Process for preparing an enantiomeric pure diels-alder adduct

Abstract

The present invention refers to a process for preparing an enantiomeric pure Diels-Alder Adduct, in particular a santalol derivative, i.e. (-)-(Z)-β-santalol.

Description

[0001] Process for preparing an enantiomeric pure Diels-Alder adduct

[0002] The present invention refers to a process for preparing an enantiomeric pure Diels-Alder adduct, in particular a santalol derivative, i.e. (— )-(Z)-p-santalol.

[0003] Sandalwood oil obtained from the trees of nowadays-protected species S. album is of a great demand for perfumery industry because of its distinctive soft, warm, creamy and woody scent. Chemical composition of sandalwood oil is mainly presented by two components: a- and p-santalols with last one being mainly responsible for the characteristic smell of sandalwood oil. It’s worth mentioning that from four possible isomers of p-santalol only (— )-(Z)-p-santalol possess sandalwood odor while the opposite enantiomer is odorless and E-regioisomer is characterized by phenolic, medicinal odor.

[0004] Many attempts were made towards chemical synthesis of pure (— )-(Z)-p-santalol. Only two methods though were relevant for the industry. The approach reported by Fehr in Angew. Chem., Int. Ed. 48, 7221-7223 (2009) comprises 9 steps with the total yield of enantiopure (-)-(Z)-|3-santalol 13.8% as disclosed in W02009141781A.

[0005] A different approach reported by Chapuis as disclosed in W02015067470A1 includes 8 steps with the total yield of (-)-(Z)-|3-santalol 8%. Both routes as shown in Figure 1 require fine organic chemicals (not commercially available on large scales) and several chromatographic resolutions.

[0006] A more efficient approach for the assembling of (-)-(Z)-|3-santalol backbone is an option via an enantioselective Diels-Alder reaction - as shown for the invention in Figure 2 - of geranial (1a) and cyclopentadiene (2) — commercially available bulk chemicals and this strategy was basically realized by Weyerstahl in Liebigs Ann. Chem. 6, 1089-1099 (1981) albeit with very low yield (2%) and in non-asymmetric fashion leading to racemic mixtures.

[0007] Further reactions involving enals in a Diels-Alder reaction are known in the prior art. For example, Hayashi et al. describe (Chem. Eur. J. 22, 15874-15880 (2016)), the Diels-Alder reaction of p,p-substituted enals containing methyl and electron withdrawing groups (CO2R, COH, Ac) at the p-position. The only relatable example 5 in the Table 4 (CH2OBZ) provides a cyclic adduct in 88:12 exo:endo ratio thus yielding predominantly exo-isomer which can’t be used for the synthesis of (-)-(Z)-p-santalol on the basis of geranial (1a). Furthermore, Kim et al. disclose (Nat. Commun. 10, 1-6 (2019)) a general approach to Diels-Alder reactions of enals and in particular to a Diels-Alder reaction of enals other than P,P-substituted enals. The application of the method (namely procedure, conditions and additives) and catalysts described in said reference to the Diels-Alder reactions of unactivated p,p-substituted enals does not yield significant amounts of the desired cyclic adducts.

[0008] In the present inventive approach, all carbon atoms of the target molecule will be installed in one step together with both stereocenters, providing valuable intermediate 3, which can be converted to 4 via simple carbonyl reduction and selective double bond hydrogenation. Alcohol elimination can be done via intermediating mesylate / tosylate or acetate 5, but also another economically feasible option would be carbonateintermediate. The final regioselective allylic oxidation can be performed via deprotonation with a strong potassium 2,2,6,6-tetramethylpiperidin-1-ide (KTMP) base, borylation and oxidation using hydrogen peroxide as described in Org. Lett. 25, 277-281 (2023) for similar terpene-based susbtrates. The similar strategy of deprotonation-oxidation was employed by Schlosser et al. in Syn / ett 3, 173-174 (1994) specifically for p-santalene oxidation, however this approach requires “solvent-free butyllithium” and fluorodimethoxyborane diethyl etherate which are not available commercially, making this approach hardly suitable for a large scale applications.

[0009] In contrast, enzymatic approaches are less developed, but gaining a lot of attention recently. Most of them producing mixtures chemically resembling sandalwood oil rather than pure compounds or enriching natural products in [3-santalol content.

[0010] Therefore, there is a need for an enantioselective and efficient route for production of (-)- (Z)-|3-santalol which will be of a great importance for the industry.

[0011] The present inventors have considered to solve the problem of the invention by providing a more convenient, atom-economic and sustainable process for the synthesis of enantiopure (-)-(Z)-|3-santalol and derivatives thereof.

[0012] The considerations of the inventors for the synthetic approach to (-)-(Z)-|3-santalol are based on an enantioselective Diels-Alder reaction between enal (1) potentially represented by geranial (1a) or its mixture with neral (“citral”) and cyclopentadiene (2) in the presence of an IDPi catalyst (IV) as a first reaction step which reaction is represented in the following reaction scheme: which reaction is catalyzed by a strong organic Bronsted acid imidophosphoroimidate (IDPi) as represented by general Formula (IV): wherein in said formula (IV):

[0013] R is the same or different on each position and is each selected from hydrogen, halogen, SF5, NO2, cyano, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, preferably F or Cl, SF5, NO2 or cyano on the aliphatic hydrocarbon, C6to 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, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, Ce to C18 aromatic hydrocarbons or C5 to Cis heteroaromatic hydrocarbons optionally having one or more halogens, preferably F and / or Cl, SF5, NO2 or cyano on the aliphatic or aromatic hydrocarbon, wherein any dashed line independently represents a double bond or two hydrogens, wherein X and Y are the same or different and represent NRN; wherein:

[0014] RNis an electron withdrawing 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 Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from Ci to C6alkoxy, halogen, preferably F and / or Cl, 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 Ce to C18 aromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen, Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro, or SFs; iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinyl heteroaryl, sulfonyl heteroaryl, -(P=O)-di-heteroaryl, phosphinyl diheteroaryl, phosphinyl aryl heteroaryl, 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 Ci to Ce alkyl optionally substituted by at least one halogen, Ci to C6alkoxy, halogen, preferably F and / or Cl, cyano, nitro, or SF5; and wherein 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 -BRIRIIRI" or a substituted silicon -SiRlRllRl", wherein R1, R" and R111may be same or different and each stands for hydrogen, halogen, an optionally - O- bonded Ci 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 Cis heteroaromatic hydrocarbon, a Ce to C18 aromatic hydrocarbon or partially arene- hydrogenated forms thereof, each hydrocarbon optionally being substituted by one or more groups selected from Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, or one or more heterosubstituents, W being preferably selected from hydrogen, alkali metal or earth alkaline metal.

[0015] Thus, the present invention is directed in a first aspect to a process of an enantioselective Diels-Alder reaction between cyclopentadiene (2) and an enal compound of Formula (1) as a first step which reaction is represented in the following reaction scheme:

[0016] (1) (2) (3) and which is catalyzed by a strong organic Bronsted acid imidophosphoroimidate (IDPi) as represented by general Formula (IV) as detailed before.

[0017] As substrates for the reaction, different exemplified compounds can be used such as an enal component of Formula (1) O=C-C=CR1R2wherein R1represents straight chain, cyclic or branched CrCw-alkyl, C Cw-alkenyl, CrCw-alkynyloptionally containing one or more heteroatoms, R2represents CrCe-alkyl, preferably methyl, and the ID Pi-catalyst is represented by Formula (IV).

[0018] As enal compounds, terpene based enals may be used. When the enal of Formula (1) is geranial (1a), the intermediate of Formula (3a) for (-)-(Z)-[3-santalol can be obtained.

[0019] As diene compound, cyclopentadiene is preferably used.

[0020] In the first step of the inventive synthesis, the following reactions conditions preferably apply. The loading of catalyst IDPi of Formula (IV) can be as low as 1.5 mol% (0.015 equiv. per 1 equiv. of geranial) with no limitation for further increasing.

[0021] The starting materials can be used in wide range of ratios, but the best results were obtained when 4 equivalents of cylcopentadiene were used in respect to geranial.

[0022] The reaction can be conducted in the presence of drying agents such as molecular sieves or inorganic salts (Na2SC>4, CaC , MgSC ), but best results were obtained in the presence of molecular sieves 5 or CaSC

[0023] The drying reagents can be used in wide range of loading (180:1 to 600:1 [mg of drying agent: mmol of ena]l (1)), but best results were obtained with the ratio 500:1. The described reaction proceeds in many organic solvents (for example, chlorinated solvents, ethers, hydrocarbons) at wide range of concentration (from 0.5 M up to 3 M [M=mol / L]), the best results in terms of yield and enantioselectivity, however, were obtained in MTBE with 1.7 M concentration of the starting materials.

[0024] The reaction proceeds in wide temperature interval (-80 - -10°C), however best results were obtained at -40°C. Correspondingly, different reaction times can be chosen depending on the used temperature (from 2 to 10 days), with the optimal reaction time 5 days at -40°C.

[0025] In another embodiment of the inventive process, geranial (1a) is used a starting material. Since said described process provides access to (-)-(Z)-|3-santalol precursor (3a) when geranial and cyclopentadiene are used as substrates, the present invention also describes the use of this precursor for the synthesis of (-)-(Z)-|3-santalol (7).

[0026] As a next step on the way to (-)-(Z)-[3-santalol (7) from cycloadduct (3a), aldehyde reduction can be performed using a variety of hydride reducing agents, including but not limited to NaBH4, UAIH4, NaBHsCN, diisobutylaluminium hydride. NaBH4 can be used as one of the safest and most robust options.

[0027] The internal double bond in the compounds (3) can be selectively hydrogenated using the method described by Brown and Ahuja in Org. Chem. 35, 1900-1904 (1970).

[0028] When NaBH4 used as a reducing agent for the discussed above steps, these steps can be performed in one-pot fashion.

[0029] The exo-double bond in [3-santalene (6) has previously been reported to be formed via alcohol functionalization and subsequent elimination. For example, converting the alcohol moiety into an acetate, mesylate or tosylate can be performed, followed by an elimination under pyrolytic or basic conditions, correspondingly. However, the present inventors found all these conditions to be insufficient toward (-)-(Z)-|3-santalol precursor (4). Therefore, the present work also describes a novel approach for the formation of exo-double bond in (-)- (Z)-|3-santalol precursors.

[0030] The approach of the inventors utilizes a transformation of the alcohol moiety into a carbonate using methyl chloroform ate, and subsequent pyrolysis of the obtained carbonate. The formation of the carbonate allows obtaining an intermediate labile enough to undergo elimination under pyrolytic conditions, which was not possible in the case of acetate (5) (X=Ac). The advantages of this approach include: simple reaction set up, elimination reaction that does not require use of additional chemicals, simple non-toxic side products that do not require special handling (CO2 and MeOH). Described sequence results in formation of [3-santalene (6).

[0031] In a final step, the unsaturated aliphatic side chain of [3-santalene (6) can be converted into the desired allylic alcohol containing fragment of (— )-(Z)-|3-santalol (7). In a one-pot procedure first [3-santalene (6) is deprotonated using freshly generated potassium tetramethyl pi peridine (from tetramethylpiperidine, potassium terf-butoxide and n- butyllithium), then in situ borylated with triisopropyl-borate and finally intermediate borate is oxidized with 35% hydrogen peroxide solution in water. ln another embodiment of the inventive process, the catalyst is represented by the following formula (IVa) or (IVb) : wherein the substituent R is the same or different on each position and is defined as in claim 1 ,

[0032] X and Y have the meanings as defined in claim 1 , any dashed line independently represents two hydrogens or preferably a double bond and W represents hydrogen, an alkali metal or an earth alkaline metal, preferably hydrogen. In another embodiment of the inventive process, the substituent R is the same or different on each position and represents halogen, a straight chain, branched chain or cyclic Ci to C20 aliphatic hydrocarbon or a C6to C18 aromatic hydrocarbon, said aliphatic hydrocarbon and / or aromatic hydrocarbon being substituted by one or more halogens, preferably F and / or Cl, SF5, NO2 or a straight chain, branched chain or cyclic Ci to C20 aliphatic hydrocarbon, optionally being substituted by one or more halogens, preferably F and / or Cl, SF5, NCh on the aliphatic hydrocarbon.

[0033] In a further embodiment of the inventive process as defined above for any formula (IV), (IVa) or (IVb), X and Y are the same or different and represent NRN, wherein RNis an electron withdrawing group, being the same or different on each position and being selected from: i. sulfinyl alkyl or sulfonyl alkyl, wherein alkyl is a Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; ii. sulfinyl aryl, or sulfonyl aryl, wherein aryl is a Ce to Cis aromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen , Ci to C6alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; iii. sulfinyl heteroaryl, or sulfonyl heteroaryl, wherein heteroaryl is a C2 to Cis heteroaromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen, Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; and wherein R and W have the meanings as defined before. ln yet another embodiment of the inventive process , the catalyst is represented by Formula (IVc)

[0034] (IVc) wherein R is the same on each position and is selected from hydrogen, C6to 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, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, C6to C18 aromatic hydrocarbons or C5 to C18 heteroaromatic hydrocarbons, optionally having one or more halogens, preferably F and / or Cl, SF5, NO2 or cyano on the aliphatic, aromatic or heteroaromatic hydrocarbon.

[0035] The catalyst as represented by formulae (IV), (IVa), (IVb) and (IVc) may be used as such in in the reaction system or in an immobilized form where the catalyst is bonded to a carrier or forms part thereof, prepared according to the process as described in W02025061703A1.

[0036] In the formulae (IV), (IVa), (IVb) and (IVc) , the broken / dashed line might optionally present a double bond, thus demonstrating a naphthalene ring system, or a hydrogenated double bond, demonstrating a 4H-naphthalene ring system, and both forms might be present in the catalysts as used in the inventive process.

[0037] The catalyst used here is based on imidodiphosphate (I DP) catalyst, the iminoimidodiphosphorimidate (iIDP) catalyst (List et al., J. Am. Chem. Soc. 2016, 138, 34, 10822) and imidodiphosphorimidate (IDPi) catalyst and may be prepared using the process as described in EP20200632.6. Used solvents are dried before use.

[0038] Definitions

[0039] The following definitions apply to the individual groups R, RNand W equally as follows.

[0040] A heteroatom or heterosubstituent as defined according to the invention can be selected from OH, F, Cl, Br, I, CN, NO2, l-Rs2, NO, NCO, -NCS, -SON, SO3H, a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF3)2, SF5, aliphatic, aromatic, heteroarmatic, primary, secondary, tertiary amine or ammonium bound through N atom, -O-alkyl (alkoxy), -O-aryl, -O-heteroaryl -O-SiRs3,-S-S-Rs, -S-Rs, -S(O)-RS, -S(O)2- Rs, -COOH, -CO2-RS, -BRS2, -PRS2, -OPRS2, amide, bound through C or N atom, formyl group, -C(O)-RS, -COOM, where M is a metal such as Li, Na, K, Cs, Ag. Rsmay be, independently from each other, the same or different and is each an aliphatic, heteroaliphatic, aromatic or heteroaromatic group, each optionally being further substituted by one or more heterosubstituents, aliphatic, heteroaliphatic, aromatic or heteroaromatic groups; and / or optionally bridged by an -O- atom, represents a halogenide. Aliphatic hydrocarbons including alkyl, alkenyl and alkinyl and may comprise straight-chain, branched and cyclic hydrocarbons.

[0041] Heteroaliphatic is a hydrocarbon including alkyl, alkenyl and alkinyl which may comprise straight-chain, branched and cyclic hydrocarbons with one or more carbon atoms substituted with at least one heteroatom.

[0042] In more detail, Ci-C2o-alkyl can be straight chain or branched and has 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Alkyl might be Ci-Ce-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewise 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.

[0043] Cycloalkyl might be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0044] Alkenyl might be C2-C20 alkenyl. Alkinyl might be C2-C20 alkinyl.

[0045] Said unsaturated alkenyl- or alkinyl groups can be used for linking the inventive compounds to a carrier such as a polymer to serve for an immobilized catalyst.

[0046] Halogen such as F, Cl, Br or I.

[0047] Alkoxy is preferably C1-C10 alkoxy such as methoxy, ethoxy, propoxy, terf-butoxy, butoxy, pentoxy, hexyloxy, etc and isomers thereof.

[0048] Cs-Cs-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-di hydro-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.

[0049] Optionally substituted means unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted for each hydrogen, such as persubstituted, on the hydrocarbon.

[0050] Aryl might be a Ce to C22 aromatic hydrocarbon and may be phenyl, naphthyl, anthracenyl, phenanthryl or biphenyl.

[0051] Arylalkyl might be benzyl.

[0052] Heteroaryl may be a C5 to C18 heteroaromatic hydrocarbon and may have one or more heteroatoms selected from among 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-pyrimidinyl, also 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-lndolyl, 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- or 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.

[0053] The present invention is further illustrated by the attached Figures. In the Figures, it is shown in:

[0054] Figure 1 : Routes to (— )-(Z)-p-santalol known in the prior art

[0055] Figure 2: Inventive route to (— )-(Z)-p-santalol

[0056] Experimental Part

[0057] Materials and Characterization llnless otherwise stated, all reactions were magnetically stirred and conducted in oven- dried (90 °C) or flame-dried glassware in anhydrous solvents under argon, applying standard Schlenk techniques. Solvents and liquid reagents, as well as solutions of solid or liquid reagents were added via syringes, stainless steel or polyethylene cannulas through rubber septa or through a weak argon counter-flow. Solid reagents were added through a weak argon counter-flow. Cooling baths were prepared in Dewar vessels, filled with ice / water (0 °C) or dry ice / acetone (-78 °C). Heated oil baths were used for reactions requiring elevated temperatures. Solvents were removed under reduced pressure at 40 °C using a rotary evaporator, and unless otherwise stated, the remaining compound was dried in high vacuum (103mbar) at rt. All given yields are isolated yields of chromatographically and NMR-spectroscopically pure materials, unless otherwise stated.

[0058] Chemicals were purchased from commercial suppliers (including abcr, Acros, Alfa Aesar, Fluorochem, Sigma-Aldrich, and TCI) and used without further purification unless otherwise stated.

[0059] Solvents were dried by distillation from an appropriate drying agent in the technical department of the Max-Planck-lnstitut fur Kohlenforschung and received in Schlenk flasks under argon. Other anhydrous solvents were purchased from commercial suppliers and used as received.

[0060] Reactions were monitored by thin layer chromatography (TLC) on silica gel pre-coated plastic sheets (0.2 mm, Macherey-Nagel). Visualization was accomplished by irradiation with UV light (254 nm and 366 nm) and / or p-anisaldehyde stain.

[0061] Column chromatography was carried out using Merck silica gel (60 A, 230-400 mesh, particle size 0.040-0.063 mm) using technical grade solvents. Elution was accelerated using compressed air. All fractions containing a desired substance were combined and concentrated in vacuo, then redissolved in an appropriate solvent and filtered through cotton to remove silica residues.

[0062] 1H,13C,19F,31P nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AV- 500, AV-400 or DPX-300 spectrometer in a suitable deuterated solvent. The solvent employed and respective measuring frequency are indicated for each experiment. Chemical shifts are reported with Me4Si serving as a universal reference of all nuclides and with two or one digits after the comma. The resonance multiplicity is described as s (singlet), d (doublet), t (triplet), q (quadruplet), p (pentet), hept (heptet), m (multiplet), and b (broad). All spectra were recorded at 298 K unless otherwise noted, processed with the program MestReNova 14.3, and coupling constants are reported as observed. The residual deuterated solvent signal relative to Me4Si was used as the internal reference in1H NMR spectra (e.g. CDCI3 = 7.26 ppm) and are reported as follows: chemical shift in ppm (multiplicity, coupling constant J in Hz, number of protons).13C,19F,31P NMR spectra were referenced according to H-values (IIIPAC recommendations 2008)2relative to the internal references set in1H NMR spectra (e.g.13C: Me4Si,19F: CCI3F,31P: H3PO4; each 0.00 ppm). Gas chromatography (GC) analyses on a chiral stationary phase were performed on HP 6890 and 5890 series instruments (split-mode capillary injection system, flame ionization detector (FID), hydrogen carrier gas). The conditions employed are described in detail for the individual experiments.

[0063] Specific rotations [a] were measured with a Rudolph RA Autopol IV Automatic Polarimeter at the indicated temperature (T) with a sodium lamp (sodium D line, A = 589 nm). Measurements were performed in an acid resistant 1 mL cell (50 mm length) with concentrations (g / (100 mL)) reported in the corresponding solvent.

[0064] EXAMPLES

[0065] General Procedure for the Preparation of Cvcloadduct (3a) [Diels-Alder Reaction! with Geranial (1a) as Enal:

[0066] Activated molecular sieves 5 (35 g) and BINOL-based IDPi catalyst of Formula I b wherein R = p-tBuCeH4, Y = X = NSO2C6F5, and W = H (1.5 mol%, 1.48 mmol, 2.47 g) were added in a flame-dried reaction vessel together with a stirring bar. MTBE (1.8M, 60 mL) was added and the obtained mixture was stirred for 15 min at room temperature until the catalyst is fully dissolved. Then geranial (1a) (1 equiv., 100 mmol, 17.05 mL) was added and the reaction mixture was stirred for additional 15 min before being cooled down in dry ice bath. To the cool reaction mixture cyclopentadiene (2) was added (4 equiv., 400 mmol, 33.05 mL) and the reaction vessel was put into -40°C cryostat for 5 days. After completion of the reaction (tracked by NMR) it was quenched by the addition of triethylamine (0.03 equiv., 0.4 mL) and allowed to warm up to room temperature. Molecular sieves were removed by filtration through a fritted glass filter and obtained solution was concentrated under reduced pressure. The crude product was purified by column chromatography hexane / MTBE (6:1) to afford 16.7 g (76.5% yield) of the pure product as yellowish oil with 99:1 er of major isomer (29.5 m BGB-178 / BGB-15 G / 615 column, injection temperature: 220°C, 110-230°C (1 °C / min), 0.6 bar H2).

[0067] The catalyst was recovered by washing the chromatography column with hexane / MTBE (1 :1) and acidified over Dowex resin.

[0068] 1H NMR (501 MHz, CDCI3): mixture of two diastereomers -10:1 , NMR data for the major diastereomer is reported. 5 9.36 (d, J = 4.0 Hz, 1 H), 6.36 (dd, J = 5.7, 2.8 Hz, 1 H), 6.31 (dd, J = 5.8, 3.2 Hz, 1 H), , 5.13 (tp, J = 7.1 , 1.4 Hz, 1 H), 3.02 (t, J = 2.9 Hz, 1 H), 2.57 (p, J = 1.7 Hz, 1 H), 2.52 (t, J = 3.7 Hz, 1 H), 2.12 - 2.04 (m, 2H), 1.75 - 1.59 (m, 10H), 0.93 (s, 3H).

[0069] 13C NMR (126 MHz, CDCI3) 6 206.71 , 138.25, 134.14, 131.61 , 124.35, 61.65, 52.67, 48.80, 47.17, 45.88, 44.43, 26.91 , 25.67, 23.68, 20.46.

[0070] [a]D25= - 66.55 (c = 0.57, CHCI3)

[0071] General Procedure for the Preparation of Cvcloadduct (3a) Using Solid Supported IDPi Catalyst

[0072] Activated molecular sieves 5 (80 mg) and solid supported catalyst based on a Binole based IDPi catalyst Formula IVb [R = p-tBuC6H4, Y = X = NSO2C10F7, W = H] (~1.5 mol%, 8 mg) were added in a flame-dried reaction vessel together with a stirring bar. MTBE (1.8M, 120 mcL) was added and the obtained mixture was stirred for 15 min at room temperature until the catalyst is fully dissolved. Then geranial (1 equiv., 0.2 mmol, 34 mcL) was added and the reaction mixture was stirred for additional 15 min before being cooled down in dry ice bath. To the cool reaction mixture cyclopentadiene was added (4 equiv., 0.8 mmol, 66 mcL) and the reaction vessel was put into -40°C cryostat for 5 days.

[0073] After completion of the reaction it was quenched by the addition of triethylamine and allowed to warm up to room temperature. Molecular sieves and the solid supported catalyst were removed by filtration through a fritted glass filter and obtained solution was concentrated under reduced pressure.

[0074] The crude product was purified by column chromatography hexane / MTBE (6:1) to afford the 10.5 mg (24 % yield) of pure product as mixture of two diastereomers -10:1 , with 99:1 er of the major isomer (29.5 m BGB-178 / BGB-15 G / 615 column, injection temperature: 220°C, 110-230°C (1°C / min), 0.6 bar H2).

[0075] General Procedure for Aldehyde Reduction with NaBH4:

[0076] To a stirred solution of aldehyde obtained in previous step (1 .0 equiv., 6.89 mmol, 1505 mg) in EtOH (0.17M, 40 mL) was added NaBH4(1.5 equiv., 10.34 mmol, 391 mg) at room temperature and stirring was continued for 3 h. The reaction mixture was diluted with Et2O (40 mL), washed with H2O (3x100 mL) and saturated aqueous NaCI (100 mL), dried over anhydrous MgSO4and concentrated under reduced pressure to give crude alcohol in 84% yield (1280 mg) as colorless oil. The crude product was used directly in the next step.

[0077] Analytical sample was purified by column chromatography hexane / MTBE (4:1) to afford the pure product in 80% yield.

[0078] 1H NMR (501 MHz, CDCI3) mixture of two diastereomers 10:1 , NMR data for the major diastereomer is reported. 5 6.23 (dd, J = 5.7, 3.1 Hz, 1 H), 6.18 - 6.13 (m, 1 H), 5.13 (tdd, J = 7.2, 2.9, 1.5 Hz, 1 H), 3.45 (dd, J = 10.5, 6.1 Hz, 1 H), 3.27 - 3.19 (m, 2H), 2.90 (d, J = 3.7 Hz, 1 H), 2.45 (q, J = 1.7 Hz, 1 H), 2.04 (dq, J = 12.7, 6.7 Hz, 2H), 1.70 (d, J = 1.6 Hz, 3H), 1.69 - 1.60 (m, 5H), 1.56 (ddd, J = 13.4, 11.1 , 5.7 Hz, 1 H), 1.51 - 1.38 (m, 2H), 0.75 (s, 3H).

[0079] 13C NMR (126 MHz, CDCI3) 6 138.4, 133.8, 131.2, 125.0, 64.6, 53.1 , 51.3, 46.6, 45.4, 44.7, 43.7, 25.7, 23.9, 18.8, 17.6.

[0080] [a]D25= - 17.59 (c = 0.71 , CHCI3)

[0081] Reduction of the Double Bond with Ni P2 to Afford Compound (4):

[0082] To a solution of Ni(OAc)2x4H2O (0.2 equiv., 240 mg, 0.96 mmol) in 95% ethanol (100 mL) was added in one portion a solution of NaBH4 (0.16 equiv., 29 mg, 0.77 mmol) and NaOH (0.008 equiv., 1 .5 mg, 0.038 mmol) in aqueous ethanol (35 mL EtOH + 0.5 mL of H2O). The reaction flask was purged with hydrogen and the substrate unsaturated alcohol (1 equiv., 1050 mg, 4.8 mmol) was added as a solution in 20 mL of EtOH. Reaction mixture was stirred at room temperature for 3 h under H2 atmosphere.

[0083] The reaction mixture was then poured into 1 M HCI (150 mL) and the mixture was extracted with diethyl ether (2x100 mL). The organic phases were washed with brine, dried over MgSO4 and evaporated to afford the product as yellow oil in 82% yield, which was used without purification in the next step.

[0084] 1H NMR (501 MHz, CDCI3) mixture of two diastereomers -10:1 , NMR data for the major diastereomer is reported. 5 5.10 (dddd, J = 8.5, 5.7, 2.9, 1.4 Hz, 1 H), 3.74 (q, J = 7.0 Hz, 1 H), 3.66 - 3.60 (m, 2H), 2.30 (t, J = 3.2 Hz, 1 H), 2.01 - 1.89 (m, 3H), 1.71 - 1.56 (m, 10H), 1.34 - 1.21 (m, 5H), 0.84 (s, 3H).

[0085] 13C NMR (126 MHz, CDCI3) 6 131.09, 125.04, 61.32, 51.65, 47.24, 44.65, 39.92, 39.34, 37.01 , 25.69, 24.57, 22.87, 20.65, 17.60, 17.02.

[0086] [a]D25= - 3.55 (c = 0.56, CHCI3)

[0087] Two discussed above steps can also be performed in a one-pot fashion starting with reduction of double bond and then adding excess of NaBH4 (2 equiv.) to provide product (4) in 62% overall yield.

[0088] Synthesis of Carbonate (5) (X = C(=O)OMe):

[0089] To a solution of the alcohol (4) (1 equiv., 714 mg, 3.21 mmol) in THF (40 ml) cooled to - 15°C was added 2.5 M n-BuLi in hexanes (1.05 equiv., 1.35 mL, 3.37 mmol). After complete addition, the solution was stirred for 15 min and then treated with methyl chloroformate (1 .05 equiv., 0.266 mL, 3.37 mmol). Stirring was continued at 0°C for 20 min. After addition of Et2O (30 mL) and H2O (40 mL), organic layer was separated and the aqueous layer was extracted with ether (40 mL). Combined organic layers were washed with H2O (50x3 mL), then sat. aq. NaCI (50 mL), dried over Na2SC>4, and evaporated to afford the crude carbonate (5) which was purified by column chromatography (hexane:MTBE 10:1) to afford the pure product in 85% yield.

[0090] 1H NMR (501 MHz, CDCI3) mixture of two diastereomers 10:1 , NMR data for the major diastereomer is reported. 5 5.10 (tdp, J = 6.9, 4.2, 1.4 Hz, 1 H), 4.19 - 4.13 (m, 2H), 3.79 (s, 3H), 2.27 (td, J = 3.9, 2.0 Hz, 1 H), 2.01 - 1.90 (m, 3H), 1.83 - 1.75 (m, 1 H), 1.72 - 1.55 (m, 8H), 1.47 - 1.18 (m, 6H), 0.87 (s, 3H).

[0091] 13C NMR (126 MHz, CDCI3) 6 155.91 , 131.15, 124.96, 67.24, 54.61 , 47.73, 47.52, 47.22, 44.38, 39.82, 37.04, 25.68, 24.50, 22.79, 20.81 , 17.58, 17.16.

[0092] [a]D25= - 14.36 (c = 0.59, CHCI3)

[0093] Pyrolysis of the Carbonate (5) to Yield Product (6) (B-Santalene):

[0094] Carbonate obtained in the previous step (288 mg, 1 mmol) was pyrolyzed at 580 °C (10 ml / min, quartz tube, N2). Obtained oil was purified column chromatography hexane / MTBE (9:1) to afford the pure product in 64% (135 mg) yield as yellowish oil.

[0095] 1H NMR (501 MHz, CDCI3) 6 5.19 - 5.04 (m, 1 H), 4.77 (s, 1 H), 4.51 (s, 1 H), 2.69 (dd, J = 4.7, 1.7 Hz, 1 H), 2.18 - 1.85 (m, 3H), 1.72 (s, 3H), 1.65 (m, 3H), 1.59 - 1.01 (m, 8H), 1.03 (s, 3H).

[0096] 13C NMR (126 MHz, CDCI3) 6 166.4, 130.9, 124.9, 99.2, 46.8, 44.8, 44.4, 41.2, 37.0, 29.6, 25.5, 23.7, 23.5, 22.7, 17.4.

[0097] [a]D25= - 107.16 (c = 0.69, CHCI3)

[0098] Allylic Oxidation of B-Santalene (6) to Yield (-)-(Z)-B-Santalol (7):

[0099] To solution of potasium terf-butoxide (3 equiv., 222 mg, 1.98 mmol) in THF (10 mL) cooled down to -78°C was added dropwise a 2.5 M n-butyllithium in hexanes (3 equiv., 0.80 mL, 1.98 mmol). The resulting yellow solution was stirred for 15 min before adding dropwise 2,2,6,6-tetramethylpiperidine (3 equiv., 0.33 mL, 1.98 mmol). The obtained solution was further stirred for 15 min before adding [3-santalene (6) from the previous step (1 equiv., 0.33 m, 0.66 mmol). The reaction mixture was stirred for 1 hour at -78°C. Then triisopropylborate (3 equiv., 0.46 mL, 1.98 mmol) was added and the reaction was allowed to warm to room temperature. 35% Aqueous solution of hydrogen peroxide (6 equiv., 0.39 mL, 3.96 mmol) was added slowly and the reaction was stirred for an additional 30 minutes. The reaction is then diluted with water (20 mL) and extracted with MTBE (3 x 15 mL), washed twice with 1 M HCI (20 mL), and brine (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (hexane:ethyl acetate 4:1) to afford the pure product (7) in 35% yield with 8:1 ZE ratio.

[0100] 1H NMR (501 MHz, CDCI3) 65.31 (td, J= 7.5, 1.6 Hz, 1H), 4.76 (s, 1H), 4.50 (s, 1H), 4.14 (s, 2H), 2.69 (dd, J= 4.5, 1.7 Hz, 1H), 2.17-1.97 (m, 3H), 1.79 (q, J= 1.3 Hz, 2H), 1.75- 1.66 (m, 3H), 1.50 - 1.39 (m, 2H), 1.33-1.23 (m, 4H), 1.08 (s, 3H).

[0101] 13C NMR (126 MHz, CDCI3) 5166.2, 134.1, 126.6, 99.6, 69.0, 46.7, 44.7, 44.5, 40.9, 37.3, 29.6, 23.7, 23.2, 22.5, 13.6.

[0102] [a]D25= - 104.47 (c = 0.52, CHCI3)

Claims

Claims1. Process of an enantioselective Diels-Alder reaction whereby an enal compound of Formula (1) O=C-C=CR1R2is reacted with cyclopentadiene (2) in the presence of an IDPi catalyst (IV) whereby a cycloaddition compound (3) is obtained which reaction is represented in the following reaction scheme:Wherein:R1represents straight chain, cyclic or branched Ci-Cw-alkyl, Ci-Cw-alkenyl, C1-C18- alkynyl, each alkyl, alkenyl or alkynyl optionally containing one or more heteroatoms, R2represents C Ce-alkyl, preferably methyl,, and the IDPi-catalyst is represented by Formula (IV):wherein in said formula (IV):R is the same or different on each position and is each selected from hydrogen, halogen, SF5, NO2, cyano, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, optionally having one or more halogens, preferably F or Cl, SF5, NO2 or cyano on the aliphatic hydrocarbon, C6to 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, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons,C6to Cis aromatic hydrocarbons or C5 to C18 heteroaromatic hydrocarbons optionally having one or more heteroatoms, preferably F and / or Cl, SF5, NO2 or cyano on the aliphatic or aromatic hydrocarbon, wherein any dashed line independently represents a double bond or two hydrogens, wherein X and Y are the same or different and represent NRN; wherein:RNis an electron withdrawing 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 Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro, or SFs; 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 C6to C18 aromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen, Ci to C6alkoxy, halogen, preferably F and / or Cl, cyano, nitro, or SF5; iii. -heteroaryl, -CO-heteroaryl, -(CO)-O-heteroaryl, sulfinyl heteroaryl, sulfonyl heteroaryl, -(P=O)-di-heteroaryl, phosphinyl diheteroaryl, phosphinyl aryl heteroaryl, 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 Ci to Ce alkyl optionally substituted by at least one halogen, Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro, or SFs; and wherein 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 -BRIRIIRIHor a substitutedsilicon -SiRlRllRl", wherein R1, R" and R111may be same or different and each stands for hydrogen, halogen, an optionally -O- bonded Ci 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 Ce to C18 aromatic hydrocarbon or partially arene-hydrogenated forms thereof, each hydrocarbon optionally being substituted by one or more groups selected from Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, or one or more heterosubstituents, W being preferably selected from hydrogen, alkali metal or earth alkaline metal.

2. Process according to claim 1 , wherein the IDPi catalyst is represented by the following formula (IVa) or (IVb) :wherein the substituent R is the same or different on each position and is defined as in claim 1 ,X and Y have the meanings as defined in claim 1;any dashed line independently represents two hydrogens or preferably a double bond and W represents hydrogen, an alkali metal or an earth alkaline metal.

3. Process according to any one of claims 1 to 2, wherein the substituent R is the same or different on each position and represents halogen, a straight chain, branched chain or cyclic Ci to C20 aliphatic hydrocarbon or a Ce to C18 aromatic hydrocarbon, saidaliphatic hydrocarbon and / or aromatic hydrocarbon being substituted by one or more halogens, preferably F and / or Cl, SF5, NO2 or a straight chain, branched chain or cyclic Ci to C20 aliphatic hydrocarbon, optionally being substituted by one or more halogens, preferably F and / or Cl, SF5, NCh on the aliphatic hydrocarbon.

4. Process according to any one of the preceding claims, wherein, in any formula (IV), (IVa) or (IVb), X and Y are the same or different and represent NRN, wherein RNis an electron withdrawing group, being the same or different on each position and being selected from: j. sulfinyl alkyl or sulfonyl alkyl, wherein alkyl is a Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; ii. sulfinyl aryl, or sulfonyl aryl, wherein aryl is a Ce to Cis aromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen , Ci to Ce alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; iii. sulfinyl heteroaryl, or sulfonyl heteroaryl, wherein heteroaryl is a C2 to Cis heteroaromatic hydrocarbon, optionally having at least one substituent selected from Ci to Ce alkyl optionally substituted by at least one halogen, Ci to C6alkoxy, halogen, preferably F and / or Cl, cyano, nitro or SF5; and wherein R and W have the meanings as defined in any one of the preceding claims.

5. Process according to any one of the preceding claims, wherein the IDPi catalyst is represented by Formula (IVc)(IVc)wherein R is the same on each position and is selected from hydrogen, C6to C18 aromatic hydrocarbons or C5 to C18 heteroaromatic hydrocarbons, each aromatic or heteroaromatic hydrocarbon optionally being substituted by one or moresubstituents selected from halogen, SF5, NO2, cyano, Ci to C20 straight chain, branched chain or cyclic aliphatic hydrocarbons, C6to C18 aromatic hydrocarbons or C5 to Cis heteroaromatic hydrocarbons, optionally having one or more halogens, preferably F and / or Cl, SF5, NO2 or cyano on the aliphatic, aromatic or heteroaromatic hydrocarbon, and wherein RNis an electron withdrawing group, being the same or different on each position; and RNand W have the meanings as defined in any one of the preceding claims.

6. Process according to any one of the preceding claims wherein geranial (1a) is used as enal compound (1) which is reacted with cycylopentadiene (2) whereby an enantiopure Diels-Alder cycloaddition adduct of Formula (3a) is obtained.

7. Process according to claim 6, comprising the additional steps of converting the enantiopure Diels-Alder cycloaddition adduct of Formula (3a) via a carbonyl reduction and selective double bond hydrogenation into compound (4), eliminating the hydroxyl group of compound (4), preferably via intermediating mesylate / tosylate / acetate or carbonate, to compound (6), and followed by a final regioselective allylic oxidation whereby enantiopure (-)-(Z)-[3-santalol (7) is obtained.(-)-(Z)-p-santalol(7)

Images