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Abstract

Objective

This study aims to convert cativic acid, which was isolated from Ageratina jocotepecana, into cistendiol (5), an analog of cistenolic acid isolated from Cistus symphytifolius. The position of hydroxyl at C-7 in compound 5 could be achieved by applying the Schenck reaction with singlet oxygen (¹O₂) through photooxidation reaction of 6. Additionally, epoxidation reaction of 1, followed by further reduction and acid treatment, can serve as another pathway to obtain compound 5.

Methods

Cativic acid was isolated from Ageratina jocotepecana flowers, reduction methodology was realized with THF and LiAlH₄, epoxidation reaction was carried out with mCPBA in CH₂Cl₂ and K₂CO₃, oxidation of alcohol with PCC in CH₂Cl₂ and MgSO₄, photooxidation reaction was realized with blue and white light using singlet oxygen (¹O₂) and photosensitizers such as eosin, methylene blue and Ru(bpy)₃(PF₆)₂ in acetonitrile. Geometry optimizations for transition states were performed using MMFF94 with Monte Carlo protocol, and G_DFT was used B3LYP/DGDZVP level of theory with Gaussian 09.

Results

Cistendiol was synthesized by photooxidation reaction of 6 with Ru(bpy)₃(PF₆)₂ and air such oxidant with a ratio of 8:1, while epoxidation of 1 further reduction and acid treatment afforded cistendiol with a ratio of 9:1, the ratio was determined by NMR, additionally the global minimum energy structures G_DFT calculated values supports the results described by NMR ratio. The stereochemistry was also confirmed by NOESY experiment and the comparison is in agreement with literature data.

Conclusion

Herein, we described the conversion of cativic acid isolated from Ageratina jocotepecana employing a new photooxidation methodology and classic epoxidation techniques, to produce an analog of cistenolic acid isolated from Cistus symphytifolius. The results, which include Supplemental material, enable comparison of stereochemistry, specifically the 13S for C-13 of Ageratina jocotepecana with other compounds such as cistenolic or salvic acid, which had been the subject of study by researchers.

Keywords

cativic acid cistenolic acid photooxidation epoxidation

Introduction

Labdane-type diterpenes are widely distributed compounds in nature that display numerous pharmacological activities.^1,2 Several of these compounds exhibit antifungal, antibacterial, cytotoxic, anti-inflammatory, or analgesic properties. These bicyclic-based skeletons occur naturally in two series of antipodal labdane, referred to as “normal” and the “ent”-labdanes.³

On the other hand, cativic acid [1, (−)-(5S,9S,10S,13S)-labd-7-en-15-oic acid] was initially extracted from the exudate of the subtropical tree Prioria copaifera, commonly known as the cativa tree,^4,5 and more recently from the leaves and flowers from Ageratina jocotepecana, this compound displays noteworthy antibacterial activity against Bacillus subtilis (MIC 0.15 mg/mL) and Staphylococcus aureus (MIC 0.78 mg/mL).

Furthermore, the 13S configuration of C-13 has been determined by vibrational circular dichroism.⁶ Previously, a study of Cistus symphytifolius species resulted in the identification of two labdane-type diterpenes, cativic acid (1) and cistenolic acid (2), both belonging to the “normal” series of labdanes (Figure 1). Additionally, the report also described the first labdane interconversion of cativic acid methyl ester by epoxidation reaction leading to cistenolic acid methyl ester, the chemical correlation indicated the same “normal” labdane absolute configuration. Acid 2 is the enantiomer of salvic acid (3) and assigned to the ent-labdane series, still with unknown configuration at C-13,⁷ which was firstly isolated in 1979.⁸ The absolute configuration of all stereocenters has been the subject of several publications, leading to the conclusion that salvic acid belongs to the ent-labadane series.^9–11 In particular, the analysis of stereochemistry of the C-13 allowed assign its absolute configuration in 2012. The 13R configuration was ultimately established thanks to reliable calculations using vibrational circular dichroism and X-ray diffraction studies of compound 3.¹² Encouraged by these results, the interconversion of natural products plays an important role in structural diversification.¹³ The synthetic transformations of labdanes provide interesting results that could lead to the development of more efficient, stereo-controlled derivatives displaying remarkable biological activities or explaining a biosynthetic pathway.^14,15

Figure 1.

Structures of cativic acid (1), cistenolic acid (2) and salvic acid (3).

The oxygen-dependent photosensitization reaction is extensively employed in natural products synthesis, and is found ubiquitously within nature.¹⁶

The transformation of cativic acid (1) 13S was achieved to produce the analog reduced product of cistenolic acid (2)¹⁷ using both classical chemical transformations and a photooxidation reaction.

This serves as a supplementary confirmation of the stereochemistry of C-13 in both enantiomer 2 with 13S and enantiomer 3 with 13R, to our knowledge there is only one report for the determination of the C-13 configuration.¹²

Results and Discussion

Cistenolic acid (2, [α]_D −21.5) is a natural compound exclusively found in Cistus symphytifolius. It is the enantiomer of salvic acid (3, [α]_D + 21.5),⁷ based on the results obtained in this study allowed the determination of absolute configuration of acid 3, which had been the subject of study by researchers. The purpose of the study was to use cativic acid from Ageratina jocotepecana as a source for converting it into an analog of cistenolic acid (2), being a Supplemental material to compare stereochemistry of C-13 as 13S.

Diterpene 1 was initially epoxidized with mCPBA in CH₂Cl₂ to provide the epoxide 4 as mixture of diastereomers alpha:beta in C-7 and C-8 with an 85% yield. Analysis of the peak attributed to H-7 on the ¹H NMR spectrum revealed a ratio 9:1 between the (7R,8S) and (7S,8R) configurations, leading us to favor the (7R,8S) stereoisomer based on steric hindrance during peracid approach.

The reduction of the carboxylic functional group of 4 by LiAlH₄ followed by acid treatment afforded the cistendiol product (5) in one pot reaction with 26% of yield after purification by silica gel (Scheme 1).

Scheme 1.

Reagents and conditions: (i) mCPBA, K₂CO₃, CH₂Cl₂, 3 h, R.T.; 85%, (7R,8S)-4a:(7S,8R)-4b 9:1; (ii) LiAlH₄, THF, 4 h then HCl 10%; 26%, (7R)-5a:(7S)-5b 9:1.

The ratio of 7R and 7S isomers remained constant 9:1 after these procedures. The main isomer was confirmed to have (7R)-5 configuration through the comparison of the ¹H and ¹³C NMR data with previous reports.¹⁷ The results were further corroborated by the NOESY experiment, which revealed no correlation between H-7 and H-9, supporting the opposite orientation corresponding to configuration 7R of derivative 5 (Supplemental material).

In an effort to improve both, the yield and diastereoselectivity of achieving compound 5, other alternatives pathways were explored (Scheme 2). Reduction of compound 1 using LiAlH₄ was realized to give the alcohol 6 with a yield of 94%. Subsequently, oxidation of compound 6 using PCC resulted in the formation of aldehyde 8 with 92% of yield.¹⁸

Scheme 2.

Reagents and conditions: (i) LiAlH₄, THF, 4 h, 94%; (ii) PCC, MgSO₄, CH₂Cl₂, 5 h, 92%; (iii) mCPBA, K₂CO₃, CH₂Cl₂; 3 h, R.T, 93% for 7, 7a:7b 9:1 or 12 h, 0 °C, 70% for 9, 9a:9b 9:1.

The epoxidation reaction of 6 and 8 in dichloromethane with mCPBA was evaluated. Epoxidation of 6 afforded a mixture of epoxides 7 with a yield of 93% and a similar ratio 9:1. The epoxidation of aldehyde 8 at room temperature resulted in the corresponding 4 with 88% of yield, or the expected 9 with a 70% of yield at 0 °C with the same ratio 9:1. The configuration of the major isomer for epoxides 4, 7 and 9 was confirmed by the NOESY experiment, revealing the correlation between Me-17 with Me-19 and Me-20 (Supplemental material).

Molecular modeling of transition states structures of alpha and beta epoxides 4a and 4b for the cativic acid (1), in the presence of mCPBA, was performed to illustrate stereoselectivity and stability based on Gibbs free energy expression for minimum energy conformations. The results indicated a concerted mechanism reaction that includes the formation of a cyclic intermediary followed by carbonyl protonation via peroxyacid to produce the epoxide product.¹⁹

The global minimum energy conformers for 4a, 4a', 4b and 4b' were found by identifying two transition states for each molecule with varying hydrogen atom orientations (Figure 2). The energy difference between the transition states corresponding to favored and disfavored epoxide products, indicates that the alpha epoxide orientation 4a-a is favored with 6.11 kcal/mol for 4a'-a, 16.69 kcal/mol for 4b-a and 4.41 kcal/mol for 4b'-a.

Figure 2.

Transition states of epoxides of cativic acid (1) employing mCPBA, global minimum energy structures for 4a-a, 4a'-a, 4b-a and 4b'-a (kcal/mol).

Epoxides 7a and 7b were synthetized in the epoxidation reaction using alcohol 6 and mCPBA, with the same preference for the alpha position with a 9:1 ratio, to explain this stereoselectivity, molecular modeling of the transition states of alfa and beta epoxides 7a and 7b were realized (Figure 3). The results showed that the alpha epoxide 7a-a was preferred with 6.06 kcal/mol for 7a'-a, 13.99 kcal/mol for 7b-a and 4.94 kcal/mol for 7b'-a, respectively, these calculated values results support the preference of alpha epoxide and the relationship observed in the ¹H NMR spectra when H-7 signals were analyzed.

Figure 3.

Transition states of epoxides of alcohol 6 employing mCPBA, global minimum energy structures for 7a-a, 7a'-a, 7b-a and 7b'-a (kcal/mol).

A comparable pattern was noted with the epoxides alpha 9a and beta 9b derived from the aldehyde 8. The global minimum energy conformer for orientation alpha 9a-a was favored over the beta position epoxide (Figure 4), with a preference respecting energy values of 4.40 kcal/mol for 9a'-a, 14.04 kcal/mol for 9b-a and 6.15 kcal/mol for 9b'-a.

Figure 4.

Transition states of epoxides of aldehyde 8 employing mCPBA, global minimum energy structures for 9a-a, 9a'-a, 9b-a and 9b'-a (kcal/mol).

All calculations realized demonstrate that the alpha epoxide is the favored, being in agreement with the NMR results. The preference is attributed to steric hindrance of peracid approach with the allylic chain located in C-9 in a beta orientation.

As the separation of the diastereomers a/b of compounds 4, 5, 7 and 9 remained not possible by column chromatography, we changed the strategy in an attempt to improve diastereoselectivity and decided to obtain 5 by another pathway, namely a photooxidation reaction (Scheme 3). Unlike classical oxidation methods using stronger oxidizers, numerous reactions employ molecular oxygen (O₂) as green oxidant, such as the ene reaction discovered by Schenck.²⁰

Scheme 3.

Reagents and conditions: (i) Ru(bpy)₃(PF₆)₂, air, white light, in CH₃CN, 50%, 10a:10b 8:1 or in CH₂Cl₂, 40%, 10a:10b 1:0; (ii) (I) Ru(bpy)₃(PF₆)₂, air, white light, CH₃CN; (II) NaBH₄, MeOH, 2 h; 34% in two steps, 5a:5b 8:1.

The active form of molecular oxygen is formed in situ through a photosensitizer that absorbs energy to excite oxygen, resulting in an excited singlet state ¹O₂,²¹ which is involved in the oxidation reactions in certain natural products synthesis.²² The reactions between ¹O₂ and organic compounds involve: [4 + 2], ene, and [2 + 2] additions to alkenes,²³ the unbiased alkenes react with atmospheric oxygen under visible light irradiation with a photosensitizer to give allyl hydroperoxides.²⁴

Encouraged by the target position of hydroxyl group at C-7 in compound 5, we achieved the allylic oxidation of 6 through the Schenck reaction with singlet oxygen (¹O₂). We tested air or oxygen as the oxidant for alcohol 6 under photooxidation conditions, employing catalysts such as eosin, methylene blue or Ru(bpy)₃(PF₆)₂ (Table 1). Initially, the assay yielded a mixture of hydroperoxides 10a and 10b, with 10a being the principal product.

Table 1.

Reactions of Photooxidation of 6.

Entry	Catalyst	Solvent	Time	Oxidant^a	Yield (%)	Ratio 10a/10b
1	—	CH₃CN	24 h	O₂	—	—
2	Eosin 5 mol%	CH₃CN	40 h	O₂	65	1.3:1
3	Eosin 5 mol%	CH₃CN	72 h	O₂	68	1.7:1
4	Methylene blue 5 mol%	CH₃CN	18 h	O₂	44	4.2:1
5	Ru(bpy)₃(PF₆)₂ 10 mol%	CH₃CN	16 h	O₂	45	4.4:1
6	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₃CN	19 h	O₂	45	4.4:1
7	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₃CN	20 h	Air	50	8:1
8	Ru(bpy)₃(PF₆)₂ 5 mol%	Acetone	72 h	Air	46	2.6:1
9	Ru(bpy)₃(PF₆)₂ 5 mol%	EtOAc	24 h	Air	—	—
10	Ru(bpy)₃(PF₆)₂ 5 mol%	Toluene	24 h	Air	—	—
11	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₂Cl₂	5 days	Air	40	1:0
12	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₃CN	20 h	Air (Blue light)	63	1.3:1
13	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₃CN	Flow chemistry	Air (Blue light)	21	1:1
14	Ru(bpy)₃(PF₆)₂ 5 mol%	CH₃CN	Flow chemistry	Air	25	1:1

white light, except when indicated.

In particular, the mass spectrometry analysis of the mixture exhibited the molecular ion [M − OH]⁺ at m/z 307.2634 corresponding with the expected formula C₂₀H₃₅O₂. The ¹H NMR spectrum of 10a/10b presented a peak at 7.89 ppm, attributed to the proton signal of hydroperoxide. The ¹³C NMR spectrum exhibited a signal at 87.2 ppm, which is attributed to C-7 of 10a, showing significant deshifting compared to the equivalent carbon atom of 5 (74.3 ppm).

In a first time, the influence of the catalysts has been tested (Table 1, entries 2-6) for the photooxidation reaction of compound 6 in acetonitrile using white light (400–700 nm) under an O₂ atmosphere at room temperature. After purification, 65% yield of hydroperoxides mixture consisting of 10a:10b with a ratio of 1.3:1 was obtained using 5 mol% of eosin (entry 2). However, prolonging the reaction for 72 h (entry 3) did not significantly enhanced the results. The use of methylene blue at 5 mol% (entry 4) or Ru(bpy)₃(PF₆)₂ in the range of 10 mol% to 5 mol% (entries 5-6) achieved a higher ratio of 10a:10b of 4.2:1 to 4.4:1, but with lower yields at 44–45%. The first results encouraged us to continued experimentation with the use of ruthenium catalyst.

It is interesting to note, a variation in the source of oxidant from O₂ (bottle) to air induced a slight increase in yield to 50% and a notable stereoselectivity ratio up to 8:1 after 20 h of reaction (entry 7). Different solvents were evaluated (entries 8-11), and found that acetone led the product over 72 h of reaction with no notable change in the ratio compared with acetonitrile, while at 24 h, ethyl acetate and toluene solvents proved to be ineffective.

The reaction in dichloromethane was particularly interesting, despite extended reaction time: only the epimer 10a was acquired with a 40% yield (entry 11). All attempts to enhance yield or shorten reaction time failed, even with changes in oxygen sourcing or higher temperatures.

To further demonstrate the effect of wavelength, according to the maximum absorption of the catalyst Ru(bpy)₃(PF₆)₂, the reaction was conducted under conditions similar to entry 7, but with blue light (400-490 nm). The results obtained showed a higher yield of 63%, however with a reduced ratio to 1.3:1 (entry 12). Finally, the reaction of 6 was subjected to flow chemistry conditions with a photochemical reactor equipped with a light and power sources. However, the yields were poor and the ratio of 10a:10b was 1:1 (entries 13 and 14). Further optimization conditions (entry 7) afforded the best results, when the reaction was performed in acetonitrile as the solvent, air as oxidant, Ru(bpy)₃(PF₆)₂ as the catalyst under white light giving the compound 10 with an 8:1 ratio, which is similar to the ratio obtained by the epoxidation pathway (9:1). Additionally, a one pot reaction including of the photooxidation reaction followed by reduction in the presence of NaBH₄/MeOH, provided allylic alcohol 5 with a yield of 34%.

In addition, this study employs molecular modeling to examine the transition state of the photooxidation reaction for the alcohol 6 with singlet oxygen, which describes the stereoselectivity of hydroperoxides alpha 10a and beta 10b (Figure 5). The structures were built based on the previously reported concerted mechanism reaction,²² which involves the formation of a six-atom ring between the double bond, the allylic proton and the singlet oxygen, resulting in the allylic hydroperoxide.

Figure 5.

Transition states of photooxidation reaction of alcohol 6 with singlet oxygen, global minimum energy conformers for 10a-a and 10b-a in kcal/mol.

According to results, the alpha transition state 10a-a is preferred over the beta position 10b-a with a difference of 4.96 kcal/mol for the hydroperoxide reaction 10a-a with singlet oxygen. Molecular modeling analyses for epoxides and hydroperoxides, as well as the calculation of the global minimum energy structures G_DFT, supports the previously described results by NMR ratio and NOESY spectra correlations. This confirms the significance of steric hindrance in determining the stereoselectivity of the final products.

Conclusions

In this study, we present the first interconversion reaction of cativic acid, which was isolated from Ageratina jocotepecana, using two pathways: epoxidation and photooxidation reaction to afford the cistendiol the reduced product of cistenolic acid, which was previously only isolated from Cistus symphytifolius. Furthermore, has already determinate its configuration as 13S to cativic acid, providing a supplementary proof of the stereochemistry as 13S for cistendiol compared with their enantiomer salvic acid. The relationship of analytical values of cistendiol and their enantiomer is in agreement. Additionally, is a contribution to understanding a possible biochemical pathway for the synthesizing cistenolic acid from cativic acid in the Cistus symphytifolius species.

Experimental

General Experimental Procedures

Commercially grade chemicals were used. The 1D and 2D NMR spectra were acquired on Bruker AVANCE1 300MHz spectrometer. Chemical shifts (δ) were reported in parts per million (ppm), as internal reference was used TMS at 0.00 ppm. Coupling constants (J) are reported in Hertz (Hz). Silica gel Merck 60 (230−400 mesh) was used for column chromatography and reactions were monitored by TLC. HRESIMS were acquired on Xevo Q-Tof WATERS Quadrupole Hybrid Time-of-Flight Mass Spectrometer, Versailles France. In the Supplemental material are fully described the compounds 4–10.

Plant Materials

The procedure and isolation were realized as reported by del Rio et al⁶ Ageratina jocotepecana (B.L. Turner) specimens were collected during the flowering stage, on March-February, 2018, near km 51 of the Morelia-Carapan federal road no. 15. A voucher specimen (No.188459) is deposited at the Herbarium of Instituto de Ecología, A. C., Centro Regional del Bajío, Pátzcuaro, Michoacán, Mexico, where Prof. Jerzy Rzedowski identified the plant material.

Extraction and Isolation

Flowers from A. jocotepecana were macerated employing hexanes at room temperature 3 times (7 d each). After evaporating the solvents under reduced pressure, the dried extract was acquired. Aliquots of extracts were column chromatographed using mixtures of hexanes-EtOAc in ascending polarity, to afford cativic acid [1, (−)-(5S,9S,10S,13S)-labd-7-en-15-oic acid] from starting material (10-20%).

Reduction Methodology with LiAlH₄

Acid 1 (102.9 mg, 1 eq) dissolved in THF anhydrous (5 mL) under argon atmosphere, LiAlH₄ (16.57 mg, 1.3 eq) was added. After 4 h was quenched with HCl 10% (1 mL) and extracted with ethyl acetate (25 mL), organic layer washed with H₂O distilled (40 mL), aqueous solution of NaHCO₃ (60 mL) and H₂O distilled (60 mL), organic layer dried and filtered over MgSO₄, concentrated under reduced pressure to afford 6 (92.5 mg, 94%).

Epoxidation Methodology with mCPBA

Cativic acid (1, 40 mg) or alcohol (6, 86.5 mg, 1 eq) stirred in CH₂Cl₂ and K₂CO₃ (36.07 mg to 1 or 81.74 mg to 6 and 20.93 mg to 8, 2 eq) at R.T., mCPBA (27.03 mg to 1 or 61.24 mg to 6 and 15.68 mg to 8, 1.2 eq) was added and stirred for 3 h, in case of 8 (22 mg) at 0 °C 12 h, reaction was quenched with saturated solution of NaHCO₃ and extracted with ethyl acetate, organic layer was washed five times with aqueous NaHCO₃ (100 mL), H₂O distilled (60 mL) and dried over MgSO₄, concentrated under reduced pressure to afford a mixture by column chromatography of alpha:beta epoxides for 4 (35.9 mg, 85%), 7 (84 mg, 92%) or 9 (16.2 mg, 70%) with ratio 9:1 in all cases.

Oxidation Methodology with PCC

Compound 6 (143 mg, 1 eq) was stirred in CH₂Cl₂ (5 mL) and MgSO₄ (44.13 mg, 0.75 eq), PCC (158.07 mg, 1.5 eq) was added and stirred for 5 h. Solvent was evaporated carefully and pentane (20 mL) was added; solvent was filtered over celite and washed with pentane. The solvent was evaporated under reduced pressure to afford pure compound 8 (132 mg, 93%).

Photooxidation Methodology

To alcohol 6 (27.8 mg, 1 eq) was stirred in acetonitrile (2 mL), catalyst 5 mol% (4.08 mg) was added and stirred under white light until reaction complete, reaction quenched with solution of NaHCO₃ and extracted with ethyl acetate, organic layer washed with aqueous NaHCO₃ (60 mL) and H₂O distilled (60 mL), dried and filtered over MgSO₄, concentrated under reduced pressure and purified by column chromatography with a mixture of pentane:ethyl acetate to afford a mixture by column chromatography for alpha:beta hydroperoxide 10 (15.3 mg, 50%).

Preparation of Compound 5 from 4 or by Photooxidation Reaction of 6

I. Epoxide 4 (49 mg, 1 eq) stirred in THF anhydrous (5 mL) with argon atmosphere, LiAlH₄ (11.53 mg, 2 eq) was added, after 4 h the reaction was quenched with HCl 10% and extracted with ethyl acetate, organic layer washed two times with H₂O distilled (40 mL), aqueous NaHCO₃ (60 mL) and H₂O distilled (60 mL), dried over MgSO₄ and concentrated under reduced pressure, reaction purified by column chromatography with a mixture of pentane:ethyl acetate to afford compound 5 (12 mg, 26%) and epimer in C-7 as a mixture by column chromatography.

II. Alcohol 6 (35.5 mg, 1 eq) stirred in acetonitrile (2 mL), catalyst 5 mol% (5.21 mg) was added and stirred under white light, until reaction complete, reaction was reduced in situ with NaBH₄/MeOH (6.79 mg, 1.5eq), quenched with NaHCO₃ and extracted with ethyl acetate, organic layer washed with aqueous solution NaHCO₃ (60 mL) and H₂O distilled (60 mL), dried over MgSO₄ and concentrated under reduced pressure, reaction purified by column chromatography with a mixture of pentane:ethyl acetate to afford to afford compound 5 (12.8 mg, 34%) and epimer in C-7 as a mixture by column chromatography.

Molecular Modeling

Geometry optimizations for transition states from epoxides 4a, 4b, 7a, 7b, 9a, 9b and hydroperoxides 10a and 10b were carried out using MMFF94 force-field calculations in Spartan'14. The E_MMFF data used as convergence criterion followed by a search with Monte Carlo protocol without considering an energy cutoff. Minimum energy structures were found, Gaussian 09 was used at the B3LYP/DGDZVP level theory. No solvent effects were considered in calculations. The B3LYP/DGDZVP calculations needed 60 min each conformer of computational time with a processing node having 20 Cores at 2.3 GHz with 128 Gb RAM at the High-Performance Computing Laboratory at the IIQB-UMSNH.

Spectral Data

7α,8α-epoxy-cativic acid (4)

Colorless oil. HRESIMS m/z 323.2586 (calcd for C₂₀H₃₄O₃ + H⁺, 323.2581). ¹H NMR (300 MHz, CDCl₃) δ 2.96 (1H, br s, H-7), 2.37 (1H, dd, J = 15.1, 5.8 Hz, H-14a), 2.13 (1H, dd, J = 15.1, 8.1 Hz, H-14b), 2.06 (1H, m, H-6a), 1.92 (1H, m, H-13), 1.76 (1H, m, H-1a), 1.69 (1H, m, H-6b), 1.57 (1H, m, H-11a), 1.55 (1H, m, H-12a), 1.49 (1H, m, H-2a), 1.40 (1H, m, H-2b), 1.37 (1H, m, H-3a), 1.30 (3H, s, H-17), 1.21 (1H, m, H-11b), 1.18 (1H, m, H-12b), 1.17 (1H, m, H-9), 1.08 (1H, m, H-3b), 0.99 (1H, m, H-5), 0.99 (3H, d, J = 6.6 Hz, H-16), 0.84 (3H, s, H-19), 0.83 (1H, m, H-1b), 0.82 (3H, s, H-18), 0.72 (3H, s, H-20). ¹³C NMR (75 MHz, CDCl₃) δ 179.2 (C-15), 61.1 (C-7), 59.1 (C-8), 55.8 (C-9), 46.0 (C-5), 42.2 (C-3), 41.5 (C-14), 39.0 (C-12), 38.9 (C-1), 36.1 (C-10), 33.2 (C-18), 32.8 (C-4), 30.9 (C-13), 23.4 (C-11), 23.0 (C-6), 22.8 (C-17), 22.1 (C-19), 19.9 (C-16), 18.8 (C-2), 14.3 (C-20).

Labd-8,17-ene-7α,15-diol (5)

The HRESIMS m/z 309.2790 (calcd for C₂₀H₃₆O₂ + H⁺, 309.2788) and spectral NMR data of 5 were in agreement with their enantiomer of literature data.¹⁷

(−)-(5S,9S,10S,13S)-labd-7-en-15-ol (6)

The HRESIMS m/z 293.2847 (calcd for C₂₀H₃₆O + H⁺, 293.2839) and spectral NMR data of 6 were in agreement with their literature data.¹⁸

7α,8α-epoxylabdan-15-ol (7)

Colorless oil. HRESIMS m/z 309.2788 (calcd for C₂₀H₃₆O₂ + H⁺, 309.2788). ¹H NMR (300 MHz, CDCl₃) δ 3.67 (2H, m, H-15), 2.95 (1H, br s, H-7), 2.26 (1H, br s, OH), 2.08 (1H, dd, J = 15.3, 4.7 Hz, H-6a), 1.78 (1H, m, H-1a), 1.70 (2H, m, H-14a and H-14b), 1.63 (1H, m, H-6b), 1.52 (1H, m, H-1b), 1.51 (1H, m, H-13), 1.49 (1H, m, H-12a), 1.46 (1H, m, H-11a), 1.37 (2H, m, H-2a and H-2b), 1.35 (1H, m, H-3a), 1.30 (3H, s, H-17), 1.20 (1H, m, H-11b), 1.16 (1H, m, H-9), 1.09 (1H, m, H-12b), 1.03 (1H, m, H-3b), 1.00 (1H, dd, J = 12.5, 4.7 Hz, H-5), 0.91 (3H, d, J = 6.1 Hz, H-16), 0.84 (3H, s, H-19), 0.82 (3H, s, H-18), 0.71 (3H, s, H-20). ¹³C NMR (75 MHz, CDCl₃) δ 61.2 (C-15), 61.0 (C-7), 59.1 (C-8), 55.9 (C-9), 46.0 (C-5), 42.2 (C-3), 38.9 (C-14), 39.7 (C-12), 39.6 (C-1), 36.1 (C-10), 33.2 (C-18), 32.8 (C-4), 30.3 (C-13), 23.2 (C-11), 23.0 (C-6), 22.9 (C-17), 22.1 (C-19), 19.8 (C-16), 18.8 (C-2), 14.3 (C-20).

(−)-(5S,9S,10S,13S)-labd-7-en-15-al (8)

The spectral NMR data of 8 were in agreement with their literature data.¹⁸

7α,8α-epoxylabdan-15-al (9)

Colorless oil. HRESIMS m/z 307.2628 (calcd for C₂₀H₃₄O₂ + H⁺, 307.2632). ¹H NMR (300 MHz, CDCl₃) δ 9.77 (1H, br s, H-15), 2.95 (1H, br s, H-7), 2.45 (1H, dd, J = 16.2, 5.4 Hz, H-14a), 2.25 (1H, dd, J = 16.2, 8.0 Hz, H-14b), 2.08 (1H, m, H-6a), 2.04 (1H, m, H-13), 1.74 (1H, m, H-1a), 1.63 (1H, m, H-6b), 1.57 (1H, m, H-12a), 1.51 (1H, m, H-11a), 1.40 (2H, m, H-2a and 2b), 1.34 (1H, m, H-3a), 1.31 (3H, s, H-17), 1.21 (1H, m, H-12b), 1.16 (1H, m, H-11b), 1.45 (1H, m, H-9), 1.07 (1H, m, H-3b), 1.00 (1H, m, H-5), 0.99 (3H, d, J = 6.6 Hz, H-16), 0.86 (3H, s, H-19), 0.84 (3H, s, H-18), 0.82 (1H, m, H-1b), 0.73 (3H, s, H-20). ¹³C NMR (75 MHz, CDCl₃) δ 203.0 (C-15), 58.8 (C-8), 61.0 (C-7), 55.8 (C-9), 46.0 (C-5), 42.2 (C-3), 51.0 (C-14), 39.3 (C-12), 39.0 (C-1), 36.1 (C-10), 33.2 (C-18), 32.8 (C-4), 28.8 (C-13), 23.4 (C-11), 23.0 (C-6), 22.9 (C-17), 22.1 (C-19), 20.2 (C-16), 18.8 (C-2), 14.3 (C-20).

7α-hydroperoxylab-8(17)-en-15-ol (10)

Colorless oil. HRESIMS m/z 307.2634 (calcd for C₂₀H₃₅O₂ − OH⁻, 307.2632). ¹H NMR (300 MHz, CDCl₃) δ 7.89 (1H, br s, OOH), 5.16 (1H, s, H-17a), 4.85 (1H, s, H-17b), 4.50 (1H, s, H-7), 3.67 (2H, m, H-15), 2.02 (1H, m, H-6a), 1.94 (1H, m, H-9), 1.76 (1H, m, H-1a), 1.66 (1H, m, H-14a), 1.56 (1H, m, H-2a), 1.55 (1H, m, H-6b), 1.53 (1H, m, H-13), 1.53 (1H, m, H-11a), 1.44 (1H, m, H-12a), 1.42 (1H, m, H-5), 1.37 (1H, m, H-3a), 1.36 (1H, m, H-2b), 1.34 (1H, m, H-14b), 1.15 (1H, m, H-11b), 1.14 (1H, m, H-3b), 1.04 (1H, m, H-1b), 1.00 (1H, m, H-12b), 0.90 (3H, d, J = 4.8 Hz, H-16), 0.85 (3H, s, H-18), 0.78 (3H, s, H-19), 0.66 (3H, s, H-20). ¹³C NMR (75 MHz, CDCl₃) δ 146.0 (C-8), 113.3 (C-17), 87.2 (C-7), 61.3 (C-15), 52.1 (C-9), 48.5 (C-5), 42.1 (C-3), 39.8 (C-10), 39.6 (C-14), 38.8 (C-1), 36.1 (C-12), 33.3 (C-18), 33.3 (C-4), 30.1 (C-13), 27.6 (C-6), 21.3 (C-19), 20.5 (C-11), 20.0 (C-16), 19.4 (C-2), 13.6 (C-20).

Supplemental Material

sj-docx-1-npx-10.1177_1934578X231222764 - Supplemental material for Chemical Correlation of Cistendiol Obtained from Cativic Acid in Two Different Pathways^†

Supplemental material, sj-docx-1-npx-10.1177_1934578X231222764 for Chemical Correlation of Cistendiol Obtained from Cativic Acid in Two Different Pathways^† by David Calderón-Rangel, Hugo A García-Gutiérrez, Rosa E del Río and Christine Thomassigny in Natural Product Communications

Footnotes

Acknowledgements

Thanks CIC-UMSNH and CONAHCYT-Mexico (Grant No. A1-S-47352) for partial financial support. D.C.R. is grateful to CONAHCYT-Mexico for scholarships 576044 and 291276 (international exchange scholarship). Molecular modeling at the High-Performance Computing Laboratory at IIQB-UMSNH.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical Approval is not applicable to this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the CIC-UMSNH, Consejo Nacional de Humanidades, Ciencias y Tecnologías (grant number A1-S-47352).

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Human and Animal Rights

There are no human subjects in this article and informed consent is not applicable.

ORCID iDs

David Calderón-Rangel:

Hugo A García-Gutiérrez:

Rosa E del Río

Christine Thomassigny:

Supplemental Material

NMR spectra and supplementary data of molecular modeling for the compounds can be found online at .

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Supplementary Material

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Chemical Correlation of Cistendiol Obtained from Cativic Acid in Two Different Pathways †

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Results and Discussion

Conclusions

Experimental

General Experimental Procedures

Plant Materials

Extraction and Isolation

Reduction Methodology with LiAlH4

Epoxidation Methodology with mCPBA

Oxidation Methodology with PCC

Photooxidation Methodology

Preparation of Compound 5 from 4 or by Photooxidation Reaction of 6

Molecular Modeling

Spectral Data

7α,8α-epoxy-cativic acid (4)

Labd-8,17-ene-7α,15-diol (5)

(−)-(5S,9S,10S,13S)-labd-7-en-15-ol (6)

7α,8α-epoxylabdan-15-ol (7)

(−)-(5S,9S,10S,13S)-labd-7-en-15-al (8)

7α,8α-epoxylabdan-15-al (9)

7α-hydroperoxylab-8(17)-en-15-ol (10)

Supplemental Material

sj-docx-1-npx-10.1177_1934578X231222764 - Supplemental material for Chemical Correlation of Cistendiol Obtained from Cativic Acid in Two Different Pathways †

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Ethical Approval

Funding

Statement of Human and Animal Rights

Statement of Human and Animal Rights

ORCID iDs

Supplemental Material

References

Supplementary Material

Reduction Methodology with LiAlH₄

sj-docx-1-npx-10.1177_1934578X231222764 - Supplemental material for Chemical Correlation of Cistendiol Obtained from Cativic Acid in Two Different Pathways^†