Method for the asymmetric synthesis of isopiperitenor

Abstract

The present invention relates to a method for the asymmetric synthesis of isopiperitenol and subsequent compounds.

Description

[Technical Field]

[0001] The present invention relates to a method for the asymmetric synthesis of isopiperitenol and subsequent compounds. [Background technology]

[0002] Isopiperitenol 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 key methods for the industrial synthesis of menthol stereoisomers in the prior art is the so-called BASF method.

[0003] The aforementioned BASF menthol process involves two hydrogenation steps starting from geranial or neral. Thus, the first asymmetric C=C-bond hydrogenation is used to introduce a stereocenter at the β-position of citronellal, as shown in the following scheme. Cyclization of citronellal in the presence of a Lewis acid or Brønsted acid yields isopulegol, which undergoes further C=C-bond hydrogenation to produce a reaction mixture containing several menthol stereoisomers.

[0004] [ka] Very few scientific papers and patent applications mention the synthesis of isopiperitenol as an alternative, industrially useful precursor, and these can be summarized as follows: - CH oxidation starting from limonene (J.-P.Rioult et al., Flavour Fragr.J.2000,15,223 (Non-Patent Literature 1); WO2004 / 013339 (Patent Literature 1); Verhoeven et al., The Plant Journal 2004,39,135 (Non-Patent Literature 2)), - Use of modified citral derivatives or other monoterpenes as starting materials (Marshall et al., J. Org. Chem. 1988, 53, 4108 (Non-Patent Literature 3); Nakamura et al., Bull. Chem. Soc. Jpn. 1992, 65, 929-931 (Non-Patent Literature 4); Semikolenov et al. Kinet. Catal. Lett. 2004, 82, 165 (Non-Patent Literature 5)); - Reduction of cyclic ketones (Tetrahedron:Asymmetry 2007,17,717,Rao (Non-patent Literature 6)) - Diels-Alder reaction (Tetrahedron Asymmetry 2003,14,3313 Serra (Non-Patent Document 7)), and - Cyclization of citral.

[0005] From the end of the 19th century, the acid-catalyzed conversion of citral to unsaturated cyclic alcohols was known through the work of A. Verley (Bull. Soc. Chim III 1899, 21, 408) (Non-Patent Literature 8) and O. Zeitschel and H. Schmidt (Journal fuer praktische Chemie 1932, Volume 133, 370-373) (Non-Patent Literature 9), but these yielded very low yields and complex mixtures of substances. Later, kinetic studies on this conversion by C. Price (Industrial and Engineering Chemistry 1948, 40, 2, 257) (Non-Patent Literature 10) and B. Clark (Tetrahedron 1977, 33, 17, 2187) (Non-Patent Literature 11) confirmed that the cyclization was a very complex conversion yielding several cyclic products, and isopiperitenol was considered an unstable intermediate under acidic reaction conditions.

[0006] Furthermore, thermocyclization starting from citral in the absence of acid is possible (G. Ohloff, THL 1960, 11, 10 (Non-Patent Document 12)), and by adding a catalytic amount of weak acid (DE2305629C2 (Patent Document 2)), the desired product is obtained as a mixture of stereoisomers. Since achiral inorganic / organic acids are used, the yield is very good for the latter method, but the product is obtained as a mixture of stereoisomers.

[0007] In the prior art, no method is known for producing enantiopurine isopiperitenol from commercially available citral that can be carried out in a single high-yield step and yields isopiperitenol in an enantiopurine form. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO2004 / 013339 [Patent Document 2] DE2305629C2 [Non-patent literature]

[0009] [Non-Patent Document 1] J.-P.Rioult et al.,Flavor Fragr.J.2000,15,223 [Non-Patent Document 2] Verhoeven et al.,The Plant Journal 2004,39,135 [Non-Patent Document 3] Marshall et al.,J.Org.Chem.1988,53,4108 [Non-Patent Document 4] Nakamura et al.,Bull.Chem.Soc.Jpn.1992,65,929-931 [Non-Patent Document 5] Semikolenov et al.Kinet.Catal.Lett.2004,82,165 [Non-Patent Document 6] Tetrahedron:Asymmetry 2007,17,717,Rao [Non-Patent Document 7] Tetrahedron Asymmetry 2003,14,3313 Serra [Non-Patent Document 8] A.Verley(Bull.Soc.Chim III 1899,21,408) [Non-Patent Document 9] O. Zeitschel and H. Schmidt (Journal fuer praktische Chemie 1932, Volume 133, 370-373) [Non-Patent Document 10] C.Price(Industrial and Engineering Chemistry 1948,40,2,257) [Non-Patent Document 11] Clark(Tetrahedron 1977,33,17,2187) [Non-Patent Document 12] G. Ohloff, THL 1960, 11, 10 [Overview of the project] [Problems that the invention aims to solve]

[0010] The problem that this invention aims to solve is to develop a method that enables the production of enantiomerically enriched isopiperitenol as a precursor compound of menthol, CBD, and THC, and thus overcomes the shortcomings of the prior art. [Means for solving the problem]

[0011] The inventors have developed a method, as illustrated in the scheme below, that utilizes the asymmetric cyclization from citral / neral to isopiperitenol, thereby shortening the current industrial process to menthol and opening up options for finding variable means to other substances, such as cannabidiol (CBD) and tetrahydrocannabinol (THC).

[0012] [ka] The aforementioned problem is solved by an improved method for the asymmetric synthesis of isopiperitenol, wherein neral [(Z)-3,7-dimethylocta-2,6-dienal] is optionally cyclized in a solvent in the presence of a chiral dimer phosphazene-derived catalyst.

[0013] More specifically, the present invention relates to an improved method for the asymmetric synthesis of isopiperitenol of formula (I),

[0014] [ka] A substrate containing at least one of neral [(Z)-3,7-dimethylocta-2,6-dienal] and geranial [(E)-3,7-dimethylocta-2,6-dienal] is optionally treated in an organic solvent with a catalyst derived from a dimer phosphazene represented by the following formula (II), thereby obtaining a reaction mixture containing isopiperitenol.

[0015] [ka] In the above equation (II), - R is either the same or different at each position, and each is hydrogen, halogen, SF5, NO2, cyano, C1-C 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally having one or more halogens on the aliphatic hydrocarbon, preferably F or Cl, SF5, NO2, or cyano), C6-C 18 Aromatic hydrocarbons, or C5-C 18 Selected from heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon is optionally a halogen, SF5, NO2, cyano, C1-C 20Selected from one or more substituents of linear, branched or cyclic aliphatic hydrocarbons (optionally having one or more halogens, preferably F and / or Cl, SF5, NO2 or cyano on the aliphatic hydrocarbon), - R P is the same or different at each position and has the meaning of R, or two Rs on the same aryl ring P may form a ring that can be an aromatic ring structure or an aliphatic ring structure with each other, and the aromatic ring structure and / or aliphatic ring structure may be substituted with one or more substituents R, - X and Y are the same or different and are either oxygen or NR N either, where R N is an electron-withdrawing or electron-donating group, the same or different at each position, and is selected from: i. -Alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphinyldialkyl, phosphinylalkyl, alkylphosphorane, N,N'-alkylimidazolidine-2-imino, where alkyl is C1-C 20 a linear, branched or cyclic aliphatic hydrocarbon (optionally having at least one substituent selected from C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5); ii. -Aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, phosphinyldiaryl, phosphinylalkylaryl, phosphinylaryl, arylphosphoranes, arylalkylphosphoranes, N,N'-arylimidazolidine-2-imino, N-aryl-N'-alkylimidazolidine-2-imino, where aryl is C6-C 18Aromatic hydrocarbons (optionally, at least one halogen) C is optionally replaced by 1 ~C 6 Alkyl, C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or science fiction 5 from (having at least one selected substituent); iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-diheteroaryl, phosphinyldiheteroaryl, phosphinylarylheteroaryl, phosphinylheteroarylalkyl, phosphonylheteroaryl, heteroarylphosphoranes, heteroarylarylphosphoranes, heteroarylarylalkylphosphoranes, N,N'-heteroarylimidazolidine-2-iminyl, N-heteroaryl-N'-alkylimidazolidine-2-iminyl, N-heteroaryl-N'-arylimidazolidine-2-iminyl, where heteroaryl is C2~C 18 Heteroaromatic hydrocarbons (optionally, at least one halogen) C is optionally replaced by 1 ~C 6 Alkyl, C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or science fiction 5 from (having at least one selected substituent); and - W is a metal selected from hydrogen, halogens, 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, or a cationic organic group, substituted borane-BR I R II R III , or substituted silicon-SiR I R II R III Selected from, here, R I , RII and R III These may be the same or different, and each may be hydrogen, a halogen, or optionally a C1-C bonded by -O- 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally having one or more unsaturated bonds or one or more heteroatoms in the chain), C5-C 18 Heteroaromatic hydrocarbons, C6~C 18 Represents aromatic hydrocarbons or their partially areneed hydrogenated forms, where each hydrocarbon is optionally C1-C1 20 It is substituted with one or more groups selected from linear, branched, or cyclic aliphatic hydrocarbons, or with one or more heterosubstituted groups, where W is preferably hydrogen and substituted silicon-SiR I R II R III (In the formula, R I , R II and R III (is selected from the above definitions) Regarding the aforementioned method.

[0016] The reaction conditions for the method of the present invention are not critical, and the reaction can be carried out in a temperature range of -100°C to 30°C, or even in a higher temperature range up to 80°C. The reaction can be carried out without a solvent, or in a non-proton organic solvent, such as CH2Cl2, CHCl3, Et2O, THF, PhMe, pentane, hexane, or cyclohexane, generally under atmospheric pressure.

[0017] In one embodiment of the above method, the catalyst derived from a dimeric phosphazene has formula (III):

[0018] [ka] [In the formula, the substituents R are either identical or different at each position as defined above, X and Y have the meanings defined above, and W represents hydrogen, an alkali metal, or an alkaline earth metal.]

[0019] In one embodiment of the above method, the catalyst derived from a dimeric phosphazene has formula (IVa):

[0020] [ka] [In the formula, the substituents R are either identical or different at each position as defined above, X and Y have the meanings defined above, and W represents hydrogen, an alkali metal, or an alkaline earth metal.]

[0021] In formulas (III), (IVa), and below (IVb), the dashed line represents a double bond and therefore a naphthalene ring system, or a hydrogenated double bond and a 4H-naphthalene ring system, and both forms may be present in the catalyst used in the method of the present invention.

[0022] In another embodiment of the method of the present invention, the catalyst derived from a dimeric phosphazene is represented by the following formula (IVb):

[0023] [ka] [In the formula, the substituents R are either identical or different at each position as defined above, X and Y have the meanings defined above, and W represents hydrogen, an alkali metal, or an alkaline earth metal.]

[0024] 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 is a halogen, linear, branched, or cyclic C1-C 20 Aliphatic hydrocarbons, or C6-C6 18 This represents aromatic hydrocarbons, and the aliphatic hydrocarbon and / or aromatic hydrocarbon is one or more halogens, preferably F and / or Cl, SF5, NO2, or linear, branched or cyclic C1-C 20It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon with one or more halogens, preferably F and / or Cl, SF5, NO2), where X and Y have the meanings defined above, and W represents hydrogen, an alkali metal, or an alkaline earth metal.

[0025] In another embodiment of the method of the present invention, in any one of formulas (II), (III), (IVa), or (IVb), Y is O or NR N Defined as such, X is NR N Defined as, where R N is an electron-withdrawing or electron-donating group, which is identical or different at each position, and is selected from the following: i. Sulfinylalkyl or sulfonylalkyl, where alkyl is C1-C1 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally having at least one substituent selected from C1-C6 alkoxys, halogens, preferably F and / or Cl, cyano, nitro, or SF5); ii. Sulfinylaryl or sulfonylaryl, where aryl is C6-C 18 Aromatic hydrocarbons (optionally, at least one halogen) C is optionally replaced by 1 ~C 6 Alkyl, C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or science fiction 5 from (having at least one selected substituent); iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, where heteroaryl is C2-C 18 Heteroaromatic hydrocarbons (optionally, at least one halogen) C is optionally replaced by 1 ~C 6 Alkyl, C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or science fiction 5 from (having at least one substituent selected); and R has the meaning defined above, preferably being the same or different at each position, and is a halogen, linear, branched or cyclic C1-C 20 Aliphatic hydrocarbons, or C6-C6 18 This represents aromatic hydrocarbons, and the aliphatic hydrocarbon and / or aromatic hydrocarbon is one or more halogens, preferably F and / or Cl, SF5, NO2, or linear, branched or cyclic C1-C 20 It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon with one or more halogens, preferably F and / or Cl, SF5, NO2), and W represents hydrogen, an alkali metal, or an alkaline earth metal.

[0026] In any preferred embodiment of the method of the present invention, in formula (II), (III), (IVa), or (IVb), Y is O or NR. N , preferably defined as O, where X is NR N Defined as, where R N The group is an electron-withdrawing group, preferably a sulfonyl alkyl group (where the alkyl is a partially or completely hydrogenated linear, branched, or cyclic C1-C group). 20 (Aliphatic hydrocarbons), or sulfonylaryls (aryls are C6-C6) 18 Aromatic hydrocarbons, optionally containing at least one halogen C is optionally replaced by 1 ~C 6 Alkyl, C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or science fiction 5 from R has the meaning defined above (having at least one selected substituent), preferably is the same or different at each position, and is a halogen, linear, branched or cyclic C1-C 20 Aliphatic hydrocarbons, or C6-C6 18This represents aromatic hydrocarbons, and the aliphatic hydrocarbon and / or aromatic hydrocarbon is one or more halogens, preferably F and / or Cl, SF5, NO2, or linear, branched or cyclic C1-C 20 It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon with one or more halogens, preferably F and / or Cl, SF5, NO2), and W represents hydrogen, an alkali metal, or an alkaline earth metal.

[0027] In yet another preferred embodiment of the method of the present invention, the dimeric phosphazene-derived catalyst is represented by the following formula (IVb):

[0028] [ka] [In the formula, substituents R are either the same or different at each position, and C6~C 18 Aromatic hydrocarbons, wherein the aromatic hydrocarbons include one or more halogens, preferably F and / or Cl, SF5, NO2, or linear, branched, or cyclic C1-C12. 20 It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon with one or more halogens, preferably F and / or Cl, SF5, NO2), where Y is O and X is NR N And here, R N This refers to sulfonyl alkyl (alkyl is a partially or completely hydrogenated linear, branched, or cyclic C1-C) 20 It is an aliphatic hydrocarbon, the dashed lines each represent a double bond, and W represents hydrogen, an alkali metal, or an alkaline earth metal.

[0029] The method of the present invention makes it possible to use a substrate having a neral-to-geranial ratio ranging from neral (Z:E=>99:1) to geranial (Z:E=<1:99), preferably a higher neral content in the range of Z:E=80:20 or greater.

[0030] The resulting reaction mixture containing isopiperitenol can be further subjected to hydrogenation, which is particularly useful in obtaining a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol. The hydrogenation of the reaction mixture is generally carried out using hydrogen and a hydrogenation catalyst.

[0031] The resulting reaction mixture can be separated into individual compounds, or it can be further reacted with olivetol or its substituted derivatives in the presence of a Lewis acid or Brønsted acid to obtain a reaction mixture containing cannabidiol (CBD) and / or tetrahydrocannabinol (THC) and their isomers.

[0032] [ka] Therefore, the present invention also enables the production of THC and CBD derivatives to be initiated using the neral derivative of formula (V),

[0033] [ka] The neral derivative of formula (V) is cyclized in the presence of a catalyst derived from the dimeric phosphazene of formula (II) as defined above, preferably a catalyst of formula (II), (III), (IVa), or (IVb) as defined by various modifications above, and the reaction mixture is further reacted with a substituted olivetol-like resorcinol compound of formula (VI) in the presence of a Lewis acid or a Brønsted acid.

[0034] [ka] This yields a reaction mixture containing racemic or optically active THC- and / or CBD- analogs of general formulas (VIIa and VIIb);

[0035] [ka] In the formula, R A These are, independently of each other, identical or different, and each is a hydrogen, C1-C6 alkyl group, particularly methyl, -CH2OH, or -COOR e And here R e is H or a C1-C6 alkyl group; R B These are, independently of each other, identical or different, and each is a hydrogen atom, a C1-C6 alkyl group, especially a methyl atom; or two R B or two R's C Each of them may form a ring with respect to the others. R C These are, independently of each other, identical or different, and each is a C1-C6 alkyl group, particularly methyl; or two R B or two R's C Each of them may form a ring with respect to the others. R 5 and R 7 They are independent of each other, either identical or different, and each is hydrogen or -COOR e And here R e is H or a C1-C6 alkyl group; R 6 hydroxy, C1-C 12 The alkyl group represents an alkyl group, preferably a C3-C7 alkyl group, and is optionally further substituted with one or more hydroxyl groups.

[0036] In particular for continuous processes, it is desirable to use one of the catalysts of formula (II), (III), (IVa), or (IVb) in an immobilized form in any of the above processes.

[0037] In one embodiment, the catalyst derived from the dimer phosphazene of formula (II) (wherein Y, X, and R are as defined above) may optionally be bonded to a solid support via a linker, the linker being an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each hydrocarbon group having up to 50 carbon atoms, each optionally further substituted with one or more heterosubstituted groups, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and the solid support being insoluble in the reaction mixture and 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, hydroxy, sulfonyl, alkoxy, or halogen-substituted alkoxy on the aliphatic hydrocarbon, and / or oxygen in the aliphatic hydrocarbon chain.

[0038] In another embodiment, the dimerized phosphazene-derived catalyst of formula (II), (III), (IVa), or (IVb) as defined above may be bonded to the solid support via a linker between the solid support and the aromatic or alicyclic basic skeleton, preferably at the 6-position of one, two, three, or all of the aromatic or alicyclic basic skeletons of the dimerized phosphazene-derived catalyst, where the linker and solid support are as defined above.

[0039] In yet another embodiment, the catalyst derived from the dimer phosphazene of formula (II), (III), (IVa), or (IVb) as defined above is NR N The substituent may be bonded to the solid support as a stationary phase via a linker between the substituent and the solid support, and in the catalyst derived from the dimer phosphazene of formula (II), (III), (IVa) or (IVb), Y is O or NR N Therefore, X is NR N And here, R Nis a linear or branched alkyl chain or polyetheralkyl chain, wherein the alkyl chain has at least one halogen, preferably fluorine, and R and R P As defined above, the solid carrier is, for example, the sulfonated tetrafluoroethylene polymer Nafion (registered trademark).

[0040] Process description: Currently, neral and geranial can be synthesized by allyl oxidation of nerol and geraniol using MnO2, and after subsequent distillation, the corresponding aldehydes are obtained with a Z:E purity of at least 96:4 (for neral) and 2:98 (for geraniol in the case of geranial).

[0041] The catalysts used herein are based on imidodiphosphate (IDP) catalysts, iminoimidodiphosphorimidate (iIDP) catalysts (List et al., J. Am. Chem. Soc. 2016, 138, 34, 10822), and imidodiphosphorimidate (IDPi) catalysts, and can be prepared using the methods described in EP20200632.6. The solvents used should be dried before use.

[0042] The catalyst can be dissolved in a solvent and cooled to different temperatures depending on the solvent used. Neral was added, the reaction was stirred, and then, for example, triethylamine was added after a certain period of time to stop the reaction.

[0043] definition The following definitions apply to individual groups R, R P , R N And it applies equally to W as follows:

[0044] The heterosubstituted elements defined according to the present invention are OH, F, Cl, Br, I, CN, NO2, and IR. S 2、NO, NCO, -NCS, -SCN, SO3H, monohalogenomethyl group, dihalogenomethyl group, trihalogenomethyl group, CF(CF3)2, SF5, aliphatic, aromatic, heteroaromatic, primary, secondary, tertiary amine or ammonium (bonded via N atom), -O-alkyl (alkoxy), -O-aryl, -O-heteroaryl -O-SiR S 3, -S-S-R S , -S-R S , -S(O)-R S , -S(O)2-R S , -COOH, -CO2-R S , -BR S 2, -PR S 2、 -OPR S 2, amide (bonded via C or N atom), formyl group, -C(O)-R S , -COOM (where M is a metal, such as Li, Na, K, Cs, Ag). R S are, independently of each other, may be the same or different, and each is an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each of which is optionally further substituted with one or more hetero substituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups; and / or optionally bridged by -O- atoms, representing a halide.

[0045] Aliphatic hydrocarbons including alkyl, alkenyl and alkynyl may include linear, branched and cyclic hydrocarbons.

[0046] Heteroaliphatic is a hydrocarbon including alkyl, alkenyl and alkynyl, which may include linear, branched and cyclic hydrocarbons having one or more carbon atoms replaced by at least one heteroatom.

[0047] More specifically, C1-C 20-Alkyl can be linear 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. Alkyl may be C1-C6-alkyl, particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, as well as 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.

[0048] Cycloalkyls can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Alkenyls are C2-C 20 It may also be an alkenyl. Alkinyl is C2-C 20 Alkinyl may also be used.

[0049] The aforementioned unsaturated alkenyl- or alkynyl group can be used to link the compound of the present invention to a support such as a polymer that serves as an immobilized catalyst.

[0050] Halogens are F, Cl, Br, or I.

[0051] The alkoxy is preferably C1-C 10 These include alkoxys, such as methoxy, ethoxy, propoxy, tert-butoxy, butoxy, pentoxy, hexyloxy, and their isomers.

[0052] C3-C8 heterocycloalkyls having one or more heteroatoms selected from N, O, and S are preferably 2,3-dihydro-2-,-3-,-4- or -5-furyl, 2,5-dihydro-2-,-3-,-4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-,-2- -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl , 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-,-5- or-6-pyridyl, 1-,2-,3- or 4-piperidinyl, 2-,3- or 4-morpholinyl, tetrahydro-2-,-3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-,-4- or -5-yl, hexahydro-1-,-3- or -4-pyridazinyl, hexahydro-1-,-2-,-4 -or -5-pyrimidinyl, 1-,2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-,-5-,-6-,-7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-,-5-,-6-,-7- or -8-isoquinolyl, 2-,3-,5-,6-,7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl.

[0053] "Optionally substituted" means that on a hydrocarbon, it is either unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or further substituted with respect to each hydrogen, for example, hypersubstituted.

[0054] Aryl is C6~C 22It may be an aromatic hydrocarbon and may also be phenyl, naphthyl, anthracenyl, phenanthryl or biphenyl.

[0055] The arylalkyl may be benzyl.

[0056] The heteroaryl is C5 - C 18The heteroaromatic hydrocarbon may have one or more heteroatoms selected from N, O, and S, preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrim Dinyl, and preferably 1,2,3-triazole-1-,-4- or -5-yl, 1,2,4-triazole-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or -5-yl, 1,2,4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazole-2- or -5-yl, 1,2,4-thiadiazole-3- or -5-yl, 1,2,3-thiadiazole-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-benzoxazolyl, 3-,4-,5-,6- or 7-benzisoxazolyl, 2-,4-,5-,6- or 7-benzothiazolyl, 2-,4-,5-,6- or 7-benzisothiazolyl, 4-,5-,6- or 7-benz-2,1,3-oxadiazolyl, 2-,3-,4-,5-,6-,7- The compounds are 8-quinolyl, 1-,3-,4-,5-,6-,7- or 8-isoquinolyl, 3-,4-,5-,6-,7- or 8-sinnolinyl, 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 preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4- or -5-yl, or 2,1,3-benzoxadiazole-5-yl. [Examples]

[0057] Experiment section Material and property analysis Chemical Substances: Chemical substances (Abcr, Acros, Aldrich, Gelest, Fluka, Fluorochem, Strem, TCI) were purchased as reagent grade and used without further purification unless otherwise noted. Neral and geranial can be synthesized by allyl oxidation of nerol and geraniol using MnO2, and after subsequent distillation, the corresponding aldehydes are obtained with a Z:E purity of at least 96:4 (for neral) and 2:98 (for geranial).

[0058] Solvents: The solvents (CH2Cl2, CHCl3, Et2O, THF, PhMe) were dried by distillation from a suitable drying agent at the technical department of the Max Planck Institute for Coal Research and placed in a Schlenk flask under argon. Other solvents (n-pentane and pyridine) were purchased from a commercial supplier and dried on molecular sieves.

[0059] Glassware: Unless otherwise specified, screw-cap vials, round-bottom flasks, or Schlenk flasks were used in the reactions. Thin-layer chromatography: Thin-layer chromatography (TLC) was performed using silica gel pre-coated plastic sheets (Polygram SIL G / UV254, 0.2 mm, with fluorescent indicator; Macherey-Nagel), visualized with a UV lamp (254 or 366 nm), and stained with potassium permanganate (KMnO4). KMnO4 staining: KMnO4 (1.5 g), K2CO3 (10 g), 10% NaOH (1.25 mL) in water (200 mL).

[0060] Flash column chromatography: Flash column chromatography (FCC) was performed using Merck silica gel (60 Å, 230-400 mesh, particle size 0.040-0.063 mm) with a technical-grade solvent. Elution was accelerated using compressed nitrogen. All reported yields represent the spectroscopically and chromatographically pure compound unless otherwise specified.

[0061] Gas Chromatography: Gas chromatography (GC) analysis on chiral solid supports was performed using HP6890 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 Coal Research Institute. The conditions used are described in detail for each experiment.

[0062] Catalytic synthesis The catalyst used in this invention was synthesized by a method using a phosphazene reagent, as disclosed in EP application 20200632.6, or by preparation according to WO2017 / 037141.

[0063] Catalyst synthesis procedure: A flame-dried Schlenk flask was charged with the phosphazene reagent and the corresponding substituted (S)- or (R)-binol or biphenol (2.0 equivalents). Dried pyridine was added, and both solids were dissolved to obtain a clear solution. The amount of pyridine was 1 mL for approximately 50 mg of phosphazene reagent used. The clear solution slowly formed a precipitate, and after 3 hours, sulfonamide (5.0 equivalents) was added to the reaction mixture, followed by stirring overnight. Water (10% by weight) was added to the reaction mixture, and stirring was continued for a further 3 hours. After adding an excess of aqueous HCl (10%), the reaction was work-treated, 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.

[0064] Acidification by DOWEX: DOWEX was packed into the column and washed with 0.05 M H2SO4 aqueous solution and CH2Cl2. The purified catalyst was dissolved in CH2Cl2 and passed through the column, and the column was rinsed with CH2Cl2 until no more UV-active material was released. The solvent was evaporated to obtain the catalyst. After drying in high vacuum, the corresponding catalyst was analyzed by NMR and MS.

[0065] Exemplary reaction protocol for the method of the present invention Exemplary catalytic asymmetric cyclizations of citral, neral, and geranial are shown below.

[0066] [ka] A magnetic stirrer bar, iIDP catalyst (1 mol%), and dichloromethane (0.1 M) were charged into a screw-cap vial. The reaction solution was cooled to -20°C and stirred for 10 minutes. Neral (Z:E ratio 96:4) was added to the reaction vial, and the reaction was stirred at the aforementioned temperature for 16 hours. The reaction mixture was treated with Et3N, and the reaction was then slowly warmed to room temperature. The solvent was evaporated at 40°C and 500 mbar. The reported yield was determined by NMR using mesitylene or triphenylmethane as an internal standard. [Brief explanation of the drawing]

[0067] Figure 1 shows exemplary reaction protocol evaluations for several parameters under various reaction conditions, including different amounts of various substrates and catalysts. The results demonstrate that the general reaction protocol described above is applicable to a variety of conditions and substrates.

[0068] Experimental results Catalyst class 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) show little conversion but maintain a pure reaction profile, while strong acids (pKa < 8 in MeCN) result in a more complex reaction profile. The complexity of reactions using stronger acids can be explained by the rapid decomposition pathway of the cyclization intermediate isopiperitenol to several elimination products (e.g., trienes), as described in the literature. Catalyst classes spanning the pKa scale between weak and strong acids (IDP, iIDP, and IDPi) can combine the advantages of both: higher conversion rates to the desired product and maintenance of a pure reaction profile.

[0069] concentration The cyclization reaction of citral can be carried out in several organic solvents at different concentrations, ranging from solvent-free to very dilute 0.005 M reaction conditions. The diastereomer and enantiomer excesses of the desired cyclization product are nearly constant under different dilutions of the reaction mixture. Control experiments were performed by determining the enantiomer excess at different stages of the reaction to eliminate kinetic separation in the product decomposition pathway.

[0070] Catalyst loading The cyclization reaction of citral can be carried out without significantly impairing the diastereomer and enantiomer excess of the desired product by using various catalytic amounts ranging from 0.05 to 100 mol%, depending on the solvent and temperature used.

[0071] Moisture content / Molesieves The cyclization reaction of citral can be carried out under modified reaction conditions (e.g., in the presence of water) that yield similar diastereomer and enantiomer ratios.

[0072] conclusion The citral / neral cyclization reaction using the catalyst of the present invention can be carried out at temperatures of -80°C to 25°C, reaction times of 30 minutes to 48 hours, concentrations of solvent-free to 0.005 M in several solvents, and catalytic amounts ranging from 0.05 mol% to 100 mol%. Screening of various catalysts is shown in Figure 1. The citral cyclization reaction is carried out in high yield when a catalyst with an electron-deficient group is used. Screening of several different cores combined with the best 3,3'- substituents leads to the conclusion that the smallest internal core CF3 provides the highest yield and diastereomer-enantiomer ratio of the product under optimized standard reaction conditions.

[0073] Exemplary catalytic asymmetric cyclizations of citral, neral, and geranial are shown above.

[0074] Product isolation and catalyst recovery A magnetic stirrer bar, iIDP catalyst (2.5 mol%), and dry pentane (0.1 M) were charged into a round-bottom flask and cooled to 0°C. After 20 minutes, neral (5.8 mmol, ratio 96:4) was added to the reaction flask, and the reaction mixture was stirred at the aforementioned temperature for 16 hours. The reaction mixture was treated with triethylamine, and the reaction mixture was then slowly warmed to room temperature. Upon evaporation of the solvent, a crude reaction product containing the cyclization product was obtained. Purification of the crude reaction mixture with silica (CC) yielded a cyclic allyl alcohol (yield 40%, dr 12:1 (trans:cis), er 96:4).

[0075] Synthesis of different substrates and their cyclization (Z)-4,4,7-trimethylocta-2,6-dienal: 4,4,7-trimethylocta-6-en-2-inal

[0076] [ka] Triphenylphosphine (26.2 g, 99.8 mmol, 4.0 equivalents) was added at 0°C to a stirred solution of CBr4 (16.55 g, 49.9 mmol, 2.0 equivalents) in CH2Cl2 (20 mL), and the resulting reaction mixture was stirred for 15 minutes. To this suspension, (Z)-4,4,7-trimethylocta-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, and the mixture was stirred at room temperature for 30 minutes. 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. Next, the crude reaction product was dissolved in THF (130 mL), and nBuLi (2.5 M in hexane, 24 mL, 59.9 mmol, 2.4 equivalents) was added dropwise at -78°C. The reaction mixture was slowly warmed to 0°C and stirred for 20 minutes, after which the reaction mixture was allowed to reach room temperature. After the starting materials had been completely converted, 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 flash column chromatography (10% DCM / pentane) to obtain 4,4,7-trimethylocta-6-en-2-inal as a colorless oil (1.74 g, yield 42%).

[0077] (Z)-4,4,7-trimethylocta-2,6-dienal

[0078] [ka] 4,4,7-trimethylocta-6-ene-2-inal (500 mg, 3.0 mmol, 1.0 equivalent), a solvent mixture of cyclohexane / ethyl acetate (1:5), and quinoline (0.36 mL, 3.0 mmol, 1.0 equivalent) were charged into a flame-drying flask. Lindlar catalyst was added at room temperature, and the reaction suspension was subjected to hydrogenation conditions (H2 at 1 atm via balloon). After nearly complete conversion, the reaction product was filtered through a Celite pad and thoroughly washed with siRNA. The solvent was evaporated under reduced pressure, and the crude product was purified by flash column chromatography to obtain the desired α,β-unsaturated aldehyde 4,4,7-trimethylocta-2,6-dienal (120 mg, yield 24%) and a mixture of diastereoisomers (Z:E=93:7) as a pale yellow oil.

[0079] Cyclization of (Z)-4,4,7-trimethylocta-2,6-dienal

[0080] [ka] The cyclization reaction was carried out according to the general reaction procedure, and the desired cyclic allyl alcohol was obtained in 95% yield (dr=98:2, er(major)=0.4:99.6).

[0081] (Z)-2,7-dimethylocta-2,6-dienal Ethyl(Z)-2,7-dimethylocta-2,6-dienoate

[0082] [ka] To a stirred solution of ethyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)propanoate (925 mg, 2.67 mmol, 1.0 equivalent) in THF (21 mL), 18-crown-6 (735 mg, 2.78 mmol, 1.05 equivalent) in THF was added. The reaction mixture was cooled to -78°C, and KHMDS (5.3 mL, 2.67 mmol, 0.5 M solution in PhMe) was added dropwise to the reaction mixture. After stirring at -78°C for 20 minutes, 5-methylhexa-4-enal (prepared according to 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 the mixture was stirred at the same temperature until complete conversion occurred. After complete conversion, the reaction was quenched with saturated aqueous NH4Cl. 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 flash column chromatography to obtain α,β-unsaturated ester (223 mg, 42% yield).

[0083] (Z)-2,7-dimethylocta-2,6-dienal

[0084] [ka] Ethyl (Z)-2,7-dimethylocta-2,6-dienoate (344 mg, 1.75 mmol, 1.0 equivalent) and DCM (7 mL) were charged into a flame-drying flask, and DIBAL-H was added dropwise at -78°C (3.8 mL, 1 M, 3.8 mmol, 2.2 equivalents). After the starting material had completely converted to the desired alcohol, the reaction was quenched with a 1:1 water / MeOH mixture. The mixture was stirred at room temperature for 2 hours. The resulting gel was filtered over a Na2SO4 / Celite pad and washed extensively with dichloromethane. The solvent was evaporated under reduced pressure, and the crude reaction product (Z)-2,7-dimethylocta-2,6-dien-1-ol was dissolved again in DCM (2 mL). Manganese dioxide (685 mg, 7.89 mmol, 4.5 equivalents) was added to the reaction flask, and the reaction mixture was stirred at room temperature until the starting material had completely converted. After complete conversion, the reaction product was filtered through a Celite pad and thoroughly washed with DCM. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by flash column chromatography to obtain (Z)-2,7-dimethylocta-2,6-dienal as a mixture of diastereoisomers (160 mg, yield 60%, Z:E=86:14).

[0085] Cyclization of (Z)-2,7-dimethylocta-2,6-dienal:

[0086] [ka] The cyclization reaction was carried out according to the general reaction procedure, and the desired cyclic allyl alcohol was obtained in 72% yield (dr=2:1, er(major)=97:3, er(minor)=93:7).

[0087] Synthesis of CBD and THC Chiral catalyst phosphoric acid, IDP-, iIDP-, or IDPi- catalyst (5 mol%) was charged into the reaction vessel, and anhydrous CH2Cl2 (0.1 M), oliveitol (1.1 equivalents), and enantiomerically pure isopiperitenol (0.3 mmol) were added via syringe. The reaction mixture was stirred at room temperature and quenched with triethylamine upon complete conversion of isopiperitenol. The solvent was evaporated, and the reaction was carried out using CBD and / or THC compounds (Δ 9 -THC (cis and trans), Δ 8 -THC, Δ 9 A reaction mixture containing -regio-THC (cis and trans) was obtained.

[0088] Synthesis of a reaction mixture containing cannabidiol (CBD) 5-20 mol% of catalyst or Lewis acid (e.g., BF3OEt2), dried CH2Cl2, oliveitol, and purified enantiomerically pure isopiperitenol were added to a screw-cap vial. The reaction mixture intensified in color and faded after a few minutes. The reaction mixture was stirred at room temperature and treated with triethylamine upon complete conversion of the two starting materials. The solvent was evaporated, and the crude reaction mixture was purified with CC (silica) to obtain cannabidiol as the major compound.

[0089] Synthesis of a reaction mixture containing cannabidiol (CBD) Olivetol (1 mmol, 180 mg), isopiperitenol (cis:trans = 5:1, 1.5 equivalents, 0.16 mL), and BF3·Et2O (62.5 μL, 0.5 mmol) were appropriately added to 6.25 mL of DCM under argon at 0°C in a flame-dried Schlenk tube. After 1.5 hours, the starting materials were completely consumed as indicated by TLC (5-20% siRNA / hexane). The reaction was quenched with 100 mg of NaHCO3, filtered, and washed with DCM. The solvent was evaporated under reduced pressure, and the crude mixture was purified by flash column chromatography (SiO2, 5-30% siRNA / hexane). Three major compounds could be isolated, one of which was CBD (yield 32%, 101.2 mg).

[0090] Synthesis of reaction mixtures containing THC Molesieve and 5 mol% iIDP catalyst were charged into a flame-dried Schlenk flask. Dry CH2Cl2, oliveitol, and purified enantiomerically pure isopiperitenol were added to the flask. The reaction mixture intensified in color and faded after a few minutes. The reactants were stirred at room temperature and quenched with Et3N upon complete conversion of the two starting materials. The solvent was evaporated, and the crude reaction mixture was purified by preparative TLC to obtain the THC substance (Δ) as the main product. 9 -THC (cis and trans), Δ 8 -THC, Δ 9 -regio-THC (cis and trans) was obtained.

[0091] One-pot synthesis of CBD / THC iIDP catalyst (5 mol%) and anhydrous CH2Cl2 (0.1 M) were charged into the reaction vessel. The reaction mixture was cooled to the desired temperature and stirred for several minutes, then neral (0.3 mmol) was added to the reaction mixture and the reaction mixture was stirred for a certain period of time. After complete conversion of the starting materials was reached, oliveitol (1 equivalent) was added to the reaction mixture and the reaction mixture was allowed to reach room temperature. At the time of complete conversion of oliveitol, the reaction was quenched with triethylamine. The solvent was evaporated and the CBD and / or THC substances (Δ 9 -THC (cis and trans), Δ 8 -THC, Δ 9 A reaction mixture containing -regio-THC (cis and trans) was obtained.

[0092] Δ 8 -THC synthesis: In a flame-dried Schlenk flask, oliveitol (36 mg, 0.2 mmol), enantiopurine isopiperitenol (dr cis:trans = 5:1, 1.1 equivalents), and BF3·Et2O (0.2 equivalents) were appropriately added to 4 mL of DCM at 60°C under argon. After 14 hours, the starting material (oliveitol) had completely converted as indicated by TLC analysis (using 5% siRNA / hexane), and the reaction was treated with one drop of triethylamine. The solvent was evaporated under reduced pressure, and the crude mixture was purified by flash column chromatography (SiO2, 5% siRNA / hexane) to obtain Δ 8 -THC was obtained as the desired product (53% yield, 33.3 mg, er 99:1).

[0093] Δ 9 -THC synthesis: In a flame-dried Schlenk flask, olivetol (0.42 mmol, 75.7 mg), isopiperitenol (cis:trans = 5:1, 73 μL, 1.1 equivalents), and BF3·Et2O (0.2 equivalents) were appropriately added to 8 mL of DCM at room temperature under argon. After 22 hours, the ratio of the resulting product was THC:CBD = 2.3:1, and after 42 hours, it was THC:CBD = 13.5:1. The reaction was quenched with one drop of triethylamine. The solvent was evaporated under reduced pressure, and the crude reaction mixture was purified by flash column chromatography (SiO2, 5% siRNA / hexane) to obtain Δ 9 -THC was obtained as the desired product (55% yield, 72 mg).

[0094] Exemplary hydrogenation of isopiperitenol: A heterogeneous hydrogenation catalyst (64 mg, 10 mol% Pt / C, 0.2 equivalents) was transferred to a round-bottom flask, and a methanol solution of the corresponding isopiperitenol (3 mL, 0.2 M) was added to the reaction flask. The reaction mixture was flushed with hydrogen (1 atm), and the reactants were vigorously stirred at room temperature under a hydrogen atmosphere (1 atm) for 48 hours. Upon complete conversion of the starting materials, the heterogeneous catalyst was removed by filtration, and the filtrate was evaporated to obtain a reaction mixture containing menthol, isomenthol, neomenthol, and neoisomenthol.

[0095] menthol: Enantioenriched isopiperitenol (dr=11:1, er98.5:1.5) (31 mg, 0.20 mmol, 1.0 equivalent), 3 mL of MeOH, and Lindlar catalyst (48.7 mg, 0.11 equivalents) were charged into a flame-drying flask. After stirring for several minutes, the reaction mixture was exposed to 1 atm of H2 gas (by balloon). After 2 days, the reaction reached complete conversion (shown by TLC) and was filtered. After evaporation of the solvent, the crude reaction mixture was subjected to GC analysis (>99% conversion rate, 92% product, menthol to isomenthol ratio 74.3:25.7, er(menthol / isomenthol)=98.5:1.5).

[0096] Synthesis of solid-supported catalysts 2-(allyloxy)-1,1,2,2-tetrafluoroethane-1-sulfonamide: A Schlenk flask, dried over a direct flame, was fitted with a magnetic stirrer bar, and ammonia (approximately 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 mixture was stirred at the aforementioned temperature for 1.5 hours, after which it was gradually warmed to room temperature. After another 1.5 hours, the resulting white slurry was acidified to approximately 2 pH with 1 M H2SO4. The aqueous layer was extracted with diethyl ether, and the resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure. The corresponding sulfonamide was obtained as a colorless solid after drying under high vacuum (4.9 g, 90% yield).

[0097] The catalyst used in the following production of solid-supported confined acids was prepared according to a general reaction protocol using 2-(allyloxy)-1,1,2,2-tetrafluoroethane-1-sulfonamide.

[0098] Synthesis of solid styrene-divinylbenzene-supported catalysts: 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 short silica pad before use) and AIBN were added to the flask. The resulting mixture was placed in the tube and copolymerization was carried out at 80°C. After 16 hours, the heat source was removed and the resulting solid was crushed. The resulting polymer powder was thoroughly washed with dichloromethane and acidified by suspension in 6 M HCl for 3 hours. The suspension was filtered and washed with water and dichloromethane. The resulting solid-supported catalyst was dried overnight at 40°C under high vacuum.

[0099] Synthesis of solid-supported sulfonamides: Nafion® R-1100 resin (sulfonyl fluoride form, 500 mg) was pulverized to a fine grayish powder using a cryomil at -196°C. The resulting 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 the initial temperature of -78°C, residual ammonia was released, and the mixture was heated from room temperature to 90°C for 2 hours. The resulting solid-supported sulfonamide was precipitated from water, washed with deionized water, and dried under vacuum at 60°C for 24 hours (497 mg, quant.). The corresponding solid-supported catalyst was prepared using the general procedure described above.

[0100] Exemplary catalytic asymmetric cyclization of citral, neral, and geranial using solid-supported catalysts: A magnetic stirrer bar, solid-supported iIDP catalyst, and dried n-pentane (0.5 M) were charged into a screw-cap vial. Neral (Z:E 96:4) was added to the reaction vial, and the reaction mixture was stirred overnight at room temperature. After complete conversion of the starting materials, the solid-supported catalyst was removed using a syringe filter, the filter was further rinsed with pentane, and the resulting filtrate was treated with trimethylamine. The solvent was evaporated, and the yield and dr were determined by NMR spectroscopy using mesitylene as an internal standard, and the enantiomer excess was determined by GC (28% yield, dr 15:1 (trans:cis), er 96:4).

[0101] Cyclization of neral using a solid-supported catalyst A 10 mol% solid-supported catalyst and dichloromethane were charged into a flame-dried vial. 5 μL of neral was added to the vial, and the reaction was stirred at room temperature for 16 hours. After quenching the reaction with a drop of triethylamine, the reaction was filtered and analyzed by 1H-NMR spectroscopy using an internal standard. The desired product was obtained in 13% yield (dr (trans / cis) = 5:1, er = 96:4). The enantiomer and diastereomer ratios were determined by GC analysis. While this application relates to the invention described in the claims, it may also encompass the following other embodiments. 1. A method for the asymmetric synthesis of isopiperiterol of formula (I), [ka] A substrate containing at least one of neral [(Z)-3,7-dimethylocta-2,6-dienal] and geranial [(E)-3,7-dimethylocta-2,6-dienal] is optionally treated in an organic solvent with a catalyst derived from a dimer phosphazene represented by the following formula (II), thereby obtaining a reaction mixture containing isopiperitenol. [ka] In the above formula, - R is either the same or different at each position, and each is hydrogen, halogen, SF6, etc. 5 NO 2 , cyano, C 1 ~C 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally, one or more halogens, preferably F or Cl, SF6 on the aliphatic hydrocarbon). 5 NO 2 (or containing cyano), C 6 ~C 18 Aromatic hydrocarbons, or C 5 ~C 18 Selected from heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon is optionally a halogen, SF6 5 NO 2 , cyano, C 1 ~C 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally, one or more halogens, preferably F and / or Cl, SF6 on the aliphatic hydrocarbon). 5 NO 2 It is substituted with one or more substituents selected from (or having cyano), - R P These are identical or different at each position, and have the meaning of R, or two Rs on the same aryl ring. P These rings may form a ring structure that can be either an aromatic ring structure or an aliphatic ring structure, and the aromatic and / or aliphatic ring structure may be substituted with one or more substituents R. - X and Y are either the same or different, and oxygen or NR N It is one of the following: R N is an electron-withdrawing or electron-donating group, which is identical or different at each position, and is selected from the following: i.-alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphinyldialkyl, phosphonylalkyl, alkylphosphoran, N,N'-alkylimidazolidin-2-iminyl, where alkyl is C 1 ~C 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally, C 1 ~C 6 Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF6 5 (having at least one substituent selected from; ii. -aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, phosphinyldiaryl, phosphinylalkylaryl, phosphonylaryl, arylphosphoranes, arylalkylphosphoranes, N,N'-arylimidazolidine-2-iminyl, N-aryl-N'-alkylimidazolidine-2-iminyl, where aryl is C 6 ~C 18 Aromatic hydrocarbons (C) that are optionally substituted with at least one halogen. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF6 5 (having at least one substituent selected from; iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-diheteroaryl, phosphinyldiheteroaryl, phosphinylarylheteroaryl, phosphinylheteroarylalkyl, phosphonylheteroaryl, heteroarylphosphoranes, heteroarylarylphosphoranes, heteroarylarylalkylphosphoranes, N,N'-heteroarylimidazolidine-2-iminyl, N-heteroaryl-N'-alkylimidazolidine-2-iminyl, N-heteroaryl-N'-arylimidazolidine-2-iminyl, where heteroaryl is C 2 ~C 18 Heteroaromatic hydrocarbons (C) that are optionally substituted with at least one halogen. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF6 5 (having at least one substituent selected from; and - W is a metal selected from hydrogen, halogens, 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, or a cationic organic group, substituted borane-BR I R II R III , or substituted silicon-SiR I R II R III Selected from, here, R I 、R II and R III These may be the same or different, and each may be hydrogen, a halogen, or optionally a C bonded by -O-. 1 ~C 20 Linear, branched, or cyclic aliphatic hydrocarbons (optionally having one or more unsaturated bonds or one or more heteroatoms in the chain), C 5 ~C 18 Heteroaromatic hydrocarbons, C 6 ~C 18 Represents aromatic hydrocarbons or their partially areneed hydrogenated forms, where each hydrocarbon is optionally C 1 ~C 20 It is substituted with one or more groups, or one or more heterosubstituted groups, selected from linear, branched, or cyclic aliphatic hydrocarbons, where W is preferably hydrogen and substituted silicon-SiR I R II R III (In the formula, R I 、R II and R III (as defined above) is selected from The aforementioned method. 2. The catalyst derived from the dimer phosphazene described above is represented by the following formula (III), according to the method described in 1 above:

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Claims

1. A method for the asymmetric synthesis of isopiperiterol of formula (I), 【Chemistry 1】 A substrate containing at least one of neral [(Z)-3,7-dimethylocta-2,6-dienal] and geranial [(E)-3,7-dimethylocta-2,6-dienal] is optionally treated in an organic solvent with a dimer phosphazene-derived catalyst represented by the following formula (IVb), thereby obtaining a reaction mixture containing isopiperitenol. 【Chemistry 2】 In the above formula, - R is the same or different at each position and each is C １ ~C ２０ a linear, branched or cyclic aliphatic hydrocarbon (optionally having one or more halogens, SF ５ , NO ２ or cyano on the aliphatic hydrocarbon), C ６ ~C １８ an aromatic hydrocarbon, or C ５ ~C １８ a heteroaromatic hydrocarbon, each aromatic or heteroaromatic hydrocarbon being optionally substituted with one or more substituents selected from halogens, SF ５ , NO ２ , cyano, C １ ~C ２０ a linear, branched or cyclic aliphatic hydrocarbon (optionally having one or more halogens, SF ５ , NO ２ or cyano on the aliphatic hydrocarbon), - X and Y are either the same or different, and oxygen or NR Ｎ It is one of the following: R Ｎ These are electron-withdrawing groups, which are identical or different at each position, and are selected from the following: i. -alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphinyldialkyl, phosphonylalkyl, alkylphosphoran, where alkyl is C １ ~C ２０ Linear, branched, or cyclic aliphatic hydrocarbons (halogens selected from F or Cl, cyano, nitro, or SF) ５ (having at least one substituent selected from; ii. -aryl, -CO-aryl, -(CO)-O-aryl, sulfinylaryl, sulfonylaryl, sulfonyliminoaryl, sulfonyliminosulfonylaryl, sulfonylbisiminoaryl, where aryl is C ６ ~C １８ Aromatic hydrocarbons (halogens selected from F or Cl, cyano, nitro or SF) ５ (having at least one substituent selected from; iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, where heteroaryl is C ２ ~C １８ Heteroaromatic hydrocarbons (halogens selected from F or Cl, cyano, nitro or SF) ５ (having at least one substituent selected from; and - W represents hydrogen, alkali metals, or alkaline earth metals. The aforementioned method.

2. The substituent R is either identical or different at each position, and the C is linear, branched, or cyclic. １ ~C ２０ Aliphatic hydrocarbons, or C ６ ~C １８ Represents aromatic hydrocarbons, wherein the aliphatic hydrocarbon and / or aromatic hydrocarbon is one or more halogens, SF ５ NO ２ , or linear, branched, or cyclic C １ ~C ２０ Aliphatic hydrocarbons (one or more halogens on an aliphatic hydrocarbon, SF ５ NO ２ The method according to claim 1, wherein the substitution is made by (substituted by).

3. In formula (IVb), Y is O or NR Ｎ Defined as, and X is NR Ｎ Defined as, where R Ｎ However, it is an electron-withdrawing group, which is identical or different at each position, and is selected from the following: i. Sulfinylalkyl or sulfonylalkyl, where alkyl is C １ ~C ２０ Linear, branched, or cyclic aliphatic hydrocarbons (halogens selected from F or Cl, cyano, nitro, or SF) ５ (having at least one substituent selected from; ii. Sulfinylaryl or sulfonylaryl, where aryl is C ６ ~C １８ Aromatic hydrocarbons (halogens selected from F or Cl, cyano, nitro or SF) ５ (having at least one substituent selected from; iii. Sulfinyl heteroaryl or sulfonyl heteroaryl, where heteroaryl is C ２ ~C １８ Heteroaromatic hydrocarbons (halogens selected from F or Cl, cyano, nitro or SF) ５ (having at least one substituent selected from; and The method according to claim 1 or 2, wherein R and W have the meanings defined in claim 1 or 2.

4. The method according to any one of claims 1 to 3, wherein the substrate includes a ratio of neral to geranial in the range from neral (Z:E => 99:1) to geranial (Z:E = < 1:99).

5. The method according to any one of claims 1 to 4, wherein the obtained reaction mixture is further subjected to hydrogenation treatment to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol.

6. The method according to any one of claims 1 to 4, wherein the resulting reaction mixture is further reacted with olivetol in the presence of a Lewis acid or a Brønsted acid to obtain a reaction mixture containing THC and / or CBD.

7. The neral derivative of formula (V) 【Transformation 3】 The reaction is cyclized in the presence of a catalyst derived from a dimer phosphazene of the formula defined in any one of claims 1 to 3, and the reaction is further reacted with a resorcinol-derived compound of formula (VI) in the presence of a Lewis acid or a Brønsted acid. 【Chemistry 4】 This yields a reaction mixture containing racemic or optically active CBD- and / or THC- derivatives of general formulas (VIIa) and (VIIb); 【Transformation 5】 In the formula, R Ａ They are independent of each other, either identical or different, and each is hydrogen, C １ ~C ６ Alkyl alkyl group, -CH ２ OH, or -COOR ｅ And here R ｅ is H or C １ ~C ６ It is an alkyl group; R Ｂ They are independent of each other, either identical or different, and each is hydrogen, C １ ~C ６ It is an alkyl group; or it is two R's Ｂ or two R's Ｃ Each of them may form a ring with respect to the others. R Ｃ They are independent of each other, either identical or different, and each is C １ ~C ６ It is an alkyl group; or it is two R's Ｂ or two R's Ｃ Each of them may form a ring with respect to the others. R ５ and R ７ They are independent of each other, either identical or different, and each is hydrogen or -COOR ｅ And here R ｅ is H or C １ ~C ６ It is an alkyl group; R ６ is hydroxy, C １ ~C １２ The method according to any one of claims 1 to 3, wherein the alkyl group is optionally further substituted with one or more hydroxyl groups.

8. The dimerized phosphazene-derived catalyst, wherein R, Y, X, and W are as defined in any one of claims 1 to 3, is optionally bonded to a solid support via a linker; The linker is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, and each hydrocarbon group is optionally further substituted with one or more heterosubstituted groups, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups; and The aforementioned solid support is insoluble in the reaction mixture and is selected from wool, cotton, polystyrene, polysiloxane, polyacrylate, polyethylene, polypropylene, polyethylene glycol, and polyamide, and their copolymers, each optionally having at least one halogen, hydroxyl, sulfonyl, alkoxy, halogen-substituted alkoxy on an aliphatic hydrocarbon, or having oxygen in the aliphatic hydrocarbon chain. The method according to any one of claims 1 to 7.

9. A catalyst derived from a dimer phosphazene of formula (IVb) as defined in claim 1 is bonded to a solid support via a linker between the solid support and an aromatic or alicyclic basic skeleton, wherein the linker and the solid support are as defined in claim 7; Y and X are oxygen or NR Ｎ Defined as, R Ｎ The method according to claim 8, wherein R is as defined in claim 1 and R is as defined in claim 1.

10. The method according to claim 9, wherein the dimer phosphazene-derived catalyst is bonded to the solid support at the 6-position of one, two, three, or all of the aromatic or alicyclic basic skeletons of the dimer phosphazene-derived catalyst via a linker between the solid support and the aromatic or alicyclic basic skeleton.

11. A catalyst derived from the dimer phosphazene of formula (IVb) as defined in claim 1 is NR Ｎ The substituent is bonded to the solid support via a linker between the substituent and the solid support, wherein the linker and the solid support are as defined in claim 7, and in the catalyst derived from the dimer phosphazene of formula (IVb), Y is oxygen or NR Ｎ And X is NR Ｎ And R Ｎ The method according to claim 8, wherein is a linear or branched alkyl chain or polyetheralkyl chain, the alkyl chain having at least one halogen, and R is as defined in claim 1.

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