Methods for the Asymmetric Synthesis of Isopiperitenol

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 important methods for the industrial synthesis of menthol stereoisomers in the prior art is the so-called BASF process.

[0003] The BASF menthol process involves two hydrogenation steps starting from geranial or neral. Thus, a 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 Lewis or Bronsted acids gives isopulegol, which undergoes further C=C-bond hydrogenation to give a reaction mixture containing several menthol stereoisomers.

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

[0005] Since the end of the 19th century, the acid-catalyzed conversion of citral to unsaturated cyclic alcohols has been known from the work of A. Verley (Bull. Soc. Chim III 1899, 21, 408) (Non-Patent Document 8) and O. Zeitschel and H. Schmidt (Journal für praktische Chemie 1932, Volume 133, 370-373) (Non-Patent Document 9), but the yields were very low and complex mixtures of substances were obtained. Later, in kinetic studies on this conversion from C. Price (Industrial and Engineering Chemistry 1948, 40, 2, 257) (Non-Patent Document 10) and B. Clark (Tetrahedron 1977, 33, 17, 2187) (Non-Patent Document 11), the cyclization was identified as a very complex transformation leading to several cyclic products, and isopiperitenol was considered to be an intermediate that was not stable under acidic reaction conditions.

[0006] Furthermore, thermal cyclization starting from citral in the absence of acid (G. Ohloff, THL 1960, 11, 10) is possible, as well as by adding catalytic amounts of weak acids (DE 2305629 C2), which leads to the desired product as a mixture of stereoisomers. The yields are very good for the latter method since achiral inorganic / organic acids are used, but the product is obtained as a mixture of stereoisomers.

[0007] In the prior art, no process is known for preparing enantiopure isopipeperitenol starting from commercially available citral, which can be carried out in a single high-yielding step and which results in isopipeperitenol in enantiopure 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 Summary of the Invention [Problem to be solved by the invention]

[0010] The problem that the present invention aims to solve is to develop a process that allows the preparation of enantiomerically enriched isopiperitenol as a precursor compound for menthol, CBD and THC, thus overcoming the drawbacks of the prior art. [Means for solving the problem]

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

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

[0013] More particularly, the present invention relates to an improved process for the asymmetric synthesis of isopiperitenol of formula (I), comprising:

[0014] [ka] A substrate comprising at least one of neral [(Z)-3,7-dimethylocta-2,6-dienal] and geranial [(E)-3,7-dimethylocta-2,6-dienal] is treated, optionally in an organic solvent, with a dimeric phosphazene-derived catalyst represented by formula (II):

[0015] [ka] In the formula (II), R is the same or different at each position and is selected from hydrogen, halogen, SF, NO, cyano, C, C 20 Linear, branched or cyclic aliphatic hydrocarbons (optionally with one or more halogens on the aliphatic hydrocarbon, preferably F or Cl, SF, NO or cyano), C6-C 18 Aromatic hydrocarbons, or C5-C 18 and heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon being optionally selected from halogen, SF, NO, cyano, C1-C 20substituted with one or more substituents selected from linear, branched or cyclic aliphatic hydrocarbons, optionally bearing one or more halogens on the aliphatic hydrocarbon, preferably F and / or Cl, SF, NO or cyano; - R P are the same or different at each position and have the meaning of R, or two R on the same aryl ring P may together form a ring which may be an aromatic or an aliphatic ring structure, said aromatic and / or aliphatic ring structure being optionally substituted with one or more substituents R; X and Y are the same or different and are oxygen or NR N Either Here, R N is an electron withdrawing or electron donating group, is the same or different at each position, and is selected from: i. -Alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphinyldialkyl, phosphonylalkyl, alkylphosphorane, N,N'-alkylimidazolidine-2-iminyl, where alkyl is C1-C 20 a linear, branched or cyclic aliphatic hydrocarbon (optionally bearing 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, phosphonylaryl, arylphospholanes, arylalkylphospholanes, N,N'-arylimidazolidine-2-iminyl, N-aryl-N'-alkylimidazolidine-2-iminyl, where aryl is C6-C 18an aromatic hydrocarbon (optionally having at least one substituent selected from at least one halogen, C1-C6 alkoxy, C1-C6 alkyl, optionally substituted with halogen, preferably F and / or Cl, cyano, nitro or SF5); iii. -Heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-di-heteroaryl, phosphinyldiheteroaryl, phosphinylarylheteroaryl, phosphinylheteroarylalkyl, phosphonylheteroaryl, heteroarylphospholanes, heteroarylarylphospholanes, heteroarylarylalkylphospholanes, 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 having at least one substituent selected from at least one halogen, C1-C6 alkoxy, C1-C6 alkyl, optionally substituted with halogen, preferably F and / or Cl, cyano, nitro or SF5); and - W is hydrogen, halogen, a metal 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, or a cationic organic group, a substituted borane-BR I R II R III , or substituted silicon -SiR I R II R III where R I , R II and R IIImay be the same or different, each of which is selected from hydrogen, halogen, C1-C optionally bonded with -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 Aromatic hydrocarbons or their partially hydrogenated arene forms, each of which is optionally selected from C1 to C 20 and is substituted with one or more groups selected from linear, branched or cyclic aliphatic hydrocarbons, or one or more heterosubstituents, W being preferably hydrogen and substituted silicon -SiR I R II R III (In the formula, R I , R II and R III is defined above), The present invention relates to the above method.

[0016] The reaction conditions for the process of the present invention are not critical and the reaction can be carried out at a temperature range of −100° C. to 30° C., or even at a higher temperature range up to 80° C. The reaction can be carried out neat or in an aprotic organic solvent such as CH2Cl2, CHCl3, Et2O, THF, PhMe, pentane, hexane, cyclohexane, typically under atmospheric pressure.

[0017] In one embodiment of the process, the dimeric phosphazene derived catalyst has formula (III):

[0018] [ka] in which the substituents R are identical or different in each position and are 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 process, the dimeric phosphazene derived catalyst has formula (IVa):

[0020] [ka] in which the substituents R are identical or different in each position and are 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 formulae (III), (IVa) and below in formula (IVb), the dashed lines represent either a double bond and thus a naphthalene ring system, or a hydrogenated double bond and thus a 4H-naphthalene ring system, and both forms may be present in the catalyst used in the process of the present invention.

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

[0023] [ka] in which the substituents R are identical or different in each position and are 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 process of the present invention, in any one of formulas (II), (III), (IVa) or (IVb), the substituents R are preferably identical or different at each position and are selected from the group consisting of halogen, linear, branched or cyclic C1-C 20 Aliphatic hydrocarbons, or C6-C 18 represents an aromatic hydrocarbon, said aliphatic and / or aromatic hydrocarbon being substituted with one or more halogens, preferably F and / or Cl, SF, NO, or linear, branched or cyclic C1-C 20is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon by one or more halogens, preferably F and / or Cl, SF5, NO2), 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 where X is NR N where R N is an electron withdrawing or electron donating group, is the same or different at each position, and is selected from: i. Sulfinylalkyl or sulfonylalkyl, where alkyl is C1-C 20 a linear, branched or cyclic aliphatic hydrocarbon (optionally bearing at least one substituent selected from C1-C6 alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5); ii. Sulfinylaryl or sulfonylaryl, where aryl is C6-C 18 an aromatic hydrocarbon (optionally having at least one substituent selected from at least one halogen, C1-C6 alkoxy, C1-C6 alkyl, optionally substituted with halogen, preferably F and / or Cl, cyano, nitro or SF5); iii. Sulfinylheteroaryl or sulfonylheteroaryl, where heteroaryl is C2-C 18 a heteroaromatic hydrocarbon (optionally having at least one substituent selected from at least one halogen, C1-C6 alkoxy, C1-C6 alkyl, optionally substituted with halogen, preferably F and / or Cl, cyano, nitro or SF5); and R has the meaning defined above, is preferably identical or different in each position, and is halogen, linear, branched or cyclic C1-C20 Aliphatic hydrocarbons, or C6-C 18 represents an aromatic hydrocarbon, said aliphatic and / or aromatic hydrocarbon being substituted with one or more halogens, preferably F and / or Cl, SF, NO, or linear, branched or cyclic C1-C 20 It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon by 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 a preferred embodiment of any of the methods of the present invention, in said formula (II), (III), (IVa) or (IVb), Y is O or NR N , preferably defined as O, and X is NR N where R N is an electron-withdrawing group, preferably a sulfonylalkyl (alkyl is a partially or fully hydrogenated linear, branched or cyclic C1-C 20 aliphatic hydrocarbons), or sulfonylaryl (aryl is C6-C 18 aromatic hydrocarbons, optionally bearing at least one substituent selected from at least one halogen, C1-C6 alkoxy, halogen, preferably F and / or Cl, C1-C6 alkyl, optionally substituted with cyano, nitro or SF5, R has the meanings defined above and is preferably identical or different in each position and is selected from halogen, linear, branched or cyclic C1-C 20 Aliphatic hydrocarbons, or C6-C 18 represents an aromatic hydrocarbon, said aliphatic and / or aromatic hydrocarbon being substituted with one or more halogens, preferably F and / or Cl, SF, NO, or linear, branched or cyclic C1-C 20It is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon by 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 process of the present invention, the dimeric phosphazene derived catalyst is represented by formula (IVb):

[0028] [ka] [wherein the substituents R are the same or different at each position and are C6 to C 18 Aromatic hydrocarbons, which may be substituted with one or more halogens, preferably F and / or Cl, SF, NO, or linear, branched or cyclic C1-C 20 is substituted with an aliphatic hydrocarbon (substituted on the aliphatic hydrocarbon by one or more halogens, preferably F and / or Cl, SF5, NO2), Y is O, and X is NR N where R N is a sulfonylalkyl (alkyl is a partially or fully hydrogenated linear, branched or cyclic C1-C 20 aliphatic hydrocarbons), each dashed line represents 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 substrates with a ratio of neral and geranial ranging from neral (Z:E=>99:1) to geranial (Z:E=<1:99), preferably with a higher content of neral in the range of more than Z:E=80:20.

[0030] The resulting reaction mixture containing isopiperitenol can be further subjected to a hydrogenation treatment, which is particularly useful to obtain a reaction mixture containing at least one of menthol, isomenthol, neomenthol and neoisomenthol. Said hydrogenation treatment 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 can be further reacted with olivetol or a substituted derivative thereof in the presence of a Lewis or Bronsted acid, thereby obtaining a reaction mixture containing cannabidiol (CBD) and / or tetrahydrocannabinol (THC) and their isomers.

[0032] [ka] The invention therefore also makes it possible to start the production of derivatives of THC and CBD with the neral derivative of formula (V),

[0033] [ka] The neral derivative of formula (V) is cyclized in the presence of a dimeric phosphazene derived catalyst of formula (II) as defined above, preferably a catalyst of formula (II), (III), (IVa) or (IVb) as defined in 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 Bronsted acid,

[0034] [ka] This results in a reaction mixture containing racemic or optically active THC- and / or CBD-analogues of general formula (VIIa and VIIb);

[0035] [ka] In the formula, R A are, independently of one another, identical or different and each represents hydrogen, a C1-C6 alkyl group, in particular methyl, -CH2OH, or -COOR e where R e is H or a C1-C6 alkyl group; R B are, independently of one another, identical or different and each is hydrogen, a C1-C6 alkyl group, in particular methyl; or two R B or two R's C may each form a ring between themselves, R C are, independently of one another, identical or different and each is a C1-C6 alkyl group, in particular methyl; or two R B or two R's C may each form a ring between themselves, R 5 and R 7 are, independently of one another, the same or different, and each represents hydrogen or -COOR e where R e is H or a C1-C6 alkyl group; R 6 is hydroxy, C1-C 12 It represents an alkyl group, preferably a C3-C7 alkyl group, optionally further substituted by one or more hydroxyl groups.

[0036] It may be desirable to use a catalyst of any of formulae (II), (III), (IVa) or (IVb) in immobilised form in any of the above processes, particularly for continuous processes.

[0037] In one embodiment, the dimeric phosphazene derived catalyst of formula (II), where Y, X and R are as defined above, may be attached to a solid support, optionally via a linker, which is 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 heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic hydrocarbon groups, each hydrocarbon group optionally substituted with one or more heterosubstituents; and said 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, hydroxy, sulfonyl, alkoxy, halogen-substituted alkoxy on the aliphatic hydrocarbon, and / or oxygen in the aliphatic hydrocarbon chain.

[0038] In another embodiment, the dimeric phosphazene derived catalyst of formula (II), (III), (IVa) or (IVb) as defined above may be bound to a solid support via a linker between the solid support and the aromatic or alicyclic base, preferably at the 6-position of one, two, three or all of the aromatic or alicyclic bases of the dimeric phosphazene derived catalyst, wherein said linker and solid support are as defined above.

[0039] In yet another embodiment, the dimeric phosphazene derived catalyst of formula (II), (III), (IVa) or (IVb) as defined above is selected from the group consisting of NR N In the dimeric phosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb), Y is O or NR N and X is NR N where R Nis a linear or branched alkyl chain or polyether alkyl chain, said alkyl chain carrying at least one halogen, preferably fluorine, R and R P is as defined above, for example the sulfonated tetrafluoroethylene polymer Nafion® as the solid support.

[0040] Process description: Currently, neral and geranial can be synthesized by allylic oxidation of nerol and geraniol using MnO2, and after subsequent distillation, the corresponding aldehydes are obtained with Z:E purities of at least 96:4 (for neral) and 2:98 (and higher 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 are dried before use.

[0042] The catalyst is dissolved in a solvent, which can be cooled to different temperatures depending on the solvent used. Neral is added, the reaction is stirred, and after a certain time is stopped, for example, by the addition of triethylamine.

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

[0044] Hetero substituents as defined in accordance with the present invention are OH, F, Cl, Br, I, CN, NO2, IR S 2、NO, NCO, -NCS, -SCN, SO3H, monohalogenomethyl, dihalogenomethyl, trihalogenomethyl, CF(CF3)2, SF5, aliphatic, aromatic, heteroaromatic, primary, secondary, tertiary amine or ammonium (bonded through 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 S 2, amide (bonded through a C or N atom), formyl group, -C(O)-R S , -COOM (wherein M is a metal, such as Li, Na, K, Cs, Ag). S may be, independently of one another, the same or different, and each is an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally further substituted with one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups; and / or optionally bridged by an -O- atom and represents a halogenide.

[0045] The aliphatic hydrocarbons, including alkyl, alkenyl and alkynyl, can include straight chain, branched and cyclic hydrocarbons.

[0046] Heteroaliphatic is a hydrocarbon, including alkyl, alkenyl, and alkynyl, which can include straight chain, branched, and cyclic hydrocarbons having one or more carbon atoms replaced with 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 can be C1-C6-alkyl, in particular 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. Substituted alkyl groups are trifluoromethyl, pentafluoroethyl and 1,1,1-trifluoroethyl.

[0048] Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Alkenyl can be any of C2-C 20 Alkenyl may be any of the C2-C 20 It may also be alkynyl.

[0049] The unsaturated alkenyl- or alkynyl groups can be used to link the compounds of the invention to supports such as polymers useful for immobilized catalysis.

[0050] Halogen is F, Cl, Br or I.

[0051] Alkoxy is preferably C-C 10 Alkoxy is, for example, methoxy, ethoxy, propoxy, tert-butoxy, butoxy, pentoxy, hexyloxy, and the like, and their isomers.

[0052] C3-C8-Heterocycloalkyl having one or more heteroatoms selected from among N, O and S is 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 unsubstituted, or mono-, di-, tri-, tetra-, penta- or further substituted, e.g., per-substituted, on the hydrocarbon.

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

[0055] The arylalkyl may be benzyl.

[0056] Heteroaryl is C5-C 18It may be a heteroaromatic hydrocarbon, which may have one or more heteroatoms selected from N, O and S, and is 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-pyrimidin ... and 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-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 ...-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6- or 7-benz-3,4-diphenylphosphine, 2-, 3-, 4-, 5-, 6- or 7-benz-4,4-diphenylphosphine, 2-, 3-, 4-, 5-, 6- or 7-benz-5,4-diphenylphosphine, 2-, 3-, 4-, 5-, 6- or 7-benz-6,6-diphenylphosphine Preferably it is 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, also preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl. EXAMPLES

[0057] Experiment column Materials and property analysis Chemicals: Chemicals (Abcr, Acros, Aldrich, Gelest, Fluka, Fluorochem, Strem, TCI) were purchased as reagent grade and used without further purification unless otherwise stated. Neral and geranial can be synthesized by allylic oxidation of nerol and geraniol with MnO2, and after subsequent distillation, the corresponding aldehydes are obtained with Z:E purities of at least 96:4 (for neral) and 2:98 (for geranial).

[0058] Solvents: Solvents (CH2Cl2, CHCl3, Et2O, THF, PhMe) were dried by distillation from appropriate drying agents at the Technical Department of the Max-Planck-Institut für Kohlenforschung and placed in Schlenk flasks under argon. Other solvents (n-pentane and pyridine) were purchased from commercial suppliers and dried over molecular sieves.

[0059] Glassware: Screw-cap vials, round-bottom flasks or Schlenk flasks were used for reactions unless otherwise stated. Thin-layer chromatography: Thin-layer chromatography (TLC) was performed using silica gel precoated plastic sheets (Polygram SIL G / UV254, 0.2 mm, with fluorescent indicator; Macherey-Nagel), which were visualized with a UV lamp (254 or 366 nm) and stained with potassium permanganate (KMnO4). KMnO4 stain: 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 technical grade solvents. Elution was accelerated with compressed nitrogen. All reported yields represent spectroscopically and chromatographically pure compounds unless otherwise stated.

[0061] Gas chromatography: Gas chromatography (GC) analyses on chiral solid supports were performed on HP6890 and 5890 series instruments (split mode capillary injection system, flame ionization detector (FID), hydrogen carrier gas). All analyses were performed at the GC department of the Max Planck Institute for Coal Research. The conditions used are described in detail in the individual experiments.

[0062] Catalyst synthesis The catalysts used in the present invention were synthesised by the method using phosphazene reagents as disclosed in EP application 20200632.6 or by preparation according to WO2017 / 037141.

[0063] Catalyst synthesis procedure: A flame-dried Schlenk was charged with the phosphazene reagent and the corresponding substituted (S)- or (R)-BINOL or biphenol (2.0 equiv.). Dry pyridine was added to dissolve both solids to obtain a clear solution. The amount of pyridine is 1 mL for approximately 50 mg of phosphazene reagent used. The clear solution slowly forms a precipitate and after 3 h, sulfonamide (5.0 equiv.) is added to the reaction, which is then stirred overnight. Water (10 wt%) is added to the reaction and stirred for another 3 h. After adding an excess of aqueous HCl (10%), the reaction was worked up 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] DOWEX Acidification: DOWEX was packed into a column and washed with 0.05M H2SO4 aqueous solution and CH2Cl2. The purified catalyst was dissolved in CH2Cl2 and subsequently passed through the column, which was rinsed with CH2Cl2 until no UV-active substances were released. The solvent was evaporated to obtain the catalyst. After drying under high vacuum, the corresponding catalyst was analyzed by NMR and MS.

[0065] Exemplary Reaction Protocols for the Methods of the Invention Exemplary catalytic asymmetric cyclizations of citral, neral, and geranial are shown below.

[0066] [ka] A screw-capped vial was charged with a magnetic stir bar, iIDP-catalyst (1 mol%) and dichloromethane (0.1 M). The reaction solution was cooled to -20°C and stirred for 10 min. Neral (Z:E 96:4 ratio) was added to the reaction vial and the reaction was stirred at said temperature for 16 h. The reaction mixture was treated with Et3N, followed by allowing the reaction to slowly warm to room temperature. The solvent was evaporated at 40°C and 500 mbar. Reported yields are determined by NMR using mesitylene or triphenylmethane as internal standards. [Brief description of the drawings]

[0067] Exemplary reaction protocol evaluations of several parameters for a variety of reaction conditions, including different amounts of various substrates and catalysts, are shown in Figure 1. Results indicate that the general reaction protocol described above is applicable to a variety of conditions and various substrates.

[0068] Experimental Results Catalyst Class Several Brönsted acid catalysts (organic or inorganic and achiral or chiral acids) covering a wide range on the pKa scale are able to catalyze the cyclization reaction of citral. Weak acids (pKa>10 in MeCN) show little conversion but maintain a pure reaction profile, while strong acids (pKa<8 in MeCN) lead to a more complex reaction profile. The complexity of the reaction with stronger acids can be explained by the fast decomposition pathway of the cyclization intermediate isopiperitenol to several elimination products (e.g. trienes), as described in the literature. Catalyst classes (IDP, iIDP and IDPi) spanning the pKa scale between weak and strong acids can combine the advantages of both, i.e. higher conversion to the desired products and maintaining a pure reaction profile.

[0069] concentration The cyclization reaction of citral can be carried out in several organic solvents with different concentrations ranging from solvent-free to very dilute 0.005M reaction conditions. The diastereomeric and enantiomeric excess of the desired cyclization product is nearly constant under different dilutions of the reaction mixture. Control experiments were carried out by determining the enantiomeric excess at different stages of the reaction to exclude kinetic partitioning in the degradation pathway of the product.

[0070] Catalyst loading The cyclization reaction of citral can be carried out without significant loss of diastereomeric and enantiomeric excess of the desired product by using various amounts of catalyst 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 (eg, in the presence of water) to give similar diastereomeric and enantiomeric ratios.

[0072] conclusion The cyclization reaction of citral / neral using the catalyst of the present invention can be carried out at temperatures from -80°C to 25°C, reaction times from 30 minutes to 48 hours, concentrations from neat to 0.005M in several solvents, and catalyst amounts ranging from 0.05 mol% to 100 mol%. Screening of various catalysts is shown in Figure 1. The cyclization reaction of citral is carried out in high yields when using catalysts with electron-deficient groups. Screening of several different cores in combination with the best 3,3'-substituents leads to the conclusion that the smallest inner core CF3 provides products in the highest yields and diastereomeric and enantiomeric ratios 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 round bottom flask was charged with a magnetic stir bar, iIDP-catalyst (2.5 mol%) and dry pentane (0.1M) and cooled to 0°C. After 20 min, neral (5.8 mmol, 96:4 ratio) was added to the reaction flask and the reaction was stirred at said temperature for 16 h. The reaction mixture was treated with triethylamine, followed by allowing the reaction to warm slowly to room temperature. Evaporation of the solvent afforded the reaction crude containing the cyclized product. Purification of the crude reaction mixture by CC (silica) afforded the cyclic allylic alcohol (40% yield, 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-Trimethyloct-6-en-2-ynal

[0076] [ka] To a stirred solution of CBr4 (16.55 g, 49.9 mmol, 2.0 equiv.) in CHCl2 (20 mL) was added triphenylphosphine (26.2 g, 99.8 mmol, 4.0 equiv.) at 0 °C, and the resulting reaction mixture was stirred for 15 min. To this suspension was added (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 equiv.) in CHCl2 (15 mL), 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 CHCl2. The combined organic layers were washed with H2O2 (5% in H2O), water, brine, dried over Na2SO4, and evaporated. The crude reaction product was then dissolved in THF (130 mL) and nBuLi (2.5 M in hexanes, 24 mL, 59.9 mmol, 2.4 equiv.) was added dropwise at -78 °C. The reaction mixture was slowly warmed to 0 °C and stirred for 20 min, after which the reaction was allowed to reach room temperature. After complete conversion of the starting material, the reaction was quenched with saturated aqueous 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 give 4,4,7-trimethyloct-6-en-2-ynal as a colorless oil (1.74 g, 42% yield).

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

[0078] [ka] A flame-dried flask was charged with 4,4,7-trimethyloct-6-en-2-ynal (500 mg, 3.0 mmol, 1.0 equiv), a solvent mixture of cyclohexane / ethyl acetate (1:5), and quinoline (0.36 mL, 3.0 mmol, 1.0 equiv). Lindlar's 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 pad of Celite, which was washed extensively with EtOAc. The solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography to give the desired α,β-unsaturated aldehyde 4,4,7-trimethylocta-2,6-dienal (120 mg, 24% yield) as a pale yellow oil, and a mixture of diastereoisomers (Z:E=93:7).

[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 to give the desired cyclic allylic alcohol 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 equiv) in THF (21 mL) was added 18-crown-6 (735 mg, 2.78 mmol, 1.05 equiv) in THF. The reaction 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. After stirring for 20 min at -78 °C, 5-methylhex-4-enal (prepared according to references Braddock et al., Chem. Commun. 2006, 2483 and Nakada et al., Tett. Let. 2014, 55, 50, 6847) (300 mg, 2.67 mmol, 1.0 equiv.) 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 flash column chromatography to give the α,β-unsaturated ester (223 mg, 42% yield).

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

[0084] [ka] A flame-dried flask was charged with ethyl (Z)-2,7-dimethylocta-2,6-dienoate (344 mg, 1.75 mmol, 1.0 equiv) and DCM (7 mL) and DIBAL-H was added dropwise (3.8 mL, 1 M, 3.8 mmol, 2.2 equiv) at -78 °C. After complete conversion of the starting material to the desired alcohol, the reaction was quenched with a 1:1 water / MeOH mixture. The mixture was stirred at room temperature for 2 h. The resulting gel was filtered over a Na2SO4 / Celite pad, which was 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 again dissolved in DCM (2 mL). Manganese dioxide (685 mg, 7.89 mmol, 4.5 equiv) was added to the reaction flask and the reaction was stirred at room temperature until complete conversion of the starting material. After complete conversion, the reaction was filtered through a pad of Celite, which was washed extensively with DCM. The solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography to give (Z)-2,7-dimethylocta-2,6-dienal as a mixture of diastereoisomers (160 mg, 60% yield, 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 to give the desired cyclic allylic alcohol in 72% yield (dr=2:1, er(major)=97:3, er(minor)=93:7).

[0087] CBD and THC synthesis The chiral catalyst phosphoric acid, IDP-, iIDP- or IDPi-catalyst (5 mol%) was charged to a reaction vessel and anhydrous CHCl (0.1 M), olivetol (1.1 equiv.) and enantiomerically pure isopiperitenol (0.3 mmol) were added via syringe. The reaction was stirred at room temperature and quenched with triethylamine upon complete conversion of isopiperitenol. The solvent was evaporated and the 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 reaction mixtures containing cannabidiol (CBD) To a screw-cap vial, 5-20 mol% of a catalyst or Lewis acid (e.g., BF3OEt2), dry CHCl2, olivetol and purified enantiomerically pure isopiperitenol were added. The reaction mixture intensified its color, which faded after a few minutes. The reaction mixture was stirred at room temperature and upon complete conversion of the two starting materials, treated with triethylamine. The solvent was evaporated and purification of the crude reaction mixture by CC (silica) afforded cannabidiol as the major compound.

[0089] Synthesis of reaction mixtures containing cannabidiol (CBD) In a flame-dried Schlenk tube, olivetol (1 mmol, 180 mg), isopiperitenol (cis:trans = 5:1, 1.5 equiv, 0.16 mL) and BF3·Et2O (62.5 μL, 0.5 mmol) were appropriately added in 6.25 mL of DCM under argon at 0 °C. After 1.5 h, the starting material was completely consumed as shown by TLC (5-20% EtOAc / Hexanes). 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% EtOAc / Hexanes). Three major compounds could be isolated, one of which is CBD (32% yield, 101.2 mg).

[0090] Synthesis of THC-containing reaction mixtures A flame-dried Schlenk flask was charged with molesieve and 5 mol% of iIDP catalyst. Dry CH2Cl2, olivetol and purified enantiomerically pure isopiperitenol were added to the flask. The reaction mixture intensified in color and faded after a few minutes. The reaction was 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 give the THC material (Δ 9 -THC (cis and trans), Δ 8 -THC, Δ 9 -regio-THC (cis and trans) was obtained.

[0091] One-pot CBD / THC synthesis The reaction vessel was charged with iIDP catalyst (5 mol%) and anhydrous CH2Cl2 (0.1 M). After the reaction was cooled to the desired temperature and stirred for a few minutes, neral (0.3 mmol) was added to the reaction mixture and the reaction was stirred for a period of time. After reaching full conversion of the starting material, olivetol (1 equiv.) was added to the reaction mixture and the reaction was allowed to reach room temperature. Upon complete conversion of olivetol, 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, olivetol (36 mg, 0.2 mmol), enantiopure isopiperitenol (dr cis:trans = 5:1, 1.1 equiv.) and BF3·Et2O (0.2 equiv.) were appropriately added in 4 mL of DCM under argon at 60 °C. After 14 h, the starting material (olivetol) was completely converted as shown by TLC analysis (using 5% EtOAc / hexanes) and the reaction was treated with a drop of triethylamine. The solvent was evaporated under reduced pressure and the crude mixture was purified by flash column chromatography (SiO2, 5% EtOAc / hexanes) to give 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 equiv.) and BF3·Et2O (0.2 equiv.) were appropriately added in 8 mL of DCM at room temperature under argon. After 22 h, the product ratio formed is THC:CBD = 2.3:1, and after 42 h, 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% EtOAc / hexanes) to give Δ 9 -THC was obtained as the desired product (55% yield, 72 mg).

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

[0095] menthol: A flame-dried flask was charged with enantioenriched isopiperitenol (dr=11:1, er 98.5:1.5) (31 mg, 0.20 mmol, 1.0 equiv), 3 mL of MeOH, and Lindlar's catalyst (48.7 mg, 0.11 equiv). After stirring for a few minutes, the reaction was subjected to 1 atm of H2 gas (by balloon). After 2 days, the reaction reached complete conversion (as indicated by TLC) and was filtered. After evaporation of the solvent, the crude reaction mixture was subjected to GC analysis (>99% conversion, 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 flame-dried Schlenk flask was equipped with a magnetic stir bar and ammonia (ca. 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 equiv., 21 mmol) was slowly added to the flask and the reaction was stirred at said temperature for 1.5 h before being gradually warmed to room temperature. After an additional 1.5 h, the resulting white slurry was acidified with 1 M H2SO4 to a pH of ca. 2. 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 catalysts used for the following preparation of solid supported confined acids were prepared according to the general reaction protocol by 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 pad of silica before use) and AIBN were added to the flask. The resulting mixture was placed in a tube and copolymerization was carried out at 80° C. After 16 h, the heat source was removed and the resulting solid was crushed. The resulting polymer powder was washed extensively with dichloromethane and acidified by suspending in 6 M HCl for 3 h. The suspension was filtered and washed with water and dichloromethane. The resulting solid supported catalyst was dried overnight under high vacuum at 40° C.

[0099] Synthesis of solid supported sulfonamides: Nafion® R-1100 resin (sulfonyl fluoride form, 500 mg) was ground to a fine greyish powder using a cryomill at −196° C. The resulting powder was suspended in anhydrous DMF (3 mL) and excess liquid ammonia was condensed into the 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, 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 screw-capped vial was charged with a magnetic stir bar, solid supported iIDP catalyst, and dry n-pentane (0.5M). Neral (Z:E 96:4) was added to the reaction vial and the reaction was stirred at room temperature overnight. After complete conversion of the starting material, the solid supported catalyst was removed using a syringe filter, the filter was rinsed with additional 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 enantiomeric excess was determined by GC (28% yield, dr 15:1 (trans:cis), er 96:4).

[0101] Cyclization of neral using solid-supported catalysts A flame-dried vial was charged with 10 mol% solid supported catalyst and dichloromethane. Neral (5 μL) was added to the vial and the reaction was stirred at room temperature for 16 h. After quenching the reaction with a drop of triethylamine, the reaction was filtered and the reaction was 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 enantiomeric and diastereomeric ratios were determined by GC analysis.

Claims

1. 1. A process for the asymmetric synthesis of isopipeperitenol of formula (I), comprising: 【Chemical 1】 A substrate comprising at least one of neral [(Z)-3,7-dimethylocta-2,6-dienal] and geranial [(E)-3,7-dimethylocta-2,6-dienal] is treated, optionally in an organic solvent, with a dimeric phosphazene-derived catalyst represented by formula (II): 【Chemistry 2】 In the above formula, R is the same or different at each position and is hydrogen, halogen, SF ５ , NO ２ , Cyano, C １ ~C ２０ A linear, branched or cyclic aliphatic hydrocarbon (optionally with one or more halogens, preferably F or Cl, SF, on the aliphatic hydrocarbon) ５ , NO ２ or cyano), C ６ ~C １８ Aromatic hydrocarbons, or C ５ ~C １８ and heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon optionally containing a halogen, SF ５ , NO ２ , Cyano, C １ ~C ２０ Linear, branched or cyclic aliphatic hydrocarbons (optionally with one or more halogens, preferably F and / or Cl, SF on the aliphatic hydrocarbon) ５ , NO ２ or cyano), -R Ｐ are the same or different at each position and have the meaning of R, or two R on the same aryl ring Ｐ may together form a ring which may be an aromatic or aliphatic ring structure, said aromatic and / or aliphatic ring structure being optionally substituted with one or more substituents R; X and Y are the same or different and are oxygen or NR Ｎ Either R Ｎ is an electron-withdrawing or electron-donating group, is the same or different at each position, and is selected from: i. -alkyl, -CO-alkyl, -(CO)-O-alkyl, sulfinylalkyl, sulfonylalkyl, sulfonyliminoalkyl, sulfonylbisiminoalkyl, phosphinyldialkyl, phosphonylalkyl, alkylphosphorane, N,N'-alkylimidazolidin-2-iminyl, wherein 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 SF 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'-arylimidazolidin-2-iminyl, N-aryl-N'-alkylimidazolidin-2-iminyl, where aryl is C ６ ~C １８ Aromatic hydrocarbons (optionally containing at least one halogen, C １ ~C ６ Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF ５ C optionally substituted with １ ~C ６ alkyl); iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinylheteroaryl, sulfonylheteroaryl, -(P=O)-di-heteroaryl, phosphinyldiheteroaryl, phosphinylarylheteroaryl, phosphinylheteroarylalkyl, phosphonylheteroaryl, heteroarylphospholanes, heteroarylarylphospholanes, heteroarylarylalkylphospholanes, N,N'-heteroarylimidazolidin-2-iminyl, N-heteroaryl-N'-alkylimidazolidin-2-iminyl, N-heteroaryl-N'-arylimidazolidin-2-iminyl, where heteroaryl is C ２ ~C １８ Heteroaromatic hydrocarbons (optionally containing at least one halogen, C １ ~C ６ Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF ５ C optionally substituted with １ ~C ６ alkyl); and W is hydrogen, halogen, a metal 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, or a cationic organic group, a substituted borane -BR Ｉ R ＩＩ R ＩＩＩ or substituted silicon -SiR Ｉ R ＩＩ R ＩＩＩ where R Ｉ , R ＩＩ and R ＩＩＩ may be the same or different, and each is selected from hydrogen, halogen, C optionally 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 hydrogenated arene forms, each hydrocarbon optionally having a C １ ~C ２０ and is substituted with one or more groups selected from linear, branched, or cyclic aliphatic hydrocarbons, or one or more hetero-substituted groups, and W is preferably hydrogen and substituted silicon—SiR Ｉ R ＩＩ R ＩＩＩ (In the formula, R Ｉ , R ＩＩ and R ＩＩＩ is as defined above), The method.

2. 10. The method of claim 1, wherein the dimeric phosphazene-derived catalyst is represented by formula (III): 【Chemistry 3】 wherein the substituents R are identical or different in each position and are as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, an alkali metal or an alkaline earth metal.

3. 10. The method of claim 1, wherein the dimeric phosphazene-derived catalyst is represented by formula (IVa): 【Chemistry 4】 wherein the substituents R are identical or different in each position and are as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, an alkali metal or an alkaline earth metal.

4. 10. The method of claim 1, wherein the dimeric phosphazene-derived catalyst is represented by formula (IVb): 【Chemistry 5】 wherein the substituents R are identical or different in each position and are as defined in claim 1, X and Y have the meanings defined in claim 1, and W represents hydrogen, an alkali metal or an alkaline earth metal.

5. The substituents R are the same or different at each position and are selected from halogen, linear, branched or cyclic C １ ~C ２０ Aliphatic hydrocarbons, or C ６ ~C １８ It represents an aromatic hydrocarbon, wherein the aliphatic and / or aromatic hydrocarbon is / are one or more halogens, preferably F and / or Cl, SF ５ , NO ２ or linear, branched or cyclic C １ ~C ２０ an aliphatic hydrocarbon (on which one or more halogens, preferably F and / or Cl, SF ５ , NO ２ 5. The method of any one of claims 2, 3 or 4, wherein the aryl group is substituted with

6. In any of formulas (II), (III), (IVa) or (IVb), Y is O or NR Ｎ and X is NR Ｎ where R Ｎ is an electron-withdrawing or electron-donating group, is the same or different at each position, and is selected from: i. sulfinylalkyl or sulfonylalkyl, 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 SF ５ having at least one substituent selected from ii. sulfinylaryl or sulfonylaryl, where aryl is C ６ ~C １８ Aromatic hydrocarbons (optionally containing at least one halogen, C １ ~C ６ Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF ５ C optionally substituted with １ ~C ６ alkyl); iii. sulfinylheteroaryl or sulfonylheteroaryl, where heteroaryl is C ２ ~C １８ Heteroaromatic hydrocarbons (optionally containing at least one halogen, C １ ~C ６ Alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF ５ C optionally substituted with １ ~C ６ alkyl); and R, R Ｐ and W has the meaning defined in claim 1 or claim 5.

7. 7. The method of any one of claims 1 to 6, wherein the substrate comprises a ratio of neral to geranial ranging from neral (Z:E = > 99:1) to geranial (Z:E = < 1:99).

8. The method according to any one of claims 1 to 7, wherein the obtained reaction mixture is further subjected to a hydrogenation treatment, thereby obtaining a reaction mixture containing at least one of menthol, isomenthol, neomenthol, and neoisomenthol.

9. 8. The method according to any one of claims 1 to 7, wherein the obtained reaction mixture is further reacted with olivetol in the presence of a Lewis acid or a Bronsted acid, preferably a catalyst of formula (II), (III) or (IV), thereby obtaining a reaction mixture containing THC and / or CBD.

10. The neral derivative of formula (V) 【Chemistry 6】 cyclized in the presence of a dimeric phosphazene-derived catalyst of the formula defined in any one of claims 1 to 6, and further reacting the reaction mixture with a resorcinol-derived compound of formula (VI) in the presence of a Lewis acid or a Bronsted acid, preferably a catalyst of formula (II), (III), (IVa) or (IVb), 【Chemistry 7】 Thereby, a reaction mixture containing racemic or optically active CBD- and / or THC-derivatives of general formulae (VIIa) and (VIIb) is obtained; 【Chemistry 8】 In the formula, R Ａ are independently the same or different and each represents hydrogen, C １ ~C ６ Alkyl groups, especially methyl, —CH ２ OH, or -COOR ｅ where R ｅ is H or C １ ~C ６ is an alkyl group; R Ｂ are independently the same or different and each represents hydrogen, C １ ~C ６ alkyl groups, especially methyl; or two R Ｂ or two R's Ｃ may form a ring between themselves, R Ｃ are independently the same or different, and each １ ~C ６ alkyl groups, especially methyl; or two R Ｂ or two R's Ｃ may form a ring between themselves, R ５ and R ７ are independently the same or different and each represents hydrogen or -COOR ｅ where R ｅ is H or C １ ~C ６ is an alkyl group; R ６ is hydroxy, C １ ~C １２ Alkyl group, preferably C ３ ~C ７ The method of any one of claims 1 to 6, wherein the alkyl group is optionally further substituted by one or more hydroxyl groups.

11. R, R Ｐ wherein Y, X and W are as defined in any one of claims 1 to 6, and the dimeric phosphazene-derived catalyst is bound to a solid support, optionally via a linker; the linker is an aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon group, each of which is optionally further substituted with one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic, or heteroaromatic hydrocarbon groups, each of which is optionally substituted with one or more heterosubstituents; 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, preferably F and / or Cl, hydroxy, sulfonyl, alkoxy, halogen-substituted alkoxy on the aliphatic hydrocarbon, or oxygen in the aliphatic hydrocarbon chain; The method according to any one of claims 1 to 10.

12. The dimeric phosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 4 is attached to a solid support via a linker between the solid support and the aromatic or alicyclic base, preferably at the 6-position of one, two, three or all of the aromatic or alicyclic bases of the dimeric phosphazene-derived catalyst, said linker and solid support being as defined in claim 10; Y and X are oxygen or NR Ｎ is defined as R Ｎ is defined in claim 1, and R and R Ｐ The method according to claim 11, wherein is as defined in any one of claims 1 to 4.

13. The dimeric phosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb) as defined in any one of claims 1 to 4 is Ｎ and is connected to a solid support via a linker between the substituent and the solid support, said linker and solid support being as defined in claim 10; and in the dimeric phosphazene-derived catalyst of formula (II), (III), (IVa) or (IVb), Y is oxygen or NR Ｎ and X is NR Ｎ and R Ｎ is a linear or branched alkyl chain or polyether alkyl chain, said alkyl chain carrying at least one halogen, preferably fluorine, and R and R Ｐ The method according to claim 11, wherein is as defined in any one of claims 1 to 4.

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