2.R3.1/HKP.05.00/2018. The APC was funded by Universitas Indonesia.

Acknowledgments

The authors are grateful to the Directorate of Research and Community Services, Universitas Indonesia, Depok, Indonesia, for the financial support of this study. Additional thanks go out to the Synthesis Laboratory, Center of Pharmaceutical and Medical Technology, The Agency for the Assessment and Application of Technology (BPPT), Republic of Indonesia, for providing the facilities for this study; to the Chemistry Study Program, Faculty of Natural Sciences, Bandung Institute of Technology (ITB), Bandung, Indonesia, for recording NMR and HR-MS spectra; and to the Ministry of Research, Technology, and Higher Education of the Republic of Indonesia, for the provision of Science and Technology Scholarship (to M.D. Rahayu).

Conflicts of Interest

The authors declare no conflict of interest.

Figure, Scheme and Table

Scheme 1. Synthesis of the title compound 2 from 1-O-Acetyl-xanthorrizol (1).

Figure 1. Two-dimensional (2D)-Heteronuclear Multiple Bond Correlation (HMBC) spectrum of the title compound 2.

Table 1

HMBC Correlations for the title compound 2.

	Proton	H-1	H-2	H-3	H-4	H-6’	H-7	H-1”	H-2’	H-3 Ar	H-4 Ar	H-6 Ar	H-O
Carbon	ppm	1.25	2.67	1.82 & 1.91	2.41	1.26	1.27	2.31	2.14	6.95	7.14	6.79	3.71
C-1	22.7	DB *	α	β	γ
C-2	38.9	α	DB *	α	β					γ		β
C-3	31.8	β	α	DB *	α
C-4	33.6			α	DB *
C-5	214.6
C-6	76.3					α	α						α
C-6’	26.6					DB *							β
C-7	26.5						DB *						β
C-1’	169.4							α
C-1”	21.0							DB *
C-2’	15.9								DB *		γ
C-1 Ar	149.5								β		γ	α
C-2 Ar	127.9								α	α		β
C-3 Ar	131.3								β	DB *
C-4 Ar	124.7		β								DB *	β
C-5 Ar	145.4	β	α	β							α	α
C-6 Ar	120.6		β							γ		DB *

* DB = Directly bonded proton-carbon, which are not seen in HMBC; α = due to a two-bond coupling (²J_CH); β = due to a three-bond coupling (³J_CH); γ = due to a four-bond coupling (⁴J_CH).