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Molecules 2017, 22(4), 652; doi:10.3390/molecules22040652

Article
Modification of Natural Eudesmane Scaffolds via Mizoroki-Heck Reactions
1
Institut de Chimie Organique et Analytique, University d’Orléans, UMR CNRS 7311, B.P. 6759, 45067 Orléans CEDEX 2, France
2
Laboratoire de Chimie Physique & Chimie Bioorganique, Département de chimie, URA C 22, Pôle RéPAM, F. S. T. University Hassan II de Casablanca, B.P. 146 Yasmina, 28800 Mohammedia, Morocco
*
Author to whom correspondence should be addressed.
Academic Editor: Isabel C.F.R. Ferreira
Received: 3 March 2017 / Accepted: 5 April 2017 / Published: 20 April 2017

Abstract

:
The Mizoroki-Heck reaction was applied to substrates derived from isocostic and ilicic acids, important sesquiterpene components of Dittrichia viscosa L. Greuter that were extracted directly from plant material collected in Morocco. After optimization of the metallo-catalysis conditions, various aryl-groups were successfully introduced on the exocyclic double bond with an exclusive E-configuration and without racemization.
Keywords:
eudesmane; isocostic and ilicic acids; Dittrichia viscosa L. Greuter; sesquiterpenes; Mizoroki-Heck reaction

1. Introduction

Natural products are a well-known continuous source of inspiration for the design of new bioactive agents with applications in the therapeutic, cosmetic or agricultural areas [1]. They can serve as building blocks for the synthesis of more complex bioactive compounds [2]. Based on traditional use, numerous plants of medicinal interest have been identified and conventional drugs developed from their extracts [3,4]. As part of our program studying Moroccan plants [5,6], our interest is focused on Dittrichia viscosa L. Greuter [7,8], an invasive perennial plant particularly abundant in wasteland areas. Its extract is used in traditional Moroccan medicine for its antipyretic, antiseptic and anti-inflammatory properties [9,10], and also exhibits antifungal activity [11,12,13]. Recent studies reported that the aerial parts of the plant are a rich source of eudesmane sesquiterpenes, among which ilicic acid (1) and isocostic acid (2) (Figure 1) represent up to 2.5% and 2% of the aerial part dry weight, respectively [5]. This plant, like others, could represent a renewable source of enantiopure compounds to obtain diversified libraries of products of interest.
Indeed, sesquiterpene derivatives have attracted considerable attention lately [14] due to their pharmacological and phytochemical activities, in particular sesquiterpene lactones [15,16,17] which have already been submitted to various structural modifications, including the Mizoroki-Heck reaction [18,19,20,21,22,23]. However, only a few modifications have been reported for analogues such as eudesmane-carboxylic acids, aldehydes or eudesmanols, and none included modifications of the exocyclic alkene part [24,25,26]. In view of the great biological potential of ilicic and isocostic acid derivatives [27,28,29,30], we decided to apply the Mizoroki-Heck cross-coupling reaction to these natural compounds to generate some novel eudesmane analogues. We report herein the behavior of these compounds extracted from plants in palladium-catalyzed reactions [31,32,33,34].

2. Results and Discussion

2.1. Optimization of the Mizoroki-Heck Reaction on Ilicic Acid

We first examined the behavior of ilicic acid methyl ester in a model Mizoroki-Heck reaction (Scheme 1). Unfortunately only starting material was recovered [20]. Protection of the alcohol was then considered and the methoxymethyl-ether (MOM) group was selected as the most efficient protecting group allowing the isolation of compound 3 in 60% yield. With 3 as starting material, compound 4b was then obtained in 30% yield in presence of Pd(OAc)2 (0.1 equiv), p-tolyl iodide (1.1 equiv) and Et3N (3 equiv) in N,N-dimethylformamide (DMF) (Table 1, entry 1). The use of silver acetate as oxidizing agent and base offered no significant advantages (entry 2) [35,36]. Next a bulky electron-rich phosphine, tri(o-tolyl)phosphine was used, enabling the isolation of 4b in 65% yield, and acetonitrile was used to replace DMF as solvent, but a reduced yield was noted (entry 5) [21,22]. An increase in the catalytic system loading failed to improve this result (entry 6). The optimized conditions were as follows: 3 (1 equiv), aryl iodide (1.1 equiv), Et3N (3 equiv), Pd(OAc)2 (0.1 equiv) and P(o-Tol)3 (0.1 equiv) in DMF at 120 °C for 24 h. These conditions were extended to aryl bromides without any significant loss of reactivity (entry 8).

2.2. Substrate Scope and Deprotection

Various aryl iodides and bromides were then used to generate a library of eudesmane analogues using the optimized cross-coupling reaction conditions (Scheme 2 and Table 2). The reactions were clean and the expected products were synthesized in good yields. As expected, the palladium coupling reaction tolerated different aromatic halides bearing electron-donating (Me, OMe) and withdrawing groups (F, CO2Me, CHO) in the ortho, meta and para-positions (compounds 4a–i). Then, sesquiterpenes 5ai were rapidly generated under acidic conditions in good to excellent yields. When the fluoro substituent was in ortho position, deprotection occurred simultaneously with the Mizoroki-Heck reaction, compound 4g was never observed and 5g was isolated in one step in 62% yield (entry 7). The methodology was also extended to heterocyclic derivatives and the desired product 4i was isolated with good yield (entry 9).
A Nuclear Overhauser Effect Spectroscopy (NOESY)-NMR experiment on 5b allowed us to determine the double bond configuration. Interactions between H7-HAr and H7–H22 involved an E-olefin geometry emphasized by the absence of signals between H7 and H13 (Figure 2). Our stereochemical result is in accordance with the work reported by Colby and co-workers [20].

2.3. Mizoroki-Heck Reaction on Esterified Isocostic Acid

Next we focused on the other major constituent found on the acidified dichloromethane (DCM) extracts of Dittrichia viscosa L. Greuter. Isocostic acid (2) was esterified and submitted to our optimized Mizoroki-Heck conditions leading to a complex mixture of products. When an epoxidation was carried out on esterified compound 6 in order to prevent the migration of the endocyclic double bond, the epoxide 7 was obtained as a unique enantiomer (Scheme 3) [6].
After the cross-coupling reaction, a new double bond signal appeared both in 1H-NMR (δ 4.57 and δ 4.91 ppm) and 13C-NMR (δ 109.4 (C-15) and δ 151.7 ppm (C-4)). The Distortionless Enhancement by Polarization Transfer (DEPT) experiment confirmed the exocyclic position of this unsaturation. Furthermore, a significant shielding effect was observed for H3 in 1H-NMR (δ 2.86 vs. 4.27 ppm) and C3 in 13C-NMR (δ 61.1 vs. 73.8 ppm), which corroborates the formation of an allylic alcohol from the epoxide ring opening. The double bond activated by the presence of the ester in the α-position reacted in the Mizoroki-Heck reaction giving access chemoselectively to 8a in 70% yield (Figure 3).
The reaction was successfully performed with ortho-, meta- and para-aryl iodides substituted with electron donating groups (compounds 8ae). However, the steric hindrance of aryl iodides substituted in the ortho-position had a negative effect on the transformation, as compound 8e was isolated only in 33% yield. When an electron-deficient aryl iodide was used, only traces of the expected product 8f were obtained. Unfortunately, aryl bromides proved incompatible with our optimized conditions as only the opening of the epoxide was observed (Scheme 4).
The lack of reactivity of the aryl bromide was confirmed by heating 7 in DMF in the absence of the other reagents. This experiment showed the formation of 9a and 9b in almost the same proportions. The isolation of 9a and 9b was possible by column chromatography and each compound was fully characterized by comparing their spectroscopic data with the literature [6,37]. Further investigation was then conducted on the major product 9a resulting from the epoxide ring opening. The protection of the alcohol 9a was made as before with a MOM group leading to compound 10 then cross coupling conditions were applied and expected compound 11 was obtained in good yield. When 9a was submitted directly to the cross coupling reaction with a more reactive aryl iodide, only 27% of 8b was isolated along with degradation products, indicating that our cross-coupling conditions are not compatible with the presence of an unprotected alcohol. For this other major constituent found on the acidified DCM extracts of Dittrichia viscosa L. Greuter, the configuration of the trisubstituted double bond synthetized was examined though the correlations obtained by the NOESY-NMR experiment. A spatial correlation was observed between the aromatic proton and H7 when no signal was noticed between H7 and H13 led us conclude on the E-olefin geometry.

3. Materials and Methods

3.1. General Methods

All reagents were purchased from commercial suppliers and were used without further purification except for DMF, which was stored under argon and activated molecular sieves. The reactions were monitored by thin-layer chromatography (TLC) analysis using silica gel (60 F254) plates. Compounds were visualized by UV irradiation. Flash column chromatography was performed on silica gel 60 (230–400 mesh, 0.040–0.063 mm). 1H-NMR and 13C-NMR spectra were recorded on Avance spectrometers (Bruker, France, SAS) at 250.13 MHz (13C, 62.9 MHz) or 400.13 MHz (13C, 100.62 MHz). Chemical shifts are given in parts per million from tetramethylsilane (TMS) as internal standard. The following abbreviations are used for the proton spectra multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, qt: quintuplet, m: multiplet. Coupling constants (J) are reported in Hertz (Hz). Multiplicities were determined by DEPT-135 sequences. Attributions of protons and carbons were made with the help of Heteronuclear Single Quantum Correlation (HSQC) and Heteronuclear Multiple Bond Correlation (HMBC) 2D NMRs. Eudesmane numbering of carbons was used instead of the IUPAC numbering. High-resolution mass spectra (HRMS) were performed on a Maxis 4G instrument (Bruker, France, SAS).

3.2. Procedure for the Synthesis of Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]prop-2-enoate (3)

To a solution of methyl 2-((2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyldecahydronaphthalen-2-yl) acrylate (126 mg, 2.25 mmol, 1 equiv) in anhydrous CH2Cl2 (10 mL) were added DPA (1.56 mL, 9.02 mmol, 4 equiv) and MOMCl (0.68 mL, 9.02 mmol, 4 equiv). The reaction mixture was stirred for 12 h at room temperature under argon. Then water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give the desired product 3 (419 mg, 1.35 mmol, 60% yield) after purification by flash chromatography on a silica gel column (petroleum ether/EtOAc:90/10). Colorless oil, [α] D 20 −39.5 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 6.10 (d, J = 1.2 Hz, 1H, H-13), 5.53 (dd, J = 1.2, 1.2 Hz, 1H, H-13), 4.69 (dd, J = 7.4, 6.0 Hz, 2H, OCH2), 3.73 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 2.51 (dddd, J = 12.7, 11.7, 4.4, 3.2 Hz, 1H, H-7), 1.96–1.74 (m, 2H), 1.68–1.17 (m, 10H), 1.17–1.01 (m, 4H), 0.92 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3) δ 168.0 (C-12), 146.1 (C-11), 122.5 (C-13), 90.1 (OCH2), 78.2 (C-4), 55.2 (OCH3), 52.6 (OCH3), 51.8 (C-5), 45.1 (CH2), 40.9 (CH2), 40.6 (C-7), 39.2 (CH2), 34.7 (C-10), 27.7 (CH2), 26.7 (CH2), 19.9 (CH2), 19.7 (C-15), 19.3 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C18H30NaO4 333.2036; found 333.2036.

3.3. General Procedure for the Synthesis of Compounds 4a4i

A solution of substrate 3 (1 equiv, 100 mg), Pd(OAc)2, (0.1 eqiv) and an appropriate haloaryl compound (1.1 eqiv) in the presence of triethylamine (3 equiv) and P(o-Tol)3 (0.1 equiv) in DMF (2 mL) was stirred for 24 h at 120 °C. After cooling, water (10 mL) was added to the reaction mixture which is extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 30 mL), dried (MgSO4), filtered and concentrated under reduce pressure. Expected compounds were obtained after purification by flash chromatography on silica gel (petroleum ether/EtOAc:90/10).

3.3.1. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-phenylprop-2-enoate (4a)

Colorless oil, [α] D 20 −42.7 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.57 (s, 1H, H-13), 7.42–7.25 (m, 5H, HAr), 4.67 (s, 2H, OCH2), 3.81 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 2.86 (dddd, J = 12.3, 12.2, 4.0, 3.8 Hz, 1H, H-7), 2.27–2.13 (m, 1H), 1.94 (dd, J = 12.5, 12.5 Hz, 1H), 1.89–1.80 (m, 1H), 1.75–1.66 (m, 1H), 1.61–1.44 (m, 4H), 1.44–1.23 (m, 5H), 1.15 (s, 3H, H-15), 1.03 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.6 (C-12), 138.7 (C-13), 138.0 (C-11), 136.1 (CAr), 129.0 (2CHAr), 128.5 (2CHAr), 128.2 (CHAr), 90.1 (OCH2), 78.3 (C-4), 55.1 (OCH3), 52.8 (OCH3), 51.7 (C-5), 45.0 (CH2), 40.9 (CH2), 39.4 (CH2), 39.1 (C-7), 34.7 (C-10), 26.0 (CH2), 25.5 (CH2), 19.9 (CH2), 19.7 (C-15), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C24H34NaO4 409.2348; found 409.2349.

3.3.2. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-methylphenyl)prop-2-enoate (4b)

Colorless oil, [α] D 20 +68.3 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.55 (s, 1H, H-13), 7.21 (d, J = 8.2 Hz, 2H, HAr), 7.18 (d, J = 8.2 Hz, 2H, HAr), 4.68 (s, 2H, OCH2), 3.80 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 2.88 (dddd, J = 12.2, 12.2, 4.1, 4.0 Hz, 1H, H-7), 2.37 (s, 3H), 2.28–2.14 (m, 1H), 1.96 (dd, J = 12.5, 12.4 Hz, 1H), 1.87–1.80 (m, 1H), 1.76–1.67 (m, 1H), 1.58–1.45 (m, 3H), 1.45–1.29 (m, 5H), 1.22–1.11 (m, 4H), 1.03 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.6 (C-12), 138.7 (CAr), 138.2 (C-13), 137.3 (C-11), 133.2 (CAr), 129.2 (2CHAr), 129.1 (2CHAr), 90.1 (OCH2), 78.3 (C-4), 55.1 (OCH3), 52.8 (OCH3), 51.6 (C-5), 45.0 (CH2), 40.9 (CH2), 39.4 (CH2), 39.0 (C-7), 34.7 (C-10), 25.9 (CH2), 25.5 (CH2), 21.4 (C-15), 19.9 (CH2), 19.7 (CH3), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C25H36NaO4 423.2506; found 423.2505.

3.3.3. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-methoxyphenyl)prop-2-enoate (4c)

Colorless oil, [α] D 20 +86.0 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.52 (s, 1H, H-13), 7.27 (d, J = 8.5 Hz, 2H, HAr), 6.90 (d, J = 8.5 Hz, 2H, HAr), 4.68 (s, 2H, OCH2), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 2.90 (dddd, J = 12.3, 12.0, 4.2, 4.0 Hz, 1H, H-7), 2.22 (dddd, J = 13.7, 12.8, 12.8, 3.8 Hz, 1H), 1.96 (dd, J = 12.4, 12.4 Hz, 1H), 1.88–1.85 (m, 1H), 1.76–1.66 (m, 1H), 1.64–1.45 (m, 4H), 1.44–1.30 (m, 4H), 1.24–1.12 (m, 4H), 1.04 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.7 (C-12), 159.7 (CAr), 138.4 (C-13), 136.3 (C-11), 130.8 (2CHAr), 128.5 (CAr), 114.0 (2CHAr), 90.2 (OCH2) , 78.4 (C-4), 55.5 (OCH3), 55.2 (OCH3), 52.9 (OCH3), 51.6 (C-5), 45.1 (CH2), 40.9 (CH2), 39.5 (CH2), 39.0 (C-7), 34.8 (C-10), 25.9 (CH2), 25.5 (CH2), 19.9 (CH2), 19.7 (C-15), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C25H36NaO5 439.2455; found 439.2454.

3.3.4. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-formylphenyl)prop-2-enoate (4d)

Colorless oil, [α] D 20 +14.3 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 10.02 (s, 1H, CHO), 7.89 (d, J = 8.0 Hz, 2H, HAr), 7.56 (s, 1H, H-13), 7.45 (d, J = 7.9 Hz, 2H, HAr), 4.66 (s, 2H, OCH2), 3.82 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 2.77 (dddd, J = 12.3, 11.8, 3.7, 3.7 Hz, 1H, H-7), 2.20 (qd, J = 13.1, 3.9 Hz, 1H), 1.94 (dd, J = 12.7, 12.3 Hz, 1H), 1.88–1.80 (m, 1H), 1.76–1.67 (m, 1H), 1.61 (s, 1H), 1.57–1.19 (m, 8H), 1.14 (s, 3H, H-15), 1.02 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 191.8 (CHO), 168.1 (C-12), 142.4 (CAr), 140.3 (CAr), 137.0 (C-13), 135.7 (C-11), 129.9 (2CHAr), 129.6 (2CHAr), 90.2 (OCH2), 78.3 (C-4), 55.2 (OCH3), 52.8 (OCH3), 51.9 (C-5), 44.8 (CH2), 40.8 (CH2), 39.5 (C-7), 39.4 (CH2), 34.7 (C-10), 26.0 (CH2), 25.6 (CH2), 19.8 (CH2), 19.7 (C-15), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C25H34NaO5 437.2294; found 437.2298.

3.3.5. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-fluorophenyl)prop-2-enoate (4e)

White solid, m.p. 126–128 °C. [α] D 20 +55.0 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.51 (s, 1H, H-13), 7.32–7.23 (m, 2H, HAr), 7.06 (dd, J = 8.4, 8.4 Hz, 2H, HAr), 4.67 (s, 2H, OCH2), 3.80 (s, 3H, OCH3), 3.29 (s, 3H, OCH3), 2.80 (dddd, J = 12.2, 12.1, 4.2, 4.1 Hz, 1H, H-7), 2.20 (qd, J = 13.6, 13.0, 4.2 Hz, 1H), 1.94 (dd, J= 12.5, 12.4 Hz, 1H), 1.87–1.81 (m, 1H), 1.73–1.65 (m, 1H), 1.60 (s, 1H), 1.58–1.44 (m, 3H), 1.44–1.23 (m, 5H), 1.15 (s, 3H, H-15), 1.03 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.4 (C-12), 162.5 (d, J= 248.4 Hz, CAr), 138.0 (C-13), 137.5 (C-11), 132.1 (d, J= 3.4 Hz, CAr), 130.9 (d, J= 8.1 Hz, 2CHAr), 115.6 (d, J= 21.5 Hz, 2CHAr), 90.2 (OCH2), 78.3 (C-4), 55.2 (OCH3), 52.9 (OCH3), 51.7 (C-5), 45.0 (CH2), 40.9 (CH2), 39.4 (CH2), 39.1 (C-7), 34.8 (C-10), 25.9 (CH2), 25.5 (CH2), 19.9 (CH2), 19.7 (C-15), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C24H33FNaO4 427.2255; found 427.2255.

3.3.6. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(3-methoxyphenyl)prop-2-enoate (4f)

Colorless oil, [α] D 20 +92.0 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.55 (s, 1H, H-13), 7.31–7.24 (m, 1H, HAr), 6.91–6.82 (m, 3H, HAr), 4.70–4.63 (m, 2H, OCH2), 3.82 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 2.88 (dddd, J= 12.5, 12.3, 3.5, 3.5 Hz, 1H, H-7), 2.19 (dddd, J = 13.0, 13.0, 13.0, 3.6 Hz, 1H), 1.95 (dd, J = 12.5, 12.5 Hz, 1H), 1.89–1.82 (m, 1H), 1.78–1.70 (m, 2H), 1.61 (s, 1H), 1.56–1.51 (m, 1H), 1.51–1.43 (m, 1H), 1.43–1.31 (m, 4H), 1.31–1.23 (m, 1H), 1.16 (s, 3H, H-15), 1.03 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.5 (C-12), 159.6 (CAr), 138.6 (C-13), 138.2 (C-11), 137.4 (CAr), 129.5 (CHAr), 121.5 (CHAr), 114.3 (CHAr), 113.9 (CHAr), 90.2 (OCH2), 78.3 (C-4), 55.4 (OCH3), 55.1 (OCH3), 53.0 (OCH3), 51.7 (C-5), 45.0 (CH2), 40.9 (CH2), 39.5 (CH2), 39.2 (C-7), 34.7 (C-10), 25.9 (CH2), 25.6 (CH2), 19.9 (CH2), 19.5 (C-15), 19.4 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C25H36NaO5 439.2452; found 439.2454.

3.3.7. Methyl-2-[(1E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-methoxy-3-oxoprop-1-en-1-yl]benzoate (4h)

Colorless oil, [α] D 20 +107.3 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 7.9, 1.4 Hz, 1H, HAr), 7.99 (s, 1H, H-13), 7.51 (td, J = 7.6, 1.4 Hz, 1H, HAr), 7.42–7.35 (m, 1H, HAr), 7.25–7.19 (m, 1H, HAr), 4.63 (s, 2H, OCH2), 3.86 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.47 (tt, J = 12.1, 4.2 Hz, 1H, H-7), 2.21–2.06 (m, 1H), 1.92–1.75 (m, 2H), 1.67–1.56 (m, 2H), 1.54–1.37 (m, 3H), 1.31 (ddt, J = 12.1, 8.6, 4.0 Hz, 3H), 1.23–1.13 (m, 2H), 1.11 (s, 3H, H-15), 0.97 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.1 (C-12), 167.0 (CO2Me), 140.1 (C-13), 138.4 (C-11), 136.2 (CAr), 132.2 (CHAr), 130.8 (CHAr), 129.7 (CHAr), 129.0 (CAr), 128.0 (CHAr), 90.1 (OCH2), 78.3 (C-4), 55.1 (OCH3), 52.5 (OCH3), 52.2 (OCH3), 51.7 (C-5), 44.9 (CH2), 40.8 (CH2), 39.6 (C-7), 39.3 (CH2), 34.7 (C-10), 26.0 (CH2), 25.5 (CH2), 19.8 (CH2), 19.8 (C-15), 19.3 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C26H36NaO6 467.2405; found 467.2404.

3.3.8. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-(methoxymethoxy)-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-{3-methyl-2-oxo-2H,3H-[1,3oxazolo[4,5-b]pyridine-6-yl]}prop-2-enoate (4i)

White solid, m.p. 152–154 °C. [α] D 20 +92.7 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 8.07 (s, 1H, Hpyr), 7.48 (s, 1H, H-13), 7.35 (s, 1H, Hpyr), 4.67 (dd, J = 7.5, 3.6Hz, 2H, OCH2), 3.82 (s, 3H, OCH3), 3.50 (s, 3H, CH3), 3.29 (s, 3H, OCH3), 2.73 (dddd, J = 12.3, 12.0, 4.0, 3.4 Hz, 1H, H-7), 2.23 (qd, J = 12.9, 3.4 Hz, 1H), 1.95 (dd, J = 12.6, 12.5 Hz, 1H), 1.85 (bd, J = 11.1 Hz, 1H), 1.74–1.63 (m, 2H), 1.59–1.51 (m, 1H), 1.51–1.22 (m, 5H), 1.21–1.11 (m, 4H), 1.10–0.99 (m, 4H) ppm. 13C-NMR (101 MHz, CDCl3): δ = 167.8 (C-12), 153.6 (CO), 145.5 (Cpyr), 144.0 (CHpyr), 139.8 (Cpyr), 137.1 (C-11), 134.1 (C-13), 127.2 (Cpyr), 116.2 (CHpyr), 90.2 (OCH2), 78.2 (C-4), 55.2 (OCH3), 53.0 (OCH3), 51.9 (C-5), 44.8 (CH2), 40.8 (CH2), 39.5 (C-7), 39.4 (CH2), 34.7 (C-10), 27.2 (CH3), 25.9 (CH2), 25.5 (CH2), 19.8 (CH2), 19.6 (C-15), 19.3 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C25H35N2O6 459.2488; found 459.2489.

3.4. General Procedure for Synthesis of Compounds 5a5i

To a solution of the previous substrates 4 (1 equiv) in diethyl ether (10 mL) HCl solution in ether (2 equiv) was added. The reaction mixture was stirred for 30 min at room temperature then water (10 mL) was added and mixture was extracted with diethyl ether (3 × 10 mL). The organic layers were dried (MgSO4), filtered and concentrated under reduce pressure leading to the desired products after purification by flash chromatography on silica gel (petroleum ether/EtOAc: 80/20).

3.4.1. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-phenylprop-2-enoate (5a)

Colorless oil, [α] D 20 −33.2 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.60 (s, 1H, H-13), 7.42–7.34 (m, 2H, HAr), 7.34–7.24 (m, 3H, HAr), 3.81 (s, 3H, OCH3), 2.85 (dddd, J = 12.4, 12.0, 3.7, 3.4 Hz, 1H, H-7), 2.28–2.15 (m, 1H), 1.98 (dd, J = 12.5, 12.5 Hz, 1H), 1.81–1.72 m, 1H), 1.69–1.61 (m, 1H), 1.61–1.47 (m, 3H), 1.46–1.28 (m, 5H), 1.20–1.13 (m, 2H), 1.12 (s, 3H, H-15), 1.00 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.4 (C-12), 138.9 (C-13), 137.8 (C-11), 136.1 (CAr), 128.9 (2CHAr), 128.6 (2CHAr), 128.2 (CHAr), 72.4 (C-4), 55.0 (OCH3), 51.7 (C-5), 44.6 (CH2), 43.5 (CH2), 41.1 (CH2), 39.1 (C-7), 34.7 (C-10), 26.1 (CH2), 25.2 (CH2), 23.0 (C-15), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C22H30NaO3 365.2087; found 365.2087.

3.4.2. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-methylphenyl)prop-2-enoate (5b)

Yellow oil, [α] D 20 +43.0 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 7.57 (s, 1H, H-13), 7.18 (s, 4H, HAr), 3.80 (s, 3H, OCH3), 2.88 (dddd, J = 12.2, 12.1, 4.0, 3.9 Hz, 1H, H-7), 2.37 (s, 3H), 2.32–2.12 (m, 1H), 1.98 (dd, J = 12.5, 12.4 Hz, 1H), 1.81–1.71 (m, 1H), 1.70–1.60 (m, 1H), 1.60–1.48 (m, 2H), 1.48–1.29 (m, 4H), 1.28–1.13 (m, 3H), 1.14–1.04 (s, 4H), 1.00 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.5 (C-12), 139.0 (CAr), 138.2 (C-13), 137.1 (C-11), 133.1 (CAr), 129.3 (2CHAr), 129.0 (2CHAr), 72.3 (C-4), 55.1 (OCH3), 51.6 (C-5), 44.6 (CH2), 43.4 (CH2), 41.1 (CH2), 39.1 (C-7), 34.7 (C-10), 26.0 (CH2), 25.2 (CH2), 23.0 (C-15), 21.4 (CH3), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C23H32NaO3 379.2242; found 379.2243.

3.4.3. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-methoxyphenyl)prop-2-enoate (5c)

White solid, m.p. 112–114 °C. [α] D 20 +73.0 (c 1.0, CH2Cl2); 1H-NMR (400 MHz, CDCl3): δ = 7.54 (s, 1H, H-13), 7.24 (d, J = 8.4 Hz, 2H, HAr), 6.91 (d, J = 8.4 Hz, 2H, HAr), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 2.88 (dddd, J = 12.2, 12.0, 3.8, 3.8 Hz, 1H, H-7), 2.30–2.14 (m, 3H), 1.99 (dd, J = 12.6, 12.5 Hz, 1H), 1.81–1.72 (m, 1H), 1.70–1.61 (m, 1H), 1.57–1.48 (m, 2H), 1.46–1.23 (m, 4H), 1.23–1.14 (m, 2H), 1.12 (s, 3H, H-15), 1.00 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.6 (C-12), 159.7 (CAr), 138.7 (C-13), 136.1 (C-11), 130.6 (2CHAr), 128.4 (CAr), 114.1 (2CHAr), 72.3 (C-4), 55.4 (OCH3), 55.1 (OCH3), 51.6 (C-5), 44.6 (CH2), 43.4 (CH2), 41.1 (CH2), 39.1 (C-7), 34.7 (C-10), 26.0 (CH2), 25.2 (CH2), 23.0 (C-15), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C23H32NaO4 395.2191; found 395.2192.

3.4.4. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-formylphenyl)prop-2-enoate (5d)

White solid, m.p. 132–134°C. [α] D 20 −29.0 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 10.02 (s, 1H, CHO), 7.89 (d, J = 8.1 Hz, 2H, HAr), 7.58 (s, 1H, H-13), 7.42 (d, J = 7.9 Hz, 2H, HAr), 3.82 (s, 3H, OCH3), 2.75 (dddd, J = 12.1, 12.1, 3.8, 3.7 Hz, 1H, H-7), 2.21 (qd, J = 13.8, 4.5 Hz, 1H), 1.96 (dd, J = 12.5, 12.3 Hz, 1H), 1.82–1.72 (m, 1H), 1.71–1.63 (m, 1H), 1.62–1.48 (m, 2H), 1.47–1.27 (m, 5H), 1.27–1.19 (m, 1H), 1.18–1.03 (m, 5H), 0.99 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 191.8 (CHO), 167.9 (C-12), 142.4 (CAr), 140.1 (CAr), 137.3 (C-13), 135.7 (C-11), 130.0 (2CHAr), 129.5 (2CHAr), 72.3 (C-4), 55.0 (OCH3), 51.9 (C-5), 44.4 (CH2), 43.5 (CH2), 41.0 (CH2), 39.6 (C-7), 34.7 (C-10), 26.1 (CH2), 25.2 (CH2), 23.0 (C-15), 20.2 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C23H30NaO4 393.2039; found 393.2036.

3.4.5. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(4-fluorophenyl)prop-2-enoate (5e)

White solid, m.p. 101–103 °C, [α] D 20 −68.4 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.54 (s, 1H, H-13), 7.33–7.20 (m, 2H, HAr), 7.07 (dd, J = 8.5, 8.4 Hz, 2H, HAr), 3.80 (s, 3H, OCH3), 2.79 (dddd, J = 12.2, 12.1, 4.0, 3.8 Hz, 1H, H-7), 2.21 (qd, J = 13.8, 12.8, 4.3 Hz, 1H), 1.97 (dd, J = 12.6, 12.3Hz, 1H), 1.80–1.73 (m, 1H), 1.69–1.61 (m, 1H), 1.60–1.47 (m, 4H), 1.46–1.29 (m, 5H), 1.21–1.13 (m, 1H), 1.12 (s, 3H, H-15), 0.99 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.3 (C-12), 162.5 (d, J = 248.3 Hz, CAr), 137.9 (C-13), 137.8 (C-11), 132.1 (d, J = 3.4 Hz, CAr), 130.8 (d, J = 8.2 Hz, 2CHAr), 115.7 (d, J = 21.7 Hz, 2CHAr), 72.3 (C-4), 55.0 (OCH3), 51.7 (C-5), 44.6 (CH2), 43.5 (CH2), 41.1 (CH2), 39.2 (C-7), 34.7 (C-10), 26.0 (CH2), 25.2 (CH2), 23.0 (C-15), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C22H29FNaO3 383.1992; found 383.1992.

3.4.6. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(3-methoxyphenyl)prop-2-enoate (5f)

Colorless oil, [α] D 20 +71.3.5 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.56 (s, 1H, H-13), 7.32–7.24 (m, 1H, HAr), 6.90–6.79 (m, 3H, HAr), 3.81 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.86 (dddd, J = 12.3, 12.3, 3.9, 3.8 Hz, 1H, H-7), 2.28–2.14 (m, 1H), 1.97 (dd, J = 12.5, 12.5 Hz, 1H), 1.81–1.72 (m, 1H), 1.71–1.65 (m, 1H), 1.63–1.49 (m, 3H), 1.46–1.24 (m, 5H), 1.22–1.13 (m, 2H), 1.12 (s, 3H, H-15), 0.99 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.4 (C-12), 159.7 (CAr), 138.8 (C-13), 138.0 (C-11), 137.4 (CAr), 129.6 (CHAr), 121.3 (CHAr), 114.2 (CHAr), 114.0 (CHAr), 72.3 (C-4), 55.4 (OCH3), 55.1 (OCH3), 51.7 (C-5), 44.6 (CH2), 43.5 (CH2), 41.1 (CH2), 39.3 (C-7), 34.7 (C-10), 26.1 (CH2), 25.3 (CH2), 23.0 (C-15), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C23H32NaO4 395.2188; found 395.2192.

3.4.7. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-(2-fluorophenyl)prop-2-enoate (5g)

Colorless oil, [α] D 20 −52.8 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.57 (s, 1H, H-13), 7.30 (bdd, J = 6.9, 6.8 Hz, 1H, HAr), 7.22 (dd, J = 7.4, 7.3 Hz, 1H, HAr),7.14 (dd, J = 7.6, 7.4 Hz, 1H, HAr), 7.08 (dd, J = 9.2, 9.1 Hz, 1H, HAr),3.81 (s, 3H, OCH3), 2.69 (dddd, J = 12.2, 12.2, 3.9, 3.6 Hz, 1H, H-7), 2.20 (qd, J = 13.5, 12.8, 4.3 Hz, 1H), 1.97 (dd, J = 12.5, 12.5 Hz, 1H), 1.81–1.71 (m, 1H), 1.69–1.59(m, 1H), 1.45–1.28 (m, 2H), 1.45–1.20 (m, 5H), 1.19–1.12 (m, 2H), 1.11 (s, 3H, H-15), 1.10–1.00 (m, 1H), 0.98 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 167.8 (C-12), 160.3 (d, J = 248.6 Hz, CAr), 139.7 (C-11), 131.9 (d, J = 3.2 Hz, C-13), 130.2 (d, J = 1.9 Hz, CHAr), 130.1 (d, J = 3.3 Hz, CHAr), 124.1 (d, J = 3.6 Hz, CHAr), 123.9 (d, J = 14.7 Hz, CAr), 115.8 (d, J = 21.9 Hz, CHAr), 72.3 (C-4), 55.0 (OCH3), 51.8 (C-5), 44.6 (CH2), 43.4 (CH2), 41.1 (CH2), 39.9 (C-7), 34.7 (C-10), 25.8 (CH2), 25.1 (CH2), 23.1 (C-15), 20.2 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C22H29FNaO3 383.1992; found 383.1992.

3.4.8. Methyl-2-[(1E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-methoxy-3-oxoprop-1-en-1-yl]benzoate (5h)

White solid, m.p. 115–117 °C. [α] D 20 +82.1 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.9 Hz, 1H, HAr), 8.00 (s, 1H, H-13), 7.53 (dd, J = 7.7, 7.4 Hz, 1H, HAr), 7.40 (dd, J = 7.7, 7.4 Hz, 1H, HAr), 7.22 (d, J = 7.7 Hz, 1H, HAr), 3.88 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.46 (dddd, J = 12.3, 12.1, 4.2, 4.2 Hz, 1H, H-7), 2.15 (qd, J = 13.4, 12.7, 4.1 Hz, 1H), 1.92 (dd, J = 12.5, 12.4Hz, 1H), 1.78–1.69 (m, 1H), 1.62–1.45 (m, 6H), 1.40–1.28 (m, 5H), 1.21–1.13 (m, 1H), 1.09 (s, 3H, H-15), 1.07–0.97 (m, 2H), 0.95 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.1 (C-12), 167.0 (CO2Me), 140.3 (C-13), 138.4 (C-11), 136.1 (CAr), 132.3 (CHAr), 130.9 (CHAr), 129.6 (CHAr), 129.1 (CAr), 128.0 (CHAr), 72.3 (C-4), 55.0 (OCH3), 52.3 (OCH3), 51.8 (C-5), 44.5 (CH2), 43.4 (CH2), 41.1 (CH2), 39.7 (C-7), 34.6 (C-10), 26.1 (CH2), 25.2 (CH2), 23.0 (C-15), 20.2 (CH2), 18.8 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C24H32NaO5 423.2142; found 423.2141.

3.4.9. Methyl-(2E)-2-[(2R,4aR,8R,8aR)-8-hydroxy-4a,8-dimethyl-decahydronaphthalen-2-yl]-3-{3-methyl-2-oxo-2H,3H-[1,3oxazolo[4,5-b]pyridine-6-yl]}prop-2-enoate (5i)

Colorless oil, [α] D 20 +87.4 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 8.07 (s, 1H, Hpyr), 7.49 (s, 1H, H-13), 7.32 (s, 1H, Hpyr), 3.82 (s, 3H, OCH3), 3.50 (s, 3H), 2.74 (dddd, J = 12.3, 12.0, 4.2, 4.0 Hz, 1H, H-7), 2.31–2.18 (m, 1H), 1.98 (dd, J = 12.5, 12.3 Hz, 1H), 1.81–1.73 (m, 1H), 1.71–1.61 (m, 2H), 1.59–1.49 (m, 1H), 1.48–1.29 (m, 5H), 1.22–1.13 (m, 2H), 1.12 (s, 3H, H-15), 1.00 (s, 3H, H-14), 0.90 (dq, J = 12.5, 7.4 Hz, 1H) ppm. 13C-NMR (101 MHz, CDCl3): δ = 167.7 (C-12), 153.6 (CO), 145.6 (Cpyr), 143.7 (CHpyr), 139.7 (Cpyr), 137.1 (C-11), 134.2 (C-13), 127.1 (Cpyr), 116.2 (CHpyr), 72.3 (C-4), 55.1 (OCH3), 51.9 (C-5), 44.4 (CH2), 43.6 (CH2), 41.0 (CH2), 39.5 (C-7), 34.7 (C-10), 27.2 (CH3), 26.0 (CH2), 25.0 (CH2), 22.9 (C-15), 20.3 (CH2), 18.9 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C23H31N2O5 415.2217; found 415.2227.

3.5. Synthesis of Compounds 6 and 7

3.5.1. Methyl-2-[(2R,4aR,8aR)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-yl]acrylate (6) [37]

Compound 1 (200 mg, 0.85 mmol) was dissolved in a mixture of toluene–methanol (8:2, 10 mL). The solution was cooled to 0 °C then TMSCHN2 (0.5 mL, 2M in diethyl-ether) was added. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate: 98/2) provided 6 (158 mg, 75%) as a colorless oil; [α] D 20 +26.8 (c 1.0, CH2Cl2); 1H-NMR (250.13 MHz, CDCl3) δ = 0.82 (s, 3H, H-14), 1.16 (dd, 1H, J = 12.4, 12.4 Hz), 1.29–1.41 (m, 3H), 1.44 (dd, 1H, J = 3.4, 2.9 Hz), 1.47–1.53 (m, 1H), 1.54–1.69 (m, 4H), 1.75–1.88 (m, 1H), 1.90–2.14 (m, 3H), 2.52 (ddd, 1H, J = 11.9, 4.3, 4.0 Hz), 3.76 (s, 3H, OMe), 5.31 (bs, 1H, H-3), 5.56 (bs, 1H, H-13), 6.14 (bs, 1H, H-13); 13C-NMR (62.9 MHz, CDCl3) δ = 15.8 (C-15), 21.3 (C-14), 23.1 (C-2), 27.6 (C-8), 29.5 (C-6), 32.4 (C-10), 38.0 (C-1), 40.3 (C-9), 40.7 (C-7), 47.0 (C-5), 51.9 (OMe), 121.2 (C-3), 122.7 (C-13), 135.0 (C-4), 146.1 (C-11), 168.1 (C-12).

3.5.2. Methyl-2-[(1aR,3aS,6R,7aR,7bS)-3a,7b-dimethyldecahydronaphtho[1,2-b]oxiren-6-yl]acrylate (7) [38]

To a solution of ester 6 (315 mg, 1.3 mmol) in 10 mL of dichloromethane were added (220 mg, 1.3 mmol) of m-chloroperbenzoic acid. The reaction mixture was stirred at room temperature for 3 h then washed with a solution of sodium bisulfite (10%) (3 × 10 mL) then a solution of sodium hydrogen carbonate (5%) (10 mL). The aqueous layers were combined and extracted with DCM (3 × 10 mL). The organic layers were combined, washed with water (10 mL), dried with MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel. (petroleum ether/ethyl acetate:9.7/0.3) provided 7 (236 mg, 70%) as a colorless oil; [α] D 20 +10.7 (c 1.0, CH2Cl2); 1H-NMR (250.13 MHz, CDCl3) δ = 0.83 (s, 3H, H-14), 1.03–1.22 (m, 7H), 1.33 (ddd, 1H, J = 13.4, 3.5, 3.3 Hz), 1.40–1.48 (m, 1H), 1.48-1.53 (m, 1H), 1.57 (dd, 1H, J = 13.4, 3.3 Hz), 1.77–1.84 (m, 1H), 1.87 (ddd, 1H, J = 12.1, 6.7, 3.1 Hz), 1.94 (dd, 1H, J = 15.1, 6.1 Hz), 2.43 (dddd, 1H, J = 12.1, 12.0, 3.9, 3.9 Hz), 2.86 (bs, 1H, H-3), 3.70 (s, 3H, CO2Me), 5.50 (s, 1H, H-13), 6.09 (s, 1H, H-13); 13C-NMR (62.9 MHz, CDCl3) δ = 16.5 (C-14), 21.3 (C-15), 21.7 (CH2), 27.3 (CH2), 30.1 (CH2), 31.6 (C-10), 34.8 (CH2), 39.8 (CH2), 40.7 (C-7), 48.2 (C-5), 52.1 (OMe), 58.8 (C-4), 61.1 (C-3), 123.1 (C-13), 145.5 (C-11), 168.0 (C-12). HRMS (ESI): calcd. For C16H25O3 [M + H]+ 265.1800; found 265.1798.

3.6. Synthesis of Compounds 8a–8e, 9a and 9b

A solution of substrate 3 (1 equiv), Pd(OAc)2, (0.1 equiv) and the appropriate haloaryl compound (1.1 equiv) in the presence of triethylamine (3 eqiv) and P(o-Tol)3 (0.1 equiv) in DMF (2 mL) was stirred for 24 h at 120 °C. After cooling, water (10 mL) was added to the reaction mixture which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 30 mL), dried (MgSO4), filtered and concentrated under reduce pressure. The expected compounds were obtained after purification by flash chromatography on silica gel (petroleum ether/EtOAc:80/20).

3.6.1. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]-3-phenylprop-2-enoate (8a)

Yellow oil, [α] D 20 −15.4 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.61 (s, 1H, H-13), 7.37 (dd, J = 8.3, 6.9 Hz, 2H, HAr), 7.30 (dd, J = 7.3, 7.2 Hz, 1H, HAr), 7.24 bs, 2H, HAr), 4.91 (d, J = 1.7 Hz, 1H, H-15), 4.57 (s, 1H, H-15), 4.27 (s, 1H, H-3), 3.80 (s, 3H, OCH3), 2.92 (dddd, J = 12.3, 12.0, 3.7, 3.4 Hz, 1H, H-7), 2.29–2.14 (m, 2H), 2.06 (dd, J = 12.5, 12.4 Hz, 1H), 1.91–1.56 (m, 3H), 1.54–1.12 (m, 6H), 0.80 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.4 (C-12), 151.7 (C-4), 139.1 (C-13), 137.8 (C-11), 136.0 (CAr), 128.9 (2CHAr), 128.6 (2CHAr), 128.2 (CHAr), 109.4 (C-15), 73.8 (C-3), 51.7 (OCH3), 43.7 (C-5), 40.7 (CH2), 38.5 (C-7), 35.9 (C-10), 35.6 (CH2), 29.9 (CH2), 28.1 (CH2), 25.8 (CH2), 15.7 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C22H29O3 341.2111; found 341.2111.

3.6.2. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]-3-(4-methylphenyl)prop-2-enoate (8b)

Yellowish oil, [α] D 20 +63.1 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 7.60 (s, 1H, H-13), 7.18 (s, 4H, HAr), 4.93 (dd, J = 1.6, 1.6 Hz, 1H, H-15), 4.59 (dd, J = 1.8, 1.8 Hz, 1H, H-15), 4.28 (dd, J = 2.8, 2.8 Hz, 1H, H-3), 3.81 (s, 3H, OCH3), 2.96 (dddd, J = 12.3, 12.2, 4.1, 3.9 Hz, 1H, H-7), 2.37 (s, 3H), 2.32–2.19 (m, 1H), 2.08 (dd, J = 12.5, 12.4 Hz, 1H), 1.87–1.64 (m, 3H), 1.55–1.31 (m, 5H), 1.30–1.09 (m, 2H),0.82 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.5 (C-12), 151.7 (C-4), 139.2 (C-13), 138.3 (CAr), 137.1 (C-11), 133.1 (CAr), 129.3 (2CHAr), 128.9 (2CHAr), 109.5 (C-15), 73.8 (C-3), 51.6 (OCH3), 43.8 (C-5), 40.8 (CH2), 38.5 (C-7), 35.9 (C-10), 35.6 (CH2), 29.9 (CH2), 28.1 (CH2), 25.8 (CH2), 21.4 (CH3), 15.8 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C23H31O3 355.2266; found 355.2267.

3.6.3. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]-3-(4-methoxyphenyl)prop-2-enoate (8c)

Yellow solid, m.p. 107–109 °C. [α] D 20 +114.6 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 7.57 (s, 1H, H-13), 7.23 (d, J = 8.7 Hz, 2H, HAr), 6.91 (d, J = 8.7 Hz, 2H, HAr), 4.93 (dd, J = 1.6, 1.6 Hz, 1H, H-15), 4.59 (dd, J = 1.8, 1.8 Hz, 1H, H-15), 4.29 (dd, J = 2.8, 2.8 Hz, 1H, H-3), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 2.98 (dddd, J = 12.2, 12.2, 3.9, 3.8 Hz, 1H, H-7), 2.35–2.20 (m, 2H), 2.09 (dd, J = 12.3, 12.2 Hz, 1H), 1.95–1.59 (m, 4H), 1.56–1.28 (m, 5H), 0.82 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.6 (C-12), 159.7 (CAr), 151.7 (C-4), 138.9 (C-13), 136.1 (C-11), 130.6 (2CHAr), 128.4 (CAr), 114.1 (2CHAr), 109.5 (C-15), 73.8 (C-3), 55.4 (OCH3), 51.6 (OCH3), 43.8 (C-5), 40.8 (CH2), 38.4 (C-7), 35.9 (C-10), 35.6 (CH2), 29.9 (CH2), 28.1 (CH2), 25.8 (CH2), 15.8 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C23H31O4 371.2215; found 371.2216.

3.6.4. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]-3-(3-methoxyphenyl)prop-2-enoate (8d)

Colorless oil, [α] D 20 +91.0 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 7.59 (s, 1H, H-13), 7.33–7.24 (m, 1H, HAr), 6.89–6.77 (m, 3H, HAr), 4.94–4.90 (m, 1H, H-15), 4.57 (dt, J = 3.5, 1.7 Hz, 1H, H-15), 4.28 (t, J = 2.6 Hz, 1H, H-3), 3.81 (d, J = 0.6 Hz, 6H, 2OCH3), 2.94 (tt, J = 12.1, 3.9 Hz, 1H, H-7), 2.33–2.16 (m, 2H), 2.06 (q, J = 12.3 Hz, 1H), 1.89–1.12 (m, 9H), 0.81 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.6 (C-12), 159.8 (CAr), 151.9 (C-4), 139.2 (C-13), 138.2 (C-11), 137.5 (CAr), 129.8 (CHAr), 121.3 (CHAr), 114.5 (CHAr), 114.0 (CHAr), 109.6 (C-15), 73.9 (C-3), 55.5 (OCH3), 51.9 (OCH3), 43.9 (C-5), 40.9 (CH2), 38.8 (C-7), 36.1 (C-10), 35.8 (CH2), 30.0 (CH2), 28.3 (CH2), 26.0 (CH2), 15.9 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C23H31O4 371.2216; found 371.2216.

3.6.5. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]-3-(2-methylphenyl)prop-2-enoate (8e)

Colorless oil, [α] D 20 +42.3 (c 1.0, CHCl3). 1H-NMR (250 MHz, CDCl3): δ = 7.65 (s, 1H, H-13), 7.25–7.01 (s, 4H, HAr), 4.91 (dd, J = 1.6, 1.6 Hz, 1H, H-15), 4.57 (dd, J = 1.8, 1.8 Hz, 1H, H-15), 4.26 (dd, J = 2.3, 2.3 Hz, 1H, H-3), 3.82 (s, 3H, OCH3), 2.69 (dddd, J = 12.3, 12.1, 4.1, 3.8 Hz, 1H, H-7), 2.26 (s, 3H), 2.23–2.13 (m, 2H), 2.03 (q, J = 12.2, 12.4 Hz, 1H), 1.85–1.53 (m, 3H), 1.51–1.10 (m, 6H), 0.78 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.3 (C-12), 151.7 (C-4), 139.2 (C-13), 138.0 (CAr), 136.4 (C-11), 135.6 (CAr), 130.1 (CHAr), 128.2 (CHAr), 128.1 (CHAr), 125.8 (CHAr), 109.4 (C-15), 73.8 (C-3), 51.7 (OCH3), 43.6 (C-5), 40.7 (CH2), 38.8 (C-7), 35.8 (C-10), 35.6 (CH2), 29.9 (CH2), 28.1 (CH2), 25.9 (CH2), 20.2 (CH3), 15.7 (C-14). HRMS (ESI): m/z [M + H]+ calcd. for C23H31O3 355.2268; found 355.2269.

3.6.6. Methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidene-decahydronaphthalen-2-yl]prop-2-enoate (9a) [6]

Colorless oil, [α] D 20 +35.3 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 6.15 (d, J = 1.1 Hz, 1H, H-13), 5.56 (dd, J = 1.1, 1.1 Hz, 1H, H-13), 4.93 (dd, J = 1.1, 1.1 Hz, 1H, H-15), 4.55 (dd, J = 1.8, 1.7 Hz, 1H, H-15), 4.34–4.24 (m, 1H, H-3), 3.75 (s, 3H, OCH3), 2.68–2.50 (m, 1H, H-7), 2.44 (ddt, J = 12.2, 3.2, 1.8 Hz, 1H), 1.87–1.70 (m, 3H), 1.69–1.36 (m, 5H), 1.30–1.14 (m, 3H), 0.72 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 168.0 (C-12), 151.8 (C-4), 145.9 (C-11), 122.7 (C-13), 109.2 (C-15), 73.6 (C-3), 51.9 (OCH3), 43.8 (C-5), 40.8 (CH2), 39.8 (C-7), 35.9 (C-10), 35.8 (CH2), 29.8 (CH2), 29.7 (CH2), 27.3 (CH2), 15.7 (C-14) ppm. HRMS (ESI): m/z [M + Li]+ calcd. for C16H24LiO3 271.1881; found 271.1880.

3.6.7. Methyl-2-[(2R,4aS,7R)-7-hydroxy-4a,8-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl]prop-2-enoate (9b) [37]

Colorless oil, [α] D 20 −4.7 (c 1.0, CH2Cl2). 1H-NMR (250 MHz, CDCl3): δ = 6.18 (d, J = 0.7 Hz, 1H, H-13), 5.57 (dd, J = 1.1, 1.0 Hz, 1H, H-13), 3.89 (s, 1H, H-3), 3.76 (s, 3H, OCH3), 2.68–5.56 (m, 1H, H-7), 2.53–2.35 (m, 1H), 1.85–1.79 (m, 1H), 1.79–1.72 (m, 4H), 1.72–1.45 (m, 6H), 1.45–1.21 (m, 2H), 1.03 (s, 3H, H-14) ppm. 13C-NMR (63 MHz, CDCl3): δ = 167.8 (C-12), 145.5 (C-11), 139.7 (C-5), 126.5 (C-4), 122.9 (C-13), 69.9 (C-3), 51.9 (OCH3), 42.3 (CH2), 40.5 (C-7), 35.0 (C-10), 34.2 (CH2), 31.6 (CH2), 27.8 (CH2), 23.1 (C-15), 17.2 (C-14) ppm. HRMS (ESI): m/z [M + Na]+ calcd. for C16H24NaO3 287.1618; found 287.1617.

3.7. Synthesis of Methyl-2-[(2R,4aS,7R,8aR)-7-(methoxymethoxy)-4a-methyl-8-methylidenedecahydro-naphthalen-2-yl]prop-2-enoate (10)

To a solution of methyl-2-[(2R,4aS,7R,8aR)-7-hydroxy-4a-methyl-8-methylidenedecahydro-naphthalen-2-yl]prop-2-enoate (9a, 8 mg, 0.37 mmol, 1 equiv) in anhydrous CH2Cl2 (10 mL) were added DPA (0.26 mL, 1.51 mmol, 4 equiv) and MOMCl (0.12 mL, 1.51 mmol, 4 equiv). The reaction mixture was stirred for 12 h at room temperature under argon. Then water (10 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The organic layers were dried (MgSO4), filtered and concentrated under reduce pressure to give the desired product 10 (82 mg, 0.26 mmol, 70% yield) after purification by flash chromatography on silica gel (petroleum ether/EtOAc; 90:10). Colorless oil, [α] D 20 +28.8 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 6.15 (d, J = 1.1 Hz, 1H, H-13), 5.57 (dd, J = 1.1, 1.0 Hz, 1H, H-13), 4.93 (bs, 1H, H-15), 4.67 (dd, J = 1.7, 1.6 Hz, 1H, H-15), 4.62 (d, J = 6.6 Hz, 1H, OCH2), 4.50 (d, J = 6.6 Hz, 1H, OCH2), 4.12 (dd, J = 3.0, 2.7Hz, 1H, H-3), 3.75 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 2.57 (dddd, J = 11.9, 11.9, 3.3, 2.7 Hz, 1H, H-7), 2.26 (bd, J = 12.3, 1H), 1.88–1.79 (m, 2H), 1.74–1.34 (m, 6H), 1.32–1.21 (m, 2H), 0.74 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.0 (C-12), 148.4 (C-4), 146.0 (C-11), 122.7 (C-13), 111.0 (C-15), 93.1 (OCH2), 76.4 (C-3), 55.3 (OCH3), 51.9 (OCH3), 44.3 (C-5), 40.8 (CH2), 39.8 (C-7), 36.4 (C-10), 35.8 (CH2), 29.7 (CH2), 28.7 (CH2), 27.4 (CH2), 16.0 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C18H29O4 309.2061; found 309.2060.

3.8. Synthesis of Methyl-2-[(2R,4aS,7R,8aR)-7-(methoxymethoxy)-4a-methyl-8-methylidenedecahydro-naphthalen-2-yl]-3-(4-methylphenyl)prop-2-enoate (11)

A solution of substrate 10 (180 mg, 0.58 mmol, 1 equiv), Pd(OAc)2, (13 mg, 0.06 mmol, 0.1 equiv) and 4-bromotoluene (110 mg, 0.64 mmol, 1.1 equiv) in the presence of triethylamine (0.24 mL, 1.75 mmol, 3 equiv) and P(o-Tol)3 (18 mg, 0.06 mmol, 0.1 equiv) in DMF (2 mL) was stirred for 24 h at 120 °C. After cooling, water (10 mL) was added to the reaction mixture which was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 30 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The expected compound 11 (157 mg, 0.40 mmol) was obtained after purification by flash chromatography on silica gel (petroleum ether/EtOAc:90/10). Colorless oil, [α] D 20 +42.5 (c 1.0, CH2Cl2). 1H-NMR (400 MHz, CDCl3): δ = 7.59 (s, 1H, H-13), 7.18 (s, 4H, HAr), 4.92 (bs, 1H, H-15), 4.69 (bs, 1H, H-15), 4.60 (d, J = 6.6 Hz, 1H, OCH2), 4.50 (d, J = 6.6 Hz, 1H, OCH2), 4.11 (dd, J = 2.8, 2.8 Hz, 1H, H-3), 3.80 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.00–2.89 (m, 1H, H-7), 2.37 (s, 3H), 2.26 (qd, J = 13.0, 3.7 Hz, 1H), 2.13–2.05 (m, 2H), 1.85–1.78 (m, 2H), 1.68–1.57 (m, 1H), 1.54–1.40 (m, 2H), 1.39–1.20 (m, 3H), 0.84 (s, 3H, H-14) ppm. 13C-NMR (101 MHz, CDCl3): δ = 168.4 (C-12), 148.4 (C-4), 139.0 (C-13), 138.2 (CAr), 137.1 (C-11), 133.1 (CAr), 129.3 (2CHAr), 128.9 (2CHAr), 111.0 (C-15), 93.2 (OCH2), 76.7 (C-3), 55.3 (OCH3), 51.6 (OCH3), 44.2 (C-5), 40.8 (CH2), 38.5 (C-7), 36.2 (C-10), 35.8 (CH2), 28.6 (CH2), 28.0 (CH2), 25.8 (CH2), 21.4 (CH3), 16.0 (C-14) ppm. HRMS (ESI): m/z [M + H]+ calcd. for C25H35O4 399.2532; found 399.2529.

4. Conclusions

The ilicic and isocostic acids used in this study were extracted directly from Dittrichia viscosa L. Greuter. These readily accessible enantiopure compounds were submitted to the Mizoroki-Heck reaction after some minor modifications. Various aryl halides were introduced, with moderate to good yields, on the α,β-unsaturated methyl ester group with an E configuration. No racemization was observed and the mild experimental conditions could be used to synthesize a wide variety of compounds, starting from the plant extract, in a limited number of steps.

Supplementary Files

Supplementary File 1

Acknowledgments

This work was supported by the Region Centre, France in ValPAMMeT Program. Work in collaboration with Meknes-Tafilalet area of Morocco.

Author Contribution

S.B.-R. and M.A. conceived and designed the experiments, M.Z. performed the experiments, M.Z. and S.B.-R. analyzed the data, S.B.-R. contributed reagents/material/analysis tools. M.Z. and S.B.-R. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of all compounds described are available from the authors.
Figure 1. Isocostic and ilicic acids as eudesmane scaffolds.
Figure 1. Isocostic and ilicic acids as eudesmane scaffolds.
Molecules 22 00652 g001
Scheme 1. Mizoroki-Heck reaction of ilicic acid.
Scheme 1. Mizoroki-Heck reaction of ilicic acid.
Molecules 22 00652 sch001
Scheme 2. MOM deprotection conditions.
Scheme 2. MOM deprotection conditions.
Molecules 22 00652 sch002
Figure 2. NOESY-NMR experiment of 5b.
Figure 2. NOESY-NMR experiment of 5b.
Molecules 22 00652 g002
Scheme 3. Epoxidation and Mizoroki-Heck reaction on esterified isocostic acid.
Scheme 3. Epoxidation and Mizoroki-Heck reaction on esterified isocostic acid.
Molecules 22 00652 sch003
Figure 3. Mizoroki-Heck reaction on esterified isocostic acid.
Figure 3. Mizoroki-Heck reaction on esterified isocostic acid.
Molecules 22 00652 g003
Scheme 4. Control experiments.
Scheme 4. Control experiments.
Molecules 22 00652 sch004
Table 1. Optimization of the Mizoroki-Heck reaction of ilicic acid.
Table 1. Optimization of the Mizoroki-Heck reaction of ilicic acid.
EntryXPd(OAc)2 (equiv)Additive (equiv)Et3N (equiv)Yield (%) a
1I0.1-330
2I0.1AgOAc (1)-20
3I0.1P(oTol)3 (0.4)330
4I0.1P(oTol)3 (0.2)360
5I0.1P(oTol)3 (0.1)365 (45) b
6I0.2P(oTol)3 (0.2)358
7I0.1P(oTol)3 (0.1)251
8Br0.1P(oTol)3 (0.1)360
a Isolated yields. b Reaction performed in MeCN.
Table 2. Scope of substrates and deprotection.
Table 2. Scope of substrates and deprotection.
EntryArXProduct 4, YieldProduct 5, Yield
1X = I Molecules 22 00652 i001
4a, 62%
Molecules 22 00652 i002
5a, 90%
2X = I Molecules 22 00652 i003
4b, 65%
Molecules 22 00652 i004
5b, 88%
3X = I Molecules 22 00652 i005
4c, 63%
Molecules 22 00652 i006
5c, 80%
4X = Br Molecules 22 00652 i007
4d, 58%
Molecules 22 00652 i008
5d, 76%
5X = Br Molecules 22 00652 i009
4e, 64%
Molecules 22 00652 i010
5e, 75%
6X = I Molecules 22 00652 i011
4f, 60%
Molecules 22 00652 i012
5f, 79%
7X = I Molecules 22 00652 i013
4g,—(c)
Molecules 22 00652 i014
5g, 62%
8X = Br Molecules 22 00652 i015
4h, 55%
Molecules 22 00652 i016
5h, 78%
9X = Br Molecules 22 00652 i017
4i, 50%
Molecules 22 00652 i018
5i, 80%
a Experimental conditions: 3 (1 mmol), aryl-halide (1.1 mmol) dissolved in DMF (2 mL), 120 °C, for 24 h; b Isolated yields; c Compound 4g was not observed during the reaction, 5g was directly obtained.

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