Process for the asymmetric synthesis of isopiperitenol

A process for the asymmetric synthesis of isopiperitenol of formula (I),

• wherein a Neral-derivative of the formula (V)
• is cyclized in the presence of a dimeric phosphazene-derived catalyst of formula (II):
• wherein in said formula (II):
• R is the same or different on each position and is each selected from hydrogen, halogen, SF5, NO2, cyano, C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF5, NO2 or cyano on the aliphatic hydrocarbon, C6 to C18 aromatic hydrocarbons or C5 to C18 heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon optionally being substituted by one or more substituents selected from halogen, SF5, NO2, cyano, C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, SF5, NO2 or cyano on the aliphatic hydrocarbon,
• RP is the same or different on each position and has the meaning of R, or two RP on the same aryl ring may form a ring with each other which may be an aromatic ring structure or an aliphatic ring structure, which aromatic ring 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 NRN;
• wherein:
• RN is an electron withdrawing or electron donating group, being the same or different on each position and being selected from:
• i. -alkyl, —CO-alkyl, —(CO)—O-alkyl, sulfinyl alkyl, sulfonyl alkyl, sulfonyl iminoalkyl, sulfonyl bisiminoalkyl, phosphinyl dialkyl, phosphonyl alkyl, alkyl phosphorane, N,N′-alkylimidazolidin-2-iminyl wherein alkyl is a C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from C1 to C6 alkoxy, halogen, cyano, nitro, or SF5;
• ii. -aryl, —CO-aryl, —(CO)—O-aryl, sulfinyl aryl, sulfonyl aryl, sulfonyl iminoaryl, sulfonyl iminosulfonylaryl, sulfonyl bisiminoaryl, phosphinyl diaryl, phosphinyl alkylaryl, phosphonyl aryl, aryl phosphoranes, aryl alkyl phosphoranes, N,N′-arylimidazolidin-2-iminyl, N-aryl-N′-alkylimidazolidin-2-iminyl wherein aryl is a C6 to C18 aromatic hydrocarbon, optionally having at least one substituent selected from C1 to C6 alkyl optionally substituted by at least one halogen, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5;
• iii. -heteroaryl, —CO-heteroaryl, —(CO)—O-heteroaryl, sulfinyl heteroaryl, sulfonyl heteroaryl, -(P=O)-di-heteroaryl, phosphinyl diheteroaryl, phosphinyl arylheteroaryl, phosphinyl heteroaryl alkyl, phosphonyl heteroaryl, heteroaryl phosphoranes, heteroaryl aryl phosphoranes, heteroaryl aryl alkyl phosphoranes, N,N′-heteroarylimidazolidin-2-iminyl, N-heteroaryl-N′-alkylimidazolidin-2-iminyl, N-heteroaryl-N′-arylimidazolidin-2-iminyl wherein heteroaryl is a C2 to C18 heteroaromatic hydrocarbon, optionally having at least one substituent selected from C1 to C6 alkyl optionally substituted by at least one halogen, C1 to C6 alkoxy, halogen, cyano, nitro, or SF5;
• and
• W is selected from 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 —BRIRIIRIII or a substituted silicon —SiRIRIIRIII, wherein RI, RII and RIII may be same or different and each stands for hydrogen, halogen, an optionally —O— bonded C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having one or more unsaturated bonds or one or more hetero atoms in the chain, a C5 to C18 heteroaromatic hydrocarbon, a C6 to C18 aromatic hydrocarbon or partially arene-hydrogenated forms thereof, each hydrocarbon optionally being substituted by one or more groups selected from C1 to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, or one or more heterosubstituents,
• and the reaction mixture is further reacted, in the presence of a Lewis or Brønsted acid with a resorcin-derived compound of the formula (VI)
• whereby a reaction mixture containing racemic or optically active CBD- and/or THC-derivatives of the general formula (VIIa) and (VIIb) is obtained;
• wherein RA is, independently from each other, the same or different and is each hydrogen, a C1 to C6 alkyl group, —CH2OH, or —COORe with Re being H or a C1 to C6 alkyl group;
• RB is, independently from each other, the same or different and is each hydrogen, a C1 to C6 alkyl group, or two of RB or two of RC, respectively, may form a ring amongst each other,
• RC is, independently from each other, the same or different and is each a C1 to C6 alkyl group, or two of RB or two of RC, respectively, may form a ring amongst each other,
• R5 and R7 are, independently from each other, the same or different and are each hydrogen or —COORe with Re being H or a C1 to C6 alkyl group;
• R6 represents hydroxy, a C1 to C12 alkyl group, optionally being further substituted by one or more hydroxyl groups.