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Article

Kerlinic Acid Preserves the Furan Moiety in Regio- and Diastereoselective Oxidations Giving Beta-Lactones and Oxirane Derivatives

by
Eva E. Soto-Guzmán
1,
Antonio J. Oliveros-Ortiz
1,
Armando Talavera-Alemán
1,
Mónica A. Calderón-Oropeza
2,
Gabriela Rodríguez-García
1,
Brenda Y. Bedolla-García
3,
Mario A. Gómez-Hurtado
1,
Carlos M. Cerda-García-Rojas
4,
Jérôme Marrot
5,
Christine Thomassigny
5,* and
Rosa E. del Río
1,*
1
Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad Universitaria, Morelia 58030, Mexico
2
Instituto de Genética, Universidad del Mar Campus Puerto Escondido, Carretera Vía Sola de Vega km 1.5, Juquila 71980, Mexico
3
Instituto de Ecología, A.C. Centro Regional del Bajío, Pátzcuaro 61600, Mexico
4
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, Mexico City 07000, Mexico
5
ILV-UMR CNRS 8180, Université de Versailles-St-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
*
Authors to whom correspondence should be addressed.
Reactions 2025, 6(3), 47; https://doi.org/10.3390/reactions6030047
Submission received: 29 April 2025 / Revised: 29 August 2025 / Accepted: 30 August 2025 / Published: 2 September 2025
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Versions Notes

Abstract

Strategic scaffolds in molecules increase the possibility of obtaining derivatives with potential uses in scientific and industrial areas. The regio- and stereoselective reactions can be considered to gain these tactical motifs. Natural diterpenes are key molecules for reaching such aims. Among this class of compounds, neo-clerodanes are highlighted by the presence of a furan moiety in their chemical structure. This work describes a regio- and stereoselective strategy to gain beta-lactone and oxirane derivatives from kerlinic acid (1) when the β,γ-unsaturated carboxylic acid system is oxidized, preserving the furan moiety. Oxidation of 1 yielded salviaolide (2), suggesting regio- and stereoselective means. A reaction mechanism was proposed when oxidation of the acetate (1a), benzoate (1b), and methyl ester (1c) derivatives from 1 were gained. The obtention of the epoxide derivative 3, kernolide (4), and kernolide epoxide (5) also supported the reaction mechanism. X-ray diffraction analysis of 3, Karplus-type analyses, and DFT calculations from hypothetical intermediates revealed conformational preferences that guide the regioselectivity. The stereoselectivity was attributed to the natural origin of 1. All compounds were characterized by their physical and spectroscopical data. These results suggest the feasibility of promoting regioselective oxidation on neo-clerodane compounds, preserving the furan moiety.

Graphical Abstract

1. Introduction

In chemical reactions aimed at the obtention of chiral compounds, the control of selectivity is workable using those properties given by the inherent nature of the reagents [1,2], the catalysts [3,4], or the substrate [5]. This last strategy, also called active substrate control or substrate-directed reaction, involves the interaction between reagents and a functional group from the substrate (i.e., hydroxyl, sulfonyl, carbamate, amide), allowing specific intramolecular interactions, thereby influencing the stereochemical outcome of the process [1,6,7,8,9].
The regio- and stereoselective semisynthesis from chiral natural products with structural complexity and enantiopurity (terpenoids and their derivatives), is highlighted due to their interesting described biological activities [10,11,12]. Diterpene compounds are widely distributed in nature, and strategic chemical modifications could increase their applicative potential [13,14]. Clerodane compounds are diterpenes with extensive distribution, including terrestrial, marine, and microbial (bacteria and fungi) species [15,16]. These natural products have attracted scientific research interest due to their pharmacological properties [15,17]. Kerlinic acid (1), a neo-clerodane diterpene isolated from Salvia kerlii [18], possesses a monosubstituted furan which can be easily oxidized to obtain butenolides [19,20], hydroxybutenolides [21,22], epoxides [23,24], and furan degradation products [25] using several oxidative conditions and reagents including photooxidation [26,27], MCPBA [28], citocrome P450 [29], ozone [30,31], and electrochemistry [32]. On the other hand, preserving the furan moiety is important due to biological activities such as cytotoxic, antiinflammatory, antiviral, antibacterial, and antifungal, as well as its presence in compounds usable for agrochemicals and fuel purposes [33,34,35,36,37]. Consequently, its presence in strategic molecules is essential, and broad synthetic methodologies can be applied to prepare compounds bearing a furan pattern [38]. Interestingly, 1 also contains a β,γ-unsaturated carboxylic acid system, which could act as a directing group for stereo- and regioselective modifications. Despite the above, a lack of reports about using a strategy to gain new diterpene derivatives preserving the furan ring is noticed. Furthermore, including additional heterocycles in neo-clerodane compounds using these strategies becomes pertinent. For example, lactonization from β,γ-unsaturated carboxylic acids [39,40], or asymmetric epoxidation [41,42,43,44,45,46], can lead to the obtention of compounds with medicinal value [47,48]. These chemical transformations can be used to synthesize chiral epoxides, which can be further utilized as building blocks for diversely functionalized compounds [49,50] or to provide lactone derivatives with remarkable bioactivity [51]. Several lactones have been obtained by our research group using the furan ring from natural diterpenoids [24,52].
This work aimed to establish the applications of the β,γ-unsaturated carboxylic acid moiety from kerlinic acid (1) as a directing group under oxidative conditions to provide regio- and diastereoselective products. The oxidation reactions for this purpose involved m-chloroperbenzoic acid (MCPBA) as the oxidant agent to yield the β-lactone 2. The influence of the OH-6 group from 1 in the lactonization process was evaluated throughout the acetate (1a) and benzoate (1b) derivatives to give 2a and 2b, respectively. The obtention of the kerlinic acid methyl ester (1c) and subsequent epoxidation yielded 3 providing information about the influence of carboxylic acid moiety in the oxidation process. In addition, β-lactone 4 was evaluated under the same oxidative conditions to give 5. From the best conditions herein explored, oxidation of the β,γ-unsaturated carboxylic acid system was feasible, preserving the furan moiety and gaining yields until 40% after chromatographic purification. All compounds were characterized by their physical and spectroscopic data, and X-ray diffraction analysis was conducted for compound 3. The results represent a guide for selective oxidation of chiral diterpene-type natural products possessing β,γ-unsaturated carboxylic acid moieties without modification of a furan moiety.

2. Materials and Methods

2.1. General Experimental Procedures

The reagents AcONa (S-8750), MCPBA (273031), TsCl (08326), and benzoic anhydride (385980) were used as purchased from Sigma-Aldrich®. Acetic anhydride (Ac2O) (0018-03) was obtained from J.T. Baker and Et3N (808352) from MERCK-Schuchardt. Solvents were distilled prior to their use. Melting points were determined on a Fisher Scientific apparatus and were uncorrected. Optical rotations were determined on a Perkin Elmer 341 polarimeter (Perkin-Elmer, Waltham, MA, USA) using CHCl3 or CH3OH solutions at 25 °C. The UV spectra were obtained from a Thermo Fisher Scientific Genesys 10S UV-Vis spectrophotometer using CHCl3 solutions. The infrared spectra were recorded on an FT-IR 200 Perkin Elmer spectrometer. NMR spectra were measured on a Varian Mercury Plus 400 (Varian Inc., Palo Alto, CA, USA) or in a Bruker AV-I 300 MHz spectrometer (Bruker BioSpin GmbH, Karlsruhe, Germany) at 400 or 300 MHz for 1H and 100 or 75 MHz for 13C, respectively, from CDCl3 solutions at 298 K, using tetramethylsilane as the internal reference or residual CHCl3 (δ = 7.26 or 77.16 ppm). Chemical shift values are reported in parts per million and coupling constants (J) are given in Hz. High-resolution mass spectra (HRMS) were obtained with a Waters Xevo QTOF instrument with an electrospray ionization source (ESI+), using enkephaline leucine as the internal calibrant or by electrospray ionization on a Thermo Fisher Scientific Orbitrap Exploris (Thermo Fisher Scientific GmbH, Dreieich, Germany) 120 mass spectrometer at Laboratorios Centrales, Cinvestav, Mexico City. Column chromatography was carried out on Merck Silica 60 (230–400 mesh) (Merck, Darmstadt, Germany).

2.2. Plant Material

Specimens of Salvia melissodora Fernald were collected near Alberca de Los Espinos Lake (19°54′26″ N, 101°46′04″ W) in Villa Jiménez municipality, Michoacán, Mexico, according to the NOM-126-ECOL-20000 Official Mexican Standard to ensure the safety of the continuity of the plant. A specimen was deposited at Herbarium del Centro Regional del Bajío, Instituto de Ecología, Pátzcuaro, Michoacán, Mexico (voucher number IEB 257299).

2.3. Extraction and Isolation of Kerlinic Acid (1)

Dried leaves of Salvia melissodora (3.1 kg) were macerated with acetone (3 × 17 L) at room temperature for three days. The solvent was removed under reduced pressure, and the crude extract was obtained as a green solid (126 g, 4%). A batch of crude extract (40 g) was column chromatographed using silica gel (previously treated with MeOH) as the stationary phase and eluted using hexanes, followed by 19:1 and 9:1 hexanes–acetone mixtures, collecting 275 fractions of 20 mL each. Fractions 135–275 (9:1) yielded 6.4 g (0.6%) of kerlinic acid (1) as white crystals.

2.4. Kerlinic Acid (1)

White crystals (m.p. 184–186 °C), lit. 183–185 °C [18]; [α]D −205 (c 0.17, CHCl3), lit. [α]D −236.8 (c 0.19, CHCl3) [15]; UV (CHCl3) λmax (log ε): 241 nm (3.33); IR νmax (cm−1): 3386, 1673, 1560, 1515, 872; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3) are concordant with data described [18]; EIMS (70 eV) m/z (rel. int.) 332 [M]+ (1), 328 (0.5), 296 (2), 269 (5), 173 (34), 105 (56), 95 (61), 91 (38), 81 (100%).

2.5. Kerlinic Acid Acetate (1a)

A batch of 1 (100 mg, 0.3 mmol, 1 eq) was dissolved in Ac2O (2 mL, 21.1 mmol, 72 eq) at room temperature; subsequently, sodium acetate (100 mg, 1.2 mmol, 4 eq) was added. The resulting mixture was refluxed at 60 °C for 3.5 h. Afterward, the crude reaction was poured on wet ice and extracted with EtOAc (3 × 20 mL). The organic layer was washed with saturated aqueous NaHCO3 solution, H2O, dried over anhydrous Na2SO4, filtered, and evaporated. The residue (119 mg) was column chromatographed using a hexanes-acetone (9:1) mixture as the eluent, obtaining 8 mL fractions, yielding 1a (84 mg; 75%) in fractions 17–39. Colorless crystals (m.p. 172–174 °C); [α]D −116, [α]578 −121, [α]546 −140, [α]436 −262, [α]365 −472 (c 0.75, MeOH); UV (CHCl3) λmax (log ε): 241 nm (2.93); IR νmax (cm−1): 3259, 1732, 1699, 1500, 1456, 876; 1H NMR (400 MHz, CDCl3) δ: 7.35 (1H, t, J = 1.7 Hz, H-15), 7.20 (1H, brs, H-16), 6.25 (1H, brs, H-14), 5.61 (1H, brs, H-3), 4.77 (1H, dd, J = 11.7, 4.8 Hz, H-6), 2.34 (1H, m, H-2), 2.31 (1H, m, H-7), 2.28 (1H, m, H-11), 2.07 (3H, s, OAc), 2.04 (1H, m, H-11′), 1.85 (1H, m, H-8), 1.76 (2H, m, H-12), 1.75 (1H, m, H-7′), 1.73 (1H, m, H-2′), 1.68 (3H, s, CH3-18), 1.63 (1H, m, H-1), 1.25 (1H, m, H-1′), 0.87 (3H, d, J = 6.7 Hz, CH3-17), 0.77 (3H, s, CH3-20); 13C NMR (100 MHz, CDCl3) were concordant with the described data [18]; EIMS (70 eV) m/z (rel. int.) 373 [M]+ (0.7), 329 (0.5), 296 (2), 270 (1), 173 (52), 105 (28), 95 (12), 91 (18), 81 (30%).

2.6. Kerlinic Acid Benzoate (1b)

A batch of 1 (100 mg, 0.3 mmol, 1 eq) was dissolved in EtOAc (3 mL); subsequently, pyridine (0.7 mL, 28.9 eq) and benzoic anhydride (215 mg, 0.9 mmol, 3 eq) were added and refluxed at 60 °C for 6 h. After, the EtOAc was removed by evaporation at lower pressure, and CH2Cl2 (6 mL) was added. The resulting solution was treated with Ba(OH)2 (500 mg) and stirred at 25 °C for 24 h, followed by column chromatography using silica gel as the stationary phase and CH2Cl2 as the eluent, collecting fractions of 5 mL to obtain 1b (84 mg; 64%) as a colorless oil in fractions 9–35. [α]D −66, [α]578 −70, [α]546 −81, [α]436 −156 (c 1.25, MeOH); UV (CHCl3) λmax (log ε): 241 nm (3.94); IR νmax (cm−1): 3252, 1710, 1693, 1502, 1451, 872; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3), see Table 1 and Table 2, respectively; HRMS (TOF ES+) m/z 437.2324 [M + H]+ (calcd for C27H33O5 + H+, 437.2328).

2.7. Kerlinic Acid Methyl Ester (1c)

Diazomethane was used as the methyl donor, prepared according to a previous report [53]. Diazomethane (20 mL) was added to a batch of 1a (1 g) dissolved in acetone (5 mL). Once the reaction concluded, the solvent was evaporated, and the crude reaction was column chromatographed using hexanes and hexanes–EtOAc (19:1) mixtures, collecting fractions of 10 mL each. Fractions 12–22 yielded 1c (590 mg, 57%). Colorless crystals (4:1 hexanes–acetone), m.p. 66–68 °C; [α]D −113, [α]578 −118, [α]546 −137, [α]436 −259, [α]365 −494 (c 0.49, MeOH); UV (CHCl3) λmax (log ε): 207 nm (3.13); IR νmax (cm−1): 3536, 1697, 1505, 1450, 872; 1H NMR (400 MHz, CDCl3) data in agreement with the literature [18]; 13C NMR (100 MHz, CDCl3) δ: 177.2 (C, C-19), 142.8 (CH, C-15), 138.4 (CH, C-16), 136.4 (C, C-4), 126.9 (CH, C-3), 125.2 (C, C-13), 110.9 (CH, C-14), 76.5 (CH, C-6), 53.8 (C, C-5), 51.7 (OMe), 48.2 (CH, C-10), 39.1 (CH2, C-1), 38.5 (C, C-9), 38.1 (CH2, C-7), 35.4 (CH, C-8), 26.3 (CH2, C-11), 23.4 (CH3, C-18), 17.7 (CH2, C-12), 17.4 (CH2, C-2), 16.0 (CH3, C-20), 15.6 (CH3, C-17); HRMS (TOF ES+) m/z 347.2232 [M + H]+ (calcd for C21H31O4 + H+, 347.2222).

2.8. General Procedure for the Regioselective Oxidation with MCPBA

The neo-clerodanes 1, 1a, 1b, 1c, and 4 (0.3 mmol, 1 eq) were separately dissolved in 3 mL CHCl3-acetone (5:1). Each solution was treated with MCPBA (0.4 mmol, 1 eq) and stirred at −50 °C for 20 min. After, HCl 10% (10 mL) was added and stirred for 20 min; subsequently, water (10 mL) was added, and the crude reaction was extracted with EtOAc (2 × 20 mL). The organic layer was washed with H2O, dried over anhydrous Na2SO4, filtered, and evaporated. Each crude was purified by column chromatography using hexanes–acetone–acetic acid or hexanes–EtOAc mixtures, collecting fractions of 3 mL each.

2.9. Salviaolide (2)

Compound 2 was yielded from 1 as a colorless oil (40 mg; 40%) from fractions 33–50 after column chromatography using 70 mL of hexanes–acetone–acetic acid (90:10:1) followed by hexanes–acetone–acetic acid (80:20:1) mixture (60 mL). Colorless crystals from hexanes–acetone (4:1) solution, m.p. 67–69 °C; [α]D +9, [α]578 +9, [α]546 +10, [α]436 +16 (c 0.62, MeOH); UV λmax (log ε): 241 nm (2.77); IR νmax (cm−1): 3473, 2961, 1790, 1501, 1454, 873; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3), see Table 1 and Table 2, respectively; HRESIMS m/z 371.1821 [M + Na]+ (calcd for C20H28O5 + Na, 371.1829).

2.10. Salviaolide Acetate (2a)

Compound 2a was obtained from 1a as a colorless oil (22 mg; 19%) from fractions 51–86 after column chromatography using 250 mL of hexanes–acetone–acetic acid (90:10:1) followed by hexanes–acetone–acetic acid (80:20:1) mixture (50 mL). [α]D +8, [α]578 +8, [α]546 +8, [α]436 +11, [α]365 +16 (c 0.36, MeOH); UV λmax (log ε): 240 nm (3.06); IR νmax (cm−1): 3475, 1815, 1737, 1454, 872; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3), see Table 1 and Table 2, respectively; HRESIMS m/z 413.1931 [M + Na]+ (calcd for C22H30O6 + Na, 413.1935).

2.11. Salviaolide Benzoate (2b)

Compound 2b was yielded from 1b as a colorless oil (19 mg; 14%) from fractions 99–112 after column chromatography using 250 mL of hexanes–acetone–acetic acid (90:10:1) followed by hexanes–acetone–acetic acid (80:20:1) mixture (100 mL). [α]D +8, [α]578 +8, [α]546 +9, [α]436 +12 (c 0.39, MeOH); UV λmax (log ε): 241 nm (3.98); νmax (cm−1): 3489, 1815, 1715, 1451, 875; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3), see Table 1 and Table 2, respectively; HRMS (TOF ES+) m/z 453.2285 [M + H]+ (calcd for C27H33O6 + H+, 453.2277).

2.12. Kerlinic Acid Methyl Ester Epoxide (3)

Compound 3 was obtained from 1c as a colorless oil (31 mg; 29%) from fractions 94–126 after column chromatography using a gradient of hexanes–EtOAc (100:0, 19:1, 9:1, 17:3) mixtures (100 mL each) obtaining 5 mL fractions. Colorless crystals (31 mg; 29%), m.p. 93–95 °C (ethanol); [α]D −38, [α]578 −41, [α]546 −45, [α]436 −77, [α]365 −126 (c 0.27, MeOH); UV (log ε) λmax: 241 nm (2.72); IR νmax (cm−1): 1700, 1505, 1451, 872; 1H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3), see Table 1 and Table 2; HRMS (TOF ES+) m/z 363.2166 [M + H]+ (calcd for C21H31O5 + H+, 363.2171).

2.13. Kernolide (4)

A solution of 1 (100 mg, 0.3 mmol, 1 eq) in THF (3 mL) was cooled at 0 °C and TsCl (114 mg, 0.96 mmol, 2 eq) and of Et3N (0.2 mL, 5 eq) were added. The mixture was stirred at 25 °C for 2.5 h. Afterward, the solvent was removed, and the crude reaction was purified by column chromatography using a hexanes–EtOAc (99:1) mixture (600 mL) as the eluent obtaining 10 mL fractions. 4 was isolated in fractions 27–61 (56 mg, 57%), as colorless crystals, m.p. 88–89 °C; [α]D −153, [α]578 −161, [α]546 −185, [α]436 −338 (c 1.06, MeOH); UV (CHCl3) λmax (log ε): 241 nm (2.97); IR νmax (cm−1): 1809, 1573, 1498, 872; 1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3), see Table 1 and Table 2, respectively; HRESIMS m/z 315.1954 [M + H]+ (calcd for C20H26O3 + H+, 315.1955).

2.14. Kernolide Epoxide (5)

Compound 5 was prepared from 4 as a colorless oil (8 mg; 8%) from fractions 40–80 after column chromatography using a gradient of hexanes–EtOAc (100:0, 99:1, 49:1, 97:3) mixtures (100 mL each) obtaining 5 mL fractions. [α]D −79, [α]578 −82, [α]546 −95, [α]436 −160, [α]365 −253 (c 0.13, MeOH); UV λmax (log ε): 240 nm (2.97); IR νmax (cm−1): 1811, 1502, 1460, 872; 1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3), see Table 1 and Table 2, respectively; HRMS (TOF ES+) m/z 331.1917 [M + H]+ (calcd for C20H27O4 + H+, 331.1909).

2.15. Conformational Analysis

Models of the derivatives 2, 2a, 2b, 3, and 5 with the H-3α- and H-3β-configuration, as well as the hypothetical intermediaries II and IIa related to the obtention of 2 and 2a were independently constructed in silico using the Spartan ’04 program and subjected to Monte Carlo conformational searches within a 10 kcal/mol energy window, employing the Merck Molecular Force Field (MMFF94) as implemented in Spartan’04. Conformers within a 0–5 kcal/mol energy range were selected for each compound and subsequently subjected to geometry optimization at the DFT B3LYP-D3BJ/6-31G(d,p) level of theory using the Gaussian 16 program, with visualization performed in GaussView 6.0. The H2–C2–C3–H3 dihedral angles were measured from the global minimum conformer of each compound to predict vicinal proton–proton coupling constants (3JH,H). Thus, the measured dihedral angles were processed using the MestReJ tool (Mnova, Version 1.1, 2004), as well as by direct calculation with the Karplus equation. Details of conformers within the 0–3 kcal/mol energy range and the thermochemical analysis for these compounds are provided in the Supplementary Material (Figures S74–S87 and Tables S3–S16). Geometry optimizations required approximately 7 h of CPU time per conformer, using an Intel Xeon ES-2680 v3 processor with 110 GB RAM operating at 2.5 GHz × 48 cores.

2.16. Single-Crystal X-Ray Diffraction Analysis of 3

Single-crystal X-ray intensity data collection was carried out at 200 K with a four-circle kappa-axis Bruker D8 Venture diffractometer equipped with Mo wavelength X-ray microsource and photon III C14 detector. The structural solution involved a dual-method approach, employing SHELXT for initial solving, followed by refinement using full-matrix least-squares methods against F2 conducted by XL with Olex2 and SHELXle. Anisotropic displacement parameters were applied to refine all non-hydrogen atoms. Hydrogen atoms underwent isotropic refinement at calculated positions, employing a riding model. C21H30O5, Mw = 362.45, orthorhombic, space group P212121; dimensions: a = 8.7445(5) Å, b = 11.6130(6) Å, c = 18.5337(9) Å, V = 1882.09(17) Å3; Z = 4; µ = 0.09 mm−1; 80,600 reflections measured at 200 K; independent reflections: 4330 [3980 I > 2σ(I)]; data were collected up to a 2Θmax value of 55.1° (99.6% coverage). Number of variables: 240; R1 = 0.032, wR2 = 0.086, S = 1.06; highest residual electron density 0.17 eÅ–3.
Crystallographic data (excluding structure factors) have been deposited at the Cambridge Crystallographic Data Centre. Copies of the data can be obtained free of charge on application to the CCDC at https://www.ccdc.cam.ac.uk/data_request/cif, accessed on 29 August 2025.

3. Results and Discussion

Kerlinic acid (1) was isolated from Salvia melissodora as colorless crystals. The 1H NMR spectra showed the signal pattern of the furan moiety as a triplet at δ 7.35 (J = 1.5 Hz) a broad singlet at δ 7.20, and a doublet of doublets at δ 6.25 (J = 1.8, 0.9 Hz). The vinyl proton (H-3) was attributed to the broad singlet at δ 5.64, while the H-6 resonance was attributed at δ 3.48 (doublet of doublets, J = 11.6, 4.7 Hz). The remaining resonances were observed in the δ 2.38–0.73 range. The 13C spectrum revealed 20 signals, of which the carboxylic acid carbon (C-19) appeared at δ 180.5, the resonances from furan carbons were observed in the δ 143.0–111.0 range, and the vinyl system signals were observed at δ 136.2 (C-3) and 127.9 (C-4), while the C-6 signal appeared at δ 76.1. The remaining resonances were observed in the δ 53.8–15.7 range. These data were in agreement with the literature (Figures S1–S5) [18].
Kerlinic acid (1) has been chemically correlated with melissodoric acid by oxidative means since the furan ring allows lactonization [18]; notwithstanding, compound 1 also possesses an OH group in ring B and an β,γ-unsaturated carboxylic acid functional group in ring A, which are helpful for chemical derivatizations, thus obtaining an increased variety of potential derivatives. Based on the knowledge of furan reactivities, an oxidation reaction can be quickly promoted to gain structural diversity [28]. On the other hand, retention of this moiety along a synthetic way could result in interest being applied to future targets. Due to the highlighted potential of furan as a scaffold to promote compounds of chemical and biological interest [38], selective oxidation methodologies are pertinent to be explored. Thus, establishing regioselective oxidation methodologies is essential for suggesting rationalized synthetic strategies in which furan and other oxidable motifs coexist.
For the above, compound 1 was oxidized using MCPBA in sight to promote oxidation products, preserving the furan motif. Our first effort considered similar conditions as those suggested in the literature when the kerlinic acid (1) was oxidized to melissodoric-type derivatives, and an epoxide kerlinic acid derivative was obtained as a minor product [18]. Thus, derivative 1 reacted with 3 eq of MCPBA during 1 h to generate a complex mixture of products (Table 3, entry 1), whose 1H NMR revealed resonances in the δ 7.00–5.80 range related to the oxidation of the furan moiety, suggesting unfavorable conditions to promote oxidation of 1 preserving the furan moiety. It follows that the concentration of used MCPBA was reduced to 1 eq (entry 2), which favors a complex mixture of products, where the major products were related to melissodoric acid-type derivatives. A chromatographic process afforded the isolation of a minor product (2) as a colorless crystal (m.p. 67–69 °C) whose HRMS revealed a molecular ion of 371.1821 (calcd 371.1829 for C20H28O5 + Na+). The 1H NMR spectrum (Table 1) showed that the signal pattern from the furan ring remained (δ 7.34–6.20). The resonance of H-3α was observed as a broad triplet at δ 4.00 (J = 3.0 Hz), revealing the oxidation of the β,γ-unsaturated carboxylic acid motif. The H-6 resonance shifted to δ 3.72 as a doublet of doublets (J = 9.3, 7.2 Hz), suggesting the obtention of a lactone moiety. The rest of the resonances were observed in the δ 2.34–0.90 range and associated with the diterpene skeleton (Figure S30). The 13C NMR (Table 2) revealed the 20 expected signals related to the diterpene skeleton, including those from the furan moiety in the δ 143.0–111.0 range. Herein, the C-19 shifted to δ 172.1, confirming a lactone moiety. The C-3 and C-6 carbon signals appeared at δ 73.2 and 69.8, respectively. The C-4 carbon signal was observed at δ 66.8. The remaining carbon resonances were observed in the δ 38.8–15.4 range (Figure S33). The IR spectrum (Figure S36) showed a vibrational band at 1790 cm−1, in favor of the formation of a β-lactone. The optical rotation provided a dextrogyre value of [α]D +9 (c 0.62, MeOH). These data were in agreement with the obtention of lactone 2 (Figure 1), whose systematic nomenclature is (+)-6-(2-(furan-3-yl)ethyl)-3,9-dihydroxy-2a,6,7-trimethyloctahydro-1H,4H-naphtho [1,8a-b]oxet-1-one.
This product suggested that obtaining oxidized derivatives from kerlinic acid (1) while preserving the furan moiety could be feasible. Thus, oxidation of 1 was achieved using 1 eq of MCPBA at a lower temperature (−3 °C) and longer reaction time (4.5 h), as set out in Table 3 (entry 3). After column chromatography from the crude reaction, compound 2 was obtained in a 24% yield, as well as furan oxidized reaction products and starting material. According to this finding, a systematic reaction time increment was carried out, maintaining 1 eq of MCPBA as the oxidant at −3 °C up to 24 h reaction time. Herein, the starting material was completely consumed when the reaction time was 21 h (Table 3, entry 4) affording a complex mixture of oxidized products. After chromatographic process, a slight increase in yield of 2 was observed. To favor the regioselective oxidation of 1, a significant decrease in reaction temperature to −50 °C was tested, providing compound 2 with a 40% yield, corresponding to the best yield herein gained (entry 5). When the reaction occurred at this temperature and the reaction time was varied, an absence of yield increment was noticed for reaction times over 0.6 h. According to the experimental results, an increase in temperature or reaction time could disfavor regioselective oxidation; in consequence, these reaction conditions result in kinetic products [54].
The regioselective oxidation herein studied could be linked with strategical intermolecular interactions, according to the literature. Interestingly, the literature suggests that a hydrogen bond between the carboxylic acid motif from monocyclic acids and MCBPA could favor selectivity, favoring stereoselective epoxidation at the same face where the interaction occurs [55]. Also, the feasibility of intermolecular interactions between acyclic homoallylic alcohols and oxidant agents can lead to regioselective oxidation on their double bond [56,57,58,59,60,61]. Thus, we studied the influence of these groups using strategic derivatives of 1.
Two esterified derivatives at OH-6 were considered to explore the homoallylic influence of this moiety, namely the acetyl derivative 1a and the benzoate derivative 1b. Thus, the acetylation reaction of 1 yielded 1a as colorless crystals (m.p. 172–174 °C). The 1H NMR data revealed the H-6 at δ 4.77 as a doublet of doublets (J = 11.7, 4.8 Hz) and a singlet at δ 2.07 from the OAc group (Figure S7). The 13C NMR data were congruent with those described in the literature [18] (Figure S10). By its part, the derivative 1b was obtained in 64% yield as a colorless oil, whose 1H NMR spectrum revealed the H-6 at δ 5.06 as a doublet of doublets (J = 11.6, 4.6 Hz) and the expected resonances of benzoyl group in the δ 8.08–7.41 range (Figure S13) [62]. The 13C NMR displayed 25 signals (Figure S16), including a carbon signal at δ 166.0 and four signals in the δ 133.2–128.5 range, attributed to the newly linked moiety. Finally, a methylation reaction of 1 yielded kerlinic acid methyl ester (1c) (Figures S22–S29) [18]. The 13C NMR spectrum revealed 21 signals, including the one attributed to the methyl ester group (OMe) at δ 51.7.
These compounds were individually submitted to an oxidation reaction with MCPBA under the best oxidation conditions described herein (Figure 1). The oxidation of 1a yielded 2a as a colorless oil in 19% yield after purification by column chromatography. The IR spectrum revealed a C=O vibration at 1815 cm−1, suggesting the presence of a β-lactone product. The 1H NMR data showed the preservation of the furan ring and significant chemical shift changes at the H-3 resonance at δ 3.98 ppm (dd; J = 3.6, 2.2 Hz) (Figure S38). In the 13C NMR spectrum (Figure S40), the C-3 and C-4 resonances were observed at δ 73.0 and 80.0, respectively. Similarly, 1b yielded 2b as colorless oil in 14% after chromatographic purification. Herein, the formed β-lactone was also evidenced by the IR band at 1815 cm−1. The 1H NMR spectrum (Figure S43) showed the H-3 at δ 3.99 (dd; J = 3.6, 2.7 Hz). The 13C NMR spectrum (Figure S44) revealed the C-3 and C-4 resonances at δ 73.1 and 80.1, respectively, suggesting regioselective oxidation at the double bond. It follows that oxidation of 1c with MCPBA yielded 3 in 29% yield. Herein, the formation of an oxirane pattern was favored. The 1H NMR spectrum (Figure S49) revealed the H-3 resonance at δ 2.93 (brd; J = 5.0 Hz) and the H-6 at δ 3.68 as a multiple signal. The 13C NMR (Figure S53) showed the C-3 and C-4 resonances at 63.0 and 63.4 ppm, respectively. The signal assignations of the 13C spectrum were supported by an HETCOR experiment.
According to these results, the hypothetical influence of the carboxylic acid or homoallylic (OH-6) motifs from 1 in the reaction course was discarded, as the afore mentioned intermolecular interactions could be unfavored probably due to steric factors.
Complementary, derivative 4 was prepared by lactonization of kerlinic acid (1) with p-toluensulfonic acid and triethylamine [63], as colorless crystals (m.p. 88–89 °C) in 57% yield (Figures S59–S65). The IR of the reaction product showed the expected vibrational band at 1809 cm−1 related to the β-lactone moiety, while the 1H and 13C NMR revealed the preserved furan and double bond motifs (see Table 1 and Table 2). According to the origin of this compound, we propose to name it kernolide (4). This derivative was oxidized with MCPBA, and the post-reaction mixture was column chromatographed to yield the respective epoxide derivative 5 in 8% yield (Figures S66–S73). The 1D NMR spectra revealed the presence of an oxirane moiety since H-3 resonances were observed as a broad doublet at δ 3.06 (J = 4.8 Hz) in 1H. This is consistent with a β-epoxidation, as expected due to steric obstruction by the lactone motif. The C-3 and C-4 resonances appeared at δ 60.7 and 59.7, respectively, in 13C. As seen, the yields of the products are reduced, which is deeply related to the fact that kinetic products are obtained in all cases [64,65]. Despite this situation representing a limitation, our methodology may lead to rapid and facile explorations aimed at determining the relevance of furane derivatives in various scientific areas, including biological [37,38], chemical [19,20,21,22,23,24,25], and materials sciences [35,36].
Efforts of crystallization of compounds herein obtained gave suitable crystals for X-ray diffraction studies of compound 3 (Figure 2). Herein, the conformational preferences of this compound were visualized, where the epoxide adopted the beta configuration while the carbonyl group appeared oriented towards the alpha face. This result enables the visualization of the conformational preferences of its carbonyl moiety as well as the chemical environment of both alpha and beta faces on the clerodane skeleton, evidencing steric influences in the alpha-face that could favor epoxidation in the opposite plane. The J coupling value at H-3 recorded in 3, as well as that for 2, 2a, 2b, and 5, also agrees with this observation. Consequently, it can be deduced that the steric environment at the alpha-face in these compounds predominates over potential intermolecular hydrogen bonds, as those suggested in the literature, thus giving the observed stereoselective products at the C-3 position. Complementarily, the structure from X-ray diffraction analysis was useful to compare its calculated JH3α/H2β value by the Karplus curve [66,67,68] with the experimental J value. The calculations resulted in JH3α/H2β = 5.67 Hz and JH3α/H2α = 0.69 Hz (Table S1), closely similar to that measured in the 1H NMR spectrum. The MestReJ tool, embedded in the Mnova software, provided similar results (Table S1).
These experimental results allowed us to approach the mechanism involved in the regioselective oxidation of 1 to yield 2 (Scheme 1). Herein, MCPBA interacts through the beta face of the double bond in diterpene (I) to produce an epoxide intermediate (II) [55]. Afterward, the acidity in the reaction media catalyzes the epoxide opening to give intermediate (III), with the imminent attack of the carboxylate at C-4 to yield a β-lactone moiety (2) [39,69]. The formation of a hypothetical intermediate IIa from Ia is discarded due to steric factors. DFT calculations supported this mechanistic proposal. Herein, the respective hypothetical epoxide intermediate (II) that promotes the obtention of 2 and 2a was analyzed at the B3LYP-D3BJ/6-31G(d,p) level of theory, a suitable computational strategy for analyzing conformational preferences in diterpene compounds [70,71]. The respective IIa intermediaries were also included. Herein, ∆G = 4.3668 kcal/mol was found when comparing the energies of the global minimum conformers II and IIa related to the mechanism to yield 2; therefore, II should be the preferred intermediate. For its part, a ∆G = 2.2860 kcal/mol was determined for those II and IIa related to 2a, thus contributing to the tendency mentioned above (Table S2). The same results were also observed when hypothetical intermediates II and IIa related to 3 were analyzed, since ∆G = 4.4195 kcal/mol was found in favor of intermediate II (Table S2). The global minimum for all calculated formulas (Figures S74–S87) were also used to compare their J value at H-3 with the experimental values (Table S1), resulting in comparable values, thereby supporting the H-3α configuration.
In turn, the systematic names of the derivatives 2, 2a, and 2b suggest complications when they need to be referred to. According to the genus of the plant (Salvia) where the precursor was isolated and following the strategy of naming organic natural products and their derivatives simplistically, we named lactone 2 as salviaolide, while compounds 2a and 2b were named as salviaolide acetate and salviaolide benzoate, respectively. It is good to highlight that Salvia melissodora actually possesses two synonyms: S. dugesii and S. rupicola [72,73].
In conclusion, regioselective oxidation products are feasible using kerlinic acid (1) as the precursor when MCPBA is used as the oxidant agent. Lowering the temperature in the reaction is essential to provide oxidized products, preserving the furan moiety. The influence of the carboxylic acid and the homoallylic hydroxyl functional groups was discarded since the steric effect at the alpha-face dominates the reaction process. According to the enantiopurity of the precursor, stereoselectivity is expected. A reaction mechanism is suggested and supported by experimental means, as well as by X-ray diffraction analysis of the derivative 3 and complemented with computational calculations of hypothetical intermediates in the oxidation of 1 and 1a to give 2 and 2a. The obtention of all derivatives discussed herein can be useful examples of the applicability of the current reaction conditions. Thus, this strategy provides the feasibility to promote oxidation in compounds containing a furan moiety, preserving this group and opening future options to continuing chemical modifications to gain novel and complex derivative compounds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions6030047/s1, Supplementary material (1D, 2D NMR, IR, and HRMS) associated with this article can be found. Figure S1: 1H NMR spectrum of kerlinic acid (1) (300 MHz, CDCl3). Figure S2: COSY spectrum of kerlinic acid (1) (300 MHz, CDCl3). Figure S3: NOESY spectrum of kerlinic acid (1) (300 MHz, CDCl3). Figure S4: 13C NMR spectrum of kerlinic acid (1) (75 MHz, CDCl3). Figure S5: HSQC spectrum of kerlinic acid (1) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S6: IR spectrum of kerlinic acid (1). Figure S7: 1H NMR spectrum of kerlinic acid acetate (1a) (400 MHz, CDCl3). Figure S8: COSY spectrum of kerlinic acid acetate (1a) (400 MHz, CDCl3). Figure S9: NOESY spectrum of kerlinic acid acetate (1a) (400 MHz, CDCl3). Figure S10: 13C NMR spectrum of kerlinic acid acetate (1a) (100 MHz, CDCl3). Figure S11: HETCOR spectrum of kerlinic acid acetate (1a) (400 MHz for 1H/100 MHz for 13C, CDCl3). Figure S12: IR spectrum of kerlinic acid acetate (1a). Figure S13: 1H NMR spectrum of kerlinic acid benzoate (1b) (300 MHz, CDCl3). Figure S14: COSY spectrum of kerlinic acid benzoate (1b) (300 MHz, CDCl3). Figure S15: NOESY spectrum of kerlinic acid benzoate (1b) (300 MHz, CDCl3). Figure S16: 13C NMR spectrum of kerlinic acid benzoate (1b) (75 MHz, CDCl3). Figure S17: HSQC spectrum of kerlinic acid benzoate (1b) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S18: HMBC spectrum of kerlinic acid benzoate (1b) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S19: IR of kerlinic acid benzoate (1b). Figure S20: High-resolution mass spectrogram of kerlinic acid benzoate (1b) (electrospray ionization). Figure S21: Elemental composition report of kerlinic acid benzoate (1b) (electrospray ionization). Figure S22: 1H NMR spectrum of kerlinic acid methyl ester (1c) (400 MHz, CDCl3). Figure S23: COSY spectrum of kerlinic acid methyl ester (1c) (400 MHz, CDCl3). Figure S24: NOESY spectrum of kerlinic acid methyl ester (1c) (400 MHz, CDCl3). Figure S25: 13C NMR spectrum of kerlinic acid methyl ester (1c) (100 MHz, CDCl3). Figure S26: HETCOR spectrum of kerlinic acid methyl ester (1c) (400 MHz for 1H/100 MHz for 13C, CDCl3). Figure S27: IR spectrum of kerlinic acid methyl ester (1c). Figure S28: High-resolution mass spectrogram of kerlinic acid methyl ester (1c) (electrospray ionization). Figure S29: Elemental composition report of kerlinic acid methyl ester (1c) (electrospray ionization). Figure S30: 1H NMR spectrum of salviaolide (2) (300 MHz, CDCl3). Figure S31: COSY spectrum of salviaolide (2) (300 MHz, CDCl3). Figure S32: NOESY spectrum of salviaolide (2) (300 MHz, CDCl3). Figure S33: 13C NMR spectrum of salviaolide (2) (75 MHz, CDCl3). Figure S34: HSQC spectrum of salviaolide (2) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S35: HMBC spectrum of salviaolide (2) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S36: IR spectrum of salviaolide (2). Figure S37: High-resolution mass spectrogram of salviaolide (2) (electrospray ionization). Figure S38: 1H NMR spectrum of salviaolide acetate (2a) (300 MHz, CDCl3). Figure S39: COSY spectrum of salviaolide acetate (2a) (300 MHz, CDCl3). Figure S40: 13C NMR spectrum of salviaolide acetate (2a) (75 MHz, CDCl3). Figure S41: IR spectrum of salviaolide acetate (2a). Figure S42: High-resolution mass spectrogram of salviaolide acetate (2a) (electrospray ionization). Figure S43: 1H NMR spectrum of salviaolide benzoate (2b) (300 MHz, CDCl3). Figure S44: 13C NMR spectrum of salviaolide benzoate (2b) (75 MHz, CDCl3). Figure S45: HSQC spectrum of salviaolide benzoate (2b) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S46: IR spectrum of salviaolide benzoate (2b). Figure S47: High-resolution mass spectrogram of salviaolide benzoate (2b) (electrospray ionization). Figure S48: Elemental composition report of salviaolide benzoate (2b) (electrospray ionization). Figure S49: 1H NMR spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz, CDCl3). Figure S50: COSY spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz, CDCl3). Figure S51: NOESY spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz, CDCl3). Figure S52: TOCSY spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz). Figure S53: 13C NMR spectrum of kerlinic acid methyl ester epoxide (3) (75 MHz, CDCl3). Figure S54: HSQC spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S55: HMBC spectrum of kerlinic acid methyl ester epoxide (3) (300 MHz for 1H/75 MHz for 13C, CDCl3). Figure S56: IR spectrum of kerlinic acid methyl ester epoxide (3). Figure S57: High-resolution mass spectrogram of kerlinic acid methyl ester epoxide (3) (electrospray ionization). Figure S58: Elemental composition report of kerlinic acid methyl ester epoxide (3) (electrospray ionization). Figure S59: 1H NMR spectrum of kernolide (4) (400 MHz, CDCl3). Figure S60: COSY spectrum of kernolide (4) (400 MHz, CDCl3). Figure S61: NOESY spectrum of kernolide (4) (400 MHz, CDCl3). Figure S62: 13C NMR spectrum of kernolide (4) (100 MHz, CDCl3). Figure S63: HETCOR spectrum of kernolide (4) (400 MHz for 1H/100 MHz for 13C, CDCl3). Figure S64: IR spectrum of kernolide (4). Figure S65: High-resolution mass spectrogram of kernolide (4) (electrospray ionization). Figure S66: 1H NMR spectrum of kernolide epoxide (5) (400 MHz, CDCl3). Figure S67: COSY spectrum of kernolide epoxide (5) (400 MHz, CDCl3). Figure S68: NOESY spectrum of kernolide epoxide (5) (400 MHz, CDCl3). Figure S69: 13C NMR spectrum of kernolide epoxide (5) (100 MHz, CDCl3). Figure S70: HETCOR spectrum of kernolide epoxide (5) (400 MHz for 1H/100 MHz for 13C, CDCl3). Figure S71: IR of kernolide epoxide (5). Figure S72: High-resolution mass spectrogram of kernolide epoxide (5) (electrospray ionization). Figure S73: Elemental composition report of kernolide epoxide (5) (electrospray ionization). Figure S74: Calculated conformers of the intermediate IIa in the oxidation of 1 in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set Figure S75: Calculated conformers of the intermediate II in the oxidation of 1 in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S76: Calculated conformers of the intermediate IIa in the oxidation of 1a in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S77: Calculated conformers of the intermediate II in the oxidation of 1a in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S78: Calculated conformers of the intermediate IIa in the oxidation of 1c in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S79: Calculated conformers of the intermediate II in the oxidation of 1c in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S80: Calculated conformers of the H-3β of product 2 in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S81: Calculated conformers of the H-3α of product 2 in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S82: Calculated conformers of the H-3β of product 2a in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S83: Calculated conformers of the H-3α of product 2a in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S84: Calculated conformers of the H-3α of product 2b in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S85: Calculated conformers of the H-3β of product 2b in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S86: Calculated conformers of the intermediate IIa in the oxidation of 4 in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Figure S87: Calculated conformers of the intermediate II in the oxidation of 4 (corresponding to 5) in the 0–3 kcal/mol energy gap with B3LYP-D3BJ/6-31G(d,p) basis set. Table S1: Comparison of the calculated J values at H-3 of the respective H-3α- and H-3β-diastereomers of compounds 2, 2a, 2b, 3, and 5 with experimental values. Table S2: Comparison of the energy values from global minimum conformers of 1-IIa, 1-II, 1a-IIa, 1a-II, 3-epi 3, and 3. Table S3: Thermochemical analysis of intermediary IIa in the oxidation of 1. Table S4: Thermochemical analysis of intermediary II in the oxidation of 1. Table S5: Thermochemical analysis of intermediate IIa of the oxidation of 1a. Table S6: Thermochemical analysis of intermediate II of the oxidation of 1a. Table S7: Thermochemical analysis of intermediate IIa of the oxidation of 1c. Table S8: Thermochemical analysis of intermediate II of the oxidation of 1c. Table S9: Thermochemical analysis of 2-H-3β. Table S10: Thermochemical analysis of 2-H-3α. Table S11: Thermochemical analysis of 2a-H-3β. Table S12: Thermochemical analysis of 2a-H-3α. Table S13: Thermochemical analysis of 2b-H-3β. Table S14: Thermochemical analysis of 2b-H-3α. Table S15: Thermochemical analysis of the diastereomer α-epoxide of 5. Table S16: Thermochemical analysis of the diastereomer β-epoxide of 5.

Author Contributions

Formal analysis, J.M.; Investigation, E.E.S.-G., A.J.O.-O., A.T.-A., M.A.C.-O., G.R.-G., B.Y.B.-G. and C.M.C.-G.-R.; Writing—original draft, E.E.S.-G. and A.T.-A.; Writing—review & editing, M.A.G.-H., C.T. and R.E.d.R.; Supervision, A.T.-A., M.A.G.-H., C.T. and R.E.d.R. All authors contributed equally to this work. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially funded by CIC-UMSNH and FCCHT123_ME-4.1-0008.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Acknowledgments

E.E.S.-G., A.J.O.-O. and A.T.-A. are grateful to CONACHYT-Mexico (764722, 800679) for doctoral and postdoctoral scholarships, respectively. We also acknowledge I.B.T. Lorena Ramírez-Reyes from Unidad de Genómica, Proteómica y Metabolómica, Laboratorio Nacional de Servicios Experimentales, Cinvestav-IPN for the high-resolution mass spectrometry analyses and Q.F.B. Verónica Reyes Olivares for optical rotation measurements.

Conflicts of Interest

The authors declare no conflicts of interest.

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Reactions 06 00047 g001
Figure 1. Chemical structures of kerlinic acid (1) and its derivatives 1a–c, 2–5.
Figure 1. Chemical structures of kerlinic acid (1) and its derivatives 1a–c, 2–5.
Reactions 06 00047 g001
Reactions 06 00047 g002
Figure 2. X-ray structure of compound 3.
Figure 2. X-ray structure of compound 3.
Reactions 06 00047 g002
Reactions 06 00047 sch001
Scheme 1. Putative mechanism for the regioselective oxidation of kerlinic acid (1).
Scheme 1. Putative mechanism for the regioselective oxidation of kerlinic acid (1).
Reactions 06 00047 sch001
Table 1. 1H NMR spectroscopic data of compounds 1b, 2, 2a, 2b, 3–5 (CDCl3, δ in ppm, J in Hz).
Table 1. 1H NMR spectroscopic data of compounds 1b, 2, 2a, 2b, 3–5 (CDCl3, δ in ppm, J in Hz).
H1b22a2b345
11.66 (m)1.76 (m)
1.57 (m)
1.65 (m)2.00 (m)
1.84 (m)		1.75 (m)
1.65 (m)		1.81 (m)
1.59 (m)
22.34 (m)
1.74 (m)		1.80 (m)
1.62 (m)		1.77 (m)1.80 (m)1.86 (m)
1.35 (m)		2.28 (m)1.82 (m)
1.51 (m)
35.63 (brs)4.00 (brt; 3.0)3.98 (dd; 3.6, 2.2)3.99 (dd; 3.6, 2.7)2.93 (brd; 5.0)5.66 (brs)3.06 (brd; 4.8)
65.06 (dd; 11.6, 4.6)3.72 (dd; 9.3, 7.2)4.87 (dd; 11.0, 5.5)5.11 (dd; 10.8, 5.4)3.68 (m)4.90 (dd; 9.0, 3.2)4.93 (dd; 9.1, 2.8)
72.42 (m)
1.91 (m)		1.55 (m)1.80 (m)2.00 (m)
1.87 (m)		1.57 (m)
1.43 (m)		2.31 (m)
1.94 (m)		2.33 (m)
1.92 (m)
81.94 (m)1.63 (m)1.70 (m)1.79 (m)1.71 (m)1.79 (m)1.76 (m)
101.78 (m)2.20 (m)2.33 (m)2.38 (m)1.60 (m)1.77 (m)1.98 (m)
112.28 (m)
2.10 (m)		2.10 (m)
1.80 (m)		2.15 (m)
1.80 (m)		2.17 (m)
1.83 (m)		2.10 (m)
1.93 (m)		2.30 (m)2.13 (m)
1.93 (m)
122.33 (m)
1.75 (m)		2.23 (m)2.25 (m)
2.32 (m)2.28 (m)
2.08 (m)		2.01 (m)
1.80 (m)		1.84 (m)
1.51 (m)
146.27 (dd; 1.9, 0.9)6.24 (dd; 1.8, 0.9)6.25 (dd; 1.7, 0.9)6.27 (dd; 1.7, 0.9)6.22 (brs)6.26 (brs)6.24 (brs)
157.36 (brt; 1.7)7.34 (brt; 1.7)7.35 (brt; 1.7)7.36 (brt; 1.7)7.33 (brt; 1.7)7.36 (brt; 1.7)7.35 (brt; 1.7)
167.23 (brs)7.19 (brs)7.20 (td; 1.7, 0.9)7.22 (brs)7.17 (brs)7.20 (brs)7.20 (brs)
170.90 (d; 6.5)0.90 (d; 6.7)0.88 (d; 6.3)0.92 (d; 6.3)0.82 (d; 6.7)0.91 (d; 6.9)0.88 (d; 6.7)
181.67 (s)1.83 (s)1.57 (s)1.56 (s)1.47 (s)1.82 (s)1.45 (s)
200.85 (s)0.95 (s)0.97 (s)1.03 (s)0.56 (s)0.90 (s)0.86 (s)
3′, 7′8.08 (d; 7.4) 8.05 (d; 7.4)
4′, 6′7.41 (t; 7.4) 7.46 (t; 7.4)
5′7.54 (t; 7.4) 7.58 (t; 7.4)
OH-6 3.12 (d; 12.0)
OAc 2.10 (s)
OMe 3.77 (s)
Table 2. 13C NMR spectroscopic data of 1b, 2, 2a, 2b, 3, 4, and 5 (CDCl3, δ in ppm).
Table 2. 13C NMR spectroscopic data of 1b, 2, 2a, 2b, 3, 4, and 5 (CDCl3, δ in ppm).
Position1b22a2b345
138.638.136.536.538.537.837.7
217.816.916.716.716.217.517.5
3128.173.273.073.163.0127.960.7
4135.980.880.080.163.4131.159.7
553.366.864.464.554.062.362.8
677.069.871.972.273.972.772.0
733.936.633.033.038.334.133.8
834.934.533.833.935.133.933.6
938.838.838.738.738.137.637.3
1048.536.837.137.142.144.838.7
1126.524.024.124.023.126.823.3
1217.918.117.817.917.618.817.6
13125.2125.2125.0125.0125.2125.1125.0
14111.0111.0110.9110.9111.0110.9110.9
15143.0143.0142.8142.9142.9143.0143.0
16138.6138.6138.5138.5138.5138.6138.6
1715.615.415.115.215.716.316.0
1822.717.818.518.422.818.418.0
19179.0172.1170.0170.6176.3174.7174.2
2016.115.915.715.815.515.815.6
1′166.0 165.2
2′130.7 129.6
3′, 7′129.9 129.8
4′, 6′128.5 128.6
5′133.2 133.5
OAc 170.5
21.6
OMe 51.9
Table 3. Oxidation reaction of kerlinic acid (1) using MCPBA as the oxidant agent.
Table 3. Oxidation reaction of kerlinic acid (1) using MCPBA as the oxidant agent.
Reactions 06 00047 i001
EntryTemperature (°C)Time (h)Yield (%)
1 a251
2 b2514
3 b−34.524
4 b−32127
5 b−500.340
a Amounts of 3.0 eq or b 1.0 eq of MCPBA were used as the oxidant agent, and 3 mL of CHCl3-acetone (5:1) was used as the reaction solvent, under stirring. Yields were determined after isolation by column chromatography.
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Soto-Guzmán, E.E.; Oliveros-Ortiz, A.J.; Talavera-Alemán, A.; Calderón-Oropeza, M.A.; Rodríguez-García, G.; Bedolla-García, B.Y.; Gómez-Hurtado, M.A.; Cerda-García-Rojas, C.M.; Marrot, J.; Thomassigny, C.; et al. Kerlinic Acid Preserves the Furan Moiety in Regio- and Diastereoselective Oxidations Giving Beta-Lactones and Oxirane Derivatives. Reactions 2025, 6, 47. https://doi.org/10.3390/reactions6030047

AMA Style

Soto-Guzmán EE, Oliveros-Ortiz AJ, Talavera-Alemán A, Calderón-Oropeza MA, Rodríguez-García G, Bedolla-García BY, Gómez-Hurtado MA, Cerda-García-Rojas CM, Marrot J, Thomassigny C, et al. Kerlinic Acid Preserves the Furan Moiety in Regio- and Diastereoselective Oxidations Giving Beta-Lactones and Oxirane Derivatives. Reactions. 2025; 6(3):47. https://doi.org/10.3390/reactions6030047

Chicago/Turabian Style

Soto-Guzmán, Eva E., Antonio J. Oliveros-Ortiz, Armando Talavera-Alemán, Mónica A. Calderón-Oropeza, Gabriela Rodríguez-García, Brenda Y. Bedolla-García, Mario A. Gómez-Hurtado, Carlos M. Cerda-García-Rojas, Jérôme Marrot, Christine Thomassigny, and et al. 2025. "Kerlinic Acid Preserves the Furan Moiety in Regio- and Diastereoselective Oxidations Giving Beta-Lactones and Oxirane Derivatives" Reactions 6, no. 3: 47. https://doi.org/10.3390/reactions6030047

APA Style

Soto-Guzmán, E. E., Oliveros-Ortiz, A. J., Talavera-Alemán, A., Calderón-Oropeza, M. A., Rodríguez-García, G., Bedolla-García, B. Y., Gómez-Hurtado, M. A., Cerda-García-Rojas, C. M., Marrot, J., Thomassigny, C., & Río, R. E. d. (2025). Kerlinic Acid Preserves the Furan Moiety in Regio- and Diastereoselective Oxidations Giving Beta-Lactones and Oxirane Derivatives. Reactions, 6(3), 47. https://doi.org/10.3390/reactions6030047

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