Maria Eugenia Alfonzo; Alexis Maldonado; Liadis Bedoya; Lisbeth Mendoza; Ajoy K Banerjee

doi:10.19080/OMCIJ.2025.14.555884

Synthesis of 5-O -Methylsclerone

Maria Eugenia Alfonzo, Alexis Maldonado, Liadis Bedoya, Lisbeth Mendoza and Ajoy K Banerjee*

Chemistry Center, Venezuelan Institute of Scientific Research (IVIC), Caracas, Venezuela

Submission:November 19, 2025;Published:February 02, 2026

*Corresponding author:Ajoy K Banerjee, Chemistry Center, Venezuelan Institute of Scientific Research (IVIC), Caracas, Venezuela

How to cite this article:Maria Eugenia A, Alexis M, Liadis B, Lisbeth Mendoza and Ajoy K B. Synthesis of 5-O -Methylsclerone. Organic & Medicinal Chem IJ. 2025; 14(2): 555884.DOI: 10.19080/OMCIJ.2026.14.555884

Abstract

Keywords:Methylsclerone; Naphthalenone; Butylhydroperoxde; Pyridine; Tetrahydropyrany

Introduction

5-O -methylsclerone (2,3-dihydro-4-hydroxy-5-methoxy-1- naphthalenone) 9 was isolated [1] from the fermentation broth of amidepsine-producing Humicola sp. FO-2942. The compound was also originally synthesized [2] from the metabolite Sclerone, isolated from the culture filtrate of Sclerotinia sclerotiorum. Humicola sp. FO-2942, originally discovered as a producing fungus of amidepsines, inhibits the accumulation of triglyceride [3,4] which can give origin of several diseases like obesity, arteriosclerosis etc.

In relation of our studies on terpenoid compounds, an attempt was sought to achieve a total synthesis of 5-O-methylsclerone 9. The synthetic details are described in Scheme 1. The already reported [5] alcohol 1 on benzoylation with benzoyl chloride and pyridine yielded the benzoate 2 in 96 % yield. Benzylic oxidation [6] of the benzoate 2 with tert-butylhydroperoxde and pyridinium dichromate afforded the ketobenzoate 3 in 62 % yield. The oxidation was also attempted with chromium trioxide in acetic acid [7] but the yield was not superior to Figure 1.

Preparation of the title compound 9. Reagents and conditions: (i) PhCOCl, pyridine, rt., 19h; (ii) PDC, Pyridine, TBHP, 70% H2O2, 24h, rt; (iii) EtOH, K2CO3, rt; (iv) DHP, p-TsOH, 1h, rt; (v) NaBH4, EtOH, 3 h, rt; (vi) Py, PhCOCl, 18 h, rt; (vii) NH4Cl, 4h, reflux; (viii) CrO3, Py, 24h, rt; (ix) EtOH, K2CO3, rt. the method [6]. It is necessary to mention here that due to the electronic and steric requirements resulting from the repulsion [8] occurring between the carbonyl oxygen atom and the bulky methoxy substituent oxidation at C-1 causes difficulty. The alcohol 4, 98% obtained by alkaline hydrolysis of the ketobenzoate 3, was converted to its tetrahydropyranyl derivative 5, in 94 % yielded by treatment with dihydropyran and a catalytic amount of p-TsOH.

Reduction of 5 with sodium borohydride in methanol followed by benzoylation of the resulting alcohol with benzoyl chloride in pyridine afforded the benzoyl derivative 6. The transformation of 6 to the alcohol 7 was accomplished by heating ammonium chloride in methanol [9]. Ketone 8, obtained in high yield by the chromic acid oxidation of the alcohol 7, yielded 8 which on alkaline hydrolysis afforded the desired product 5-O-methylsclerone 9 whose spectral data support the assigned structure. In relation to the present study an alternative attempt was made for the conversion of the ketobenzoate 8 to 8-methoxy-1-tetralone 11 [10,11]. The synthetic route is depicted in Figure 2.

The ketobenzoate 8 dissolved in ethanol was subjected to catalytic hydrogenation with platinum oxide (PtO2). The resulting compound obtained in 68 % yield as liquid was identified as 5-methoxytetraline 10 which on oxidation with chromium trioxide in acetic acid yielded 8-methoxy-1-tetralone 11 as an oil in 14 % yield. The yield of the tetralone 11 is poor compared to most of other published methods [10,11]. In addition, commercially available 5-methoxy-1-tetralone 12 was obtained in 46 %. The other products obtained could not be characterized. In conclusion a total synthesis of 5-methylsclerane and a new synthesis of 8-methoxy-1-tetralone have been developed. For the nine steps shown in Scheme 1, the method provides an over-all yield of 25 %. of 5-O- methylsclerane.

Experimental Section

Reagents were obtained from commercial sources and used without purification. Solvents were dried by distillation from appropriate drying agents immediately prior to use. For work-up, all organic extracts were dried over anhydrous MgSO₄, filtered and the solvent evaporated in vacuo. Flash column chromatography was performed on silica gel (0.04-0.63 mm) using the solvent system indicated. Unless otherwise stated, all melting points are uncorrected and were determined on an Electrothermal melting point apparatus IR spectra were taken on a Nicolet Fouriertransform (FT) instrument. Mass spectra were recorded on a Thermo Scientific TSQ Quantum Ultra AM Triple Quadruple mass spectrometer. NMR spectra were recorded on a Bruker AVANCE-500 spectrometer (at 500 MHz for H-NMR o 125 MHz for C-NMR) in a suitable deuterated solvent, as specified below. Chemical shifts (δ) are expressed in ppm. Elemental analyses were performed on Carlo-Erba 1108 Elemental Analyser.

1-Benzoyl-5-methoxytetrlin (2) To the alcohol 1 (2.01 g, 11 mmol) dissolved in dry pyridine (25 mL) was added benzoyl chloride (7.26 g, 50 mmoL) and stirred for 18 h at room temperature. To the resulting deep yellow solution was added cold water (70 mL) and extracted with ether (3 x 30 mL). The organic extracts were washed with hydrochloric acid (20 mL, 10%), copper sulfate solution (5 mL, 10 %), sodium hydroxide solution (30 mL, 10 %), with water, dried and evaporated to obtain a dark yellow liquid which was purified by column chromatography (eluant hexane) to yield the benzoylated compound 2 (3.03 g, 96 %) as white solid; mp: 53-55oC (hexane); IR (cm-1): 1713 (CO); MS(m/z): 160 (M-ArCOOH), 105 (ArCO); 1H NMR (CDCl3): δ 8.07(dd, 2H, J= 7.7 Hz, 1.4 Hz; H-15,H-18),7.56 (tt, 1H, J=7.7 Hz, 1.4 Hz; H-16), 7.43 (t, 2H, J=7.7 Hz; H-15,H-17 ), 7.21 (t, 1H, J=8Hz; H-8), 7.08(d, 1H, J=8 Hz; H-7 ), 6.78 (d, 1H, J= 8 Hz; H-6), 6.26 (t, 1H, J= 4.7 Hz; H-1), 3.87 (s, 3H,OMe), 2.89 (dt, 1H, J=17.8 Hz; J= 8.4Hz; H-4 ), 2.62 (dt, 1H, J=17.8Hz; J= 8.4 Hz,H-4), 2.12-1.91 (m, 4H, H-2, H-3); 13C NMR (CDCl3): δ 166.16 (C-12), 156.97 (C-5), 135.72 (C-9), 132.78 (C 13), 129.67 (C-14), 128.22 (C-15), 127.07 (C-10), 126.34 (C-7), 121.40 (C-8), 109.07 (C-6), 70.58 (C-1), 55.30 (OMe), 28.69 (C-2), 22.77 (C-4), 18.26 (C-3).

Anal. Calcd for C18H18O3: C, 76.57; H, 6.43. Found: C, 76.82; H, 6.61.

4-Benzoyl-8-methoxy-1-tetralone (3)

To the benzoate 2 (520 mg, 1.84 mmol) in dry benzene (30 mL) was added celite (1.52 g), pyridinium dichromate (2.67 g, 7.12 mmol) followed by the addition of t-butyl hydroperoxide (4.50 mL, 70%) (TBHP) in water. The mixture was stirred at 10oC for 15 min and 24 h at room temperature. To the resulting solution was added diethyl ether (30 mL), filtered over celite, washed the celite three times with ether (20 mL x3). The organic extracts were dried, evaporated, chromatographed. The eluant (hexane: ether 6:4) afforded the tetralone 3 (340 mg, 62%) as white solid ; mp 95oC (ether); IR(cm-1): 1716, 1613 (CO); MS: 175 (M + 1-PhCOOH); 1H NMR (CDCl3): δ 8.04 (dd,2H, J= 8Hz, 1.4 Hz, H-14, H-18), 7.61-7.42(m, 4H, H-6, H-7, H-15, H-17), 7.14 (d, 1H, J=8 Hz, H-5),7.04 (d, 1H, d=8 Hz, H-16), 6.33(t, 1H, J=4.8Hz, H-4), 3.96 (s, 3H, OMe), 2.74 (dt, 2H, J= 17.4, 8 Hz,H-2), 2.46-2.40 (m,2H, CH2); 13 C NMR (CDCl3): δ 195.97 (C-1), 165.75 (C-12), 159.99 (C-8), 143.00 (C-10), 134.62 (C-13), 133.22 (C-16), 129.86 (C-6), 129.67 (C-14), 128.40 (C-15).121.42 C-9), 120.29 (C-5), 112.62 (C-7), 70.31 (C-4), 56.13 (C-11), 35.70 (C-2), 27.91 (C-3).

Anal. Calcd forC18H16O4: C, 72.96; H, 5.44. Found:C, 73.22; H, 5.59

4-Hydroxy-8-Methoxy-1-Tetralone (4)

To a solution of the benzoate (200 mg, 0.68 mmol) in ethanol (20 mL) was added potassium carbonate (350 mg, 2.53 mmol) and stirred for 18 h at room temperature. The resulting solution was concentrated extracted with chloroform (2 x 15 mL). The organic extracts were combined, washed, dried and evaporated to obtain a brown liquid which was chromato graphed (eluant hexane: ether 30:70) to obtain the oily tetralone 4 (130 mg, 98 %); IR (cm- 1): 3412 (OH), 1664 (CO); MS: 193 [M +1], 175 [M +1-H2O]; 1H NMR (CDCl3): δ 7.51 (t, 1H, J=8 Hz ,H-6), 7.17 (d, 1H, J=8 Hz,H-5), 6.94 (d, 1H, J=8 Hz, H-7), 4.88 (dd,, 1H, J=7.8 Hz, 3.8 Hz H-4) 3.90 (s, 3H, OMe), 2.94-2.84 (m,1H,, 2.62-2.52 (m, 2H), 2.32-2.17 (m, 1H), 2.15-2.12 (m, 1H) (H-2, H-3, H-4),1.90 (s, br, OH, H-4); 13C NMR (CDCl3): δ 197.08 (C-1), 159.82 (C-8), 148.13 (C-10), 134.70 (C-6), 120.29 (C-9), 118.88 (C-5), 111.56 (C-7), 68.06 (C-4), 55.95 (C-11), 36.39 (C-2), 31.11 (C-3).

Anal.Calcd for C11H12O3: C, 68.73; H, 6.29. Found: C, 68.96; H, 6.43.

4-Tetrahydropyranyl-8-Methoxy-1-Tetralone (5)

To the hydroxytetralone 4 (630 mg, 3.28 mmol) dissolved in dihydropyran (4 mL, 21.33 mmol) was added p-toluenesulfonic acid (2 mg), stirred for 1 h room temperature, then added potassium carbonate (0.33g,2.39 mmol) stirred for 2 min and extracted with ether (120 mL). The organic extract was washed, dried and chromatographed (eluant hexane:ether 6:4) to obtain the oily tetralone 5 (850 mg, 94 %); IR (cm-1) 1680 (CO); MS(m/z): 277 [M+ 1], 176 [M+ -101]; 1H NMR (CDCl3): δ 7.46 (t, 1H, J= 8 Hz, C-6), 7.19 (d, 1H, J= 8 Hz, H-5), 6.91 (d, 1H, J = 8 Hz, H-7), 4.89 (td, 1H, J=4.2 Hz, H -12),4.86 (dd, 1H, J=7Hz,3.5 Hz , H-4), 3.87 (s, 3H, OMe), 3.85-3.78 (m, 1H,H-16), 3.51-3.46 (m,1H ,H-16), 2.89- 2.78 (m, 1H, H-2), 2.57-2.46 (m, 1H, H-2), 2.21-2.08 (m, 1H, H-16), 1.80-1.72 (m, 2H, H-15), 1.62-1.47 (m, 4H, H-13, 14); 13C NMR (CDCl3): δ 19. 66 (C-1), 159.78 (C-8), 146. 28 (C-10), 134.35 (C- 6), 121.11 (C-9), 119.73 (C-5), 111.54 (C-7), 95.89 (C-12), 71.01 (C-4), 62.39 (C-16), 56.03 (C-11), 35.98 (C-2), 30.75 (C-13), 26.96 (C-15), 25.34 (C-3), 19.28 (C-14).

Anal. Calcd for C16H20O4: C, 69.54; H, 7.30. Found: C, 69.77; H, 7.46.

1-Tetrahydropyranyl-4-Benzoyl-8-Methoxytetralin (6)

To the tetralone 5 (510 mg, 1.85 mmol) dissolved in ethanol (40 mL) was added sodium borohydride (10 mg, 2.64mmol) and stirred for 3 h at room temperature. The alcohol was partly evaporated under pressure, added water and extracted with dichloromethane (80 mL). The organic extract was dried and evaporated to dryness. The crude product (535 mg) was dissolved in pyridine (3 mL) followed by the addition of benzoyl chloride (0.7 mL, 6mmol). The reaction mixture was stirred for 20h at room temperature, diluted with cold water and extracted with ether. The organic extract was washed with a solution of copper sulfate (10 mL, 2O%), sodium hydroxide (15 mL, 10%), water, dried and evaporated. The residue was chromatographed (eluant hexane: ether 6:4) to obtain the tetralin 6 (520 mg, 73 %); mp: 119oC; IR (cm-1): 1712 (CO); MS(m/z): 159 (M+ 1-PhCOOH-C5H9O2); 1H NMR (CDCl3): δ 7.99 (dd, 2H, J= 7.4,1.4 Hz, H-19,H-23), 7.50 (tt, 1H, J= 7.4, 1.4 Hz, C-8), 7.39-7.30 (m, 3H, H-20, H-21,H-22), 7.07 (d, 1H, J=8 Hz, H-7), 6.77 (d, 1H, J=8 Hz,H-6 ), 6.37 (t, 1H, J=3.5 Hz, H-4), 4.97 (t, 1H, J= 4.2 Hz, H-1), 4.64 (1H,dd J=10,5.4 Hz, H-12 ), 4.03-3.96 (m, 1H, CH2), 3.68 (s, 3H, OMe), 2.31-1.55 (m, 1OH ); 13CNMR : δ 165.93 (C-17), 158.14 (C-5), 141.07 (C-9), 132.50 (C-21), 130.89 (C-18), 129.66 (C-19), 129.43 (C-7), 128.10 (C-20), 122.81 (C-10), 118.80 (C-8), 109.78 (C-6), 101.15 (C-12), 64.97 (C-4), 62.48 (C-16), 55.58 (C-11), 30.94 (C-13), 26.82 (C-15), 26.76 (C-3), 25.47 (C-2), 19.61 (C-14).

Anal: Calcd for C23H26O5: C,72.23; H, 6.85. Found: C, 72.42:H, 6.99.

1-Hydroxy-4-benzoyl-5-methoxytetralin (7)

To the tetralin 6 (120 mg, 0.31 mmol) in methanol (5 mL) was added ammonium chloride (5O mg, 0.93 mmol) and was heated for 4 h. The resulting was diluted with water (20mL) and extracted with ether (20 mL). The combined ethereal extracts were washed with water (10 mL), dried and evaporated. The resulting oil was chromatographed (eluant hexane: ether 6:4) to obtain the tetralin (67 mg, 76 %); mp. 134oC (ether); IR (cm-1 ): 3399 (OH), 1710 (CO); MS (m/z): 176 (M- C6H5COOH), 159 (M+1-C6H5COOH H2O); 1H NMR (CDCl3): δ 7.99 (dd, 2H, J= 7.4,1.4 Hz, H-14,H-18), 7.50 (tt, 1H, J= 7.4 ,1.4 Hz, H-16), 7.40-7.34 (m, 3H, H-8,H-15,H-17), 7.28 (d, 1H, J=8 Hz, H-7), 6.79 (d,, 1H, J=3.4 Hz, H-6), 6.39 (t,1H, J=3.4.Hz, H-4), 4.81 (dd, 1H, J=10 .0, 5.4 Hz, H-4), 3.70 (s, 3H, OMe), 1.99-2.24 (m, 4H,H-2, H-3), 1.84-1.76 (s, br, 1H, OH); 13C NMR (CDCl3): δ 165.89 (C-12), 157.66 (C-5), 142.55 (C-9), 132.58 (C-16), 130.81 (C-13), 130.04 (C-7), 129.81 (C-14), 128.15 (C-15), 122.40 (C-10), 118.43 (C-8), 109.30 (C-6), 65.09 (C-4), 64.97 (C- 1), 55.59 (C-11), 28.27 (C-2), 26.36 (C-3).

Anal: Calcd for C18H18O4: C, 72.46; H, 6.08. Found: C, 72. 69; H, 6.26.

4-Benzoyl-5-Methoxy-1-Tetralone (8)

To the Sarett reagent, prepared by the addition of chromic acid (200 mg, 20 mmol) to dry pyridine (2 mL) was added alcohol 7 (150 mg, 0.50 mmol) dissolved in dry pyridine (2 mL). The deep brown solution was stirred at room temperature for 24 h, diluted with ether (30 mL), filtered over celite-silica and washed celitesilica with ether (2x5 mL). The combined washed extract was washed with hydrochloric acid (15 mL, 30 %) and then with a solution of the copper sulfate (20 mL, 10%). The organic extract was washed, dried and evaporated. The resulting residue was chromatographed (eluant hexane: ether 7:3 ) to obtain the ketone 8 (129 mg, 87 % ); mp: 116-117 oC (ether); IR (cm-1): 1715, 1692 (CO); MS (m/z): 296 (M+),191 (M- COC6H5); 1H NMR (CDCl3): δ 8.00 (dd, 2H, J= 8.0, 1.3 Hz, C-14, C-18), 7.70 (d, 1H, J= 8 Hz, H-16), 7.52 (tt, 1H, J= 8 .0, 1.3 Hz, H-7), 7.46 (t, 1H, J= 8 Hz,H-6 ), 7.39 (t, 2H, J= 8 Hz, H-15, H-17), 7.11 (d, 1H, J= 8 Hz, ), 6.67 (t, 1H, J= 3 Hz, H-4), 3.80 (s, 3H, OMe), , 2.37-2.93(m,4H,H-2, H-3 ); 13CNMR (CDCl3): δ 197.67 (C-1), 165.80 (C-12), 133.66 (C-13), (132.94 (C-16), 130.19 (C-9), 129.65 (C-14, C-9),128. 30 (C-15), 127.99 (C- 10), 118.55 (C-8), 115.58 (C-6), 63.70 (C-4), 55.97 (C-11), 33.20 (C-2), 27.42 (C-3).

Anal. Calcd for C18H16O4: C, 72.96; H, 5.44. Found: C, 73.12; H, 5.66

5-O-Methylsclerone (9)

To a solution of the tetralone 8 (60 mg, 0.31 mmol) in ethanol (20 mL) was added potassium carbonate (240 mg, 1.25 mmol) and stirred at room temperature for 24 h. The alcohol was evaporated and the residue was extracted with dichloromethane (20 mL). The organic extract was washed, dried, filtered and evaporated. The residue was (eluant hexane: ether 1:1) to obtain the 5-O-methylsclerone 9 ( 50.5 mg, 85 %) as oil; IR(cm-1): 3420 (OH), 1683 (CO);MS( m/z): 192 (M+), 175 (M+1-H2O);1HNMR (CDCl3): δ 7.61 (dd, 1H, J= 8Hz, 1.1 Hz, H-6 ), 7.36 (t, 1H, J = 8 Hz, H-7), 7.09 (dd, 1H, j= 8.0, 1.1 Hz,H-8 ), 5.26 (t, 1H, J=8 Hz,, H-4), 3.90 (s, 3H, OMe), 3.01-2.25 (m ,4H, H-2,3) ; 13C NMR (CDCl3): δ 198.08 (C-1), 156.98 (C-5), 132.47 (C-9), 132.33 (C-10), 129.11 (C-7), 118.92 (C-8), 115.30 (C-6), 62.12 (C-4), 55.80 (C-11), 33.65 (C-2), 29.37 (C-3). Anal. Calcd for C11H12O3: C, 68.73; H, 6.29. Found: C, 68.89; H, 6.43.

5-Methoxytetralin (10)

To a solution of the benzoate 8 (80 mg, 0.27 mmol) in alcohol (10 mL) was added platinum oxide (8 mg, 0.03 mmol) and stirred for 3 h under hydrogen. The progress of the reaction was observed by TLC. The reaction mixture was filtered and washed the residue with alcohol (3 mL). The combined filtrate was evaporated and the resulting residue was chromatographed (eluant hexane) to yield the tetralin 10 ( 30 mg, 68 %) as liquid; MS(m/z): 162 (M+); 1H NMR (CDCl3): δ 7.15 (t, 1H, J= 8Hz, C-8), 6.78 (d, 1H, J= 8Hz,H-7 ), 6.73 (d, 1H, J= 8Hz,H-6 ), 3.88 (s, 3H, OMe), 2.79 (dt, 4H, J= 280, 6 Hz), 1.92-1.80(m, 4H,H-2,3 ); 13C NMR (CDCl3): δ 157.40 (C-5), 138.50 (C-9), 125.94 (C-10), 125.70 (C-7), 121.44 (C-8), 106.77(C- 6), 55.19 (C-11), 29.66 (C-1), 23.11 (C-3), 22.90 (C-2).

Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C, 81.65; H, 8.88.

8-Methoxy-1-Tetralone (11)

To a solution of the tetralin 10 (500 mg, 3.09 mmol) in acetic acid (10 mL), cooled at 15 oC, was added a solution of chromic acid (7 mL) in acetic acid-water (19:1). The reaction mixture was stirred for h at 17-21 oC, filtered over silica gel and then washed the silica gel with acetic acid (3 mL). To the combined filtrate was added dichloromethane (30 mL) and stirred for 15 min. The organic extract was washed with a solution of sodium hydroxide (2 x 8 mL, 10 %), dried and evaporated to dryness. The residue was chromatographed (eluant hexane: ether 7:3) to obtain 8-methoxy-1-tetralone 11 (76 mg, 14 %); IR(cm-1): 1672 (CO); MS(m/z): 176 (M+), 148 (M+-MeOH); 1H NMR (CDCl3): δ 7.35 (dd, 1H, J= 8.4, 7.6 Hz, H-5),6.81-6.78 (m,2H, H-6,7) ,3.87 (s, 3H ,OMe),2.89 (t, 2H, J=6.0 ,H-2),2.62 (t,2H ,J=6.0 Hz, H-3), 2.07- 1.98 (m, 2H ,H-4 ); 13C NMR (CDCl3): 197.55 (C-1), 160.33 (C-8), 147.11 (C-10), 133.88 (C-6), 122.19 (C-9), 120.68 (C-5), 109.89 (C-7), 55.92 (C-11), 40.89 (C-2), 30.78 (C-4), 22. 80 (C-3). Anal. Calcd for C11H12O2: C, 74.97; H, 6.86. Found: C, 75.16; H, 6.94.

Further elusion (eluant hexane: ether 6:4) afforded 5-methoxy-1-tetralone 12 (249 mg, 46 %) whose mp. 87-89 oC was compared with commercially available tetralone 12 (mp. 85- 89 oC) (Aldrich), the mixed mp. did not show any depression.