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  • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
  • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
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  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/75—Reactions with formaldehyde
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Definitions

• R represents a Me or Et group
• said compound is in the form of any one of its stereoisomers or mixture thereof.
• the invention concerns also the compound (I) as well as its precursors and the process to manufacturing compound (I). Furthermore, it concerns also the use of compound (I) for the synthesis of ⁇ -santalol or of derivatives thereof.
• the compounds of formula (I) are novel compounds, and are useful starting materials for the preparation of ⁇ -santalol, and derivatives thereof, in a short and effective manner.
• the ⁇ -santalol, and derivatives thereof, are well known perfuming ingredients, some of which of particular relevance. Therefore, there is always a need for alternative synthesis to produce them.
• EP 10213 however said process, besides the fact that it is very long, requires many chlorinated intermediates (not optimal for a use in perfumery) and provides a very low yield (about 13%) for the preparation of the unsaturated aldehyde (II) of the present invention (see below);
• a first object of the present invention is a compound of formula
• R represents a Me or Et group
• R a represents a hydrogen atom or a Si(R b ) 3 or (R C ) 2 COH group
• R b representing Ci_s group or a phenyl group
• R c representing a Ci_s group or a phenyl group.
• ⁇ -santalol an important perfuming ingredient
• derivatives thereof can be advantageously prepared starting from an enynol of formula (I-a) wherein R a is a hydrogen atom, i.e. a compound of formula
• a compound (I) or (I-a) wherein R is Me is the preferred embodiment, since it is a direct precursor of ⁇ -santalol.
• Said compound (I) can be advantageously prepared from the compounds (I-a) wherein R a is not a hydrogen atom.
• a second object of the present invention concerns a process for the preparation of a compound (I), as defined above, comprising the following steps: a) reacting 2-R-3-methylene-bicyclo[2.2.1]heptane, wherein R has the same meaning as for compound (I), with a compound of formula R a -C ⁇ CCHO, wherein R a represents a Si(R b ) 3 or (R C ) 2 COH group, R b and R c representing, independently from each other, Ci_s group or a phenyl group, in the presence of a Al, B or Sn derivative Lewis acid as catalyst ("ene” reaction), to obtain a compound of formula (I-a) wherein R a represents a Si(R b ) 3 or (R C ) 2 COH group, R b and R c representing, independently from each other, Ci_s group or a phenyl group; and b) treating the obtained compound (I-a) with a suitable base or a fluorine
• the starting material of the above process is 2endo-methyl-3-methylene-bicyclo[2.2.1]heptane, in an optically active or racemic form.
• the catalysts necessary for an "ene reaction” are well known by a person skilled in the art, however one may cite, as non limiting examples, the following compounds: Me 2 AlCl, EtAlCl 2 , SnCl 4 or BF 3 .
• the bases of fluorine salt necessary for step b) are well known by a person skilled in the art, however one may cite, as non limiting examples, the following compounds: KOH, borax (Na 2 B 4 O ? ) or KF.
• R b is defined as for compound (I-a);
• Ar represents a phenyl group optionally substituted by one, two or three Me, Et CF 3 , OMe or OEt;
• R d represents t-Bu, a phenyl group, a benzyl group or a 5-Me-furyl group
• R e represents a hydrogen atom, a Ci-C 3 alkyl group or a benzyl group
• R f represents t-Bu, a phenyl group, a benzyl group; (to obtain S-R-bicycloP ⁇ .ljhept-S-ene ⁇ exo-carbaldehyde);
• b' reducing the Diels Alder adduct obtained in step a') into a saturated alcohol, and optionally converting said alcohol into an ester, carbonate or a sulfonate;
• c' converting said alcohol, ester, carbonate or sulphonate, into the desired product.
• Step a' is a known reaction and a person skilled in the art is able to apply its standard knowledge to perform them (e.g. see MacMillan et al. in WO 03/002491 or in J.Am.Chem.Soc. 2005, 127, 11616 or see Hayashi et al. in Angew.Chem.Int.ed. 2008, 47,
• Steps b') and c') are well known reactions and a person skilled in the art is able to apply its standard knowledge to perform them. Examples of how performing said process is provided in the Example part of the description.
• ester, carbonate or sulfonate it is meant the usual meaning in the art, i.e. that the oxygen atom of said saturated alcohol is bonded to an acyl, alkoxycarbonyl or sulfonate group (e.g. a Ci_ 7 group).
• R is a methyl group
• enynol (I) has been found to be a useful precursor of ⁇ -santalol, and derivatives thereof. Indeed enynol (I) can be used for the preparation of an aldehyde (II), as defined below, which is known to be an important intermediate in the preparation of ⁇ -santalol and derivatives thereof.
• a second object of the present invention is a process for the preparation of a compound of formula
• M represents Zn(II), Cu(I) or Ag(I), n represents an integer from 0 to 4, L represents a C 1 -C 4 nitrile, COHSCN, or di-nitrile, or a Cs-Cs pyridine derivative, and Z a weakly or non coordinating anion.
• said M(L) n Z salt is Cu(L) 4 Z, wherein L is Ci-C 4 nitrile, or a AgZ salt.
• Z is a R 4 S(V, wherein R 4 is a chlorine or fluorine atom or an Ci-Cs alkyl, fluoroalkyl or fluoroaryl group, BF 4 -, PF 6 -, SbCl 6 ", SbF 6 -, or BR 5 4 " , wherein R 5 is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF 3 groups.
• M is Ag(I) then Z may also represent a nitrate or a perchlorate.
• Z is BF 4 -, PF 6 -, SbCl 6 " , C 6 F 5 SO 3 " , BPh 4 " , CF 3 SO 3 " or yet B[3,5-(CF 3 ) 2 C 6 H 4 ] 4 -, more preferably BF 4 " .
• an alkaline salt of the anion Z can be also added, as additive, an alkaline salt of the anion Z.
• a salt of formula KZ or CsZ can be added.
• the transformation of (I) into (II), in any of its embodiments, is preferably carried out in the presence of solvent.
• solvent Non-limiting examples of such a solvent are esters, aromatic hydrocarbons, chlorinated solvents and mixtures thereof. More preferably, the solvent is toluene or 1,2-dichloroethane and mixtures thereof.
• the temperature, at which the transformation of (I) into (II) according to the invention can be carried out in any of its embodiments, is comprised between 0 0 C and 150 0 C, preferably between 40 0 C and 70 0 C.
• a person skilled in the art is also able to select the preferred temperature as a function of the melting and boiling point of the starting and final products and/or an eventual solvent.
• the salt M(L) n Z can be added to the reaction medium in a large range of concentrations.
• the salt concentration will be comprised between 0.01 and 0.10 molar equivalents.
• the optimum concentration of the M(L) n Z will depend on the nature of the latter and on the desired reaction time.
• the additive can be added to the reaction medium in a large range of concentrations.
• the additive concentration will be comprised between 10 and 120 %, relative to the weight of the salt.
• the compounds (I-a), (I) or (II) can be in the form of any one of its stereoisomers or mixture thereof.
• stereoisomer it is intended any diastereomer, enantiomer, racemate or carbon-carbon isomer of configuration E or Z.
• compound (I-a) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1R,4S) stereoisomer, i.e. a compound having the absolute configuration as shown in formula (I-a')
• said compound (I) consists essentially in the compound (I-a').
• compound (I) is in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1R,4S) stereoisomer, i.e. a compound having the absolute configuration as shown in formula (F)
• said compound (I) consists essentially in the compound (F).
• compounds (I) one may cite l-[-3- methylbicyclo[2.2.1]hept-2-en-2-yl]-3-butyn-2-ol or its stereoisomer l-[(lR,4S)-3- methylbicyclo[2.2.1]hept-2-en-2-yl]-3-butyn-2-ol.
• compound (II) is in the form of a mixture of isomers comprising more than 50% (w/w) of the 2-endo-R configuration.
• said compound (II) can be in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1S,2S,4R) stereoisomer, i.e. a compound having the absolute configuration as shown in formula (IF)
• said compound (II) consists essentially in the compound (IF).
• compound (I) is a useful starting material for the preparation of ⁇ -santalol or a derivative thereof
• the present invention concerns also the use of a compound (I), as intermediate, in the synthesis of a compound of formula (III) as defined herein below.
• the invention concerns also a process for obtaining a compound of formula ( ⁇ -santalol or derivatives)
• R represents a Me or Et group
• R 1 represents a hydrogen atom or a Me or Et group
• X represents a CH 2 OR 2 , CHO or a CH(OR 3 ) 2 group, R 2 representing a hydrogen atom, a C 1 -C 3 alkyl, alkenyl or acyl group, R 3 representing, when taken separately, a C 1 -C 3 alkyl, alkenyl or acyl group or, when taken together, a C 2 -C 5 alkanediyl group; and the dotted lines represents a single or double bond, said compound being in the form of any one of its stereoisomers or mixture thereof; said process comprising the following steps: 1) transforming an enynol of formula (I), as defined above, into an aldehyde of formula (II), as defined above, by a process as described above; and T) transforming the aldehyde of formula (II), into a compound of formula (III), as defined above.
• R represents a methyl group.
• R 1 represents a methyl or ethyl group.
• R 2 represents a hydrogen atom or a C 1 -C 3 acyl group.
• R 3 represents, when taken separately, a methyl or ethyl group or, when taken together, a C 2 -C 4 alkanediyl group.
• the compounds (III) can be in the form of any one of its stereoisomers or mixture thereof.
• stereoisomer it is intended any diastereomer, enantiomer, racemate or carbon-carbon isomer of configuration E or Z.
• compound (III) is in the form of a mixture of isomers comprising more than 50% (w/w) of the 2-endo-R configuration.
• said compound (III) can be in the form of a mixture of stereoisomers comprising more than 50% (w/w) of the (1S,2S,4R), or even (2Z,1S,2S,4R), stereoisomer, i.e. a compound having the absolute configuration as shown in formula (HF)
• said compound (III) consists essentially in the compound (HF)-
• ⁇ -santalol As typical examples of compounds (III) one may cite the following: ⁇ -santalol, (-)- ⁇ -santalol (i.e (2Z)-2-methyl-5-[(lS,2R,4R)-2-methyl-3- methylenebicyclo[2.2.1]hept-2-yl]-2-penten-l-ol), ⁇ -santalal, ⁇ -santalyl benzoate, ⁇ - santalyl butyrate, ⁇ -santalyl formate, ⁇ -santalyl proprionate.
• the first step of said process is as defined above.
• the Wittig-hydroxyalkylation addition can be performed according to the method reported by R.Snowden et al. in Helvetica Chemica Acta, 1981, 64, 25.
• the Wittig addition allows obtaining directly compound (III) where X represents CH 2 OR 2 , wherein R 2 is a hydrogen atom or some acyl groups. If a compound (III) with a different meaning of R is desired, then said compound can be obtained by converting the alcohol (III) (X being CH 2 OH) with any standard method as well known by a person skilled in the art. For example, an aldehyde of formula (III) can be obtained by oxidation of the alcohol (III), or an ester (III) can be obtained by esterification of said alcohol (III), etc.
• the aldehyde (II) can be converted into the compound (HF), see below, by performing the following reactions: a) reducing (hydrogenation) the aldehyde (II) into and aldehyde of formula (IV)
• R 4 represents a C 1 -C 3 alkyl, alkenyl or acyl group or a C3-C8 silyl group; d) reducing the enolate (VI) into a compound (VII)
• Step e) is described as optional only because many of the compounds (VII) are already included in formula (III), and therefore, depending on the desired compound (III) the last step is not necessary.
• said compounds (IV) to (VII) possess a configuration corresponding to the one described above for compounds (IF) or (HF).
• Steps a) to e) can be performed according to standard methods well known by a person skilled in the art.
• step a) or b) may cite the following method for each step: step a) or b) according to EP 10213; step c) according to Simmons et al. in Helv.Chim.Acta, 1988, 71, 1000, or WO 2005/037243; and step d) according to Shibasaki et al., in J.Org.Chem., 1988, 53, 1227 (where is reported the [1,4] hydrogenation of a dienol acetate derivative) or according to WO 08/120175.
• step a) or b) according to EP 10213
• step c) according to Simmons et al. in Helv.Chim.Acta, 1988, 71, 1000, or WO 2005/037243
• step d) according to Shibasaki et al., in J.Org.Chem., 1988, 53, 1227 (where is reported the [1,4] hydrogenation of a dienol acetate derivative) or according to WO 08
• the orange mixture was hydrolyzed with aqueous HCl 5%.
• the aqueous layer was extracted twice with Et 2 O, and the combined organic layers were washed twice with H 2 O.
• the aqueous fraction was extracted twice with Et 2 O and the combined organic fractions were washed with H 2 O, brine, dried over Na 2 SO 4 and filtered off.
• the solvents were removed under vacuum to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the desired compound (42.24 g, 95% purity) in 86% yield.
• Ethynylmagnesium bromide in THF (0.5 M, 210.0 ml, 105.0 mmol) was placed in a reactor under a nitrogen atmosphere at room temperature and (3-Methyl- bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde (12.15 g, 80.9 mmol) in THF (200 ml) was introduced over a 90 minutes period and the mixture turned orange. The mixture was further stirred at room temperature for 30 minutes and was hydrolyzed with aqueous HCl 5% at room temperature.
• Trimethylsilylethyne (5.0 ml, 36.10 mmol) in THF (25.0 ml) was dropwsise added to a solution of EtMgBr in THF (IM, 44.0 ml, 44.0 mmol) at 10-15 0 C under nitrogen.
• IM EtMgBr
• IM EtMgBr
• Et 2 O Et 2 O
• Me 2 AlCl (IM in hexanes, 1.1 ml, 1.1 mmol) was dropwise added to a solution of trimethylsilyl-propynal (154.0 mg, 1.22 mmol) and 2-endo-methyl-3-methylene- bicyclo[2.2.1]heptane (140.0 mg, 1.15 mmol) in dichloromethane (5.0 ml) at -78°C under nitrogen. The mixture was stirred at -78°C for 15 minutes and was hydrolyzed with aqueous HCl 5%. The temperature was then slowly allowed to increase to room temperature and extracted twice with CH 2 Cl 2 .
• Pd/CaCO 3 (5% w/w, 93.0 mg) was placed into a two neck round bottom flask in methanol (30 ml) and the atmosphere was purged with N 2 before adding 3-(2-methyl-3- methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-l-al (1.886 g, 10.70 mmol). The atmosphere was further purged with nitrogen followed with hydrogen at room temperature. The mixture was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours.
• the methyl-norbornenols were hydrogenated (5% of 10% Pd on C; Et 2 O, 99% yield).
• the compound thus obtained was diluted in pentane (5%) and pyrolyzed at 415°C through a 3 m column under a nitrogen flow to afford the optically active endo-enriched title compound in ca.

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