CANNALACTONE ANALOGUES, SYNTHESIS AND USE FOR STIMULATING THE GERMINATION OF PARASITE PLANT SEEDS

Abstract

The present invention relates to the chemical synthesis of cannalactone analogues, as well as the use of these analogues for stimulating the germination of seeds of parasitic plants.

Description

Title of the invention: CANNALACTONE ANALOGUES, SYNTHESIS AND USE FOR STIMULATING THE GERMINATION OF PARASITE PLANT SEEDS Technical field of the invention

[0001] The present invention relates to the chemical synthesis of cannalactone analogues, as well as the use of these analogues for the stimulation of the germination of seeds of parasitic plants. Technical background

[0002] Hemp (Cannabis saliva) is an annual plant native to Asia that has been cultivated for over 8,000 years. It is grown worldwide and is capable of meeting the four basic needs of humanity: food, shelter, clothing, and medicine.

[0003] Hemp cultivation is widespread because it is a profitable and sustainable crop. Indeed, the plant adapts easily to diverse soils and climates and therefore requires no phytosanitary treatment. The area under hemp production in France has increased thirtyfold between 1960 and today. This interest in hemp continues to grow, partly with the aim of gradually replacing cotton, which is very water-intensive. France is currently the leading hemp producer in Europe, with production on approximately 20,000 hectares.

[0004] Known for its resistance to parasites and pests, the hemp plant is all the more attractive. However, a parasitic plant of the broomrape family, branched broomrape, Phelipanche ramosa, induces large yield losses in hemp crops, sometimes exceeding 80%. This parasite also attacks crops such as rapeseed or tobacco, but a specialization of a branched broomrape population to hemp has been demonstrated [1]-[4].

[0005] After germination, the parasitic plant connects to the root of the host plant and thus obtains nutrients for its own development [5]. This parasitism causes significant damage to hemp crops, which can even lead to the abandonment of this crop on the plot.

[0006] Strigolactones are small molecules known to be exuded into the soil at picomolar concentrations (10⁻¹² M) and have been identified as germination stimulants of Phelipanche ramosa or branched broomrape seeds [6], [7]. Strigolactones (SL) were first identified for their role in parasitic [8] and symbiotic [9] interactions in the rhizosphere and constitute the most recently discovered class of plant hormones

[10] ,

[11] . They are best known for their role in controlling plant architecture, more recently roles for SL in other aspects of plant development have been highlighted

[12] .

[0007] To make bioactive molecules more readily available, synthetic analogs of strigolactones have been developed [4], [7],

[13] ,

[14] . These analogs are molecules with a structure similar to that of SL but which do not potentially exist in nature.

[0008] Following the discovery of cannalactone, the strigolactone discovered in hemp exudates in very small quantities and which is the main germination stimulant of P. ramosa[l]-[4], the Applicant has developed analogues that are simpler to access compared to cannalactone and that exhibit biological activity in some cases superior to the biological activity of cannalactone. Summary of the invention

[0009] In particular, the present invention relates to an analogue of cannalactone, characterized in that it corresponds to the general formula 1:

[0010] [Chem.l]

[0011] in which:

[0012] - R1 designates the hydrogen atom H, the hydroxyl group OH or the OSiR43 group,

[0013] - R2 and R3 each designate the hydrogen atom H or the methyl radical CH3,

[0014] - R4 designates an alkyl group, and

[0015] - the 6-membered carbon ring which may be aromatic or of the cyclohexene type or cyclohexane.

[0016] According to a first embodiment of the invention, the cannalactone analogue according to the invention can be aromatic with "cis" and "trans" stereochemistry and corresponding to formula 2:

[0017] [Chem.2]

[0018] in which:

[0019] - R1, R2 and R3 denote the hydrogen atom H, and

[0020] - the 6-membered carbon ring is aromatic.

[0021] According to a second embodiment of the invention, the cannalactone analogue according to the invention can be of the diene type with "cis" and "trans" stereochemistry and corresponds to formula 3:

[0022] [Chem.3]

[0023] in which:

[0024] - R1 and R3 denote the hydrogen atom H,

[0025] - R2 designates the methyl group, and

[0026] - the 6-membered carbon ring is of the cyclohexene type.

[0027] According to a third embodiment of the invention, the cannalactone analogue according to the invention can be of the silylated type with "cis" and "trans" stereochemistry and corresponds to formula 4:

[0028] [Chem.4] R%SiQ |

[0029] in which:

[0030] - R1 designates the OSiR43 group,

[0031] - R2 designates the methyl group,

[0032] - R3 designates the hydrogen atom H, and

[0033] - the 6-membered carbon ring is of the cyclohexene type.

[0034] According to a fourth embodiment of the invention, the cannalactone analogue according to the invention can be of the alcohol type with "cis" and "trans" stereochemistry and corresponds to formula 5:

[0035] [Chem.5] .G

[0036] in which:

[0037] - R1 designates the hydroxyl group OH,

[0038] - R2 designates the methyl group,

[0039] - R3 designates the hydrogen atom H, and

[0040] - the 6-membered carbon ring is of the cyclohexene type.

[0041] The present invention also relates to a method for synthesizing an analogue

[0042] of cannalactone according to the first embodiment, characterized in that it comprises the following steps:

[0043] - a reaction A) coupling of commercial B-cyclocitral with a C4 bromofuran formula 6:

[0044] [Chem.6] ..O | ^OTIPS C4

[0045] to obtain a B20 alcohol of formula 7:

[0046] [Chem.7] ^0 B2G

[0047] - a step B) of reducing alcohol B20 of formula 7, to obtain a mixture of diastereomers of allylic alcohol, followed by a step of separating said diastereomers to retain the diastereomer (4R* 67?*)-B21 of formula 8:

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057] [Chem. 8] This synthesis is illustrated by [Fig.1]. - a step C2) of epoxidation of the diastereoisomer (47?*, 67?*)-B21 of formula 8 to obtain an epoxy alcohol B22 of formula 9: [Chem.9] - a step D2) of dehydration and rearrangement of the epoxy alcohol B22 of formula 9 to obtain a benzyl compound B38 of formula 10: [Chem. 10] 036 - a step E2) of formylation in basic medium with an alkyl formate of the benzyl compound B38 of formula 10 to obtain an enol B40 of formula 11: [Chem. 11] - a step F2) of O-alkylation of enol B40 to obtain the formula 2 analogue (of aromatic type). Alkyl formate (in particular ethyl or methyl formate) corresponds to formula 12

[0058] [Chem. 12]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] This synthesis is illustrated by [Fig.2] (part A). The present invention also relates to a method for synthesizing a cannalactone analogue according to the second embodiment, characterized in that it comprises the following steps: - steps A and B as defined in the process for synthesizing a cannalactone analogue according to the first embodiment, followed by - a step C3) of mesylation of the diastereoisomer (47?*, 67?*)-B21 of formula 8 to obtain after dehydration and rearrangement the diene (E)-B25 of formula 13: [Chem. 13]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] - a step E3) of formylation in basic medium of the diene (E)-B25 of formula 13 to obtain an enol B42 of formula 14: [Chem. 14] 042 Then - a step F3) of O-alkylation of enol B42 to obtain the formula 3 analogue (of the diene type). This synthesis is illustrated by [Fig.2] (part B). The present invention also relates to a method for synthesizing a cannalactone analogue according to the third embodiment, characterized in that it comprises the following steps: - steps A and B as defined in the process for synthesizing a cannalactone analogue according to the first embodiment, followed by

[0074] - a step C4) of protection of the diastereoisomer (47?*, 67?*)-B21 of formula 8 for obtain the protected compound (47?*, 67?*)-B45 of formula 15:

[0075] [Chem. 15] .-O r^o;. A / ^° (4^, 61^)4345

[0076] - a step E4) of formylation in basic medium of the protected compound of formula 14, to obtain an enol (47?*, 67?*)-B46 of formula 16:

[0077] [Chem. 16]

[0078] - a step F4) of O-alkylation of enol B46 to obtain the formula analogue 4 (of silyle type).

[0079] This synthesis is illustrated by [Fig.2] (part C).

[0080] The present invention also relates to a method for synthesizing an analogue

[0081] of cannalactone according to the fourth embodiment, characterized in that it comprises the following steps:

[0082] - steps A and B as defined in the process for synthesizing a cannalactone analogue according to the first embodiment, followed by

[0083] - the formation of a cannalactone analogue according to the third mode of production, followed by

[0084] - a step G5) of deprotection and separation of the diastereomers of the analogue formula 4, to obtain the analogue of formula 5 (of the alcohol type).

[0085] This synthesis is also illustrated by [Fig.2] (part C).

[0086] The present invention also relates to the use of a cannalactone analogue according to the invention or as obtained according to one of the synthesis processes according to the invention, as a germination stimulant for seeds of parasitic plants.

[0087] In particular, it can be used as a germination stimulant for the seeds of P. ramosa 1 and P. ramosa 2a, or for the suicide germination of parasitic plants of the Striga, Orobanche and Phelipanche type. Brief description of the figures

[0088] Other features and advantages of the invention may become apparent to a person skilled in the art upon reading the examples below, given by way of illustration and not limitation and illustrated by the attached figures:

[0089] [Fig-1] - [Fig.1] represents the scheme of the synthesis of the diastereoisomer (4 R*, 6 R*)-B21 of formula (8) carried out in example 1;

[0090] [Fig.2] - [Fig.2] represents an overall diagram of analogous syntheses of the cannalactone produced in examples 2 to 5, from the diastereoisomer (4 R*, 6R* )-B21 of formula (8) obtained in example 1;

[0091] [Fig.3] - [Fig.3] is a schematic representation of the test protocol germination implemented in example 6.

[0092] [Fig.4] - [Fig.4] is a dose-response curve of (±)-GR24 and (+)- cannalactone on the stimulation of germination of P. ramosa 2a and 1 seeds.

[0093] [Fig.5] - [Fig.5] is a histogram curve showing the maximum activities of Stimulation of germination of cannalactone analogues according to the invention of examples 3 to 6 (comprising ring A) compared to those of (+)-cannalactone and (±)-GR24 on P. ramosa 1 and 2a seeds. Data are means ± SE (n = 6-12 replicates).

[0094] [Fig.6] - [Fig.6] is a histogram curve showing the effective concentrations Median EC50 (in mol.L') of cannalactone analogues according to the invention of Examples 3 to 6, compared to those of (+)-cannalactone and (±)-GR24 on the stimulation of germination of P. ramosa 1 and 2a seeds. Data are means ± SE (n = 6-12 replicates).

[0095] [Fig.7] - [Fig.7] is a histogram curve showing the evolution of the ratio of the median effective concentration EC50 of cannalactone analogues according to the invention of examples 3 to 6 (comprising ring A) compared to that of (+)-cannalactone and (±)-GR24, on the stimulation of germination of P. ramosa 1 and 2a seeds.

[0096] rEC5o = EC5o(P. ramosa l) / EC50(P. ramosa 2a) for each analogue. EXAMPLES Solvents and reagents

[0097] The chemical reagents are commercial products marketed in particular by the companies Sigma Aldrich, Alfa Aesar, Acros Organics and TCI. They were used without further purification.

[0098] Analytical grade anhydrous solvents are commercial products marketed in particular by the companies Sigma Aldrich and Acros Organics. Tetrahydrofuran (THF) was distilled under argon over sodium in the presence of benzophenone. The deuterated solvents are commercially available from Eurisotop. Materials and Methods

[0099] The non-aqueous reactions were carried out under an inert atmosphere (argon or nitrogen), using standard techniques for handling air- and moisture-sensitive compounds.

[0100] All reactions were monitored by thin-layer chromatography (TLC) on pre-coated aluminum plates with silica gel (marketed by Merck under the trade name 60 F254 with short-wavelength UV detection (i.e. X = 254 nm), and / or by staining with a solution of KMnO4 [1% (w / w)] in water or a solution of vanillin [1% (w / w)] in a 1% (v / v) ethanoic acid solution.

[0101] Most of the separations were carried out under Flash-silica gel chromatography conditions using a packed cartridge (40-63 qm silica gel) at medium pressure (20 psi) with Armen pump and fraction collector or a Buchi Pure C-805 Flash apparatus.

[0102] Some separations were carried out on preparative thin layer chromatography (PTLC) (Merck 60 F254 silica gel on glass).

[0103] The *H NMR spectra were recorded on Bruker spectrometers at 300, 500, or 700 MHz. The 13C NMR spectra were recorded on the same instruments at 75, 125, or 175 MHz. The chemical shifts δ are expressed in parts per million (ppm) with the residual solvent signals as an internal reference (δ = 7.24 for *H NMR and 77.23 for 13C NMR in CDC13). For *H NMR, the spectra are described as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, sext = sextuplet, dd = doublet of doublet, dt = doublet of triplet, m = multiplet), coupling constant in Hertz (J), and assignment. All NMR assignments are based on 2D COSY, HSQC, and HMBC NMR experiments. NOESY experiments were recorded to confirm the double-bond configurations.

[0104] IR spectra were recorded on a PerkinElmer Spectrum 100 FT-IR spectrometer, absorptions being given in centimetres1 (cm1).

[0105] Low-resolution mass spectra were determined by electron fogging ionization on a Waters Acquity UPLC system, combined with a photodiode detector (PDA), an evaporative light scattering detector (ELSD), and a mass spectrometer with a tandem quadrupole detector (TQD). The buffers and aqueous mobile phases for UPLC were prepared using purified water with a Milli-Q system.

[0106] High-resolution mass spectra were obtained with the Waters Acquity UPLC device (by direct injection or with a BEH C[8 2.1 Â ~50 mm, 1.7 pm] column) combined with a PDA and a Waters LCT Premier XE mass instrument [ESI with a time-of-flight (ToF) analyzer].

[0107] EXAMPLE 1: Synthesis of the diastereoisomer (4 R*, 6 R* )-B21 of formula (8) (route illustrated by [Fig. 1]) 4-Bromofuran-2(5H)-one

[0108] Oxalyl dibromide (2.6 g, 10.00 mmol) in CH2Cl2 (22 mL) and DMF (1 mL) at 0 °C was added to a solution of furan-2,4(3 / 1,5H)-dione (1.0 g, 10.00 mmol) in CH2Cl2 (22 mL) and DMF (1 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and gradually warmed to room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (2 x 30 mL), a saturated aqueous solution of NaHCO3 (2 x 30 mL), and brine (2 x 30 mL) and dried over Na2SO4. The solvents were removed to obtain the crude product 4-Bromofuran-2(5 / / )-one (1.61 g, quantitative) as a brown solid. The chemical analyses are in agreement with the literature

[15] . (4-B romofuran-2-yl)oxy triisopropylsilane (C4)

[0109] To a solution of 4-bromofuran-2(5 / / )-one (720.4 mg, 4.40 mmol) in CH2 Cl2 (6.2 mL) under argon at 0 °C, Et3N (626.4 mg, 6.20 mmol, 1.4 equiv.) was added. The mixture was stirred for 1 minute, then triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) (1.42 g, 4.60 mmol, 1.05 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred for 10 minutes at 0 °C, then warmed to room temperature and stirred for another 1.5 hours. The mixture was diluted with heptane (10 mL), washed with saturated aqueous NaHCO3 solution (2 x 10 mL), water (2 x 10 mL), and brine (2 x 10 mL). The organic phase was dried over Na2SO4. The solvents were removed to obtain C4 bromofuran (1.4 g, quantitative) as a brown oil. The chemical analyses are consistent with the literature

[15] .

[0110] 4-[Hydroxy(8,12,12-trimethylcyclohex-7-en-6-yl)methyl]furan-2(5 H )-one (B20)

[0111] To a solution of C4 (89.9 mg, 0.28 mmol) in anhydrous THF (1.8 mL) under argon at -78 °C, a solution of n-BuLi (0.3 mL, 0.30 mmol, 0.98 M, 1.1 equiv.) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes. A mixture of [3-cyclocitral (51.6 mg, 0.34 mmol, 1.2 equiv.) in anhydrous THF (2 mL) was then added. The reaction mixture was stirred for 2 h at -78 °C and 12 h at room temperature. The mixture was hydrolyzed with a saturated aqueous solution of NH4Cl (5 mL) and an aqueous solution of HCl (5 mL, 2 M). The organic phase was separated and the aqueous phase was extracted with EtOAc (3x5 mL). The combined organic phases were washed with water (2 x 5 mL), a saturated aqueous solution of NaHCO3 (2 x 5 mL), water (2 x 5 mL), and brine (2 x 5 mL), then dried over Na2SO4. The solvents were removed, and the crude product was purified by silica gel chromatography (heptane / EtOAc, 95:5 to 60:40 for 20 min) to obtain pure product B20 (24.5 mg, 37%) as a brown oil:

[0112] B20

[0113] [Chem.7] 5 ..O . Chemical Formula: 4 7^' jg Exact Mass 236.1412 ts Motecyhr Weight 2 36 31W m 4 .--¾

[0114] 'H NMR (500 MHz, CDC13) ô 5.91 (1H, d, J = 1.5 Hz, H-3), 5.10 (1H, s, H-6), 4.88 (1H, d, J = 18.0 Hz, H-5a), 4.71 (1H, d, J = 18.0 Hz, H-5b), 1.96 (2H, t, J = 6.0 Hz, H-9), 1.61 (3H, s, H-15), 1.59-1.55 (2H, m, H-10), 1.50-1.46 (2H, m, H-ll), 1.13 (3H, s, H-13 or H-14), 0.98 (3H, s, H-13 or H-14).

[0115] 13C NMR (75 MHz, CDC13) ô 174.1 (C-2), 174.0 (C-4), 138.7 (C-7), 136.6 (C-8), 115.0 (C-3), 71.9 (C-5), 67.8 (C-6), 39.5 (C-ll), 35.0 (C-12), 33.7 (C-9), 28.9 (C-13 or C-14), 28.5 (C-13 or C-14), 21.4 (C-15), 19.3 (C-10).

[0116] IR (film) vmax3471, 2932, 1777, 1741, 1637, 1447, 1268, 1111, 1028 cm4.

[0117] HRESIMS m / z 237.1491 [M + H]+ (wedge, for Ci4H21O3, 237.1491).

[0118] 4-[Hydroxy(8,12,12-trimethylcyclohex-7-en-6-yl)methyl]dihydrofuran-2(3 H )-one (B21)

[0119] To a solution of B2O (696.4 mg, 2.95 mmol) in methanol (45 mL) at 15 °C, NiCl2 (350.9 mg, 1.48 mmol, 0.5 equiv.) and then sodium borohydride (358.3 mg, 9.47 mmol, 3.2 equiv.) were added in portions. The mixture was stirred at 15 °C until TLC analysis indicated complete conversion. The reaction mixture was hydrolyzed with an aqueous solution of HCl (50 mL, 2 M). The aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic phases were dried over Na2SO4 and the solvents were removed. The resulting mixture was then purified by silica gel chromatography (CH2Cl2 / EtOAc, 100:0 to 90:10 for 30 min) to obtain the pure product (47?*, 67?*)-B21 of formula 8 (327.4 mg, 47%) as a yellow oil and (47?*, 6S*)-B21 of formula 17 (131.9 mg, 19%) as a white solid.

[0120] (47?*, 67?*)-B21

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] [Chem. 8] Chèmteal Formula: Exact Mw, 238,1669 Mdecülar Weight 238,327$ RMN ‘H (500 MHz, CDC13) ô 4.50 (1H, dd, J = 9.5, 7.0 Hz, H-5a), 4.28 (1H, dd, J = 9.5, 7.0 Hz, H-5b), 4.21 (1H, d, J = 9.5 Hz, H-6), 3.21 (1H, sext, J = 9.5 Hz, H-4), 2.41 (1H, dd, J = 17.5, 8.5 Hz, H-3a), 2.18 (1H, dd, J = 17.5, 8.5 Hz, H-3b), 1.96 (2H, q, J = 5.5 Hz, H-9), 1.81 (3H, s, H-15), 1.59-1.52 (2H, m, H-10), 1.48-1.45 (1H, m, H-lla), 1.40-1.35 (1H, m, H-llb), 1.08 (3H, s, H-13 ou H-14), 0.98 (3H, s, H-13 ou H-14). RMN 13C (125 MHz, CDC13) ô 177.1 (C-2), 138.4 (C-7), 135.1 (C-8), 72.9 (C-5), 72.6 (C-6), 41.3 (C-4), 40.4(C-ll), 35.0 (C-12), 34.6 (C-9), 32.4 (C-3), 29.2 (C-13 ou C-14), 29.1 (C-13 ou C-14), 21.3 (C-15), 19.4 (C-10). IR (film) vmax 3464, 2928, 1768, 1551, 1365, 1263, 1178, 1048, 1001, 892 cm1. HRESIMS m / z 239.1640 [M + H]+ (cale, pour Ci4H23O3, 239.1647). (4R*, 65*)-B21 [Chem. 17] i Chêmicàl Formula:' Exact Mm: 238,1569’ Mdecüiar Weâghr 238,3278 RMN ‘H (500 MHz, CDC13) ô 4.17 (1H, dd, J = 9.0, 7.0 Hz, H-5a), 4.16 (1H, d, J = 9.0 Hz, H-6), 3.94 (1H, dd, J = 9.0, 7.0 Hz, H-5b), 3.19 (1H, sext, J = 9.0 Hz, H-4), 2.72 (1H, dd, J = 17.5, 7.5 Hz, H-3a), 2.57 (1H, dd, J = 17.5, 7.5 Hz, H-3b), 1.96 (2H, q, J = 5.0 Hz, H-9), 1.80 (3H, s, H-15), 1.59-1.51 (2H, m, H-10), 1.47-1.44 (1H, m, H-lla), 1.40-1.34 (1H, m, H-llb), 1.08 (3H, s, H-13 ou H-14), 0.97 (3H, s, H-13 ou H-14). RMN 13C (125 MHz, CDC13) ô 177.5 (C-2), 138.2 (C-7), 135.1 (C-8), 72.3 (C-6), 70.5 (C-5), 41.5 (C-4), 40.4 (C-ll), 35.1 (C-12), 34.6 (C-9), 33.8 (C-3), 29.2 (C-13 ou C-14), 28.8 (C-13 ou C-14), 21.4 (C-15), 19.4 (C-10). IR (film) vmax 3481, 2925, 2870, 1774, 1547, 1465, 1373, 1258, 1176, 1092, 1033, 1011, 890, 795 cm'1. HRESIMS m / z 239.1638 [M + H]+(calc. for C14H23O3 239.1647).

[0132] EXAMPLE 2: Synthesis of aromatic cannalactone analogues according to the invention, from the (4 R*, 6 R* )-B21 diastereoisomer of example 1 (of formula 8)

[0133] (4 R *)-hydroxy(8,12,12-trimethyl-7-oxabicyclo[4.1.0]heptan-6- yl)methyl]dihydrofuran-2(3H)-one ((4 / ?*,6R*)-cis-B22)

[0134] This synthesis is illustrated by [Fig.2].

[0135] A solution of (47?*, 67?*)-B21 (100.9 mg, 0.420 mmol) in anhydrous toluene (5.1 mL) was added to a solution of VO(acac)2 (3.9 mg, 0.015 mmol, 0.04 equiv.) in anhydrous toluene (0.2 mL). Tert-Butyl hydroperoxide (TBHP) (0.11 mL, 5.5 M, 0.590 mmol, 1.4 equiv.) was also added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was hydrolyzed with an aqueous solution of NaOH (5 mL, 5%). The aqueous phase was extracted with heptane and EtOAc (2:1) (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over Na2SO4 and the solvents were removed to obtain the pure product (47?*, 67?*)-cA-B22 of formula 9 (116.4 mg, quantitative) as a colorless oil used in the next step without purification.

[0136] (47?*, 67?*)-cA-B22

[0137] [Chem.9] s D — Chemical formula: Exact Mass 254.1518~ Motecdar'WeleN 2S4.32B8 w

[0138] RMN ‘H (300 MHz, CDC13) ô 4.40 (1H, dd, J = 9.5, 8.0 Hz, H-5a), 4.31 (1H, dd, J = 9.5, 8.0 Hz, H-5b), 3.96 (1H, d, J = 8.0 Hz, H-6), 2.94 (1H, sext, J = 8.0 Hz, H-4), 2.59 (1H, dd, J = 17.0, 9.0 Hz, H-3a), 2.48 (1H, dd, J = 17.0, 9.0 Hz, H-3b), 1.90-1.80 (1H, m, H-9a), 1.78-1.69 (1H, m, H-9b), 1.39 (3H, s, H-15), 1.36-1.32 (2H, m, H-10), 1.25-1.22 (1H, m, H-lla), 1.06 (3H, s, H-13 ou H-14), 1.05-1.03 (1H, m, H-llb), 1.02 (3H, s, H-13 ou H-14).

[0139] RMN 13C (75 MHz, CDC13) ô 176.4 (C-2), 71.1 (C-5), 70.5 (C-6), 70.4 (C-7), 66.3 (C-8), 40.0 (C-4), 37.6 (C-ll), 33.9 (C-13), 33.3 (C-3), 31.8 (C-9), 25.6 (C-13 et C-14), 22.2 (C-15), 17.0 (C-10).

[0140] IR (film) vmax 3464, 2928, 1768, 1551, 1365, 1263, 1178, 1048, 1001, 892 cm’1.

[0141] HRESIMS m / z 255.1607 [M + H]+(calc. pour Ci4H23O4, 255.1596)

[0142] 4-(8,ll,12-Triméthylbenzyl)dihydrofuran-2(3Zf )-one (B38)

[0143] Para-toluene sulfonic acid (PTSA) (4.8 mg, 0.02 mmol, 10 mol%) was added to a solution of B22 (62.8 mg, 0.21 mmol) in toluene (15 mL) at 120 °C, and the reaction was stirred for 2 h at this temperature before being cooled to room temperature. The mixture was diluted with water (15 mL), extracted with CH2Cl2 (3 x 10 mL), and dried over Na2SO4. The solvents were removed to obtain the crude product B38 (62.1 mg, quantitative) of formula 10. The crude product was used without purification in the next step.

[0144] B38

[0145] [Chem. 10] g Ch'wHCSl Fotmuta u 3. 1 $ tp T

[0146] RMN ‘H (500 MHz, CDC13) ô 6.93 (2H, q, J = 8.0 Hz, H-9 et H-10), 4.26 (1H, dd, J = 9.0, 5.5 Hz, H-5a)„4.02 (1H, dd, J = 9.0, 5.5 Hz, H-5b), 2.86-2.84 (2H, m, H-6), 2.78 (1H, sext, J = 8.0 Hz, H-4), 2.57 (1H, dd, J = 17.0, 8.0 Hz, H-3a), 2.28 (1H, dd, J = 17.0, 8.0 Hz, H-3b), 2.27 (3H, s, H-14), 2.23 (3H, s, H-13 ou H-15), 2.20 (3H, s, H-13 ou H-15).

[0147] RMN 13C (125 MHz, CDC13) ô 177.2 (C-2), 135.3 (C-ll or C-8), 135.2 (C-ll or C-8), 135.0 (C-7), 134.1,(C-12), 128.5 (C-9 or C-10), 128.2 (C-9 or C-10), 72.7 (C-5), 36.2 (C-4), 34.7 (C-3), 32.2 (C-6), 21.0 (C-13 ou C-15), 20.8 (C-13 ou C-15), 16.3 (C-14).

[0148] IR (film) vmax 2932, 1777, 1734, 1464, 1379, 1169, 1014, 810 cm’1.

[0149] HRESIMS m / z 219.1377 [M + H]+(calc. pour Ci4H19O2, 219.1385).

[0150] ( E )-3-(Hydroxyméthylène)-4-(8,1 l,12-triméthylbenzyl)dihydrofuran-2(3 H )- one (B40)

[0151] To a solution of B38 (62.1 mg, 0.21 mmol) in anhydrous THF (2.1 mL) at 0 °C under argon, ethyl formate (0.16 mL, 2.10 mmol, 10.0 equiv.) and tert-BuOK (235.5 mg, 2.10 mmol, 10.0 equiv.) were added. The mixture was stirred for 30 minutes at 0 °C, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was hydrolyzed with an aqueous solution of HCl (3 mL, 1 M). The mixture was extracted with EtOAc (3 x 5 mL), washed with brine (2 x 5 mL), dried over Na2SO4, and the solvents were removed. The crude product was purified by silica gel chromatography (heptane / EtOAc, 70:30) to obtain the pure product B40 of formula 11 (31.4 mg, 61% in 2 steps).

[0152] B40

[0153] [Chem. 11] Ch vr'ïœl Formi i la C. SH 150g f > «set Mass ?4ô 1 / 66 ?4G JÛGÛ

[0154] IR (film) vmax 3673, 2969, 2922, 1778, 1745, 1462, 1385, 1262, 1169, 1051, 799 cm

[0155] HRESIMS m / z 245.1176 [M - H] + (wedge, for C15H17O3, 245.1178). (±)-SdL625

[0156] To a solution of B40 (30.0 mg, 0.12 mmol) in anhydrous acetone (1.2 mL) under argon, anhydrous K2CO3 (34.5 mg, 0.24 mmol, 2.0 equiv.) was added. 5-Bromo-3-Methylfuran-2(5 / / )-one D4

[16] (32.3 mg, 0.18 mmol, 1.5 equiv.) in anhydrous acetone (1.2 mL) was added to this mixture. The reaction was stirred for 2 h at room temperature. The solvents were removed, and the mixture was dissolved in EtOAc (5 mL) and filtered to remove the salts. The solvents were removed and the crude product was purified by PTLC (heptane / EtOAc, 50:50) to obtain the pure product (±)-SdL625 Fl of formula 18 (8.3 mg, 17%) and (±)-SdL625 F2 of formula 19 (7.1 mg, 20%) as colorless oils. (±)-SdL625 Fl and (±)-SdL625 F2 are aromatic cannalactone analogs corresponding to general formula 2.

[0157] (±)-SdL625 Fl

[0158] [Chem. 18] ‘ 4 3¾ - ÇhemlcafFwmüfe: s1 Exact Mass: 342.1467 rs-A / / ... Mùtecular 342À910 C ■: X* .... « -■ 'AA'

[0159] RMN ‘H (700 MHz, CDC13) ô 7,41 (1H, d, J = 1.5 Hz, H-6’), 6.94 (1H, d, J = 8.0 Hz, H-9 or H-10), 6.90 (1H, d, J = 8.0 Hz, H-9 or H-10), 6.57 (1H, t, J = 1.5 Hz, H-3’), 5.81 (1H, t, J = 1.5 Hz, H-2’), 4.16 (1H, dd, J = 9.0, 7.0 Hz, H-5a), 4.07 (1H, dd, J = 9.0, 1.5 Hz, H-5b), 3.50 (1H, q, J = 7.5 Hz, H-4), 3.01 (1H, dd, J = 14.0, 8.5 Hz, H-6a), 2.88 (1H, dd, J = 14.0, 8.5 Hz, H-6a), 2.26 (3H, s, H-13 ou H-15), 2.23 (3H, s, H-13 ou H-15), 2.20 (3H, s, H-14), 1.97 (3H, s, H-7’).

[0160] RMN 13C (175 MHz, CDC13) ô 171.9 (C-2), 170.4 (C-5’), 150.9 (C-6’), 141.1 (C-3’), 135.6 (C-4’), 135.6 (C-12), 135.3 (C-7), 134.8 (C-8 ou C-ll), 134.7 (C-8 ou C-ll), 128.3 (C-9 ou C-10), 127.9 (C-9 ou C-10), 112.2 (C-3), 100.3 (C-2’), 71.0 (C-5), 37.1 (C-4), 33.0 (C-6), 21.0 (C-13 ou C-15), 21.0 (C-13 ou C-15), 16.4 (C-14), 10.9 (C-7’).

[0161] IR (film) vmax 2969, 2924, 2860, 1785, 1754, 1681, 1465, 1340, 1257, 1174, 1084, 1021,953, 868,794 cm1.

[0162] HRESIMS m / z 343.1538 [M + H]+(calc. pour C20H23O5, 343.1545).

[0163] (±)-SdL625 F2

[0164] [Chem. 19] 1 5 ...O , S tC / '*\ .CherwcalForn^uia. r Exact Mass 342.1467 ts ^0 rv Motecylai Weighl ':^s L >^0

[0165] RMN ‘H (700 MHz, CDC13) ô 7,38 (1H, s, H-6’), 6.88 (1H, d, J = 8.0 Hz, H-9 ou H-10), 6.84 (1H, d, J = 8.0 Hz, H-9 ou H-10), 6.68 (1H, s, H-3’), 5.93 (1H, s, H-2’), 4.15 (1H, dd, J = 9.5, 7.0 Hz, H-5a), 4.07 (1H, dd, J = 9.5, 2.0 Hz, H-5b), 3.50 (1H, q, J = 8.0 Hz, H-4), 3.02 (1H, dd, J = 14.0, 7.5 Hz, H-6a), 2.86 (1H, dd, J = 14.0, 9.5 Hz, H-6a), 2.24 (3H, s, H-13 ou H-15), 2.20 (3H, s, H-13 ou H-15), 2.19 (3H, s, H-14), 1.99 (3H, s, H-7’).

[0166] RMN 13C (175 MHz, CDC13) ô 171.9 (C-2), 170.2 (C-5’), 150.3 (C-6’), 140.7 (C-3’), 136.1 (C-4’), 135.4 (C-12), 135.1 (C-7), 134.8 (C-8 ou C-ll), 134.5 (C-8 ou C-ll), 128.3 (C-9 ou C-10), 127.9 (C-9 ou C-10), 112.1 (C-3), 100.0 (C-2’), 71.0 (C-5), 37.1 (C-4), 32.9 (C-6), 21.0 (C-13 ou C-15), 21.0 (C-13 ou C-15), 16.3 (C-14), 11.0 (C-7’).

[0167] IR (film) vmax 2966, 2922, 2848, 1781, 1756, 1682, 1347, 1260, 1184, 1090, 1024, 950, 797 cm'.

[0168] HRESIMS m / z 343.1540 [M + H]+ (hold, for C20H23O5, 343.1545).

[0169] EXAMPLE 3: Synthesis of diene-type cannalactone analogues according to the invention, from the (4 R*, 6 R* )-B21 diastereoisomer of Example 1

[0170] This synthesis is illustrated by [Fig.2].

[0171] ( E )-4-[(8,12,12-Trimethylcyclohex-8-en-6-ylidene)methyl]dihydrofuran-2(3 H )-one ((£)-B25)

[0172] To a solution of B21 (200.0 mg, 0.84 mmol) in pyridine (6.8 mL), DMAP (4-dimethylaminopyridine 5.1 mg, 0.04 mol, 5 mol%) and MsCl (0.3 mL, 3.40 mmol, 4.0 equiv.) were added. The mixture was stirred overnight at temperature ambient temperature. The reaction mixture was co-evaporated with toluene. The mixture was diluted with CH2Cl2 (10 mL), washed with water (2 x 5 mL) and brine (2 x 5 mL), and dried with Na2SO4. The solvents were removed, and the crude product was purified by silica gel chromatography (heptane / EtOAc, 80:20) to obtain the pure product (E)-B25 of formula 13 (142.2 mg, 77%).

[0173] (£j-B25

[0174] [Chem. 13] 1 5 .. 0 ... J fi Chenàjal Fsrmuh: is xj Exact Mass-220 US3 — 14 Matecubu 220 312$ ■ *3

[0175] H NMR (500 MHz, CDC13) ô 5.73 (1H, t, J = 4.5 Hz, H-9), 5.18 (1H, d, J = 10.0 Hz, H-6), 4.44 (1H, t, J = 8.0 Hz, H-5a), 3.93 (1H, t, J = 8.0 Hz, H-5b), 3.69 (1H, m, H-4), 2.69 (1H, dd, J = 17.5, 8.0 Hz, H-3a), 2.30 (1H, dd, J = 17.0, 9.5 Hz, H-3b), 2.05 (1H, m, 2 H-ll), 1.78 (3H, s, H-15), 1.46 (2H, t, J = 5.6 Hz, H-10), 1.20 (6H, s, H-13 and H-14).

[0176] 13C NMR (125 MHz, CDC13) ô 176.9 (C-2), 147.4 (C-7), 132.8 (C-8), 128.5 (C-9), 122.8 (C-6), 73.8 (C-5), 40.3 (C-ll), 36.7 (C-4), 36.5 (C-3), 35.0 (C-12), 29.5 (C-13 or C-14), 29.1 (C-13 or C-14), 22.9 (C-10), 22.0 (C-15).

[0177] IR (film) vmax 2932, 2857, 1779, 1545, 1469, 1380, 1265, 1178, 1042, 1001, 882, 739 cm *.

[0178] HRESIMS m / z 221.1542 [M + H]+ (wedge, for C14H21O2, 221.1542).

[0179] ( E )-3-(Hydroxymethylene)-4-[( E )-(8,12,12-trimethylcyclohex-8-en-6- ylidene)methyl]dihydrofuran-2(3 H )-one (B42)

[0180] To a solution of (E)-B25 (19.0 mg, 0.09 mmol) in anhydrous THF (0.9 mL) at 0 °C under argon, ethyl formate (70 pL, 0.90 mmol, 10.0 equiv.) and tert-BuOK (101.0 mg, 0.90 mmol, 10.0 equiv.) were added. The mixture was stirred for 30 minutes at 0 °C, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was hydrolyzed with an aqueous solution of HCl (1 mL, 1 M). The mixture was extracted with EtOAc (5 mL), washed with brine (2 x 5 mL), and dried over Na2SO4. The solvents were removed and the crude product was purified by silica gel chromatography (heptane / EtOAc, 70:30) to obtain the pure product B42 of formula 14 (14.8 mg, 66%) in the form of a colorless oil.

[0181] B42

[0182] [Chem. 14] >o. 1S ç >»0 Fleshy a F mma * % H S L.Adt.^. 2<$d 1412 M / 14Ve \bknthrV'Hqh1 21» VH A J7^0H 56 1Î

[0183] IR (film) vmax 3664, 2975, 2919, 1734, 1396, 1056 cm1.

[0184] HRESIMS m / z 247.1332 [M + H]+ (cale, for C15H19O3, 247.1334). (±)-SdL646

[0185] To a solution of B42 (27.7 mg, 0.11 mmol) in anhydrous acetone (1.1 mL) under argon, anhydrous K2CO3 (32.3 mg, 0.22 mmol, 2.0 equiv.) was added. 5-Bromo-3-Methylfuran-2(5 / / )-one D4

[16] (30.1 mg, 0.17 mmol, 1.5 equiv.) in anhydrous acetone (1.1 mL) was then added to this mixture. The reaction was stirred for 2 h at room temperature. The solvents were removed, and the crude product was dissolved in EtOAc (5 mL) and filtered to remove salts. The solvents were removed and the crude product was purified by PTLC (heptane / EtOAc, 50:50) to obtain the pure product (±)-SdL646 Fl of formula 20 (10.9 mg, 19%) and (±)-SdL646 F2 of formula 21 (7.3 mg, 29%) as colorless oils. (±)-SdL646 Fl and (+)-SdL646 F2 are diene-type cannalactone analogs corresponding to general formula 3.

[0186] (±)-SdL646 Fl

[0187] [Chem.20] i 'ros ns J / . ChemîcaS Formai: \ J ' Exact Mass? 344. WM > c Mcfecular Wekjht 3-44.4078 ts ” [

[0188] RMN ‘H (700 MHz, CDC13) ô 7,48 (1H, d, J = 2.0 Hz, H-6’), 6.80 (1H, t, J = 1.5 Hz, H-3’), 6.06 (1H, s, H-2’), 5.70 (1H, t, J = 4.5 Hz, H-9), 5.23 (1H, d, J = 10.0 Hz, H-6), 4.51 (1H, q, J = 8.5 Hz, H-5a), 4.49-4.47 (1H, m, H-4), 3.98 (1H, dd, J = 8.5, 4.5 Hz, H-5b), 2.11-2.05 (2H, m, H-10), 1.97 (3H, s, H-7’), 1.75 (3H, s, H-15), 1.54-1.50 (1H, m, H-lla), 1.39-1.36 (1H, m, H-llb), 1.20 (3H, s, H-13 ou H-14), 1.13 (3H, s, H-13 ou H-14).

[0189] RMN 13C (175 MHz, CDC13) ô 171.8 (C-2), 170.4 (C-5’), 151.2 (C-6’), 145.3 (C-7), 141.0 (C-3’), 135.9 (C-4’), 133.0 (C-8), 127.8 (C-9), 123.4 (C-6), 112.5 (C-3), 100.5 (C-2’), 72.5 (C-5), 40.3 (C-ll), 37.4 (C-4), 34.7 (C-12), 30.8 (C-13 ou C-14), 27.2 (C-13 ou C-14), 22.9 (C-10), 22.1 (C-15), 10.9 (C-7’).

[0190] IR (film) vmax 2969, 2925, 2848, 1782, 1757, 1679, 1471, 1344, 1184, 1088, 1029, 1007, 953 cm1.

[0191] HRESIMS m / z 345.1697 [M + H]+ (cale, pour C20H25O5, 345.1702).

[0192] (±)-SdL646 F2

[0193] [Chem.21] -.....0 , e I 7;;O VU", . 14VS’ Chemical F cumula s FWi J - r Exact Mass 344 1624 Maculât Wvighl 344 4670 55 L 3

[0194] RMN ‘H (700 MHz, CDC13) ô 7,45 (1H, d, J = 2.5 Hz, H-6’), 6.81 (1H, t, J = 1.5 Hz, H-3’), 6.07 (1H, t, J = 1.5 Hz, H-2’), 5.67 (1H, t, J = 4.0 Hz, H-9), 5.22 (1H, d, J = 10.0 Hz, H-6), 4.51 (1H, q, J = 8.5 Hz, H-5a), 4.49-4.46 (1H, m, H-4), 3.97 (1H, dd, J = 8.5, 5.5 Hz, H-5b), 2.09-2.04 (2H, m, H-10), 1.96 (3H, s, H-7’), 1.70 (3H, s, H-15), 1.54-1.50 (1H, m, H-lla), 1.38-1.35 (1H, m, H-llb), 1.21 (3H, s, H-13 ou H-14), 1.15 (3H, s, H-13 ou H-14).

[0195] 13C NMR (175 MHz, CDC13) ô 171.8 (C-2), 170.3 (C-5'), 151.0 (C-6'), 145.4 (C-7), 141.0 (C-3'), 136.0 (C-4'), 133.1 (C-8), 127.5 (C-9), 123.2 (C-6), 112.7 (C-3), 100.3 (C-2'), 72.3 (C-5), 40.3 (C-ll), 37.6 (C-4), 34.7 (C-12), 30.9 (C-13 or C-14), 27.1 (C-13 or C-14), 22.9 (C-10), 21.9 (C-15), 10.9 (C-7').

[0196] IR (film) vmax 2963, 2922, 2851, 1782, 1756, 1679, 1453, 1341, 1260, 1184, 1084, 1025, 1009,

[0197] 953 cm1.

[0198] HRESIMS m / z 345.1703 [M + H]+ (wedge, for C20H25O5, 345.1702).

[0199] EXAMPLE 4: Synthesis of silylated cannalactone analogues according to the invention, from the (4 R*, 6 R* )-B21 diastereoisomer of Example 1

[0200] This synthesis is illustrated by [Fig.2].

[0201] (4 R *)-|(6 / ? *)-(8,12,12-trimethylcyclohex-7-en-6-yl)((trimethylsil yl)oxy)methyl]dihydrofuran-2(3H)-one (4 / ?*,6R*)-B45a

[0202] A solution of (47?*, 6R*)-B21 (111.1 mg, 0.47 mmol) in TMS-imidazole (2.1 mL, 14.00 mmol, 30.0 equiv.) was stirred for 1 h at 50 °C. The reaction mixture was cooled to room temperature and stirred for 1 h. The mixture was dissolved with petroleum ether (5 mL), washed with brine (2 × 5 mL), and dried over Na2 SO4 and solvents were removed to obtain the crude product (47?*, 67?*)-B45a of formula 15, where R4 denotes a methyl group (135.5 mg, quantitative), in the form of a colorless oil. The crude product was used without purification in the next step.

[0203] (47?*, 67?*)-B45a

[0204] [Chem. 15] 1 § n „ . I F onnuh 'H vCEST 14 ¥« ':¾ '? v v J'" 3g 13 —Molf»cular WsIqM 1 lü t3

[0205] RMN ‘H (500 MHz, DMSO-d6) ô 4.63-4.54 (1H, m, H-6), 4.33 (1H, t, J = 8.0 Hz, H-5a), 4.17 (1H, t, J= 8.0 Hz, H-5b), 3.00-2.95 (1H, m, H-4), 2.45 (1H, dd, J= 17.0, 8.5, Hz, H-3a), 2.20-2.11 (1H, m, H-3b), 1.99 (2H, t, J= 6.5 Hz, H-9), 1.72 (3H, s, H-15), 1.61 (2H, quint, J= 6.5 Hz, H-10), 1.40-1.38 (2H, m, H-ll), 1.13 (3H, s, H-13 ou H-14), 1.09 (3H, s, H-13 ou H-14), 0.10 (9H, s, H-TMS).

[0206] RMN 13C (125 MHz, DMSO-d6) ô 175.8 (C-2), 137.6 (C-7), 130.7 (C-8), 71.5 (C-6), 70.2 (C-5), 41.6 (C-4), 41.0 (C-ll), 33.2 (C-9), 31.3 (C-3), 28.8 (C-12), 28.4 (C-13 ou C-14), 28.3 (C-13 ou C-14), 20.2 (C-15), 18.0 (C-10), 0.32 (C-TMS).

[0207] IR (film) vmax 2925, 2850, 1782, 1465, 1253, 1173, 1067, 883, 839, 747 cm’1.

[0208] HRESIMS m / z 311.2036 [M + H]+ (cale, pour C17H31O3Si, 311.2042).

[0209] (4 R *)-3-( E )-(Hydroxyméthylène)-4-[(6 R *)-(8,12,12-triméthylcyclohex-7-èn- 6-

[0210] yl)((trimethylsilyl)oxy)methyl]dihydrofuran-2(3 H )-one ((4 R *, 6 R *)-B46a)

[0211] To a solution of (47?*, 67?*)-B45a (13.0 mg, 0.04 mmol) in anhydrous THF (0.4 mL) at -40 °C under argon, ethyl formate (32 qL, 0.40 mmol, 10.0 equiv.) and tert-BuOK (33.3 mg, 0.28 mmol, 7.0 equiv.) were added. The mixture was stirred for 1 h at -40 °C, then warmed to -10 °C and stirred for a further 1 h. The reaction mixture was diluted with EtOAc (5 mL), washed with water (2 x 5 mL), and a saturated aqueous solution of NH4Cl (2 x 5 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain the desired crude product (47?*, 67?*)-B46a with formula 16, where R4 designates a methyl group (10.6 mg). The crude product was used without any purification in the subsequent step.

[0212] (47?*, 67?*)-B46a

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] [Chem. 16] Chemical Fbrmulà: Exact Mass; 338,1913 Moi&cdæ' Wdght 338,SI99 IR (film) vmax 3464, 2925, 1763, 1462, 1379, 1253, 1219, 1178, 1067, 977, 839 cm1. HRESIMS m / z 339.2001 [M + H]+ (cale, pour C18H31O4Si, 339.1992). (±)-SdL781 To a solution of (4R*, 6R*)-B46a (28.1 mg, 0.08 mmol) in anhydrous THF (0.8 mL) at -78 °C under argon, tert-BuOK (14.1 mg, 0.12 mmol, 1.5 equiv.) was added. 5-Bromo-3-Methylfuran-2(5 / / )-one D4

[16] (21.2 mg, 0.12 mmol, 1.5 equiv.) in anhydrous THF (0.8 mL) was then added to this mixture. The reaction mixture was warmed to room temperature and stirred overnight. It was dissolved in EtOAc (5 mL), washed with water (2 x 5 mL) and brine (2 x 5 mL), and dried over Na2SO4. The solvents were removed and the crude product was purified by PTLC (petroleum ether / EtOAc, 60:40) to obtain the products (±)-SdL781 Fl of formula 22 (14.7 mg, 32% in 3 steps) and (±)-SdL781 F2 of formula 23 (14.0 mg, 31% in 3 steps). (±)-SdL781 Fl and (±)-SdL781 F2 are silyl cannalactone analogs corresponding to the general formula R4, where R4 designates a methyl group. (±)-SdL781 Fl [Chem. 22] ©WW'<4 t UKî'Uli» Exact 434 2V5 ÎVkîteojLF Weioht 431 W RMN ‘H (500 MHz, CDC13) ô 7.45 (1H, s, H-6’), 6.89 (1H, s, H-3’), 6.09 (1H, s, H-2’), 4.59-4.51 (2H, m, H-6 et H-5a), 4.13 (1H, t, J = 8.0 Hz, H-5b), 3.60-3.54 (1H, m, H-4), 2.00 (3H, s, H-7’), 1.88-1.81 (2H, m, H-9), 1.53-1.46 (2H, m, H-10), 1.33-1.27 (2H, m, H-ll), 1.23 (3H, s, H-15), 1.08 (3H, s, H-13 ouH-14), 0.99 (3H, s, H-13 ou H-14), 0.05 (9H, s, H-TMS). RMN 13C (125 MHz, CDC13) ô 172.4 (C-2), 170.2 (C-5’), 148.6 (C-6’), 142.0 (C-7), 140.9 (C-3’), 136.2 (C-4’), 136.2 (C-12), 100.7 (C-2’), 96.9 (C-3), 72.2 (C-6), 69.2 (C-5), 45.1 (C-4), 40.9 (C-9), 34.7 (C-ll), 29.9 (C-15), 29.9 (C-8), 29.3 (C-13 et C-14), 19.1 (C-10), 11.9 (C-7’), 0.5 (C-TMS).

[0221] IR (film) vmax 2954, 2920, 2853, 1784, 1755, 1686, 1462, 1342, 1254, 1191, 1082, 1026, 955, 887, 843, 752 cm1.

[0222] HRESIMS m / z 435.2189 [M + H]+ (cale, pour C23H35O6Si, 435.2203).

[0223] (±)-SdL781 F2

[0224] [Chem.23] i TM sa 4 f 14 13 J- / / Chwic.al Founuh» ,A E>actMass 434 2125 Mstecuter Wetohl 434.6040 4ÎS “ [v

[0225] RMN ‘H (500 MHz, CDC13) ô 7.39 (1H, s, H-6’), 6.87 (1H, s, H-3’), 6.11 (1H, s, H-2’), 4.61 (1H, d, J = 5.5 Hz, H-6), 4.56 (1H, d, J = 8.5 Hz, H-5a), 4.14 (1H, t, J = 8.5 Hz, H-5b), 3.58-3.53 (1H, m, H-4), 2.01 (3H, s, H-7’), 1.92 (2H, t, J = 7.0 Hz, H-9), 1.61-1.52 (2H, m, H-10), 1.42-1.34 (2H, m, H-ll), 1.23 (9H, s, H-13, H-14 et H-15), 0.05 (9H, s, H-TMS).

[0226] RMN 13C (175 MHz, CDC13) ô 172.3 (C-2), 170.3 (C-5’), 149.6 (C-6’), 140.9 (C-7), 140.8 (C-3’), 136.4 (C-4’), 135.9 (C-12), 100.4 (C-2’), 96.2 (C-3), 72.0 (C-6), 69.0 (C-5), 45.1 (C-4), 41.0 (C-9), 34.7 (C-ll), 29.9 (C-13 et C-14), 29.6 (C-8), 29.4 (C-15), 19.3 (C-10), 11.0 (C-7’), 0.4 (C-TMS).

[0227] IR (film) vmax 2959, 2923, 2853, 1788, 1755, 1683, 1463, 1342, 1252, 1209, 1180, 1085, 1024, 958, 887, 842, 752 cm1.

[0228] HRESIMS m / z 435.2188 [M + H]+ (block, for C23H35O6Si, 435.2203).

[0229] EXAMPLE 5: Synthesis of an alcohol-type cannalactone analogue according to the invention, based on the (4 R*, 6 R* )-B21 diastereoisomer of example 1

[0230] This synthesis is illustrated by [Fig.2].

[0231] (4 R *)-|(6 / ? *)-{(Triethylsilyl)oxy}(8,12,12-trimethylcyclohex-7-en-6- yl)methyl]dihydrofuran-2(3 H )-one ((4 / ? *, 6 R *)-B45b)

[0232] To a solution of (47?*, 6R*)-B21 (12.4 mg, 0.05 mmol) in pyridine (0.4 mL), 4-Dimethylaminopyridine (DMAP) (1.9 mg, 2 pmol, 0.3 equiv.) and triethylsilyl chloride (TESC1) (50 pL, 0.30 mmol, 6.0 equiv.) were added. The mixture was stirred for 24 h. The reaction mixture was dissolved with CH2C12 (5 mL), washed with saturated aqueous NaHCO3 (2 × 5 mL), and dried over Na2SO4. The solvents were removed, and the crude product was purified by chromatography on silica column (petroleum ether / EtOAc, 100:0 to 80:20 over 10 min) to obtain the pure product (47?*, 67?*)-B45b of formula 15 with R4 denoting an ethyl group (12.3 mg, 70%) in the form of two conformers as a colorless oil.

[0233] (47?*, 67?*)-B45b

[0234] [Chem. 15] s ,, \ssrO ■ Chemical Fabula: Exact Mass: 352.2434 Mobcula? Weight: 352.5968

[0235] Confornière 1 :

[0236] RMN ‘H (500 MHz, DMSO-d6) ô 4.71 (1H, d, J = 11.0 Hz, H-6), 4.40 (1H, t, J = 8.0 Hz, H-5a), 4.22 (1H, q, J = 4.5 Hz, H-5b), 3.06-3.00 (1H, m, H-4), 2.06 (2H, dd, J = 16.5, 6.5 Hz, H-3), 2.02-1.97 (2H, m, H-9), 1.68-1.64 (2H, m, H-10), 1.63 (3H, s, H-15), 1.43-1.37 (2H, m, H-ll), 1.17 (3H, s, H-13 ou H-14), 1.10 (3H, s, H-13 ou H-14), 0.92 (9H, t, J = 7.0 Hz, H-CH3-TES), 0.58 (6H, q, J = 7.0 Hz, H-CH2-TES).

[0237] RMN 13C (125 MHz, DMSO-d6) ô 177.5 (C-2), 136.4 (C-7), 132.3 (C-8), 74.4 (C-6), 72.6 (C-5), 42.4 (C-4, C-ll), 34.4 (C-12), 33.4 (C-9), 32.1 (C-3), 30.7 (C-13 ou C-14), 30.6 (C-13 ou C-14), 21.0 (C-15), 18.9 (C-10), 7.16 (C-CH3-TES), 5.3 (C-CH2-TES).

[0238] Confornière 2 :

[0239] RMN ‘H (500 MHz, DMSO-d6) ô 4.31 (2H, d, J = 5.5.0 Hz, H-5), 4.27 (1H, d, J = 8.5 Hz, H-6), 2.99-2.94 (1H, m, H-4), 2.29 (2H, d, J = 9.5 Hz, H-3), 1.96-1.85 (2H, m, H-9), 1.78 (3H, s, H-15), 1.59-1.51 (2H, m, H-10), 1.51-1.37 (1H, m, H-lla), 1.34-1.30 (1H, m, H-llb), 1.08 (3H, s, H-13 ou H-14), 0.90 (3H, s, H-13 ou H-14), 0.92 (9H, t, J = 7.0 Hz, H-CH3-TES), 0.58 (6H, q, J = 7.0 Hz, H-CH2-TES).

[0240] RMN 13C (125 MHz, DMSO-d6) ô 177.2 (C-2), 137.0 (C-7), 133.6 (C-8), 71.5 (C-6), 71.2 (C-5), 44.1 (C-4), 40.6 (C-ll), 34.7 (C-12), 34.6 (C-9), 33.1 (C-3), 30.2 (C-13 ou C-14), 29.2 (C-13 ou C-14), 21.9 (C-15), 19.4 (C-10), 7.16 (C-CH3-TES), 5.5 (C-CH2-TES).

[0241] IR (film) vmax 2963, 2928, 2881, 1782, 1666, 1460, 1412, 1371, 1241, 1175, 1069, 1006, 819, 741 cm1

[0242] HRESIMS m / z 353.2511 [M + H]+ (cale, pour C20H37O3Si, 353.2512). (4R*, 6R*)-B48

[0243] To a solution of (47?*, 67?*)-B45b (21.5 mg, 0.06 mmol) in anhydrous THF (0.5 mL) at -40 °C under argon, ethyl formate (50 qL, 0.60 mmol, 10.0 equiv.) and tert-BuOK (47.1 mg, 0.42 mmol, 7.0 equiv.) were added. The mixture was The mixture was stirred for 1 h at 0 °C and then cooled to -78 °C. 5-bromo-3-methylfuran-2(577)-one D4

[16] (15.9 mg, 0.09 mmol, 1.5 equiv.) in anhydrous THF (0.5 mL) was added to this mixture. The reaction mixture was warmed to room temperature and stirred overnight. It was dissolved in EtOAc (5 mL), washed with water (2 x 5 mL) and brine (2 x 5 mL), and dried over Na2SO4. The solvents were removed and the crude product was purified by silica gel column chromatography (heptane / EtOAc, 100:0 to 70:30) to obtain the product (47?*, 67?*)-B48 Fl of formula 24 (6.1 mg, 21%) and (47?*, 67?*)-B48 F2 of formula 25 (7.0 mg, 25%).

[0244] (47?*, 67?*)-B48 Fl

[0245] [Chem.24] s ....<) TESÛ I u 'x-" ’s A i / ' Chemical Fermoir . r Exact Mas& 476 2S94 « J / a U, y _ ” vJ. v«g. MofecülàrW@ighf47§tœci

[0246] RMN ‘H (500 MHz, CDC13) ô 7.40 (1H, s, H-6’), 6.86 (1H, t, J = 1.5 Hz, H-3’), 6.11 (1H, s, H-2’), 4.64-4.59 (1H, m, H-5a), 4.58-4.54 (1H, m, H-6), 4.16 (1H, t, J = 8.5 Hz, H-5b), 3.57-3.53 (1H, m, H-4), 2.01 (3H, t, J = 1.5 Hz, H-7’), 1.91 (2H, t, J = 6.5 Hz, H-9), 1.59-1.54 (2H, m, H-10), 1.39-1.35 (2H, m, H-ll), 1.19 (3H, s, H-15), 1.06 (3H, s, H-13 ou H-14), 0.92 (3H, s, H-13 ou H-14), 0.90 (9H, t, J = 7.5 Hz, H-CH3-TES), 0.55 (6H, q, J = 7.5 Hz, H-CH2-TES).

[0247] RMN nC(125 MHz, CDC13) ô 172.3 (C-2), 170.3 (C-5’), 149.9 (C-6’), 140.8 (C-3’), 136.6 (C-12), 136.4 (C-4’), 133.4 (C-7), 102.0 (C-3), 100.5 (C-2’), 71.9 (C-6), 69.0 (C-5), 45.3 (C-4), 40.8 (C-9), 34.9 (C-ll), 32.1 (C-8), 30.1 (C-13 ou C-14), 29.9 (C-15), 29.5 (C-13 ou C-14), 19.3 (C-10), 11.0 (C-7’), 7.1 (C-CH3-TES), 5.3 (C-CH2-TES).

[0248] IR (film) vmax 2963, 2922, 1787, 1757, 1681, 1466, 1343, 1259, 1184, 1084, 1018, 951, 862, 800,

[0249] 743 cm1.

[0250] HRESIMS m / z 477.2659 [M + H]+ (cale, pour C26H4iO6Si, 477.2672).

[0251] (47?* 67?*)-B48 F2

[0252] [Chem.25] « r Ch&mfcal Formate.' Exact Mass: 4?& Motecuter Weight 5$5C

[0253] RMN ‘H (500 MHz, CDC13) ô 7.46 (1H, s, H-6’), 6.88 (1H, t, J = 1.5 Hz, H-3’), 6.09 (1H, s, H-2’), 4.62-4.58 (1H, m, H-5a), 4.88 (1H, s, H-6), 4.17-4.13 (1H, m, H-5b), 3.59-3.54 (1H, m, H-4), 2.01 (3H, s, H-7’), 1.88-1.83 (2H, m, H-9), 1.52-1.45 (2H, m, H-10), 1.32-1.323 (2H, m, H-ll), 1.23 (3H, s, H-15), 1.02 (3H, s, H-13 ouH-14), 0.93 (3H, s, H-13 ou H-14), 0.90 (9H, t, J = 7.0 Hz, H-CH3-TES), 0.54 (6H, q, J = 7.5 Hz, H-CH2-TES).

[0254] RMN 13C (125 MHz, CDC13) ô 172.3 (C-2), 170.2 (C-5’), 150.5 (C-6’), 140.8 (C-3’), 136.6 (C-12), 136.2 (C-4’), 133.5 (C-7), 100.6 (C-2’), 100.1 (C-3), 71.8 (C-6), 69.3 (C-5), 45.3 (C-4), 40.7 (C-9), 34.8 (C-ll), 32.1 (C-8), 29.9 (C-13 ou C-14), 29.9 (C-15), 29.5 (C-13 ou C-14), 19.2 (C-10), 10.9 (C-7’), 7.1 (C-CH3-TES), 5.3 (C-CH2-TES).

[0255] IR (film) vmax 2960, 2922, 1788, 1753, 1679, 1460, 1259, 1184, 1091, 1015, 868, 797 cm1.

[0256] HRESIMS m / z 477.2564 [M + H]+ (cale, pour C26H4iO6Si, 477.2672). (±)-SdL628 Fl

[0257] Method 1

[0258] A solution of Sc(OTf)3 (0.1 mg, 16 pmol, 0.5 mol%) in CH3CN (0.2 mL) was added to a solution of (±)-SdL781 Fl (14.3 mg, 0.032 mmol) in CH3CN (0.2 mL) and water (2 drops). The resulting mixture was stirred for 1.5 h at room temperature and hydrolyzed with aqueous phosphate buffer (2 mL, pH 7). The organic phase was extracted with CH2C12 (3 × 2 mL), and the combined extracts were washed with brine (2 × 3 mL) and then dried over Na2SO4. The solvents were removed and the crude product was purified by PTLC (petroleum ether / EtOAc, 60:40) to obtain the product (±)-SdL628 Fl of formula 26 (2.4 mg, 22%) as a colorless oil.

[0259] Method 2

[0260] A solution of (47?*, 6R*)-B48 Fl (6.1 mg, 0.01 mmol) in anhydrous THF (1 mL) under argon was added a solution of 3HF.NEt3 (20 qL, 0.13 mmol, 10.0 equiv.). The mixture was stirred overnight at 50 °C. The organic phase was cooled with a saturated aqueous solution of NaHCO3 (1 mL) and extracted with EtOAc (3 x 2 mL). The organic phase was dried over Na2SO4 and the solvents were removed. The crude product was purified by PTLC (heptane / EtOAc, 60:40) to obtain the product (±)-SdL628 Fl of formula 26 (3.9 mg, 83%) as a colorless oil.

[0261] (±)-SdL628 Fl

[0262] [Chem.26] ".....O HQ 41 Chemical Formula: C23H23Og v Exact Mass- 383.1729 « 4, / s ... Mdeculâr Weîghî 362 4220 F'' \ ' 10” * Q XO \

[0263] RMN ‘H (500 MHz, CDC13) ô 7.35 (1H, s, H-6’), 6.82 (1H, s, H-3’), 6.06 (1H, s, H-2’), 4.60 (1H, d, J = 10.0 Hz, H-6), 4.23 (1H, dd, J = 9.0, 6.0 Hz, H-5a), 4.17 (1H, d, J = 10.0 Hz, H-5b), 3.86-3.82 (1H, m, H-4), 1.83 (3H, s, H-7’), 1.82-178 (2H, m, H-9), 1.43-1.40 (2H, m, H-10), 1.39-1.34 (2H, m, H-ll), 1.23 (3H, s, H-15), 1.06 (3H, s, H-13 ou H-14), 0.83 (3H, s, H-13 ou H-14).

[0264] RMN 13C (175 MHz, CDC13) ô 172.2 (C-2), 170.2 (C-5’), 150.8 (C-6’), 140.7 (C-3’), 138.1 (C-7), 136.6 (C-12), 134.7 (C-4’), 109.9 (C-3), 100.4 (C-2’), 71.0 (C-5), 70.7 (C-6), 43.4 (C-4), 40.2 (C-9), 34.9 (C-8), 34.8 (C-ll), 29.9 (C-15), 29.2 (C-13 ou C-14), 29.1 (C-13 ou C-14), 21.7 (C-7’), 19.5 (C-10).

[0265] IR (film) vmax 3479, 2930, 2861, 1785, 1754, 1682, 1457, 1346, 1191, 1085, 1023, 958 cm1.

[0266] HRESIMS m / z 363.1808 [M + H]+ (cale, pour C20H27O6, 363.1807).

[0267] (±)-SdL628 F2

[0268] Méthode 1

[0269] A solution of (±)-SdL781 F2 (19.2 mg, 0.044 mmol) in CH3CN (0.3 mL) and water (3 drops) was added to a solution of Sc(OTf)3 (0.1 mg, 22 pmol, 0.5 mol%) in CH3CN (0.3 mL). The organic phase was extracted with CH2Cl2 (3 x 2 mL), washed with brine (2 x 3 mL), and dried over Na2SO4. The solvents were removed, and the crude product was purified by PTLC (petroleum ether / EtOAc, 60:40) to obtain the product (±)-SdL628 F2 of formula 27 (3.8 mg, 19%) as a colorless oil.

[0270] Method 2

[0271] A solution of 3HF.NEt3 (20 pL, 0.18 mmol, 10.0 equiv.) was added to a solution of (47?*, 6R*)-B48 F2 (7.0 mg, 0.02 mmol) in anhydrous THF (1 mL) under argon. The mixture was stirred overnight at 50 °C. The organic phase was The sample was cooled with a saturated aqueous solution of NaHCO3 (1 mL) and extracted with EtOAc (3 x 2 mL). The organic phase was dried over Na2SO4 and the solvents were removed. The crude product was purified by PTLC (heptane / EtOAc, 60:40) to obtain the product (±)-SdL628 F2 of formula 27 (6.3 mg, quantitative) as a colorless oil.

[0272] (±)-SdL628 F2

[0273] [Chem.27] Chemical Formula: C^H^Cg Bad Mass: 362'17* Moecular Weight 362.42

[0274] 'H NMR (500 MHz, CDC13) ô 7.46 (1H, s, H-6'), 6.87 (1H, s, H-3'), 6.04 (1H, s, H-2'), 4.59 (1H, d, J = 10.5 Hz, H-6), 4.22 (1H, dd, J = 8.5, 6.5 Hz, H-5a), 4.16 (1H, d, J = 10.5 Hz, H-5b), 3.86-3.82 (1H, m, H-4), 1.89-1.82 (1H, m, H-9a), 1.79 (3H, s, H-7'), 1.59-1.54 (1H, m, H-9b), 1.41-1.36 (2H, m, H-10), 1.31-1.25 (2H, m, H-ll), 1.23 (3H, s, H-15), 1.03 (3H, s, H-13 or H-14), 0.83 (3H, s, H-13 or H-14)

[0275] 13C NMR (175 MHz, CDC13) ô 172.2 (C-2), 170.2 (C-5'), 152.1 (C-6'), 140.7 (C-3'), 138.0 (C-7), 136.1 (C-12), 134.7 (C-4'), 109.3 (C-3), 100.9 (C-2'), 71.1 (C-5), 70.7 (C-6), 43.3 (C-4), 39.9 (C-9), 34.8 (C-8), 34.5 (C-ll), 29.9 (C-15), 29.2 (C-13 or C-14), 28.9 (C-13 or C-14), 21.6 (C-7'), 19.1 (C-10).

[0276] IR (film) vmax 3479, 2961, 2925, 2861, 1783, 1750, 1682, 1345, 1260, 1189, 1089, 1022, 955, 801 cm1.

[0277] HRESIMS m / z 363.1793 [M + H]+ (hold, for C20H27O6, 363.1807).

[0278] (±)-SdL628 Fl and (±)-SdL628 F2 are cannalactone type analogues alcohol conforming to general formula 5. EXAMPLE 6#: Evaluation of biological activity

[0279] The biological evaluation of the cannalactone analogues according to the invention synthesized in Examples 2 (aromatic type analogues SdL625 Fl + SdL625 F2), 3 (diene type analogues SdL646 Fl + SdL646 F2), 4 (sylyl type analogues SdL781Fl + SdL781F2) and 5 (alcohol type analogues SdL628 Fl + SdL628 F2) was tested for one of the activities that these analogues could provide in hemp: the germination of a parasitic plant, P. ramosa.

[0280] The results were compared with those obtained on a synthetic reference analogue, (±)-GR24

[17] ,

[18] and with natural (+)-cannalactone [1], [4] isolated from hemp exudates: (±)-GR24 (*)-Cannalactone

[0281] In particular, the activity of stimulating the germination of parasitic plant seeds was evaluated on two populations of P. ramosa. P. ramosa 1, collected from rapeseed while P. ramosa 2a was harvested from a hemp plot [2]- [4]. Protocol

[0282] The protocol used, developed by Pouvreau et al.

[19] , allows for the routine testing of the biological activity of molecules or biological extracts on the germination of seeds of parasitic plants in 96-well plates (as illustrated in [Fig. 3]). This technique eliminates the need for counting germinated seeds, which was previously used.

[0283] The cannalactone analogues synthesized in Examples 2 to 5 were tested using this protocol, and their maximum activity (Maximum Germination) (as illustrated in [Fig. 4]) and median effective concentration (EC50) (as illustrated in [Fig. 6]) were modeled from the dose-response curve (as illustrated in [Fig. 5]). This measure represents the effective concentration that induces a median response between the baseline and the maximum germination effect. [Fig. 5] shows that the analogues in Examples 2 to 5 all appear to demonstrate a maximum germination capacity on both type 2a populations of the same order as (±)-GR24. Their maximum germination capacity on type 1 appears to be reduced, with the observed trend closer to that obtained for (+)-cannalactone.

[0284] All the analogues synthesized in Examples 2 to 5 have EC50 values ​​below 10 x M for both population types ([Fig. 6]). Some molecules, such as (±)-SdL628 Fl and (±)-SdL781 F2, exhibit biological activity against P. ramosa 2a at lower concentrations, thus exceeding that of the natural molecule (EC50 [(±)-SdL628 Fl] = 9.6 x 10¹² M versus EC50 [(+)-cannalactone] = 1.0 x 10¹⁰ M). The specificity of these analogues is also enhanced (as illustrated by [Fig. 7]), rEC50[(±)-SdL628 Fl] ~ 100 versus rEC50 [(+)-SdL19] ~ 10, and approaches that of natural cannalactone. Bibliographical references

[0285] 1. Hamzaoui, O. et al., Proceedings of the 15th World Congress on Parasitic Seedlings; Amsterdam, The Netherlands (2019): 32. 2. Stojanova, B., Delourme, R., Duffé, P., Delavault, P. & Simier, P. Genetic differentiation and host preference reveal non-exclusive host races in the generalist parasitic weed Phelipanche ramosa. Weed Res. 59, 107-118, doi: 10.1111 / wre. 12353 (2019). 3. Huet, S., Pouvreau, J.-B., Delage, E., Delgrange, S., Marais, C., Bahut, M., Delavault, P., Simier, P. & Poulin, L. Populations of the Parasitic Plant Phelipanche ramosa Influence Their Seed Microbiota. Front. Plant Sci. 11, 1075, doi: 10.3389 / fpls.2020.01075 (2020). 4. Daignan Former, S., de Saint Germain, A., Retailleau, P., Pillot, J.-P., Taulera, Q., Andna, L., Miesch, L., Rechange, S., Pouvreau, J.-B. & Boyer, F.-D. Noncanonical Strigolactone Analogues Highlight Selectivity for Stimulating Germination in Two Phelipanche ramosa Populations. J. Nat. Prod. 85, 1976-1992, doi:10.1021 / acs.jnatprod.2c00282 (2022). 5. Delavault, P., Montiel, G., Brun, G., Pouvreau, J. B., Thoiron, S. & Simier, P. Communication Between Host Plants and Parasitic Plants. Adv. Bot. Res. 82, 55-82, doi: 10.1016 / bs.abr.2016.10.006 (2017). 6. Xie, X., Yoneyama, K. & Yoneyama, K. The Strigolactone Story. Annu. Rev. Phytopathol. 48, 93-117, doi: 10.1146 / annurev-phyto-073009-114453 (2010). 7. Daignan-Fomier, S.; Keita, A.; Boyer, F.-D., Chemistry of Strigolactones, Key Players in Plant Communication. ChemBioChem, n / a, (n / a), doi: 10.1002 / cbic.202400133 (2024). 8. Cook, C. E., Whichard, L. P., Turner, B. & Wall, M. E. Germination of Witchweed (Striga Lutea Lour) - Isolation and Properties of a Potent Stimulant. Science 154, 1189-1190, doi:10.1126 / science,154.3753.1189 (1966). 9. Akiyama, K., Matsuzaki, K. & Hayashi, H. Plant sesquiterpenes induce hyphal branching in arbuscular mycorrhizal fungi. Nature 435, 824-827, doi:10.1038 / nature03608 (2005). 10. Gomez-Roldan , V. , Fermas , S. , Brewer , PB , Puech-Pages , V. , Dun , EA , Pillot , J.-P. , Letisse , F. , Matusova , R. , Danoun , S. , Portais , J.-C. , Bouwmeester , H. , Bécard , G. , Beveridge , CA , Rameau , C. & . Rechange, SF Strigolactone inhibition of shoot branching. Nature 455, 189–194, doi:10.1038 / nature07271 (2008). 11. Umehara, M., A. Hanada, S. Yoshida, K. Akiyama, T. Arite, N. Takeda-Kamiya, H. Magome, Y. Kamiya, K. Shirasu, K. Yoneyama, J. Kyozuka & Yamaguchi, S. Inhibition of shoot branching by new terpenoid plant hormones. Nature 455, 195–200, doi:10.1038 / nature07272 (2008). 12. Lopez-Obando, M., Ligerot, Y., Bonhomme, S., Boyer, F.-D. & Rameau , C. Strigolactone biosynthesis and signaling in plant development . Development 142, 3615–3619. 120006 (2015). 13. Boyer, F.-D., de Saint Germain, A., Pillot, JP, Pouvreau, J.-B., Chen, VX, Ramos, S., Stevenin, A., Simier, P., Delavault, P., Beau, J.-M. & Rameau, C. Structure-activity relationship studies of strigolactone-related molecules for branching inhibition in garden pea: molecule design for shoot branching. Plant Physiol. 159, 1524-1544, doi: 10.1104 / pp. 112.195826 (2012). 14. Boyer, F.-D., de Saint Germain, A., Pouvreau, J.-B., Clavé, G., Pillot, J.-P., Roux, A., Rasmussen, A., Depuydt, S., Lauressergues, D., Frei dit Frey, N., Heugebaert, T.S.A., Geolens, D., Georman, D. Steven, Goeleg, S. & Rameau, C. New Strigolactone Analogs as Plant Hormones with Low Activities in the Rhizosphere. Mole. Plant 7, 675-690, doi:10.1093 / mp / sstl63 (2014). 15. Jas, G. A facile access to 4-bromo-2-(tert-butyldimethylsiloxy)furan from tetrahydro-2,4-dioxofuran. Synthesis 1991, 965-966, doi:10.1055 / s-1991-26618 (1991). 16. Macalpine, GA; Raphaël, RA; Shaw, A.; Taylor, AW; Wild, HJ Synthesis of Germination Stimulant (±)-Strigol. J. Chem. Soc., Perkin Trans. 1 1976, (4), 410-416. DOI: 10.1039 / P19760000410. 17. de Saint Germain, A., Retailleau, P., Norsikian, S., Servajean, V., Pelissier, F., Steinmetz, V., Pillot, J.-P., Rochange, S., Pouvreau, J.-B. & Boyer, F.-D. Contalactone, a contaminant formed during Chemical synthesis of the strigolactone reference GR24 is also a strigolactone mimic. Phytochemistry 168, 112112, doi:10.1016 / j.phytochem.2019.112112 (2019). 18. Johnson, AW, Gowda, G., Hassanali, A., Knox, J., Monaco, S., Razavi, Z. & Rosebery, G. The Préparation of Synthetic Analogs of Strigol. J. Chem. Soc., Perkin Trans. 1, 1734-1743, doi: 10.1039 / P19810001734 (1981). 19. Pouvreau, J.-B.; Gaudin, Z.; Auger, B.; Léchât, M. M.; Gauthier, M.; Delavault, P.; Simier, P. A high-throughput seed germination assay for root parasitic plants. Plant Methods 9 (1), 32. doi: 10.1186 / 1746-4811-9-32 (2013).

Claims

1. Demands An analogue of cannalactone, characterized in that it corresponds to the general formula (1): [Chem.l]

2. in which: - R1 designates the hydrogen atom H, the hydroxyl group OH or the OSiR43 group, - R2 and R3 each denote the hydrogen atom H or the methyl radical CH3, - R4 designates an alkyl group, and - the 6-membered carbon ring which can be aromatic or of the cyclohexene or cyclohexane type. Cannalactone analogue according to claim 1, characterized in that it is aromatic with "cis" and "trans" stereochemistry and corresponds to formula (2): [Chem.2]

3. in which: - R1, R2 and R3 denote the hydrogen atom H, and - the 6-membered carbon ring is aromatic. Cannalactone analogue according to claim 1, characterized in that it is of the diene type with "cis" and "trans" stereochemistry and corresponds to formula (3):

4. in which: - R1 and R3 denote the hydrogen atom H, - R2 designates the methyl group, and - the 6-membered carbon ring is of the cyclohexene type. Cannalactone analogue according to claim 1, characterized in that it is of the syllabic type with "cis" and "trans" stereochemistry and corresponds to formula (4): [Chem.4]

5. in which: - R1 designates the OSiR4? group, - R2 designates the methyl group, - R3 designates the hydrogen atom H, and - the 6-membered carbon ring is of the cyclohexene type. An analogue of cannalactone according to claim 1, characterized in that it is of the alcohol type with "cis" and "trans" stereochemistry and corresponds to formula (5): in which: - R1 designates the hydroxyl group OH, and

6. - R2 designates the methyl group, - R3 designates the hydrogen atom H, and - the 6-membered carbon ring is of the cyclohexene type. A method for synthesizing a cannalactone analogue as defined in claim 2, characterized in that it comprises the following steps: - a reaction A) coupling of commercial B-cyclocitral with a C4 bromofuran of formula (6): [Chem.6] Ç4 to obtain a B20 alcohol of formula (7): [Chem.7] 820 - a step B) of reduction of alcohol B20 of formula (7), to obtain a mixture of diastereomers of allylic alcohol, followed by a step of separation of said diastereomers to retain the diastereomer (4R*, 6R*)-B21 of formula (8): [Chem. 8] - a step C2) of epoxidation of the diastereoisomer (4R* 6R*)-B21 of formula (8) to obtain an epoxy alcohol B22 of formula (9): [Chem. 9]; - a step D2) of dehydration and rearrangement of the epoxy alcohol B22 of formula (9) to obtain a benzyl compound B38 of formula (10): [Chem. 10]; - a step E2) of formylation in basic medium of the benzyl compound B38 of formula (10) to obtain an enol B40 of formula (H): [Chem. 11];

7. - a step F2) of O-alkylation of enol B40 to obtain the analogue of formula (2). A method for synthesizing a cannalactone analogue as defined in claim 3, characterized in that it comprises the following steps: - steps A and B as defined in claim 6, followed by - a step C3) of mesylation of the diastereoisomer (47?*, 6R*)-B21 of formula (8) to obtain after dehydration and rearrangement the diene (7?)-B25 of formula (13): [Chem. 13]: . ,...0 To s. U) H25 - a step E3) of formylation in basic medium of the diene (E)-B25 of formula 13 to obtain an enol B42 of formula (14): [Chem. 14]:

8. 042 - a step F3) of O-alkylation of enol B42 to obtain the analogue of formula (3). A method for synthesizing a cannalactone analogue as defined in claim 4, characterized in that it comprises the following steps: - steps A and B as defined in claim 6, followed by - a step C4) of protection of the diastereoisomer (4R*, of formula 8 to obtain the protected compound (47?*, 67?*)-B45 of formula (15): [Chem. 15]: - a basic formylation step E4) of the protected compound of formula 16 to obtain an enol (47?*, 67?*)-B46 of formula (16): [Chem. 16]: iW:, SR" 1-846 - a step F4) of O-alkylation of enol B46 to obtain the analogue of formula (4).

9. A method for synthesizing a cannalactone analogue as defined in claim 6, characterized in that it comprises the following steps: - the formation of a cannalactone analogue as defined in claim 4 in accordance with the method as defined in claim 8, followed by - a step G5) of deprotection and separation of the diastereomers of the analogue of formula (4), to obtain the analogue of formula (5).

10. Use of a cannalactone analogue as defined according to any one of claims 1 to 5 or as obtained according to one of the synthesis processes of claims 6 to 9, as a seed germination stimulant of parasitic plants.

11. Use according to claim 10, as a germination stimulant for the seeds of P. ramosa 1 and P. ramosa 2a.

12. Use according to claim 10, for the suicide germination of parasitic plants of the Striga, Orobanche and Phelipanche type.