Process for the asymmetric synthesis of isopulegol

Abstract

The present invention relates to a process for the asymmetric synthesis of isopulegol and subsequent compounds.

Description

[0001] This invention relates to a method for the asymmetric synthesis of isomenthidedienol and subsequent compounds.

[0002] Isomenthidedienol is an important precursor compound used in the synthesis of industrially important substances such as menthol, CBD, THC, and other resorcinol-derived natural products. One of the important existing methods for the industrial synthesis of menthol stereoisomers is the so-called BASF method.

[0003] The BASF menthol process comprises two hydrogenation steps beginning with geranialdehyde or neraldehyde. Thus, as shown in the following scheme, the first asymmetric C=C-bond hydrogenation is used to introduce a stereocenter at the β-position of citronellol. Cyclation of citronellol in the presence of a Lewis acid or Brønsted acid yields isoprene, which, upon further C=C-bond hydrogenation, produces a reaction mixture containing several menthol stereoisomers.

[0004]

[0005] Only a very small number of scientific papers and patent applications concern the synthesis of isomenthedrinol (an industrially useful precursor) as an alternative, and these can be summarized as follows:

[0006] - CH oxidation starting from limonene (J.-P. Rioult et al., Flavor Fragr. J. 2000, 15, 223; WO 2004 / 013339; Verhoeven et al., The Plant Journal 2004, 39, 135),

[0007] - Use modified citral derivatives or other monoterpenes as starting materials (Marshall et al., J. Org. Chem. 1988, 53, 4108; Nakamura et al., Bull. Chem. Soc. Jpn. 1992, 65, 929-931; Semikolenov et al., Kinet. Catal. Lett. 2004, 82, 165;

[0008] - Reduction of cyclic ketones (Tetrahedron: Asymmetry 2007, 17, 717, Rao)

[0009] - The Dietrahedron-Alder reaction (Tetrahedron Asymmetry 2003, 14, 3313Serra), and

[0010] - Cyclation of citral.

[0011] Since the late 19th century, the acid-catalyzed conversion of citral to unsaturated cyclic alcohols has been studied by A. Verley (Bull. Soc. Chim III 1899, 21, 408) and O. Zeitschel and H. Schmidt (Journal). Known from the work of Praktische Chemie 1932, Vol. 133, 370-373, in which the yield was very low and a complex mixture of substances was obtained. Later kinetic studies of this transformation by C. Price (Industrial and Engineering Chemistry 1948, 40, 2, 257) and B. Clark (Tetrahedron 1977, 33, 17, 2187) confirmed that cyclization is a very complex transformation, producing several cyclic products, of which isomenthidedienol appears to be an unstable intermediate under acidic conditions.

[0012] Furthermore, thermal cyclization starting from citral in the absence of acid (G. Ohloff, THL 1960, 11, 10) is possible, as is the desired product of a mixture of stereoisomers obtained by adding a catalytic amount of a weak acid (DE2305629C2). Although the latter method yields very well due to the application of an achiral inorganic / organic acid, it yields a product of a mixture of stereoisomers.

[0013] In the prior art, there is no known method for preparing enantiomeric isomenthedrinol from commercially available citral, a method that can be carried out in a single high-yield step and in which isomenthedrinol is obtained in an enantiomeric form.

[0014] The problem to be solved by the present invention is to develop a method for producing isomenthidedienol, which is an enantiomer enriched as a precursor compound of menthol, CBD and THC, thereby overcoming the shortcomings of the prior art.

[0015] The inventors have developed a method using asymmetric cyclization to isomenthedrin starting from citral / nerol, and thus shorten current industrial methods to menthol and open up options to discover variable pathways to other substances such as cannabidiol (CBD) and tetrahydrocannabinol (THC), as illustrated in the following scheme.

[0016]

[0017] The problem is addressed by providing an improved method for the asymmetric synthesis of isomenthide dienol, wherein neraldehyde [(Z)-3,7-dimethyloctyl-2,6-dienal] is optionally cyclized in a solvent in the presence of a chiral diphosphazene-derived catalyst.

[0018] More specifically, the present invention relates to an improved method for the asymmetric synthesis of isomenthidedienol of formula (I),

[0019]

[0020] A substrate containing at least one of neraldehyde [(Z)-3,7-dimethyloctyl-2,6-dienal] and geraniol [(E)-3,7-dimethyloctyl-2,6-dienal] is optionally treated in an organic solvent with a catalyst derived from a diphosphazene of formula (II) to obtain a reaction mixture containing isomenthidedienol:

[0021]

[0022] In equation (II):

[0023] -R may be the same or different at each position and is selected from hydrogen; halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogens (preferably F or Cl), SF5, NO2, or cyano groups on the aliphatic hydrocarbon; C6 to C6 18 Aromatic hydrocarbons or C5 to C 18 Heteroaromatic hydrocarbons, each of which is optionally substituted by one or more substituents selected from the following: halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogens (preferably F and / or Cl), SF5, NO2, or cyano groups on the aliphatic hydrocarbon.

[0024] -R P The same or different at each position and having the meaning of R, or two Rs on the same aryl ring. P They can form rings with each other, which can be aromatic or aliphatic ring structures, and the aromatic and / or aliphatic ring structures can be substituted by one or more substituents R.

[0025] - X and Y are the same or different and are oxygen or NR N ,

[0026] Where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from:

[0027] i.-alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphonyldialkyl, phosphonylalkyl, alkylphosphine, N,N′-alkylimidazolidine-2-imino, wherein the alkyl group is optionally a C1 to C6 alkyl group having at least one substituent selected from C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro, or SF5. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons;

[0028] ii. -aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, phosphinodiaryl, phosphinoalkylaryl, phosphonylaryl, aryl n-phosphine, arylalkyl n-phosphine, N,N′-arylimidazolidine-2-imino, N-aryl-N′-alkylimidazolidine-2-imino, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro, or SF5, optionally substituted with at least one halogen.

[0029] iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-di-heteroaryl, phosphino-diheteroaryl, phosphino-arylheteroaryl, phosphino-arylalkyl, phosphonylheteroaryl, heteroaryl n-phosphine, heteroaryl aryl n-phosphine, heteroaryl arylalkyl n-phosphine, N,N′-heteroarylimidazolidine-2-imino, N-heteroaryl-N′-alkylimidazolidine-2-imino, N-heteroaryl-N′-arylimidazolidine-2-imino, wherein the heteroaryl group is C2 to C3. 18 Heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro, or SF5, optionally substituted with at least one halogen.

[0030] and

[0031] -W is selected from hydrogen, halogens, and metal or cationic organic groups selected from Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, Cd, W, Re, Os, Ir, Pt, Au, Hg, Al, Ga, In, Ge, Sn, Pb, As, Sb, Bi, Se, Te, La, Sm, Eu, Yb, U, substituted boranes -BR I R II R III Or replaced silicon-SiR I R II R III , where R I R II and R III They may be the same or different and each represent hydrogen, halogen, optionally -O-bonded, optionally having one or more unsaturated bonds or one or more heteroatoms in the chain, C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, C5 to C6 18 heteroaromatic hydrocarbons, C6 to C 18 Aromatic hydrocarbons or their partially aromatic hydrogenated forms, each hydrocarbon optionally being hydrogenated by one or more compounds selected from C1 to C2. 20 Substitution of a straight-chain, branched, or cyclic aliphatic hydrocarbon or one or more heterosubstituted groups, wherein W is preferably selected from hydrogen and the substituted silicon-SiR. I R II R III , where R I R II and R III As defined previously.

[0032] The reaction conditions used in the method of this invention are not harsh, and the reaction can be carried out in the range of -100°C to 30°C or even higher up to 80°C. ℃ The reaction can be carried out within a temperature range. It can be carried out in pure (neat) or in aprotic organic solvents such as CH2Cl2, CHCl3, Et2O, THF, PhMe, pentane, hexane, and cyclohexane, usually at atmospheric pressure.

[0033] In an embodiment of this method, the catalyst derived from diphosphazene has formula (III):

[0034]

[0035] Wherein the substituents R are the same or different at each position and as defined previously, X and Y have meanings as defined previously and W represents hydrogen, alkali metal or alkaline earth metal.

[0036] In an embodiment of this method, the diphosphazene-derived catalyst has the formula (IVa):

[0037]

[0038] Wherein the substituents R are the same or different at each position and as defined previously, X and Y have meanings as defined previously and W represents hydrogen, alkali metal or alkaline earth metal.

[0039] In the following formulas (III), (IVa) and (IVb), the dashed lines represent double bonds, thus indicating a naphthalene ring system, or represent hydrogenated double bonds, indicating a 4H-naphthalene ring system, and both forms can exist in catalysts as used in the methods of the present invention.

[0040] In another embodiment of the method of the present invention, the catalyst derived from diphosphazene is represented by the following formula (IVb):

[0041]

[0042] Wherein the substituents R are the same or different at each position and as defined above, X and Y have the meanings defined above, and W represents hydrogen, alkali metal or alkaline earth metal.

[0043] In another embodiment of the method of the present invention, in any one of formulas (II), (III), (IVa) or (IVb), the substituent R is preferably the same or different at each position and represents a halogen, a straight-chain, branched or cyclic C1 to C2. 20 Aliphatic hydrocarbons or C6 to C 18 Aromatic hydrocarbons, wherein the aliphatic hydrocarbons and / or aromatic hydrocarbons are reacted with one or more halogens (preferably F and / or Cl), SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 hydrocarbons. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 Aliphatic hydrocarbons are substituted with one or more halogens (preferably F and / or Cl), SF5, NO2, X and Y have the meanings defined above, and W represents hydrogen, alkali metal or alkaline earth metal.

[0044] In another embodiment of the method of the present invention, in any one of formulas (II), (III), (IVa) or (IVb), Y is defined as 0 or NR. N And X is defined as NR N , where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from:

[0045] i. A sulfinyl alkyl or sulfonyl alkyl group, wherein the alkyl group is optionally a C1 to C6 alkyl group having at least one substituent selected from C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro or SF5. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons;

[0046] ii. sulfinylaryl or sulfonylaryl, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro or SF5, optionally substituted with at least one halogen.

[0047] iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, wherein the heteroaryl group is C2 to C3. 18 Heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: C1 to C6 alkyl, C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro or SF5, optionally substituted with at least one halogen; and

[0048] Wherein R has the meaning as defined above, preferably the same or different at each position and represents a halogen, straight-chain, branched or cyclic C1 to C2. 20 Aliphatic hydrocarbons or C6 to C 18 Aromatic hydrocarbons, wherein the aliphatic hydrocarbons and / or aromatic hydrocarbons are reacted with one or more halogens (preferably F and / or Cl), SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 hydrocarbons. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 The aliphatic hydrocarbon is substituted with one or more halogens (preferably F and / or Cl), SF5, NO2, and W represents hydrogen, alkali metal or alkaline earth metal.

[0049] In any preferred embodiment of the method of the present invention, in formulas (II), (III), (IVa) or (IVb), Y is defined as 0 or NR. N Preferably, O, and X is defined as NR. N , where R N It is an electron-withdrawing group and is preferably selected from sulfonylalkyl groups (wherein the alkyl group is a partially or completely halogenated straight-chain, branched, or cyclic C1 to C2 group). 20 Aliphatic hydrocarbons) or sulfonyl aryl (where the aryl group is C6 to C7) 18 Aromatic hydrocarbons, C6 to C 18The aromatic hydrocarbon optionally has at least one substituent selected from: C1 to C6 alkyl, C1 to C6 alkoxy, halogen (preferably F and / or Cl), cyano, nitro or SF5), and wherein R has the meaning as defined above, preferably the same or different at each position and representing a halogen, straight-chain, branched or cyclic C1 to C6 alkyl group. 20 Aliphatic hydrocarbons or C6 to C 18 Aromatic hydrocarbons, wherein the aliphatic hydrocarbons and / or aromatic hydrocarbons are reacted with one or more halogens (preferably F and / or Cl), SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 hydrocarbons. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 The aliphatic hydrocarbon is substituted with one or more halogens (preferably F and / or Cl), SF5, NO2, and W represents hydrogen, alkali metal or alkaline earth metal.

[0050] In a further preferred embodiment of the method of the present invention, the catalyst derived from diphosphazene is represented by the following formula (IVb):

[0051]

[0052] The substituent R is the same or different at each position and is C6 to C6. 18 Aromatic hydrocarbons, wherein the aromatic hydrocarbons are reacted with one or more halogens (preferably F and / or Cl), SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 compounds. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 The aliphatic hydrocarbon is substituted with one or more halogens (preferably F and / or Cl), SF5, or NO2, Y is O, and X is NR. N , where R N It is a sulfonyl alkyl group, wherein the alkyl group is a straight-chain, branched, or cyclic C1 to C2 group that is partially or completely halogenated. 20 Aliphatic hydrocarbons, each dashed line represents a double bond, and W represents hydrogen, alkali metal or alkaline earth metal.

[0053] The method of the present invention allows the use of substrates having a certain ratio of nerol and geraniol ranging from nerol (Z:E=>99:1) to geraniol (Z:E=<1:99), preferably substrates having a higher content of nerol ranging from Z:E=80:20.

[0054] Of particular use is the ability to further hydrogenate the resulting reaction mixture containing isomenthidedienol to obtain a reaction mixture containing at least one of menthol, isomenthide, neomenthide, and neoisomenthide. The hydrogenation of the reaction mixture is typically carried out using hydrogen and a hydrogenation catalyst.

[0055] The resulting reaction mixture can be isolated into individual compounds or further reacted with olivetol or its substituted derivatives in the presence of Lewis or Brønsted acids to obtain a reaction mixture containing cannabidiol (CBD) and / or tetrahydrocannabinol (THC) and its isomers.

[0056]

[0057] Therefore, this invention also allows the preparation of THC and CBD derivatives starting with neraldehyde derivatives of formula (V).

[0058]

[0059] The reaction mixture is cyclized in the presence of a diphosphazene-derived catalyst of formula (II) as defined above, preferably of formulas (II), (III), (IVa), or (IVb) as defined in the various variants above, and the reaction mixture is further reacted with a substituted oleyl alcohol-like, resorcinol-based compound of formula (VI) in the presence of a Lewis acid or Brønsted acid.

[0060]

[0061] This yields a reaction mixture containing racemic or optically active THC- and / or CBD- analogs of general formulas (VIIa and VIIb);

[0062]

[0063] Where R A They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl, especially methyl, -CH2OH or -COOR e , where R e It is an H or C1 to C6 alkyl group;

[0064] R B They are independently identical or different from each other and each is hydrogen, C1 to C6 alkyl, especially methyl; or R B The two or R in C The two in the middle can each form a ring with each other.

[0065] R C They are independently identical or different from each other and are each C1 to C6 alkyl, especially methyl; or R B The two or R in C The two in the middle can each form a ring with each other.

[0066] R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR.e , where R e It is an H or C1 to C6 alkyl group;

[0067] R 6 The C1 to C1 cells represent hydroxyl groups, optionally further substituted with one or more hydroxyl groups. 12 Preferably, it is a C3 to C7 alkyl group.

[0068] In particular, for continuous methods, it is desirable to use a catalyst in an immobilized form of any of formulas (II), (III), (IVa) or (IVb) in any of the methods described above.

[0069] In one embodiment, the diphosphazene-derived catalyst of formula (II) may optionally be linked to a solid support via a linker, wherein Y, X, and R are as defined above, wherein the linker is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group having up to 50 carbon atoms and optionally further substituted by one or more heterosubstituted, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups, each hydrocarbon group optionally substituted by one or more heterosubstituted groups; and wherein the solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol, and polyamide, and copolymers thereof, each optionally having at least one halogen (preferably F and / or Cl), hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy, and / or oxygen in the aliphatic hydrocarbon chain.

[0070] In another embodiment, the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined above can be attached to the solid support via a linker between the solid support and the aromatic or alicyclic backbone preferably at the 6-position of one, two, three or all of the aromatic or alicyclic backbone of the diphosphazene-derived catalyst, wherein the linker and the solid support are as defined above.

[0071] In yet another embodiment, the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined above can be transmitted via NR N The linking group between the substituent and the solid support is incorporated into the solid support as the stationary phase, wherein in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is O or NR. N X is NR N , where R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one halogen, preferably fluorine, and wherein R and R P As defined above, such as sulfonated tetrafluoroethylene polymers As a solid carrier.

[0072] Method description:

[0073] Currently, neraldehyde and geraniol can be synthesized by allyl oxidation of nerol and geraniol using MnO2, followed by distillation, to obtain the corresponding aldehydes with a Z:E purity of at least 96:4 (in the case of neraldehyde) and 2:98 (in the case of geraniol, or even greater for geraniol).

[0074] The catalysts used herein are based on iminodiphosphate (IDP), iminoimidodiphosphorimidate (iIDP), and iminodiphosphorimidate (IDPi) catalysts (List et al., J. Am. Chem. Soc. 2016, 138, 34, 10822), and can be prepared using the methods described in EP20200632.6. The solvents used are dried before use.

[0075] The catalyst can be dissolved in a solvent and cooled to different temperatures, depending on the solvent used. Neraldehyde is added and the reaction is stirred, and the reaction is stopped, for example, by adding triethylamine after a certain time.

[0076] definition

[0077] The following definitions also apply to individual groups R, R P R N And W, as follows.

[0078] As defined in this invention, the heterosubstituents can be selected from OH, F, Cl, Br, I, CN, NO2, IR. S 2. NO, NCO, -NCS, -SCN, SO3H, monohalomethyl, dihalomethyl, trihalomethyl, CF(CF3)2, SF5, aliphatic, aromatic, heteroaromatic, primary amines, secondary amines or ammonium compounds bonded by the N atom, -O-alkyl (alkoxy), -O-aryl, -O-heteroaryl, -O-SiR S 3. -SSR S -SR S -S(O)-R S -S(O)2-R S -COOH, -CO2-R S -BR S 2. -PR S 2. -OPR S2. Amides, formyl groups, and -C(O)-R groups bonded by C or N atoms S , -COOM, where M is a metal such as Li, Na, K, Cs, Ag. R S They may be identical or different from each other independently and each is an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups; and / or optionally bridged by -O- atoms, representing halides.

[0079] Aliphatic hydrocarbons include alkyl, alkenyl, and alkynyl groups, and may contain straight-chain, branched, and cyclic hydrocarbons.

[0080] Aliphatic hydrocarbons are hydrocarbons including alkyl, alkenyl, and alkynyl groups, which may contain straight-chain, branched, and cyclic hydrocarbons having one or more carbon atoms substituted by at least one heteroatom.

[0081] More specifically, C1-C 20 The alkyl group can be straight-chain or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkyl group can be C1-C6-alkyl, particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, and similarly pentyl, 1-, 2-, or 3-methylpropyl, 1,1-, 1,2-, or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-, or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-, or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-, or 1,2,2-trimethylpropyl. The substituted alkyl groups are trifluoromethyl, pentafluoroethyl, and 1,1,1-trifluoroethyl.

[0082] The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0083] Alkenes can be C2-C 20 Alkenyl. Alkynyl groups can be C2-C. 20 Alkyne group.

[0084] The unsaturated alkenyl or alkynyl groups can be used to attach the compounds of the present invention to a support such as a polymer for use as an immobilized catalyst.

[0085] Halogens are F, Cl, Br or I.

[0086] The alkoxy group is preferably C1-C. 10 Alkoxy groups, such as methoxy, ethoxy, propoxy, tert-butoxy, butoxy, pentoxy, hexoxy, and their isomers.

[0087] The C3-C8 heterocyclic alkyl group having one or more heteroatoms selected from N, O, and S is preferably 2,3-dihydro-2-, -3-, -4-, or -5-furanyl, 2,5-dihydro-2-, -3-, -4-, or -5-furanyl, tetrahydro-2-, or -3-furanyl, 1,3-dioxolane-4-yl, tetrahydro-2-, or -3-thiophenyl, 2,3-dihydro-1-, -2-, -3-, - 4- or -5-pyrrolidinyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolidinyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazoleyl, tetrahydro-1-, -3- or -4-pyrazoleyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridinyl, 1,2 3,4-Tetrahydro-1-,-2-,-3-,-4-,-5- or-6-pyridinyl, 1-,-2-,-3- or-4-piperidinyl, 2-,-3- or-4-morpholinyl, tetrahydro-2-,-3- or-4-pyranyl, 1,4-dioxane, 1,3-dioxane-2-,-4- or-5-yl, hexahydro-1-,-3- or-4-pyridazinyl, hexahydro-1-,-2-,-4- or-5-pyrimidine 1, 2 or 3-piperazinyl, 1,2,3,4-tetrahydro-1, -2, -3, -4, -5, -6, -7 or -8-quinolinyl, 1,2,3,4-tetrahydro-1, -2, -3, -4, -5, -6, -7 or -8-isoquinolinyl, 2, 3, 5, 6, 7 or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl.

[0088] Optional substitution means that each hydrogen atom on the hydrocarbon is either unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted, such as fully substituted.

[0089] The aryl group can be C6 to C6. 22 Aromatic hydrocarbons, and can be phenyl, naphthyl, anthraceneyl, phenanthreneyl or biphenyl.

[0090] Arylalkyl groups can be benzyl groups.

[0091] Heteroaryl groups can be C5 to C6. 18The hydrocarbon is a heteroaromatic hydrocarbon and may have one or more heteroatoms selected from N, O, and S, and is preferably 2- or 3-furanyl, 2- or 3-thienyl, 1-, 2- or 3-pyrroleyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, and more preferably 1, 2,3-Triazol-1-, -4-, or -5-yl; 1,2,4-Triazol-1-, -3-, or -5-yl; 1- or 5-Tetrazolyl; 1,2,3-Oxadiazol-4-, or -5-yl; 1,2,4-Oxadiazol-3-, or -5-yl; 1,3,4-Thiadiazol-2-, or -5-yl; 1,2,4-Thiadiazol-3-, or -5-yl; 1,2,3-Thiadiazol-4-, or -5-yl; 3- or 4-pyridazinyl; pyrazinyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 4- or 5-Isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzooxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisoxiazolyl, 4-, 5-, 6- or 7-benzo-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1 -, 3, 4, 5, 6, 7 or 8-isoquinolinyl, 3, 4, 5, 6, 7 or 8-cenolinyl, 2, 4, 5, 6, 7 or 8-quinazolinyl, 5 or 6-quinoxalinyl, 2, 3, 5, 6, 7 or 8-2H-benzo-1,4-oxazinyl, and more preferably 1,3-benzodioxacyclopenten-5-yl, 1,4-benzodioxane-6-yl, 2,1,3-benzothiadiazole-4- or -5-yl or 2,1,3-benzoxadiazole-5-yl.

[0092] Experimental Section

[0093] Materials and Characterization

[0094] Chemicals: Unless otherwise specified, chemicals (Abcr, Acros, Aldrich, Gelest, Fluka, Fluorochem, Strem, TCI) are purchased as reagent grade and used without further purification. Neraldehyde and geranialdehyde can be synthesized by allyl oxidation of nerol and geraniol using MnO2, followed by distillation to obtain the corresponding aldehydes with Z:E purities of at least 96:4 (in the case of neraldehyde) and 2:98 (in the case of geranialdehyde).

[0095] Solvents: At the technical department of the Max Planck Institute for Coal Research, the solvents (CH₂Cl₂, CHCl₃, Et₂O, THF, PhMe) were dried by distillation from suitable desiccants and received in Schlenk flasks under argon atmosphere. Other solvents (n-pentane and pyridine) were purchased from commercial suppliers and dried using molecular sieves.

[0096] Glassware: Unless otherwise specified, use screw-cap vials, round-bottom flasks, or Schlenk flasks for the reaction. Thin-layer chromatography: Perform thin-layer chromatography (TLC) using silica gel pre-coated plastic sheets (Polygram SIL G / UV254, 0.2 mm, with fluorescent indicator; Macherey-Nagel), visualized under a UV lamp (254 or 366 nm), and stained with potassium permanganate (KMnO4). KMnO4 staining: KMnO4 (1.5 g), K2CO3 (10 g), and 10% NaOH (1.25 mL) in water (200 mL).

[0097] Rapid Column Chromatography (FCC): Rapid Column Chromatography (FCC) uses Merck silica gel (… Elution was performed using technical-grade solvents (230-400 mesh, particle size 0.040-0.063 mm). Compressed nitrogen was used to accelerate elution. Unless otherwise stated, all reported yields refer to spectroscopically and chromatographically pure compounds.

[0098] Gas chromatography: Gas chromatography (GC) analysis on chiral solid supports was performed on HP 6890 and 5890 series instruments (split-mode capillary injection system, flame ionization detector (FID), hydrogen carrier gas). All analyses were performed in the GC department of the Max Planck Institute for Coal Research. The conditions used are described in detail in the separate experiments.

[0099] Catalyst Synthesis

[0100] The catalyst used in this invention is synthesized by means of a phosphazene reagent disclosed in European application 20200632.6 or by a method prepared according to WO 2017 / 037141.

[0101] Catalyst synthesis procedure:

[0102] Phosphazene reagent and the corresponding substituted (S)- or (R)-BINOL or biphenol (2.0 equivalents) were added to a flame-dried Schrank flask. Dry pyridine was added and both solids dissolved to obtain a clear solution. For approximately 50 mg of phosphazene reagent used, the amount of pyridine was 1 mL. A precipitate slowly formed in the clear solution, and after 3 hours, sulfonamide (5.0 equivalents) was added to the reaction, which was then stirred overnight. Water (10 wt%) was added to the reaction and stirred for another 3 hours. The reaction was treated with excess aqueous HCl (10%), and the aqueous phase was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over NaSO₄, and the solvent was evaporated. The catalyst was purified by column chromatography and acidified with DOWEX.

[0103] Acidification using DOWEX:

[0104] The column was packed into a DOWEX column and washed with 0.05 M H₂SO₄ aqueous solution and CH₂Cl₂. The purified catalyst was dissolved in CH₂Cl₂ and then passed through the column, being washed with CH₂Cl₂ until no UV-active material was released. The solvent was evaporated, and the catalyst was obtained. After drying under high vacuum, the catalyst was analyzed by NMR and MS.

[0105] Exemplary reaction schemes of the method of the present invention

[0106] Exemplary catalytic asymmetric cyclizations of citral, neraldehyde, and geranialdehyde are given below.

[0107]

[0108] A magnetic stir bar, iIDP catalyst (1 mol%), and dichloromethane (0.1 M) were loaded into a screw-cap vial. The reaction solution was cooled to -20 °C and stirred for 10 min. Neraldehyde (Z:E ratio 96:4) was added to the vial, and the reaction was stirred at the above temperature for 16 h. The reaction mixture was treated with Et3N, and then the reaction was slowly heated to room temperature. The solvent was evaporated at 40 °C and 500 mbar. The reported yields were determined by NMR using mesitylene or triphenylmethane as internal standards.

[0109] An overall study of exemplary reaction schemes, including various reaction conditions with different amounts of various substrates and catalysts, is shown in [the following text is incomplete and requires further context]. Figure 1 The results indicate that the general reaction scheme is applicable to various conditions and substrates.

[0110] Experimental results

[0111] Catalyst categories

[0112] Several Brønsted acid catalysts (organic or inorganic, and achiral or chiral acids) covering a wide range on the pKa scale can catalyze the cyclization of citral. Weak acids (pKa > 10 in MeCN) exhibit low conversions but maintain concise reaction profiles, while strong acids (pKa < 8 in MeCN) lead to more complex reaction profiles. The complexity of reactions using stronger acids can be explained by the rapid decomposition of the cyclization intermediate isomenthidedienol to several elimination products (e.g., trienes), as described in the literature. Catalyst classes (IDP, iIDP, and IDPi) on the pKa scale between weak and strong acids combine the advantages of higher conversions to the desired product and maintaining concise reaction profiles.

[0113] concentration

[0114] The cyclization of citral can be carried out in several organic solvents at concentrations ranging from pure to very diluted 0.005 M. The desired diastereomeric and enantiomer excesses of the cyclized product remain almost constant at different dilutions of the reaction mixture. Control experiments were conducted by measuring the enantiomer excess at different stages of the reaction to rule out kinetic resolution along the product decomposition pathway.

[0115] catalyst loading

[0116] The cyclization of citral can be carried out using different catalyst loadings ranging from 0.05 to 100 mol%, depending on the solvent and temperature used, without significant loss of the diastereomers of the desired product or an enantiomer excess.

[0117] Water content / molecular sieve

[0118] The cyclization of citral can be carried out under modified reaction conditions (e.g., in the presence of water) to obtain similar diastereomer and enantiomer ratios.

[0119] in conclusion

[0120] The cyclization reaction of citral / nerol using the catalyst of this invention can be carried out at temperatures ranging from -80°C to 25°C, reaction times ranging from 30 minutes to 48 hours, concentrations ranging from pure to 0.005 M in several solvents, and catalyst loadings ranging from 0.05 mol% to 100 mol%. Screening of various catalysts is shown in... Figure 1In this study, the cyclization of citral proceeded in high yields when using catalysts with electron-deficient groups. Screening of several different nuclei with optimal 3,3'-substituents revealed that the smallest nucleus, CF3, provided the product in the highest yield and diastereomeric and enantiomer ratios under optimized standard reaction conditions.

[0121] Exemplary catalytic asymmetric cyclizations of citral, neraldehyde, and geranialdehyde are shown above.

[0122] Product separation and catalyst recovery

[0123] A round-bottom flask was fitted with a magnetic stir bar, iIDP catalyst (2.5 mol%), and dry pentane (0.1 M) and cooled to 0 °C. After 20 minutes, neraldehyde (5.8 mmol, ratio 96:4) was added to the reaction flask, and the reaction was stirred at the above temperature for 16 h. The reaction mixture was treated with triethylamine, and then the reaction was slowly heated to room temperature. After solvent evaporation, a crude reaction product containing the cyclized product was obtained. The crude reaction mixture was purified by CC (silica) to give cyclic allyl alcohol (40% yield, dr12:1 (trans:cis), er96:4).

[0124] Synthesis and Cycloning of Different Substrates

[0125] (Z)-4,4,7-Trimethyloctyl-2,6-dienal:

[0126] 4,4,7-Trimethyloct-6-en-2-ynealdehyde

[0127]

[0128] Triphenylphosphine (26.2 g, 99.8 mmol, 4.0 equivalent) was added to a stirred solution of CBr4 (16.55 g, 49.9 mmol, 2.0 equivalent) in CH2Cl2 (20 mL) at 0 °C, and the resulting reaction mixture was stirred for 15 min. (Z)-4,4,7-trimethyloctyl-2,6-dienal (prepared according to Schindler et al., Science 2018, 361, 1363-1369) (3.5 g, 24.9 mmol, 1.0 equivalent) in CH2Cl2 (15 mL) was added to this suspension, and the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with H2O2 (5%, in H2O), water, and brine, dried over Na2SO4, and evaporated. The crude reaction product was then dissolved in THF (130 mL) and nBuLi (2.5 M, in hexane, 24 mL, 59.9 mmol, 2.4 equivalences) was added dropwise at -78 °C. The reaction mixture was slowly heated to 0 °C and stirred for 20 min, then allowed to reach room temperature. After complete conversion of the starting material, the reaction was quenched with a saturated aqueous solution of NH4Cl, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The resulting crude mixture was purified by rapid column chromatography (10% DCM / pentane) to obtain 4,4,7-trimethyloct-6-en-2-acetylene aldehyde (1.74 g, 42% yield) as a colorless oil.

[0129] (Z)-4,4,7-Trimethyloctyl-2,6-dienal

[0130]

[0131] A flame-dried flask was charged with a solvent mixture of 4,4,7-trimethyloct-6-en-2-acetylanal (500 mg, 3.0 mmol, 1.0 equivalent), cyclohexane / ethyl acetate (1:5), and quinoline (0.36 mL, 3.0 mmol, 1.0 equivalent). A Lindra catalyst was added at room temperature, and the reaction suspension was subjected to hydrogenation conditions (1 atm H₂, via balloon). After near-complete conversion, the reaction was filtered through a diatomaceous earth pad, which was then thoroughly washed with EtOAc. The solvent was evaporated under reduced pressure, and the crude product was purified by rapid column chromatography to obtain the desired α,β-unsaturated aldehyde 4,4,7-trimethyloct-2,6-dienal (120 mg, 24% yield) and a mixture of diastereomers (Z:E = 93:7) as a pale yellow oil.

[0132] Cyclolation of (Z)-4,4,7-trimethyloctyl-2,6-dienal

[0133]

[0134] (Z)-2,7-Dimethyloctyl-2,6-dienal

[0135] (Z)-2,7-Dimethyloctyl-2,6-dienoic acid ethyl ester

[0136]

[0137] To a stirred solution of ethyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)propionate (925 mg, 2.67 mmol, 1.0 equivalent) in THF (21 mL), 18-crown ether-6 (735 mg, 2.78 mmol, 1.05 equivalent) in THF was added. The reaction was cooled to -78 °C and KHMDS (5.3 mL, 2.67 mmol, 0.5 M solution in PhMe) was added dropwise. After stirring at -78 °C for 20 min, 5-methylhexane-4-enal (prepared according to the literature Braddock et al., Chem. Commun. 2006, 2483 and Nakada et al., Tett. Let. 2014, 55, 50, 6847) (300 mg, 2.67 mmol, 1.0 equivalent) was added and stirred at the same temperature until complete conversion. After complete conversion, the reaction was quenched with saturated aqueous NH4Cl solution. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography to obtain an α,β-unsaturated ester (223 mg, 42% yield).

[0138] (Z)-2,7-Dimethyloctyl-2,6-dienal

[0139]

[0140] Ethyl (Z)-2,7-dimethyloctyl-2,6-dienoic acid (344 mg, 1.75 mmol, 1.0 equivalent) and DCM (7 mL) were added to a flame-dried flask, and DIBAL-H (3.8 mL, 1 M, 3.8 mmol, 2.2 equivalent) was added dropwise at -78 °C. After the starting material was completely converted to the desired alcohol, the reaction was quenched with a 1:1 mixture of water / MeOH. The mixture was stirred at room temperature for 2 h. The resulting gel was filtered through a Na₂SO₄ / diatomaceous earth mat, which was then thoroughly washed with dichloromethane. The solvent was evaporated under reduced pressure, and the crude product (Z)-2,7-dimethyloctyl-2,6-dien-1-ol was redissolved in DCM (2 mL). Manganese dioxide (685 mg, 7.89 mmol, 4.5 equivalent) was added to the reaction flask, and the reaction was stirred at room temperature until the starting material was completely converted. After complete conversion, the reaction was filtered through a diatomaceous earth mat, which was then thoroughly washed with DCM. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by rapid column chromatography to give (Z)-2,7-dimethyloctyl-2,6-dienal (160 mg, 60% yield, Z:E = 86:14) as a mixture of diastereomers.

[0141] Cyclolation of (Z)-2,7-dimethyloctyl-2,6-dienal:

[0142]

[0143] The cyclization reaction was carried out according to the general reaction procedure and yielded the desired cyclic allyl alcohol in 72% yield (dr = 2:1, er (major) = 97:3, er (minor) = 93:7).

[0144] Synthesis of CBD and THC

[0145] A chiral catalyst, phosphoric acid, IDP-, iIDP-, or IDPi catalyst (5 mol%), and anhydrous CH2Cl2 (0.1 M) were charged into a reaction vessel, and oleanol (1.1 equivalents) and enantiomeric pure isomenthidedienol (0.3 mmol) were added via syringe. The reaction was stirred at room temperature and quenched with triethylamine after complete conversion of isomenthidedienol. The solvent was evaporated, and a compound containing CBD and / or THC (Δ) was obtained. 9 -THC (cis and trans), Δ 8 -THC、Δ 9 The reaction mixture of -regio-THC (cis and trans)

[0146] Synthesis of reaction mixtures containing cannabidiol (CBD)

[0147] Add 5-20 mol% catalyst or Lewis acid (e.g., BF3OEt2), dry CH2Cl2, oleyl alcohol, and purified enantiomeric isomenthidedienol to a screw-cap vial. The reaction mixture enhances its color, which fades after a few minutes. Stir the reaction mixture at room temperature and treat it with triethylamine after complete conversion of both starting materials. Evaporate the solvent and purify the crude reaction mixture by CC (silica) to give cannabidiol as the major compound.

[0148] Synthesis of reaction mixtures containing cannabidiol (CBD)

[0149] At 0 °C, under argon atmosphere, oleuropein (1 mmol, 180 mg), isomenthidedienol (cis:trans = 5:1, 1.5 equivalents, 0.16 mL), and BF3·Et2O (62.5 μL, 0.5 mmol) in 6.25 mL DCM were added accordingly. After 1.5 h, the starting material was completely consumed as indicated by TLC (5–20% EtOAc / hexane). The reaction was quenched by 100 mg NaHCO3, filtered, and washed with DCM. The solvent was evaporated under reduced pressure, and the crude mixture was purified by rapid column chromatography (SiO2, 5–30% EtOAc / hexane). Three major compounds were isolated, one of which was CBD (32% yield, 101.2 mg).

[0150] Synthesis of reaction mixtures containing THC

[0151] Molecular sieves and 5 mol% iIDP-catalyst were packed into a flame-dried Schrank flask. Dry CH₂Cl₂, oleyl alcohol, and purified enantiomeric isomenthidedienol were added to the flask. The reaction mixture intensified its color, which faded after a few minutes. The reaction was stirred at room temperature and quenched with Et₃N after complete conversion of the two starting materials. The solvent was evaporated and the crude reaction mixture was purified by preparative TLC to give the THC compound (Δ...). 9 -THC (cis and trans), Δ 8 -THC、Δ 9 -regio-THC (cis and trans) is the main product.

[0152] One-pot synthesis of CBD / THC

[0153] iIDP catalyst (5 mol%) and anhydrous CH2Cl2 (0.1 M) were charged into the reaction vessel. After cooling the reaction to the desired temperature and stirring for several minutes, neraldehyde (0.3 mmol) was added to the reaction mixture, and the reaction was stirred for a certain period of time. After complete conversion of the starting material, oleanol (1 equivalent) was added to the reaction mixture, and the reaction was allowed to reach room temperature. After complete conversion of oleanol, the reaction was quenched with triethylamine. The solvent was evaporated, and a substance containing CBD and / or THC (Δ) was obtained. 9 -THC (cis and trans), Δ 8 -THC、Δ 9 The reaction mixture of -regio-THC (cis and trans).

[0154] Δ 8 -THC Synthesis:

[0155] At 60 °C under argon atmosphere, oleyl alcohol (36 mg, 0.2 mmol), enantiomeric isomenthidedienol (dr cis:trans = 5:1, 1.1 equivalences), and BF3·Et2O (0.2 equivalences) in 4 mL DCM were added accordingly. After 14 h, TLC analysis (with 5% EtOAc / hexane) indicated complete conversion of the starting material (oleyl alcohol), and the reaction was treated with one drop of triethylamine. The solvent was evaporated under reduced pressure, and the crude mixture was purified by rapid column chromatography (SiO2, 5% EtOAc / hexane) to obtain Δ 8 -THC as the desired product (53% yield, 33.3 mg, er99:1)

[0156] Δ 9 -THC Synthesis:

[0157] At room temperature, under Ar, oleuropein (0.42 mmol, 75.7 mg), isomenthidedienol (cis:trans = 5:1, 73 μL, 1.1 equivalents), and BF3·Et2O (0.2 equivalents) in 8 mL DCM were added accordingly to a flame-dried Schrank flask. After 22 h, the ratio of products formed was THC:CBD = 2.3:1, and after 42 h, it was THC:CBD = 13.5:1. The reaction was quenched by a drop of triethylamine. The solvent was evaporated under reduced pressure, and the crude reaction mixture was purified by rapid column chromatography (SiO2, 5% EtOAc / hexane) to give Δ 9 -THC was the desired product (55% yield, 72 mg).

[0158] Exemplary hydrogenation of isomenthidedienol:

[0159] The heterogeneous hydrogenation catalyst (64 mg, 10 mol% Pt / C, 0.2 equivalents) was transferred to a round-bottom flask, and a solution of the corresponding isomenthidedienol in methanol (3 mL, 0.2 M) was added to the reaction flask. The reaction mixture was purged with hydrogen (1 atm), and the reaction was vigorously stirred at room temperature for 48 h under a hydrogen atmosphere (1 atm). After complete conversion of the starting material, the heterogeneous catalyst was removed by filtration, and the filtrate was evaporated to obtain a reaction mixture containing menthol, isomenthide, neo-isomenthide, and neo-isomenthide.

[0160] Menthol:

[0161] An enantioenriched isomenthidedienol (dr = 11:1, er 98.5:1.5) (31 mg, 0.20 mmol, 1.0 equivalent), 3 mL of MeOH, and Lindela catalyst (48.7 mg, 0.11 equivalent) were added to a flame-dried flask. After stirring for a few minutes, the reaction was subjected to 1 atm of H2- gas (via balloon). After 2 days, the reaction reached complete conversion (indicated by TLC) and was filtered. After solvent evaporation, the crude reaction mixture was subjected to GC analysis (>99% conversion, 92% product, menthol to isomenthide ratio 74.3:25.7, er (menthol / isomenthide) = 98.5:1.5).

[0162] Synthesis of solid supported catalysts

[0163] 2-(allyloxy)-1,1,2,2-tetrafluoroethane-1-sulfonamide:

[0164] A flame-dried Schrank flask equipped with a magnetic stir bar was used, and ammonia (~25 mL, excess) was condensed into the reaction flask at -78 °C. 5.0 g of 1,1,2,2-tetrafluoro-2-(3-hydroxypropoxy)ethane-1-sulfonyl fluoride (1.0 equivalent, 21 mmol) was slowly added to the flask, and the reaction was stirred at the above temperature for 1.5 h, then gradually heated to room temperature. After another 1.5 h, the resulting white slurry was acidified to approximately pH 2 with 1 M H₂SO₄. The aqueous layer was extracted with diethyl ether, and the resulting organic layer was dried with Na₂SO₄ and concentrated under reduced pressure. After drying under high vacuum, the corresponding sulfonamide (4.9 g, 90% yield) was obtained as a colorless solid.

[0165] The catalyst used for the preparation of the following solid supported confined acid is prepared by using 2-(allyloxy)-1,1,2,2-tetrafluoroethane-1-sulfonamide and following a general reaction scheme.

[0166] Synthesis of solid styrene-divinylbenzene supported catalysts

[0167] In a flame-dried reaction tube, the corresponding iIDP (50 mg, 0.026 mmol) was dissolved in 0.25 mL of chloroform. Styrene (0.5 mL, 4.35 mmol), divinylbenzene (0.25 mL, 1.76 mmol) (filtered through a silica septum before use), and AIBN were added to a flask. The resulting mixture was placed in a tube and copolymerized at 80 °C. After 16 h, the heat source was removed and the obtained solid was crushed. The resulting polymer powder was thoroughly washed with dichloromethane and acidified by suspension in 6 M HCl for 3 h. The suspension was filtered and washed with water and dichloromethane. The obtained solid supported catalyst was dried overnight under high vacuum at 40 °C.

[0168] Synthesis of solid-supported sulfonamides

[0169] At -196°C, a cryogenic mill was used to... R-1100 resin (sulfonyl fluoride form, 500 mg) was ground into a fine, light gray powder. The obtained powder was suspended in anhydrous DMF (3 mL), and excess liquid ammonia was condensed in a reaction flask at -78 °C. The interfacial reaction was carried out with continuous stirring. After stirring overnight in liquid ammonia at an initial temperature of -78 °C, residual ammonia was released, and the mixture was heated from room temperature to 90 °C for 2 h. The resulting solid-supported sulfonamide was precipitated from water, washed with deionized water, and dried under vacuum at 60 °C for 24 h. (497 mg, quantitative). The corresponding solid-supported catalyst was prepared using the general procedure as described previously.

[0170] Exemplary catalytic asymmetric cyclization of citral, neraldehyde, and geraniol using solid-supported catalysts:

[0171] A magnetic stir bar, a solid-supported iIDP catalyst, and dry n-pentane (0.5 M) were loaded into a screw-cap vial. Neraldehyde (Z:E 96:4) was added to the reaction vial, and the reaction was stirred overnight at room temperature. After complete conversion of the starting material, the solid-supported catalyst was removed using a syringe filter, which was further rinsed with pentane, and the resulting filtrate was treated with trimethylamine. After solvent evaporation, the yield and dr were determined by NMR spectroscopy using mesitylene as an internal standard, and enantiomer excess was determined by GC. (28% yield, dr 15:1 (trans:cis), er 96:4).

[0172] Cyclohydrin using solid supported catalysts

[0173] A 10 mol% solid supported catalyst and dichloromethane were added to a flame-dried vial. Neraldehyde (5 μL) was added to the vial, and the reaction was stirred at room temperature for 16 h. After quenching the reaction with one drop of triethylamine, the reaction was filtered, and the reaction was analyzed by 1H-NMR spectroscopy using an internal standard. The desired product was given in 13% yield (dr(trans / cis) = 5:1, er = 96:4). The enantiomer and diastereomer ratio was determined by GC analysis.

Claims

1. A method for the asymmetric synthesis of isomenthidedienol of formula (I), A substrate containing at least one of neraldehyde [(Z)-3,7-dimethyloctyl-2,6-dienal] and geraniol [(E)-3,7-dimethyloctyl-2,6-dienal] is optionally treated in an organic solvent with a catalyst derived from a diphosphazene of formula (II) to obtain a reaction mixture containing isomenthidedienol: Wherein in the above formula: -R may be the same or different at each position and is selected from hydrogen; halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF5, NO2, or cyano groups on the aliphatic hydrocarbon; C6 to C6 18 Aromatic hydrocarbons or C5 to C 18 Heteroaromatic hydrocarbons, each of which is optionally substituted by one or more substituents selected from the following: halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogen, SF5, NO2, or cyano groups on the aliphatic hydrocarbon. -R P The same or different at each position and having the meaning of R, or two Rs on the same aryl ring. P They form rings with each other, which are aromatic or aliphatic ring structures, and the aromatic and / or aliphatic ring structures are substituted by one or more substituents R. - X and Y are the same or different and are oxygen or NR N ;in: R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. -alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphonyldialkyl, phosphonylalkyl, alkylphosphine, N,N′-alkylimidazolidine-2-imino, wherein the alkyl group is optionally a C1 to C6 substituent selected from alkoxy, halogen, cyano, nitro, or SF5. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons; ii. -aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, phosphinodiaryl, phosphinoalkylaryl, phosphonylaryl, aryl n-phosphine, arylalkyl n-phosphine, N,N′-arylimidazolidine-2-imino, N-aryl-N′-alkylimidazolidine-2-imino, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5, optionally substituted with at least one halogen. iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-di-heteroaryl, phosphino-diheteroaryl, phosphino-arylheteroaryl, phosphino-arylalkyl, phosphonylheteroaryl, heteroaryl n-phosphine, heteroaryl aryl n-phosphine, heteroaryl arylalkyl n-phosphine, N,N′-heteroarylimidazolidine-2-imino, N-heteroaryl-N′-alkylimidazolidine-2-imino, N-heteroaryl-N′-arylimidazolidine-2-imino, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5, optionally substituted with at least one halogen. and -W is selected from hydrogen, halogens, and metal or cationic organic groups selected from Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, Cd, W, Re, Os, Ir, Pt, Au, Hg, Al, Ga, In, Ge, Sn, Pb, As, Sb, Bi, Se, Te, La, Sm, Eu, Yb, U, substituted boranes -BR I R II R III Or replaced silicon-SiR I R II R III , where R I R II and R III Identical or different and each representing hydrogen, halogen, optionally -O-bonded, optionally having one or more unsaturated bonds or one or more heteroatoms in the chain, C1 to C2 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, C5 to C6 18 heteroaromatic hydrocarbons, C6 to C 18 Aromatic hydrocarbons or their partially aromatic hydrogenated forms, each hydrocarbon optionally being hydrogenated by one or more compounds selected from C1 to C2. 20 A straight-chain, branched, or cyclic aliphatic hydrocarbon or a group substituted with one or more heterosubstituted groups.

2. The method according to claim 1, wherein in formula (II): -R may be the same or different at each position and is selected from hydrogen; halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogens selected from F or Cl, SF5, NO2, or cyano groups on the aliphatic hydrocarbon; C6 to C6 18 Aromatic hydrocarbons or C5 to C 18 Heteroaromatic hydrocarbons, each of which is optionally substituted by one or more substituents selected from the following: halogen; SF5; NO2; cyano; C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, optionally having one or more halogens selected from F and / or Cl, SF5, NO2, or cyano groups on the aliphatic hydrocarbon. -R P The same or different at each position and having the meaning of R, or two Rs on the same aryl ring. P They form rings with each other, which are aromatic or aliphatic ring structures, and the aromatic and / or aliphatic ring structures are substituted by one or more substituents R. - X and Y are the same or different and are oxygen or NR N ;in: R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. -alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, oxyphosphonyldialkyl, phosphonylalkyl, alkyl-n-phosphine, N,N′-alkylimidazolidine-2-imino, wherein the alkyl group is optionally C1 to C6 alkoxy, a halogen selected from F and / or Cl, a cyano, a nitro, or a SF5 substituent. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons; ii. -aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, phosphinodiaryl, phosphinoalkylaryl, phosphonylaryl, aryl n-phosphine, arylalkyl n-phosphine, N,N′-arylimidazolidine-2-imino, N-aryl-N′-alkylimidazolidine-2-imino, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen selected from F and / or Cl, cyano, nitro, or SF5, optionally substituted with at least one halogen. iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-di-heteroaryl, phosphino-diheteroaryl, phosphino-arylheteroaryl, phosphino-arylalkyl, phosphonylheteroaryl, heteroaryl n-phosphine, heteroaryl aryl n-phosphine, heteroaryl arylalkyl n-phosphine, N,N′-heteroarylimidazolidine-2-imino, N-heteroaryl-N′-alkylimidazolidine-2-imino, N-heteroaryl-N′-arylimidazolidine-2-imino, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: a C1 to C6 alkyl group optionally substituted with at least one halogen, a C1 to C6 alkoxy group, a halogen selected from F and / or Cl, a cyano group, a nitro group, or SF5; and -W is selected from hydrogen and substituted silicon-SiR I R II R III , where R I R II and R III As defined previously.

3. The method according to claim 1, wherein the diphosphazene-derived catalyst is represented by the following formula (III): Wherein the substituents R are the same or different at each position and as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, alkali metal or alkaline earth metal.

4. The method according to claim 1, wherein the diphosphazene-derived catalyst is represented by the following formula (IVa): Wherein the substituents R are the same or different at each position and as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, alkali metal or alkaline earth metal.

5. The method according to claim 1, wherein the diphosphazene-derived catalyst is represented by the following formula (IVb): Wherein the substituents R are the same or different at each position and as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, alkali metal or alkaline earth metal.

6. The method according to any one of claims 3-5, wherein the substituents R are the same or different at each position and represent a halogen, a straight chain, a branched chain, or a cyclic C1 to C2 chain. 20 Aliphatic hydrocarbons or C6 to C 18 Aromatic hydrocarbons, wherein the aliphatic hydrocarbons and / or aromatic hydrocarbons are reacted with one or more halogens, SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 hydrocarbons. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 Aliphatic hydrocarbons are substituted by one or more halogens, SF5, or NO2.

7. The method of claim 6, wherein the substituents R are the same or different at each position and represent a halogen, a straight chain, a branched chain, or a cyclic C1 to C2 chain. 20 Aliphatic hydrocarbons or C6 to C 18 Aromatic hydrocarbons, wherein the aliphatic hydrocarbons and / or aromatic hydrocarbons are reacted with one or more halogens selected from F and / or Cl, SF5, NO2, or straight-chain, branched, or cyclic C1 to C2 hydrocarbons. 20 Aliphatic hydrocarbon substitution, wherein the straight-chain, branched, or cyclic C1 to C2 hydrocarbons are substituted. 20 Aliphatic hydrocarbons are substituted by one or more halogens selected from F and / or Cl, SF5, NO2.

8. The method according to any one of claims 1-5 and 7, wherein, In any of equations (II), (III), (IVa), or (IVb), Y is defined as O or NR. N And X is defined as NR N , where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. sulfinyl alkyl or sulfonyl alkyl, wherein the alkyl group is C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, wherein C1 to C2 are... 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons optionally have at least one substituent selected from the following: C1 to C6 alkoxy, halogen, cyano, nitro, or SF5; ii. sulfinylaryl or sulfonylaryl, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro or SF5 optionally substituted with at least one halogen; iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5, optionally substituted with at least one halogen; and Among them, R, R P W has the meaning as defined in any one of claims 1-2 and 6-7.

9. The method according to claim 6, wherein, In any of equations (II), (III), (IVa), or (IVb), Y is defined as O or NR. N And X is defined as NR N , where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. sulfinyl alkyl or sulfonyl alkyl, wherein the alkyl group is C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, wherein C1 to C2 are... 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons optionally have at least one substituent selected from the following: C1 to C6 alkoxy, halogen, cyano, nitro, or SF5; ii. sulfinylaryl or sulfonylaryl, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro or SF5 optionally substituted with at least one halogen; iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: C1 to C6 alkyl, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5, optionally substituted with at least one halogen; and Among them, R, R P W has the meaning as defined in any one of claims 1-2 and 6-7.

10. The method according to claim 8, wherein, In any of equations (II), (III), (IVa), or (IVb), Y is defined as O or NR. N And X is defined as NR N , where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. sulfinyl alkyl or sulfonyl alkyl, wherein the alkyl group is C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, wherein C1 to C2 are... 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons optionally have at least one substituent selected from the following: C1 to C6 alkoxy, halogen selected from F and / or Cl, cyano, nitro, or SF5; ii. sulfinylaryl or sulfonylaryl, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen selected from F and / or Cl, cyano, nitro or SF5, optionally substituted with at least one halogen. iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: a C1 to C6 alkyl group optionally substituted with at least one halogen, a C1 to C6 alkoxy group, a halogen selected from F and / or Cl, a cyano group, a nitro group, or SF5; and Among them, R, R P W has the meaning as defined in any one of claims 1-2 and 6-7.

11. The method according to claim 9, wherein, In any of equations (II), (III), (IVa), or (IVb), Y is defined as O or NR. N And X is defined as NR N , where R N It is an electron-withdrawing or electron-donating group, which may be the same or different at each position and is selected from: i. sulfinyl alkyl or sulfonyl alkyl, wherein the alkyl group is C1 to C2. 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons, wherein C1 to C2 are... 20 Straight-chain, branched, or cyclic aliphatic hydrocarbons optionally have at least one substituent selected from the following: C1 to C6 alkoxy, halogen selected from F and / or Cl, cyano, nitro, or SF5; ii. sulfinylaryl or sulfonylaryl, wherein the aryl group is C6 to C6. 18 Aromatic hydrocarbons, C6 to C 18 The aromatic hydrocarbon optionally has at least one substituent selected from the following: C1 to C6 alkyl, C1 to C6 alkoxy, halogen selected from F and / or Cl, cyano, nitro or SF5, optionally substituted with at least one halogen. iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, wherein the heteroaryl group is C2 to C3. 18 heteroaromatic hydrocarbons, C2 to C 18 The heteroaromatic hydrocarbon optionally has at least one substituent selected from: a C1 to C6 alkyl group optionally substituted with at least one halogen, a C1 to C6 alkoxy group, a halogen selected from F and / or Cl, a cyano group, a nitro group, or SF5; and Among them, R, R P W has the meaning as defined in any one of claims 1-2 and 6-7.

12. The method according to any one of claims 1-5, 7 and 9-11, wherein the substrate comprises nerol and geraniol in a ratio ranging from nerol (Z:E=>99:1) to geraniol (Z:E=<1:99).

13. The method of claim 6, wherein the substrate comprises nerol and geraniol in a ratio ranging from nerol (Z:E=>99:1) to geraniol (Z:E=<1:99).

14. The method of claim 8, wherein the substrate comprises nerol and geraniol in a ratio ranging from nerol (Z:E=>99:1) to geraniol (Z:E=<1:99).

15. The method according to any one of claims 1-5, 7, 9-11 and 13-14, wherein the obtained reaction mixture is further subjected to hydrogenation to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol and neoisomenthol.

16. The method of claim 6, wherein the obtained reaction mixture is further subjected to hydrogenation to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol.

17. The method of claim 8, wherein the obtained reaction mixture is further subjected to hydrogenation to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol.

18. The method of claim 12, wherein the obtained reaction mixture is further subjected to hydrogenation to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol.

19. The method according to any one of claims 1-5, 7, 9-11, 13-14 and 16-18, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

20. The method of claim 6, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

21. The method of claim 8, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

22. The method of claim 12, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

23. The method of claim 15, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

24. The method according to claim 19, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a catalyst of formula (II), (III) or (IV) to obtain a reaction mixture containing THC and / or CBD.

25. The method according to any one of claims 20-23, wherein the obtained reaction mixture is further reacted with oleyl alcohol in the presence of a catalyst of formula (II), (III) or (IV) to obtain a reaction mixture containing THC and / or CBD.

26. The method according to any one of claims 1-5, 7 and 9-11, wherein the nerol derivative of formula (V) is used. Cyclization is performed in the presence of a diphosphazene-derived catalyst as defined in any one of claims 1 to 11, and the reaction mixture is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a Lewis acid or a Brønsted acid. This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); Where R A They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl, -CH2OH or -COOR e , where R e It is an H or C1 to C6 alkyl group; R B They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl; or R B The two or R in C The two in the middle form a loop with each other. R C They are independently identical or different from each other and each is a C1 to C6 alkyl group; or R B The two or R in C The two in the middle form a loop with each other. R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R 6 The C1 to C1 cells represent hydroxyl groups, optionally further substituted with one or more hydroxyl groups. 12 alkyl.

27. The method according to claim 6, wherein the nerol derivative of formula (V) is used. Cyclization is performed in the presence of a diphosphazene-derived catalyst as defined in any one of claims 1 to 11, and the reaction mixture is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a Lewis acid or a Brønsted acid. This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); Where R A They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl, -CH2OH or -COOR e , where R e It is an H or C1 to C6 alkyl group; R B They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl; or R B The two or R in C The two in the middle form a loop with each other. R C They are independently identical or different from each other and each is a C1 to C6 alkyl group; or R B The two or R in C The two in the middle form a loop with each other. R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R 6 The C1 to C1 cells represent hydroxyl groups, optionally further substituted with one or more hydroxyl groups. 12 alkyl.

28. The method according to claim 8, wherein the nerol derivative of formula (V) is used. Cyclization is performed in the presence of a diphosphazene-derived catalyst as defined in any one of claims 1 to 11, and the reaction mixture is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a Lewis acid or a Brønsted acid. This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); Where R A They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl, -CH2OH or -COOR e , where R e It is an H or C1 to C6 alkyl group; R B They are independently identical or different from each other and are each hydrogen, C1 to C6 alkyl; or R B The two or R in C The two in the middle form a loop with each other. R C They are independently identical or different from each other and each is a C1 to C6 alkyl group; or R B The two or R in C The two in the middle form a loop with each other. R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R 6 The C1 to C1 cells represent hydroxyl groups, optionally further substituted with one or more hydroxyl groups. 12 alkyl.

29. The method according to claim 26, wherein the nerol derivative of formula (V) is used. Cyclization is performed in the presence of a diphosphazene-derived catalyst as defined in any one of claims 1 to 11, and the reaction mixture is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a catalyst of formula (II), (III), (IVa), or (IVb). This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); Where R A They are independently identical or different from each other and are each hydrogen, methyl, -CH2OH or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R B They are independently identical or different from each other and are each hydrogen, methyl; or R B The two or R in C The two in the middle form a loop with each other. R C They are independently identical or different from each other and each is a methyl group; or R B The two or R in C The two in the middle form a loop with each other. R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R 6 The alkyl group represents a hydroxyl group, and optionally a C3 to C7 alkyl group further substituted with one or more hydroxyl groups.

30. The method according to claim 27 or 28, wherein the nerol derivative of formula (V) is used. Cyclization is performed in the presence of a diphosphazene-derived catalyst as defined in any one of claims 1 to 11, and the reaction mixture is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a catalyst of formula (II), (III), (IVa), or (IVb). This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); Where R A They are independently identical or different from each other and are each hydrogen, methyl, -CH2OH or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R B They are independently identical or different from each other and are each hydrogen, methyl; or R B The two or R in C The two in the middle form a loop with each other. R C They are independently identical or different from each other and each is a methyl group; or R B The two or R in C The two in the middle form a loop with each other. R 5 and R 7 They are either identical or different from each other independently and are each hydrogen or -COOR. e , where R e It is an H or C1 to C6 alkyl group; R 6 The alkyl group represents a hydroxyl group, and optionally a C3 to C7 alkyl group further substituted with one or more hydroxyl groups.

31. The method according to any one of claims 1-5, 7, 9-11, 13-14, 16-18, 20-24, and 27-29, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

32. The method of claim 6, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

33. The method of claim 8, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

34. The method of claim 12, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

35. The method of claim 15, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

36. The method of claim 19, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

37. The method of claim 25, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

38. The method of claim 26, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

39. The method of claim 30, wherein the diphosphazene-derived catalyst is optionally bonded to a solid support via a linker, wherein R, R P Y, X and W are as defined in any one of claims 1 to 11; The linking group is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group optionally further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain.

40. The method of claim 31, wherein the solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen selected from F and / or Cl, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain on an aliphatic hydrocarbon.

41. The method according to any one of claims 32-39, wherein the solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol and polyamide, and copolymers thereof, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy or oxygen in the aliphatic hydrocarbon chain selected from F and / or Cl.

42. The method of claim 31, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is bonded to the solid support via a linker between the solid support and the aromatic or alicyclic backbone, wherein the linker and the solid support are as defined in claim 10; Y and X are defined as oxygen or NR. N R N As defined in claim 1, R and R P As defined in any one of claims 1 to 5.

43. The method of claim 41, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is bonded to the solid support via a linker between the solid support and the aromatic or alicyclic backbone, wherein the linker and the solid support are as defined in claim 10; Y and X are defined as oxygen or NR. N R N As defined in claim 1, R and R P As defined in any one of claims 1 to 5.

44. The method according to any one of claims 32-40, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is bonded to the solid support via a linker between the solid support and the aromatic or alicyclic backbone, wherein the linker and the solid support are as defined in claim 10; Y and X are defined as oxygen or NR. N R N As defined in claim 1, R and R P As defined in any one of claims 1 to 5.

45. The method according to claim 42 or 43, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa), or (IVb) as defined in any one of claims 1 to 5 is linked to the solid support at the 6-position of one, two, three, or all of the aromatic or alicyclic backbone of the diphosphazene-derived catalyst via a linker between the solid support and the aromatic or alicyclic backbone, wherein the linker and the solid support are as defined in claim 10; Y and X are defined as oxygen or NR. N R N As defined in claim 1, R and R P As defined in any one of claims 1 to 5.

46. ​​The method of claim 44, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa), or (IVb) as defined in any one of claims 1 to 5 is linked to the solid support at the 6-position of one, two, three, or all of the aromatic or alicyclic backbone of the diphosphazene-derived catalyst via a linker between the solid support and the aromatic or alicyclic backbone, wherein the linker and the solid support are as defined in claim 10; Y and X are defined as oxygen or NR. N R N As defined in claim 1, R and R P As defined in any one of claims 1 to 5.

47. The method of claim 31, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is transmitted via the NR N The linker between the substituent and the solid support is bonded to the solid support, wherein the linker and the solid support are as defined in claim 10, and in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR. N X is NR N R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one halogen, and wherein R and R P As defined in any one of claims 1 to 5.

48. The method of claim 41, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is transmitted via the NR N The linker between the substituent and the solid support is bonded to the solid support, wherein the linker and the solid support are as defined in claim 10, and in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR. N X is NR N R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one halogen, and wherein R and R P As defined in any one of claims 1 to 5.

49. The method according to any one of claims 32-40, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is transmitted via the NR N The linker between the substituent and the solid support is bonded to the solid support, wherein the linker and the solid support are as defined in claim 10, and in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR. N X is NR N R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one halogen, and wherein R and R P As defined in any one of claims 1 to 5.

50. The method according to claim 47 or 48, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is transmitted via the NR N The linker between the substituent and the solid support is bonded to the solid support, wherein the linker and the solid support are as defined in claim 10, and in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR. N X is NR N R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one fluorine fluoride, and wherein R and R P As defined in any one of claims 1 to 5.

51. The method of claim 49, wherein the diphosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 5 is transmitted via the NR N The linker between the substituent and the solid support is bonded to the solid support, wherein the linker and the solid support are as defined in claim 10, and in the diphosphazene-derived catalysts of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR. N X is NR N R N It is a straight-chain or branched alkyl chain or a polyether alkyl chain, wherein the alkyl chain has at least one fluorine fluoride, and wherein R and R P As defined in any one of claims 1 to 5.

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