Next Article in Journal
An Improved PIN Diode Model Design for a Tunable Frequency Selective Absorber
Next Article in Special Issue
Revitalizing Recovery: Unveiling the Potential of Apigenin and Related Flavonoids in Long COVID-19 Therapy Through Molecular Dynamics Simulation
Previous Article in Journal
Sink–Source Characteristics of Carbon and Nitrogen in Four Typical Urban Water Bodies Within a Medium-Sized City of East China
Previous Article in Special Issue
New Steroid–Alkaloid Bioconjugates as Potential Bioactive Compounds: Synthesis, Spectroscopic and In Silico Study
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin

1
College of Bangmok Basic Education, Myongji University, Myongji-Ro 116, Cheoin-Gu, Yongin 17058, Gyeonggi-Do, Republic of Korea
2
Department of Chemistry, Myongji University, Myongji-Ro 116, Cheoin-Gu, Yongin 17058, Gyeonggi-Do, Republic of Korea
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2025, 15(3), 1438; https://doi.org/10.3390/app15031438
Submission received: 4 January 2025 / Revised: 28 January 2025 / Accepted: 29 January 2025 / Published: 30 January 2025
(This article belongs to the Special Issue Research on Organic and Medicinal Chemistry)

Abstract

:

Featured Application

Total synthesis of phenolic compounds containing terpenoid chains.

Abstract

The total synthesis of biologically and pharmacologically important phenolic isoprenoids, grifolin and neogrifolin, was developed through simple allylation and cyclization procedures using only ethyl acetoacetate, ethyl crotonate, and farnesyl bromide as substrates. The regioisomeric terpenophenols, which consist solely of orcinol and farnesyl moieties, cannot be synthesized purely by direct coupling between the units. The regioselectivity issue was solved by controlling the timing of the allylation of β-ketoester with farnesyl bromide and the cyclization with ethyl crotonate. 2-Farnesyl-5-methyl-cyclohexane-1,3-dione and 6-farnesyl-5-methyl-cyclohexane-1,3-dione were prepared in a highly regioselective manner from ethyl acetoacetate in overall yields of 43% and 40%, respectively. The oxidative aromatization of the regioisomeric cyclohexane-1,3-diones produced grifolin and neogrifolin, respectively.

1. Introduction

Terpenoids are oligomers of isoprene and belong to the isoprenoid family of natural products [1]. They exhibit a variety of biological activities, which can be enhanced by the presence of antioxidant phenolic moieties. Grifolin 1 and its regioisomeric neogrifolin 2 are meroterpenoids, or more specifically, terpenophenols composed of orcinol and farnesol (Figure 1). Grifolin was first isolated from a Basidiomycete and named by Hirata and Nakanishi [2]. Grifolin and neogrifolin, along with various phenolic derivatives, have been extracted mostly from mushrooms of the genus Albatrellus and have been extensively evaluated for their antioxidant, [3] antibacterial [4], anti-inflammatory [5], antitumor [6], and anticancer activities [7]. Grifolin and its derivatives have been shown to inhibit nitric oxide production for anti-inflammation [5], and induce cell cycle arrest and apoptosis in certain cancer cells [8], including human nasopharyngeal carcinoma [7], osteosarcoma [9], and gastric cancer cells [10]. Neogrifolin exhibits tyrosinase inhibitory activity; that is, the prevention of skin pigmentation [11]. Its derivatives exhibited stronger antioxidant activity than vitamin E and butylated hydroxyanisole (BHA) in a DPPH radical scavenging assay [3].
Terpenophenolic natural products with relatively simple structures do not allow for a facile direct coupling reaction between orcinol and farnesol. Various approaches to their synthesis have been proposed and are summarized in Figure 1 and Table 1. In the first total synthesis attempted by Goto in 1968, protected orcinol 3 (P = THP) and farnesyl bromide 4 (X = Br) were coupled by n-BuLi (entry 1) [12]. Deprotection was performed with weak oxalic acid, and the sequence required a total of five steps. Although not reported, the reaction yields were probably reduced due to poor coupling and/or further cyclization to a chroman ring, a common byproduct under acidic deprotection conditions. Yamada directly coupled orcinol 3 (P = H) and farnesyl chloride 4 (X = Cl) using metallic sodium, but this resulted in a mixture of grifolin 1 (23% yield) and neogrifolin 2 (42% yield), which was difficult to separate (entry 2) [13]. Similar direct couplings between orcinol 3 (P = H) and farnesol 4 (X = OH) were reported using CoCl2 catalyst at 70 °C (entry 3) [14] or using Lewis acids including Al2O3 (entry 4) [15] and BF3·OEt2 (entry 5) [16], but all of these methods suffered from low yield and regioisomeric problems.
Figure 1. Retrosyntheses of grifolin 1 and neogrifolin 2 [12,13,14,15,16,17,18,19,20,21].
Figure 1. Retrosyntheses of grifolin 1 and neogrifolin 2 [12,13,14,15,16,17,18,19,20,21].
Applsci 15 01438 g001
To address the regiochemical issue, Ohta used n-BuLi to selectively deprotonate MOM-protected orcinol, which was then formylated and chain-extended with the farnesyl unit. However, deprotection was performed under strongly acidic p-TsOH conditions, which allowed the synthesis of grifolin in seven steps with an overall yield of 8% (entry 6) [17]. Enhanced coupling with farnesyl bromide proved possible by the selective deprotonation of methyl-protected orcinol with n-BuLi, followed by conversion to the corresponding mixed cuprate (entry 7) [18]. Once again, the greatest challenge in these methods was finding mild deprotection conditions that would ensure high yields of terpenophenols.
A unique approach for the regioselective synthesis of grifolin utilizing the thermal annulation of a cyclobutene derivative with a substituted acetylene was reported by Danheiser in 1984 (entry 8) [19]. The regiochemical problem was solved by pre-installing a farnesyl unit on the acetylene moiety. Pure grifolin was obtained in 21~43% yield from (E,E)-farnesol. Regiochemical control in the coupling with farnesol unit would be more practical using 1,3-cyclohexanedione, where the doubly activated methylene carbon could be the preferred site of alkylation. Mohr et al. attempted an alkylation between 5-methylcylclohexane-1,3-dione (7a) and farnesyl bromide 4 (X = Br), but obtained a mixture of four products, with the C,C-dialkylated compound being the major product. The dialkylation problem of 1,3-dione 7a was overcome by condensation with the aldehyde farnesal 4 (C–X = C=O, entry 9), and the synthesis of grifolin was completed by conjugate reduction followed by halogenative aromatization [20]. The creative synthesis of meroterpenoids was demonstrated by Barrett et al. utilizing the aromatization of polyketide, which was prepared starting from 2,2,6-trimethyl-4H-1,3-dioxin-4-one (8). Farnesol was introduced into a specially designed intermediate, dioxane-4,6-dione-keto-dioxinone (entry 10) [21]. Acetylation followed by Pd-catalyzed decarboxylative allylic rearrangement generated the diketo dioxinone structure required for biomimetic aromatization.
The above regioselective grifolin syntheses require highly functionalized intermediates, non-trivial reaction conditions, and even additional step sequences. We have found short and simple reaction steps to synthesize grifolin and neogrifolin in a highly regioselective manner. Herein, we report the regioselective de novo syntheses of terpenophenols utilizing only ethyl acetoacetate, ethyl crotonate, and farnesyl bromide as substrates. The sequence of their coupling reactions is sufficient to determine the regiochemistry of the products. Subsequent cyclization, decarboxylation, and aromatization complete the meroterpenoid syntheses.

2. Materials and Methods

General Procedure. Reactions were performed in a well-dried flask under an Argon atmosphere. Solvents for extraction and chromatography were of reagent grade and used as received. Solvents for the reaction were stored in molecular sieves, which were prepared by heating in a microwave for 1 min and then drying with a vacuum pump (this drying procedure was repeated three times). The column chromatography was performed with silica gel 60 (70–230 mesh) using a mixture of EtOAc/hexane as eluent. The 1H- and 13C-NMR spectra were, respectively, recorded on a 400 MHz and 100 MHz NMR spectrometer in deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as an internal reference unless noted otherwise.
Experimental Procedures for the Synthesis of Grifolin 1
Ethyl (6E,10E)-7,11,15-trimethyl-3-oxohexadeca-6,10,14-trienoate (10b). To a stirred solution of ethyl acetoacetate (10.41 g, 80.00 mmol) in THF (40 mL) at 0 °C under an argon atmosphere, NaH (60% in mineral oil, 3.84 g, 96.00 mmol) was carefully added in several portions. The mixture was stirred at 0 °C for 1 h; then, 1.6 M hexane solution of n-BuLi (55.0 mL, 88.00 mmol) was added. Stirring at 0 °C for 30 min, the mixture was treated with a THF solution (10 mL) of farnesyl bromide (21.95 g, 76.95 mmol). The reaction mixture was stirred at 0 °C for 4.5 h, and quenched with 1 M HCl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (31.45 g), which was purified by SiO2 flash column chromatography (3–20% EtOAc/hexane eluent) to produce the coupling product 10b (19.20 g, 57.41 mmol) in 75% yield as yellow oil (a mixture of keto and enol forms).
Data for 10b: Rf = 0.65 (4:1 hexane/EtOAc); 1H NMR (CDCl3) δ = 1.28 (t, J = 7.2 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.61 (s, 3H), 1.68 (s, 3H), 1.93–2.02 (m, 4H), 2.02–2.11 (m, 4H), 2.29 (dt, Jd = 6.8, Jt = 7.2 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 3.43 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 5.04–5.14 (m, 3H) ppm; 13C NMR (CDCl3, keto form) δ = 14.2, 16.0, 16.1, 17.7, 22.2, 25.7, 26.6, 26.8, 39.7, 39.8, 43.1, 49.4, 61.4, 122.2, 124.1, 124.4, 131.3, 135.1, 136.8, 167.2, 202.6 ppm; IR ν = 3469 (w), 2967, 2929, 1740, 1716, 1652, 1447, 1375, 1315, 1279, 1236, 1176, 1153, 1096, 1026, 843, 804, 750 cm−1; HRMS (ESI) calcd for C21H34O3+Na 357.2406, found 357.2401.
Ethyl 4-hydroxy-6-methyl-2-oxo-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohex-3-ene-1-carboxylate (12b). To a stirred solution of the coupling product 10b (3.00 g, 8.97 mmol) and ethyl crotonate (1.02 g, 8.97 mmol) in t-BuOH (30 mL), t-BuOK (201 mg, 1.79 mmol) was added. The mixture was heated at 90 °C for 2 h, and the solution became cloudy. A stoichiometric amount of t-BuOK (1.01 g, 8.97 mmol) was added and the mixture was heated at 90 °C for 16 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The crude mixture was diluted with EtOAc, washed with 1 M HCl, dried over anhydrous Na2SO4, filtered, and concentrated to give an orange oily product (3.76 g). The crude product was purified by SiO2 flash column chromatography (20–40% EtOAc/hexane eluent) to produce the cyclized product 12b (3.12 g, 7.76 mmol) in 86% yield as a light-yellow liquid (a mixture of diastereomers).
Data for 12b: Rf = 0.56 (2:3 EtOAc/hexane); 1H NMR (CDCl3) δ = 1.07 (d, J = 6.4 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.60 (s, 6H), 1.68 (s, 3H), 1.75 (s, 3H), 2.10–2.26 (m, 9H), 2.44–2.60 (m, 2H), 3.00–3.16 (m, 2H), 3.02 (d, J = 11.6 Hz, 1H), 4.17–4.32 (m, 2H), 5.05 (t, J = 6.8 Hz, 1H), 5.09 (t, J = 6.8 Hz, 1H), 5.23 (t, J = 7.2 Hz, 1H), 7.05 (br s, 1H) ppm; 13C NMR (CDCl3) δ = 14.3, 16.1, 16.2, 17.7, 19.7, 21.5, 25.7, 26.1, 26.7, 30.8, 35.8, 39.7, 39.7, 60.5, 61.0, 112.5, 121.4, 123.3, 124.3, 131.4, 136.0, 140.8, 170.6, 171.5, 193.0 ppm; IR ν = 3435, 2974, 2937, 2876, 1724, 1623, 1456, 1405, 1376, 1302, 1242, 1222, 1154, 1095, 1025, 925, 852, 794, 735 cm−1; HRMS (ESI) calcd. for C25H38O4+H 403.2848, found 403.2844.
3-Hydroxy-5-methyl-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohex-2-en-1-one (7b′). The above cyclized product 12b (1.37 g, 3.40 mmol) was dissolved in 1 M NaOH (20 mL) and heated at 100 °C for 2 h. The mixture was cooled to room temperature and acidified with 1 M HCl (30 mL). The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give orange sticky oil (1.34 g). The above crude product was then dissolved in toluene (20 mL) and heated to 110 °C for 17 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (20–40% EtOAc/hexane eluent) to give a keto 7b/enol 7b′ mixture of 1,3-cyclohexanedione (750 mg, 2.27 mmol) in 67% yield as an off-white solid.
Data for 7b′: Rf = 0.45 and 0.09 (2:3 EtOAc/hexane); 1H NMR (CDCl3) δ = 1.06 (d, J = 6.0 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.68 (s, 3H), 1.75 (s, 3H), 1.90–2.24 (m, 11H), 2.30–2.56 (m, 2H), 3.05 (d of A of ABq, JAB = 16.4, Jd = 7.6 Hz, 1H), 3.13 (d of B of ABq, JAB = 16.4, Jd = 7.2 Hz, 1H), 5.02–5.14 (m, 2H), 5.22 (dt, Jd = 1.2, Jt = 7.2 Hz, 1H), 6.85 (br s, 1H) ppm; 13C NMR (CDCl3) δ = 16.0, 16.1, 16.2, 17.8, 21.0, 21.3, 25.8, 25.8, 26.3, 26.7, 28.3, 39.7, 39.7, 113.5, 121.9, 123.6, 124.4, 131.4, 135.8, 139.4, 172.2, 198.4 ppm; IR ν = 3403 (w), 2962, 2918, 2849, 1732, 1614, 1456, 1380, 1249, 1215, 1059, 911, 787, 731 cm−1; HRMS (ESI) calcd for C22H34O2+H 331.2637, found 331.2639.
3-((tert-Butyldimethylsilyl)oxy)-5-methyl-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohex-2-en-1-one (13). To a stirred solution of the enol form of cyclohexane-1,3-dione 7b′ (430 mg, 1.30 mmol) in CH2Cl2 (10 mL) at 0 °C, tert-butyldimethylsilyl chloride (0.20 g, 1.37 mmol) and Et3N (0.19 mL, 1.37 mmol) were added. The mixture was stirred at room temperature for 15 min and concentrated under reduced pressure. The crude product was diluted with hexane, and the insoluble white precipitate was filtered and rinsed with hexane (5 × 10 mL). The combined hexane solutions were concentrated under reduced pressure and purified by SiO2 flash column chromatography (5–10% EtOAc/hexane) to afford TBS-ether 13 (495 mg, 1.11 mmol) in 86% yield as a colorless oil.
Data for 13: Rf = 0.56 (4:1 hexane/EtOAc); 1H NMR (CDCl3) δ = 0.24 (s, 3H), 0.25 (s, 3H), 0.97 (s, 9H), 1.05 (d, J = 6.0 Hz, 3H), 1.57 (s, 3H), 1.60 (s, 3H), 1.68 (s, 6H), 1.90–2.22 (m, 11H), 2.36–2.46 (m, 2H), 2.95 (d, J = 6.4 Hz, 2H), 5.00 (t, J = 6.4 Hz, 1H), 5.09 (t, J = 6.8 Hz, 2H) ppm; 13C NMR (CDCl3) δ = −3.4, −3.2, 16.0, 16.3, 17.7, 18.3, 21.1, 21.6, 25.6, 25.7, 26.7, 26.8, 28.6, 39.6, 39.7, 39.7, 45.2, 121.8, 122.6, 124.4, 124.4, 131.2, 134.7, 134.9, 168.1, 199.0 ppm; IR ν = 2957, 2929, 2858, 1718, 1657, 1617, 1472, 1463, 1370, 1318, 1254, 1232, 1113, 1053, 1005, 937, 899, 826, 813, 784, 741 cm−1; HRMS (FAB) calcd for C28H49O2Si 445.3502, found 445.3509.
Grifolin: 5-methyl-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)benzene-1,3-diol (1). To a stirred solution of TBS-ether 13 (98 mg, 0.22 mmol) in THF (5 mL)/hexane (10 mL) at −78 °C under an argon atmosphere, 1 M THF solution of LHMDS (1.1 mL, 1.10 mmol) was added. The mixture was stirred at −78 °C for 1 h and a solution of Ts-Br (60 mg, 0.25 mol) in THF (2 mL) was added dropwise to the reaction mixture. The reaction was quenched with saturated NH4Cl solution (2 mL) in 15 min at −78 °C. The mixture was extracted with EtOAc, washed with H2O, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was then treated with 1 M THF solution of TBAF (0.44 mL, 0.44 mol). The reaction mixture was stirred at room temperature for 15 min and quenched with 1 M HCl. The mixture was extracted with EtOAc, washed with H2O, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by SiO2 flash column chromatography (7–15% EtOAc/hexane) to give grifolin 1 (37 mg, 0.11 mmol) in 50% yield as an orange-yellow oil.
Data for 1: 1H NMR (CDCl3) δ = 1.59 (s, 3H), 1.60 (s, 3H), 1.68 (s, 3H), 1.81 (s, 3H), 1.92–2.01 (m, 2H), 2.01–2.16 (m, 6H), 2.21 (s, 3H), 3.39 (d, J = 7.2 Hz, 2H), 5.02–5.16 (m, 4H), 5.27 (t, J = 7.2 Hz, 1H), 6.24 (s, 2H) ppm; 13C NMR (CDCl3) δ = 16.0, 16.2, 17.7, 21.1, 22.2, 25.7, 26.4, 26.7, 39.7, 39.7, 109.0, 110.4, 121.7, 123.6, 124.4, 131.3, 135.6, 137.5, 138.9, 154.8 ppm; IR ν = 3608, 3430 (br), 3015, 2922, 2852, 1760, 1699, 1628, 1589, 1449, 1336, 1211, 1041, 988, 909, 822, 756 cm−1; HRMS (ESI) calcd. for C22H32O2+H 329.2481, found 329.2476.
Experimental Procedures for the Synthesis of Neogrifolin 2
Diethyl 2-acetyl-3-methylpentanedioate (9a). To a stirred solution of ethyl acetoacetate (7.00 g, 53.76 mmol) in t-BuOH (50 mL) at 25 °C under an argon atmosphere, ethyl crotonate (6.13 g, 53.76 mmol) and t-BuOK (1.21 g, 10.75 mmol) were added. The reaction mixture was heated at 90 °C for 4 h and the mixture was quenched with 1 M HCl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (12.94 g), which was purified by SiO2 flash column chromatography (7–20% EtOAc/hexane eluent) to produce the addition product 9a (11.45 g, 51.07 mmol) in 95% yield as a light-yellow liquid (~1.1:1 mixture of diastereomers).
Data for 9a: Rf = 0.36 (4:1 hexane/EtOAc); 1H NMR (CDCl3) δ = 1.03 (d, J = 7.2 Hz, 3H) 1.01* (d, J = 6.8 Hz, 3H), 1.23–1.30 (m, 6H; OCH2CH3), 2.24 (s, 3H), 2.22–2.30 (m, 1H), 2.40 (dd, J = 15.6, 6.4 Hz, 1H), 2.48* (dd, J = 15.6, 4.0 Hz, 1H), 2.70–2.82 (m, 1H), 3.47* (d, J = 8.4 Hz, 1H), 3.55 (d, J = 8.0 Hz, 1H), 3.99–4.24 (m, 4H; OCH2CH3) ppm; 13C NMR (CDCl3, major peaks) 14.2, 14.3, 17.4, 29.8, 30.1, 38.9, 60.6, 61.5, 64.1, 168.9, 172.2, 202.7 ppm; IR ν = 3370 (w), 2975, 2929, 1730, 1603, 1446, 1383, 1367, 1298, 1223, 1186, 1095, 1025, 915, 848, 732 cm−1; HRMS (ESI) calcd. for C12H20O5+Na 267.1208, found 267.1203.
*: peaks from the minor stereoisomer.
Diethyl 2-acetyl-3-methyl-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1yl)pentanedioate (9c). To a stirred solution of the coupling product 9a (1.50 g, 6.14 mmol) in DMF (20 mL) at 0 °C under an argon atmosphere, NaH (60% in mineral oil, 0.18 g, 7.37 mmol) was carefully added in several portions. Stirring at 0 °C for 1.5 h, the mixture was treated with a DMF solution (10 mL) of farnesyl bromide (1.40 g, 4.91 mmol). The reaction mixture was stirred at 0 °C for 8 h and quenched with 1 M HCl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (2.87 g), which was purified by SiO2 flash column chromatography (3–10% EtOAc/hexane eluent) to produce the coupling product 9c (1.54 g, 3.44 mmol) in 71% yield as a yellow oil (~2:1 mixture of diastereomers).
Data for 9c: Rf = 0.66 (1:4 EtOAc/hexane); 1H NMR (CDCl3) δ = 0.94 (d, J = 7.2 Hz, 3H) 0.96* (d, J = 6.8 Hz, 3H), 1.23–1.32 (m, 6H; OCH2CH3), 1.58 (s, 3H), 1.60 (s, 3H), 1.62 (s, 3H), 1.68 (s, 3H), 1.93–2.09 (m, 10H), 2.13 (s, 3H), 2.15* (s, 3H), 2.52–2.69 (m, 2H), 2.72–2.82 (m, 1H), 4.08–4.27 (m, 4H; OCH2CH3), 4.97 (t, J = 8.0 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 5.09 (t, J = 6.8 Hz, 1H) ppm; 13C NMR (CDCl3, major peaks) δ = 14.2, 14.3, 15.4, 16.0, 16.3, 17.7, 25.7, 26.6, 26.8, 28.3, 30.7, 32.5, 38.4, 39.7, 39.9, 60.4, 61.1, 66.3, 117.8, 123.9, 124.4, 131.3, 135.2, 138.8, 171.5, 172.9, 205.0 ppm; IR ν = 2979, 2929, 1733, 1708, 1446, 1374, 1354, 1301, 1266, 1221, 1178, 1095, 1029, 860, 736 cm−1; HRMS (ESI) calcd. for C27H44O5+Na 471.3086, found 471.3082.
*: peaks from the minor stereoisomer.
Ethyl 2-methyl-4,6-dioxo-1-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexane-1-carboxylate (12c). To a stirred solution of coupling product 9c (1.80 g, 4.01 mmol) in t-BuOH (20 mL), t-BuOK (0.45 g, 4.01 mmol) was added. The mixture was heated at 80 °C for 3 h. The mixture was cooled to room temperature, quenched with 1 M HCl, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (15–50% EtOAc/hexane eluent) to produce the cyclized product 12c (1.45 g, 3.63 mmol) in 91% yield as a light-yellow liquid (it contains a diastereomer).
Data for 12c: Rf = 0.37 (2:3 EtOAc/hexane); 1H NMR (CDCl3) δ = 1.09 (d, J = 6.0 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 1.58 (s, 3H), 1.60 (s, 3H), 1.66 (s, 3H), 1.68 (s, 3H), 1.91–2.11 (m, 8H), 2.46–2.62 (m, 3H), 2.70 (dd, J = 14.4, 8.8 Hz, 1H), 2.88 (dd, J = 14.4, 6.0 Hz, 1H), 3.40 (d, J = 14.4 Hz, 1H), 3.54 (d, J = 14.4 Hz, 1H), 4.10–4.24 (m, 2H; OCH2CH3), 4.93 (t, J = 7.4 Hz, 1H), 5.04 (t, J = 7.2 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H) ppm; 13C NMR (CDCl3) δ = 14.1, 15.8, 16.1, 16.4, 17.7, 25.7, 26.4, 26.7, 30.2, 30.5, 39.7, 40.0, 44.7, 57.7, 61.7, 62.9, 117.1, 123.8, 124.2, 131.4, 135.5, 140.6, 169.9, 202.9, 203.2 ppm; IR ν = 2967, 2915, 2855, 1733, 1596, 1445, 1410, 1384, 1366, 1297, 1217, 1188, 1160, 1095, 1019, 944, 850, 754 cm−1; HRMS (ESI) calcd. for C25H38O4+H 403.2848, found 403.2847.
5-methyl-4-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexane-1,3-dione (7c). The above cyclized product 12c (300 mg, 0.74 mmol) in THF was treated with 50% KOH (15 mL), and heated at reflux for 8 h. The mixture was cooled to room temperature and acidified with 50% HCl (25 mL). The reaction mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give orange sticky oil (0.27 g). The crude product was then dissolved in toluene (20 mL) and heated at 110 °C for 17 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (15–40% EtOAc/hexane eluent) to give an 1,3-cyclohexanedione 7c (160 mg, 0.48 mmol) in 65% yield as a light-yellow liquid.
Data for 7c: Rf = 0.20 (EtOAc/hexane); 1H NMR (CDCl3) δ = 1.08 (d, J = 6.8 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.65 (s, 3H), 1.68 (s, 3H), 1.93–2.13 (m, 9H), 2.18–2.55 (m, 4H), 2.73 (ddd, J = 12.0, 4.8, 1.2 Hz, 1H), 3.34 (d, J = 17.2 Hz, 1H), 3.43 (dd, J = 17.2, 1.2 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 5.08 (t, J = 6.8 Hz, 2H) ppm; 13C NMR (CDCl3) δ = 16.0, 16.2, 17.7, 20.1, 25.7, 26.4, 26.7, 26.8, 29.1, 39.7, 39.7, 46.7, 56.1, 57.5, 119.9, 123.9, 124.3, 131.4, 135.2, 138.0, 203.7, 205.6 ppm; IR ν = 2962, 2915, 1732, 1592, 1448, 1381, 1297, 1265, 1220, 1185, 1161, 1106, 1021, 910, 843, 734 cm−1; HRMS (ESI) calcd. for C22H34O2+H 331.2636, found 331.2637.
5-Methyl-6-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)cyclohexa-1,3-diene-1,3-diyl diacetate (14). To a stirred solution of cyclohexane-1,3-dione 7c (520 mg, 1.57 mmol) in THF (20 mL) at −78 °C under an argon atmosphere, 2 M THF solution of LDA (2.75 mL, 5.50 mmol) was added. The resulting mixture was stirred at −78 °C for 1 h before acetic anhydride (0.38 mL, 4.00 mmol) and DMAP (0.19 g, 1.57 mmol) were added. The reaction mixture was stirred at −78 °C for 30 min and quenched with 1 M HCl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (2.5–7% EtOAc/hexane eluent) to produce diacetate 14 (521 mg, 1.25 mmol) in 80% yield (a ~1:1 mixture of diastereomers) as a light-yellow oil.
Data for 14: Rf = 0.66 (1:4 EtOAc/hexane); 1H NMR (CDCl3) δ = 1.08 (d, J = 7.2 Hz, 3H), 1.59 (s, 3H), 1.60 (s, 6H), 1.68 (s, 3H), 1.94–2.12 (m, 10H), 2.13 (s, 3H), 2,14 (s, 3H), 2.18–2.24 (m, 1H), 2.32–2.41 (m, 1H), 5.04–5.13 (m, 3H), 5.22 (dd, J = 6.0, 1.6 Hz, 1H), 5.61 (d, J = 1.6 Hz, 1H) ppm; 13C NMR (CDCl3)* δ = 16.0 (16.0), 17.7, 19.1, 20.4 (20.9), 21.0 (21.3), 21.5, 25.7, 26.5 (26.6), 26.8, 29.3 (31.6), 31.3 (31.9), 39.7, 39.8 (39.9), 43.9 (46.0), 107.0 (108.9), 112.8 (113.4), 120.9 (121.1), 123.8 (124.3), 124.1 (124.4), 131.3 (131.4), 135.1 (135.3), 138.0 (138.5), 142.9 (153.1), 166.7 (167.8), 168.8 (169.0), 183.7 (185.1) ppm; IR ν = 2962, 2922, 2855, 1765, 1614, 1448, 1367, 1275, 1190, 1119, 1096, 1006, 896, 846, 773, 734 cm−1; HRMS (ESI) calcd. C26H38O4+H+ for. 415.2848, found 415.2845.
*: diastereomeric peaks are notified in parenthesis.
5-Methyl-4-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-1,3-phenylene diacetate. To a stirred solution of diacetate 14 (130 mg, 0.31 mmol) in CH2Cl2, DDQ (0.10 g, 0.44 mmol) was added. The mixture was stirred at 25 °C for 5 h and quenched with H2O. The mixture was then extracted with CH2Cl2, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (5–10% EtOAc/hexane eluent) to produce the aromatized diacetate (66 mg, 0.16 mmol) in 52% yield as a colorless oil.
Data: Rf = 0.54 (EtOAc/hexane); 1H NMR (CDCl3) δ = 1.58 (s, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.73 (s, 3H), 1.92–2.10 (m, 8H), 2.26 (s, 3H), 2.28 (s, 3H), 2.29 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H), 4.98 (t, J = 6.4 Hz, 1H), 5.04–5.13 (m, 2H), 6.70 (d, J = 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H) ppm; 13C NMR (CDCl3) δ = 16.0, 16.2, 17.7, 19.8, 20.9, 21.1, 25.7, 25.8, 26.6, 26.7, 39.6, 39.7, 113.5, 120.9, 121.2, 124.0, 124.4, 129.7, 131.3, 135.1, 135.8, 139.2, 148.4, 149.1, 169.3, 169.3 ppm; IR ν = 2919, 1769, 1617, 1588, 1480, 1441, 1367, 1289, 1195, 1119, 1046, 1017, 977, 902, 833, 772 cm−1; HRMS (FAB) calcd. for. C26H36O4+H+ 413.2692, found 413.2701.
Neogrifolin: 5-methyl-4-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)benzene-1,3-diol (2). To a stirred solution of the above aromatized diacetate (40 mg, 0.097 mmol) in MeOH (5 mL) at 0 °C a 50% aqueous solution of KOH (28 mg, 0.5 mmol) was added. The mixture was stirred at 25 °C for 10 min and quenched with 1 M HCl. The mixture was then extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 flash column chromatography (10–15% EtOAc/hexane) to produce neogrifolin 2 (31 mg, 0.094 mmol) in 97% yield as a colorless oil.
Data for 2: 1H NMR (CDCl3) δ = 1.58 (s, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.79 (s, 3H), 1.93–2.14 (m, 8H), 2.23 (s, 3H), 3.29 (d, J = 6.8 Hz, 2H), 4.44 (s, 1H), 5.07 (dt, Jt = 6.8, Jd = 1.2 Hz, 2H), 5.08 (s, 1H), 5.15 (dt, Jt = 6.8, Jd = 1.2 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H) ppm; 13C NMR (CDCl3) δ = 16.0, 16.2, 17.7, 20.1, 20.1, 25.1, 25.7, 26.4, 26.7, 39.7, 101.0, 109.6, 117.9, 122.0, 123.7, 124.4, 131.3, 135.5, 137.8, 138.5, 154.2, 155.5 ppm; IR ν = 3396 (br s), 2965, 2919, 2854, 1596, 1508, 1465, 1449, 1377, 1329, 1279, 1201, 1167, 1138, 1048, 980, 831, 791, 756 cm−1; HRMS (FAB)calcd. for C22H32O2 328.2402, found 328.2401.

3. Results and Discussion

In a preliminary study, we investigated the synthesis of 5-methyl-cyclohexane-1,3-dione (7a) from ethyl acetoacetate and ethyl crotonate via a possible one-pot cyclization reaction (Scheme 1) [22]. However, the reaction (using the condition of 0.2 equiv. t-BuOK in t-BuOH at 90 °C for 4 h) was stopped at the conjugate addition step, giving 9a in 95% yield. Even under forced conditions with excessive base and prolonged reaction times, the Dieckman condensation of 9a did not proceed. Decarboxylation was thus performed first (NaOH; HCl, reflux), followed by esterification (SOCl2, MeOH) to give ε-ketoester 11, which readily cyclized to 7a under common basic conditions (t-BuOK, t-BuOH, reflux).
Ironically, this unexpected three-step sequence for 7a allows us to propose a regioselective introduction of a farnesyl unit for terpenophenols. The introduction of a farnesyl unit via dianion alkylation at the γ-position of β-ketoester would produce 10b, which would give rise to 1,3-cyclohexanedione 7b, containing a 2-farnesyl group according to the cyclization process of 7a. On the other hand, the introduction of a farnesyl unit at the carbon with most acidic proton of 9a would produce 9c that would ultimately provide 1,3-cyclohexanedione 7c containing the 6-farnesyl group after the cyclization process to 7a. The halogenative aromatization [23,24,25] of 7b has been reported to yield grifolin 1 [20]. Similarly, the aromatization of 7c would afford neogrifolin 2.
Although allylation at the 2-position of cycloalkane-1,3-dione has been reported using Triton-B [26], hydrocalcite [27], and Pd catalysts [28], the direct allylation of 1,3-dione 7a was problematic, as pointed out by Mohr in the synthesis of grifolin [20], resulting in C,C-diallylation as well as O-allylation with very low yields of the desired product. We thus turned our attention to the regioselective allylation of ethyl acetoacetate (see Scheme 1). The dianion of β-ketoester was generated by a well-known procedure using NaH and then n-BuLi [29] and reacted with (E,E)-farnesyl bromide, prepared from (E,E)-farnesol, to yield the γ-allylation product 10b in 75% yield (Scheme 2). The conjugate addition of the α-anion of 10b to ethyl crotonate in the presence of catalytic (0.2 equiv.) t-BuOK in t-BuOH at 90 °C for 2 h produced 9b, which was further reacted with a stoichiometric amount of t-BuOK at 90 °C for 16 h to complete the Dieckman condensation, producing 12b in 86% yield. A trivial decarboxylation process through (1) saponification, (2) protonation, and (3) thermolysis provided 2-farnesyl-5-methyl-cyclohexane-1,3-dione (7b) in 67% yield (6:1 keto/enol forms), which completed a formal synthesis of grifolin 1 in a total 43% yield from ethyl acetoacetate. DFT calculations (using B3LYP function and 6-31G basis set) predicted the keto (7b) and enol (7b’) equilibrium constant to be 0.047, whereas the actual ratio was calculated to be 0.17 by 1H-NMR analysis in CDCl3 solvent (see Supplementary Materials).
Since diallylation was again a major problem in the α-allylation of ethyl acetoacetate for neogrifolin synthesis, the reaction sequence was switched to avoid this problem. The farnesyl unit was introduced into the conjugate addition product 9a between ethyl acetoacetate and ethyl crotonate. The most acidic and only α-hydrogen of β-ketoester 9a was deprotonated using NaH in DMF solvent, which led to smooth farnesylation to give 9c in 71% yield. The Dieckman condensation of 9c using stoichiometric t-BuOK in refluxing t-BuOH provided the cyclization product 12c (91% yield), which was then subjected to the general decarboxylation condition to yield 6-farnesyl-5-methyl-cyclohexane-1,3-dione (7c) in 65% yield. No enol form was observed in 1H-NMR spectrum. The overall yield of 7c from ethyl acetoacetate was 40%.
The syntheses of grifolin 1 and neogrifolin 2 were completed via the oxidation of the regioisomeric cyclohexanediones 7b and 7c, respectively (see Scheme 3). The oxidative aromatization of 7b (R4 = farnesyl, R5 = H) was performed via TBS-protected enol ether 13 (86% yield) following the Mohr’s halogenative aromatization procedure, affording grifolin 1 in 55% yield after the deprotection of the silicon protecting group [20]. However, the aromatization of 7c (R4 = H, R5 = farnesyl) was not efficient using the Mohr’s condition. The oxidative aromatization of the diacetylation product 14 of 7c (80% yield by LDA and Ac2O) was successful using DDQ, affording neogrifolin 2 in 50% yield after the hydrolysis of the acetate protecting groups.

4. Conclusions

Regioselective preparations of 2-farnesyl-5-methylcyclohexane-1,3-dione (7b) and 6-farnesyl-5-methylcyclohexane-1,3-dione (7c) are proposed via the appropriate timing of allylation, conjugate addition, and cyclization among ethyl acetoacetate, ethyl crotonate, and farnesyl bromide. The γ-farnesylation of ethyl acetoacetate via dianion allylation, followed by conjugate addition/Dieckman condensation with ethyl crotonate, and subsequent decarboxylation, afforded 7b in an overall yield of 43%, which was further subjected to the Mohr’s oxidative aromatization to produce grifolin 1. In contrast, β-ketoester 9a, a conjugate addition product of ethyl acetoacetate and ethyl crotonate, was α-farnesylated and cyclized via Dieckman condensation. Subsequent decarboxylation gave 7c (40% overall yield), which was further subjected to diacetylation and DDQ oxidation to give neogrifolin 2. This approach can be readily applied to the regioselective synthesis of other terpenophenols.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/app15031438/s1: The 1H/13C-NMR spectra of all the compounds in the synthesis of grifolin and neogrifolin.

Author Contributions

Conceptualization, B.L. and S.K.; methodology, B.L. and S.K.; synthesis, B.L., H.Y., S.H., D.K., and H.L.; validation, B.L and S.K.; formal analysis, B.L., H.Y., S.H., D.K., and H.L.; investigation, S.K.; resources, B.L.; data curation, B.L and S.K.; writing—original draft preparation, S.K.; writing—review and editing, B.L.; visualization, S.K.; supervision, B.L. and S.K.; project administration, B.L.; funding acquisition, B.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Research Foundation of Korea, grant number RS-2022-00166670.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data supporting this article have been included as part of the Supplementary Materials.

Acknowledgments

We would like to thank the Regional Research Center of Myongji University for their assistance in measuring the Nuclear Magnetic Resonance (NMR) spectra.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DPPH2,2-diphenyl-1-picrylhydrazyl
LDAlithium diisobutylamide
LHMDSlithium hexamethyldisilazide
TBAFtetra-n-butylammonium fluoride
TBStert-butyldimethylsilyl
THP3,4-dihydro-2H-pyran-2-yl
Tsp-toluenesulfonyl

References

  1. Cane, D.E. Comprehensive Natural Product Chemistry; Barton, D., Nakanishi, K., Eds.; Elsevier: Oxford, UK, 1999; Volume 2, pp. 1–13. [Google Scholar]
  2. Hirata, Y.; Nakanishi, K. Grifolin, an Antibiotic from a Basidiomycete. J. Biol. Chem. 1950, 184, 135–143. [Google Scholar] [CrossRef] [PubMed]
  3. Nukata, M.; Hashimoto, T.; Yamamoto, I.; Iwasaki, N.; Tanaka, M.; Asakawa, Y. Neogrifolin derivatives possessing anti-oxidative activity from the mushroom Albatrellus ovinus. Phytochemistry 2002, 59, 731–737. [Google Scholar] [CrossRef] [PubMed]
  4. Liu, X.-T.; Winkler, A.L.; Schwan, W.R.; Volk, T.J.; Rott, M.A.; Monte, A. Antibacterial Compounds from Mushrooms I: A Lanostane-Type Triterpene and Prenylphenol Derivatives from Jahnoporus hirtus and Albatrellus flettii and Their Activities Against Bacillus cereus and Enterococcus faecalis. Planta Med. 2010, 76, 182–185. [Google Scholar] [CrossRef]
  5. Quang, D.N.; Hashimoto, T.; Arakawa, Y.; Kohchi, C.; Nishizawa, T.; Soma, G.-I.; Asakawa, Y. Grifolin derivatives from Albatrellus caeruleoporus, new inhibitors of nitric oxide production in RAW 264.7 cells. Bioorg. Med. Chem. 2006, 14, 164–168. [Google Scholar] [CrossRef]
  6. Ye, M.; Luo, X.; Li, L.; Shi, Y.; Tan, M.; Weng, X.; Li, W.; Liu, J.; Cao, Y. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, induces cell-cycle arrest in G1 phase via the ERK1/2 pathway. Cancer Lett. 2007, 258, 199–207. [Google Scholar] [CrossRef]
  7. Luo, X.-J.; Li, L.-L.; Deng, Q.-P.; Yu, X.-F.; Yang, L.-F.; Luo, F.-J.; Xiao, L.-B.; Chen, X.-Y.; Ye, M.; Liu, J.-K.; et al. Grifolin, a potent antitumor natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells. Eur. J. Cancer 2011, 47, 316–325. [Google Scholar] [CrossRef]
  8. Ye, M.; Liu, J.-K.; Lu, Z.-X.; Zhao, Y.; Liu, S.-F.; Li, L.-L.; Tan, M.; Weng, X.-X.; Li, W.; Gao, Y. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, inhibits tumor cell growth by inducing apoptosis in vitro. FEBS Lett. 2005, 579, 3437–3443. [Google Scholar] [CrossRef]
  9. Jin, S.; Pang, R.-P.; Shen, J.-N.; Huang, G.; Wang, J.; Zhou, J.-G. Grifolin induces apoptosis via inhibition of PI3K/AKT signaling pathway in human osteosarcoma cells. Apoptosis 2007, 12, 1317–1326. [Google Scholar] [CrossRef]
  10. Yang, S.; Wang, X.; Zhong, G. Grifolin, a potent antitumor natural product inhibits the growth and invasion of gastric cancer cells in vitro. Int. J. Clin. Exp. Med. 2016, 9, 12659–12668. [Google Scholar]
  11. Misasa, H.; Matsui, Y.; Uehara, H.; Tanaka, H.; Ishihara, M.; Shibata, H. Tyrosinase Inhibitors from Albatrellus confluens. Biosci. Biotechnol. Biochem. 1992, 56, 1660–1661. [Google Scholar] [CrossRef]
  12. Isobe, M.; Goto, T. Synthesis of Grifolin, an Antibiotic from a Basidiomycete. Tetrahedron Lett. 1968, 24, 945–948. [Google Scholar] [CrossRef] [PubMed]
  13. Yamada, S.; Ono, F.; Katagiri, T.; Tanaka, J. Synthesis of Grifolin and its Homologues. Synth. Commun. 1978, 8, 241–244. [Google Scholar] [CrossRef]
  14. Marquet, J.; Moreno-Maňas, M. Alkylation of Active Hydrogen Compounds with Allylic and Benzylic Alcohols under CoCl2 Catalysis. A Useful Synthesis of Grifolin. Chem. Lett. 1981, 10, 173–176. [Google Scholar] [CrossRef]
  15. Jentsch, N.G.; Zhang, X.; Magolan, J. Efficient Synthesis of Cannabigerol, Grifolin, and Piperogalin via Alumina-Promoted Allylation. J. Nat. Prod. 2020, 83, 2587–2591. [Google Scholar] [CrossRef]
  16. Kamauchi, H.; Oda, T.; Horiuchi, K.; Takao, K.; Sugita, Y. Synthesis of natural product-like polyprenylated phenols and quinones: Evaluation of their neuroprotective activities. Bioorg. Med. Chem. 2020, 28, 115156. [Google Scholar] [CrossRef]
  17. Ohta, S.; Nozaki, A.; Ohashi, N.; Matsukawa, M.; Okamoto, M. A Toral Synthesis of Grifolin. Chem. Pharm. Bull. 1988, 36, 2239–2243. [Google Scholar] [CrossRef]
  18. Saimoto, H.; Ueda, J.; Sashiwa, H.; Shigemasa, Y.; Hiyama, T. A general Approach for the Synthesis of Phenolic Natural Products. Facile Synthesis of Grifolin and Colletochlorins B and D. Bull. Chem. Soc. Jpn. 1994, 67, 1178–1185. [Google Scholar] [CrossRef]
  19. Danheiser, R.L.; Gee, S.K. A Regiocontrolled Annulation Approach to Highly Substituted Aromatic Compounds. J. Org. Chem. 1984, 49, 1672–1674. [Google Scholar] [CrossRef]
  20. Grabovyi, G.A.; Mohr, J.T. Total Synthesis of Grifolin, Grifolic Acid, LL-Z1272α, LL-Z1272β, and Ilicicolinic Acid A. Org. Lett. 2016, 18, 5010–5013. [Google Scholar] [CrossRef]
  21. Ma, T.-K.; White, A.J.P.; Barrett, A.G.M. Meroterpenoid total synthesis: Conversion of geraniol and farnesol into amorphastilbol, grifolin and grifolic acid by dioxinone-β-keto-acylation, palladium catalyzed decarboxylative allylic rearrangement and aromatization. Tetrahedron Lett. 2017, 58, 2765–2767. [Google Scholar] [CrossRef]
  22. Chong, B.-D.; Ji, Y.-I.; Oh, S.-S.; Yang, J.-D.; Baik, W.; Koo, S. Highly Efficient Synthesis of Methyl-Substituted Conjugate Cyclohexenones. J. Org. Chem. 1997, 62, 9323–9325. [Google Scholar] [CrossRef]
  23. Kang, S.; Kim, D.; In, I.K.; Koo, S. Efficient preparation method of 4-hydroxybenzoic esters—Oxidation of substituted Hagemman’s ester. Tetrahedron Lett. 2017, 58, 2264–2266. [Google Scholar] [CrossRef]
  24. Saimoto, H.; Hiyama, T. A General Highly Efficient Access to Prenylated Natural Products. Synthesis of Colletochlorins B and D. Tetrahedron Lett. 1986, 27, 597–600. [Google Scholar] [CrossRef]
  25. Chen, X.; Martinez, J.S.; Mohr, J.T. Regiodivergent Halogenation of Vinylogous Esters: One-Pot, Transition-Metal-Free Access to Differentiated Haloresourcinols. Org. Lett. 2015, 17, 378–381. [Google Scholar] [CrossRef]
  26. Rajamannar, T.; Palani, N.; Balasubramanian, K.K. Alkylation of cyclic 1,3-diketones. Synth. Commun. 1993, 23, 3095–3108. [Google Scholar] [CrossRef]
  27. Cativiela, C.; Figueras, F.; García, J.I.; Mayoral, J.A.; Zurbano, M.M. Hydrotalcite-catalyzed alkylation of 1,3-pentanedione. Synth. Commun. 1995, 25, 1745–1750. [Google Scholar] [CrossRef]
  28. Gan, K.-H.; Jhong, C.-J.; Yang, S.-C. Direct palladium/carboxylic acid-catalyzed C-allylation of cyclic 1,3-diones with allylic alcohols in water. Tetrahedron 2008, 64, 1204–1212. [Google Scholar] [CrossRef]
  29. Sum, P.-E.; Weiler, L. Utilization of trimethylsilylpropyne as an acetonyl unit in the synthesis of cyclopentenones. Application to the synthesis of jasmone and dihydrojasmone. Can. J. Chem. 1978, 56, 2301. [Google Scholar] [CrossRef]
Scheme 1. Synthetic sequence for cyclohexane-1,3-diones 7a. This sequence is designed to control regiochemistry by regulating the timing of the addition of farnesyl to synthesize 7b and 7c, ultimately leading to grifolin and neogrifolin.
Scheme 1. Synthetic sequence for cyclohexane-1,3-diones 7a. This sequence is designed to control regiochemistry by regulating the timing of the addition of farnesyl to synthesize 7b and 7c, ultimately leading to grifolin and neogrifolin.
Applsci 15 01438 sch001
Scheme 2. Regioselective synthesis of cyclohexanediones 7b and 7c containing a farnesyl unit at 2- and 6-position, respectively.
Scheme 2. Regioselective synthesis of cyclohexanediones 7b and 7c containing a farnesyl unit at 2- and 6-position, respectively.
Applsci 15 01438 sch002
Scheme 3. Oxidative aromatization of cyclohexanediones 7b and 7c to grifolin 1 and neogrifolin 2 through the intermediates 13 and 14, respectively.
Scheme 3. Oxidative aromatization of cyclohexanediones 7b and 7c to grifolin 1 and neogrifolin 2 through the intermediates 13 and 14, respectively.
Applsci 15 01438 sch003
Table 1. Reactants, reagents, number of steps, and yields of the grifolin synthesis in Figure 1.
Table 1. Reactants, reagents, number of steps, and yields of the grifolin synthesis in Figure 1.
EntryRing (P)Chain (X)Reagent# StepTot. Y (%)Reference
13 (THP)4 (Br)n-BuLi5-Goto [12]
23 (H)4 (Cl)Na123Yamada [13]
33 (H)4 (OH)CoCl2117Moreno-Maňas [14]
43 (H)4 (OH)Al2O3137Magolan [15]
53 (H)4 (OH)BF3‧OEt2124 1Kamauchi [16]
63 (MOM)geranyl acetonen-BuLi78Ohta [17]
73 (OMe)4 (Br)n-BuLi/CuCN4(1)(82) 2Hiyama [18]
865 (R = farnesyl)80 °C221~43Danheiser [19]
97a4 (O=C)Hantzsch ester, proline437Mohr [20]
1084 (OH)Pd2(dba)3730Barrett [21]
# Number of steps required to synthesize grifolin. 1 The yield of neogrifolin. 2 The yield of the coupling step only.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lim, B.; Yeo, H.; Han, S.; Kim, D.; Lee, H.; Koo, S. Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin. Appl. Sci. 2025, 15, 1438. https://doi.org/10.3390/app15031438

AMA Style

Lim B, Yeo H, Han S, Kim D, Lee H, Koo S. Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin. Applied Sciences. 2025; 15(3):1438. https://doi.org/10.3390/app15031438

Chicago/Turabian Style

Lim, Boram, Huisu Yeo, Seunghyo Han, Dabin Kim, Hansuk Lee, and Sangho Koo. 2025. "Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin" Applied Sciences 15, no. 3: 1438. https://doi.org/10.3390/app15031438

APA Style

Lim, B., Yeo, H., Han, S., Kim, D., Lee, H., & Koo, S. (2025). Regioselective De Novo Synthesis of Phenolic Isoprenoids Grifolin and Neogrifolin. Applied Sciences, 15(3), 1438. https://doi.org/10.3390/app15031438

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop