WO2009141781A1 - Process for the preparation of beta-santalol and derivatives thereof - Google Patents

Process for the preparation of beta-santalol and derivatives thereof Download PDF

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Publication number
WO2009141781A1
WO2009141781A1 PCT/IB2009/052048 IB2009052048W WO2009141781A1 WO 2009141781 A1 WO2009141781 A1 WO 2009141781A1 IB 2009052048 W IB2009052048 W IB 2009052048W WO 2009141781 A1 WO2009141781 A1 WO 2009141781A1
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group
compound
formula
mixture
methyl
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PCT/IB2009/052048
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French (fr)
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Charles Fehr
Magali Vuagnoux
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Firmenich Sa
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Priority to JP2011510079A priority Critical patent/JP5550637B2/en
Priority to AT09750238T priority patent/ATE527228T1/en
Priority to EP09750238A priority patent/EP2282985B1/en
Priority to CN200980118062XA priority patent/CN102036941B/en
Priority to US12/936,325 priority patent/US7902393B2/en
Publication of WO2009141781A1 publication Critical patent/WO2009141781A1/en
Priority to IL209363A priority patent/IL209363A/en
Priority to US13/012,567 priority patent/US8119826B2/en
Priority to IL226276A priority patent/IL226276A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/05—Alcohols containing rings other than six-membered aromatic rings
    • C07C33/14—Alcohols containing rings other than six-membered aromatic rings containing six-membered rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—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
    • C07C45/62—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 hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—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
    • 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
    • C07C45/74—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—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
    • 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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    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/283—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
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    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

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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Abstract

The present invention concerns a process for the preparation of a compound of formula (I) wherein R represents a Me or Et group, as well as said compound in the form of any one of its stereoisomers or mixture thereof. The invention concerns also the use of compound (I) for the synthesis of β-santalol or of derivatives thereof.

Description

PROCESS FOR THE PREPARATION OF BETA-SANTALOL AND DERIVATIVES THEREOF
Technical field The present invention relates to the field of organic synthesis and more specifically it concerns a process for the preparation of a compound of formula
Figure imgf000002_0001
wherein R represents a Me or Et group, and 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 β-santalol or of derivatives thereof.
Prior art
The compounds of formula (I) are novel compounds, and are useful starting materials for the preparation of β-santalol, and derivatives thereof, in a short and effective manner. The β-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.
To the best of our knowledge, all known syntheses are very long or require expensive starting materials or reagents or even steps which are too expensive for an industrial process (e.g. see Brunke at al., in Rivista Italiana EPPOS, 1997, 49). In particular one may cite the following references, which are representative of the best examples of processes for the preparation of β-santalol:
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. Krotz et all, in Tet.Asym, 1990, 1, 537: relatively short synthesis , however it requires two Wittig reactions, or the equivalent, and expensive reagents. The aim of the present invention is to provide a more industrial process for the preparation of β-santalol, and derivatives thereof. Indeed the present invention shortens the overall process of preparation of the targeted compounds by allowing the one-step creation of a suitably functionalised side-chain moiety (with the correct configuration) together with the concomitant formation of the methylene function (without the mandatory need of a Wittig olefination).
Description of the invention
A first object of the present invention is a compound of formula
Figure imgf000003_0001
in the form of any one of its stereoisomers or mixture thereof , and wherein R represents a Me or Et group, and Ra represents a hydrogen atom or a Si(Rb)3 or (RC)2COH group, Rb representing Ci_s group or a phenyl group and Rc representing a Ci_s group or a phenyl group.
Indeed, we have now found that β-santalol (an important perfuming ingredient), and derivatives thereof, can be advantageously prepared starting from an enynol of formula (I-a) wherein Ra is a hydrogen atom, i.e. a compound of formula
(I)
Figure imgf000003_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein R represents a Me or Et group.
In particular, a compound (I) or (I-a) wherein R is Me is the preferred embodiment, since it is a direct precursor of β-santalol. Said compound (I) can be advantageously prepared from the compounds (I-a) wherein Ra is not a hydrogen atom. Consequently, 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 Ra-C≡CCHO, wherein Ra represents a Si(Rb)3 or (RC)2COH group, Rb and Rc 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 Ra represents a Si(Rb)3 or (RC)2COH group, Rb and Rc 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 salt to obtain compound (I).
According to a particular embodiment, 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: Me2AlCl, EtAlCl2, SnCl4 or BF3. 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 (Na2B4O?) or KF.
The compound 2-R-3-methylene-bicyclo[2.2.1]heptane, racemic or in an optically active form and wherein R has the same meaning provided above, can be obtained according to the methods described in the prior art, or more conveniently according to a new process, which is also an object of the invention, comprising the following steps: a') reacting cyclopentadiene with a trans aldehyde RHC=CHCHO, wherein R has the same meaning as above, under Diels Alder conditions, in the presence of an optically active salt obtained by: reacting together an acid H(Anion) and a racemic or optically active 2-Rd-3-Re-5-Rf-4-imidazolidinone derivative or a racemic or optically active prolinol derivative of formula (C4H8N)-2-CAr20SiRb 3; wherein Anions stand for an anion selected in the group consisting of Cl", Cl(V, a R8S(V or R8CO2 ", wherein R8 is a C1-C7 hydrocarbon group or an Ci-Cs fluoroalkyl or fluoroaryl group, ClSO3 ", FSO3 ", BF4-, PF6-, SbCl6", AsCl6", SbF6", AsF6" or B(Rh)4 ", wherein Rh is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF3 groups;
Rb is defined as for compound (I-a); Ar represents a phenyl group optionally substituted by one, two or three Me, Et CF3, OMe or OEt;
Rd represents t-Bu, a phenyl group, a benzyl group or a 5-Me-furyl group; Re represents a hydrogen atom, a Ci-C3 alkyl group or a benzyl group; and Rf 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,
6634 or in Org. Lett., 2007, 9, 2859). Examples of how performing said process is provided in the Example part of the description.
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. For the sake of clarity, by "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).
Preferably R is a methyl group, and the aldehyde RHC=CHCHO is crotonaldehyde (i.e. the product obtained by said process, i.e. of steps a') and b') and c'), is 2-Me-3-methylene-bicyclo[2.2.1]heptane).
Said process is particularly useful for the preparation of 2endo-R-3-methylene- bicyclo[2.2.1]heptane, in an optically active or racemic form, and subsequently a compound of formula (I-a'). As mentioned above, enynol (I) has been found to be a useful precursor of β-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 β-santalol and derivatives thereof.
Consequently, a second object of the present invention is a process for the preparation of a compound of formula
Figure imgf000006_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R represents a Me or Et group; by reacting (cyclisation- fragmentation step) an enynol of formula
Figure imgf000006_0002
as defined above; with a M(L)nZ salt, wherein M represents Zn(II), Cu(I) or Ag(I), n represents an integer from 0 to 4, L represents a C1-C4 nitrile, COHSCN, or di-nitrile, or a Cs-Cs pyridine derivative, and Z a weakly or non coordinating anion.
According to a particular embodiment, said M(L)nZ salt is Cu(L)4Z, wherein L is Ci-C4 nitrile, or a AgZ salt.
According to a particular embodiment Z is a R4S(V, wherein R4 is a chlorine or fluorine atom or an Ci-Cs alkyl, fluoroalkyl or fluoroaryl group, BF4-, PF6-, SbCl6", SbF6-, or BR5 4 ", wherein R5 is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF3 groups. When M is Ag(I) then Z may also represent a nitrate or a perchlorate.
According to a preferred embodiment of the invention, Z is BF4-, PF6-, SbCl6 ", C6F5SO3 ", BPh4 ", CF3SO3 " or yet B[3,5-(CF3)2C6H4]4-, more preferably BF4 ".
Optionally, to said process of the invention, it can be also added, as additive, an alkaline salt of the anion Z. In particular it can be added a salt of formula KZ or CsZ. The transformation of (I) into (II), in any of its embodiments, is preferably carried out in the presence of 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 00C and 1500C, preferably between 400C and 700C. Of course 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)nZ can be added to the reaction medium in a large range of concentrations. As non-limiting examples, one can cite salt concentrations ranging from 0.01 to 0.50 molar equivalents, relative to the molar amount of the starting enynol (I). Preferably, the salt concentration will be comprised between 0.01 and 0.10 molar equivalents. It goes without saying that the optimum concentration of the M(L)nZ 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. As non-limiting examples, one can cite additive concentrations ranging from 10 to 250%, relative to the weight of the salt. Preferably, the additive concentration will be comprised between 10 and 120 %, relative to the weight of the salt.
According to any embodiment of the invention, and independently of the specific aspects, the compounds (I-a), (I) or (II) can be in the form of any one of its stereoisomers or mixture thereof. By the term stereoisomer it is intended any diastereomer, enantiomer, racemate or carbon-carbon isomer of configuration E or Z.
According to a particular embodiment of the invention, 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')
Figure imgf000008_0001
and in a further embodiment said compound (I) consists essentially in the compound (I-a').
According to a particular embodiment of the invention, 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)
Figure imgf000008_0002
and in a further embodiment said compound (I) consists essentially in the compound (F). As typical examples of 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.
According to a particular embodiment of the invention, compound (II) is in the form of a mixture of isomers comprising more than 50% (w/w) of the 2-endo-R configuration. Furthermore, 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)
Figure imgf000009_0001
and in a further embodiment said compound (II) consists essentially in the compound (IF).
As typical examples of compounds (II) one may cite 3-[2-methyl-3- methylenebicyclo^^.llhept^-yll-acrylaldehyde or its stereoisomer 3-[(lS,2S,4R)-2- methyl-3-methylenebicyclo[2.2. l]hept-2-yl]-acrylaldehyde.
Since compound (I) is a useful starting material for the preparation of β-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. In other words, the invention concerns also a process for obtaining a compound of formula (β-santalol or derivatives)
Figure imgf000009_0002
wherein R represents a Me or Et group; R1 represents a hydrogen atom or a Me or Et group;
X represents a CH2OR2, CHO or a CH(OR3)2 group, R2 representing a hydrogen atom, a C1-C3 alkyl, alkenyl or acyl group, R3 representing, when taken separately, a C1-C3 alkyl, alkenyl or acyl group or, when taken together, a C2-C5 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. According to a particular embodiment of the invention, and independently of the specific aspects, R represents a methyl group.
According to a further embodiment of the invention, and independently of the specific aspects, R1 represents a methyl or ethyl group.
According to a further embodiment of the invention, and independently of the specific aspects, R2 represents a hydrogen atom or a C1-C3 acyl group.
According to a further embodiment of the invention, and independently of the specific aspects, R3 represents, when taken separately, a methyl or ethyl group or, when taken together, a C2-C4 alkanediyl group.
According to a particular embodiment of the invention, and independently of the specific aspects, the compounds (III) can be in the form of any one of its stereoisomers or mixture thereof. By the term stereoisomer it is intended any diastereomer, enantiomer, racemate or carbon-carbon isomer of configuration E or Z.
According to a particular embodiment of the invention, compound (III) is in the form of a mixture of isomers comprising more than 50% (w/w) of the 2-endo-R configuration. Furthermore, 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)
Figure imgf000010_0001
and in a further embodiment said compound (III) consists essentially in the compound (HF)-
As typical examples of compounds (III) one may cite the following: β-santalol, (-)-β-santalol (i.e (2Z)-2-methyl-5-[(lS,2R,4R)-2-methyl-3- methylenebicyclo[2.2.1]hept-2-yl]-2-penten-l-ol), β-santalal, β-santalyl benzoate, β- santalyl butyrate, β-santalyl formate, β-santalyl proprionate. The first step of said process is as defined above.
The transformation of the aldehyde (II) into the compound (III) can be performed in many different manners, which are well known by a person skilled in the art. Practical examples are provided in Examples herein below.
However, as non-limiting example, one of the most direct manners to transform the aldehyde (II) into the compound (III) comprises the following reactions: i) coupling of aldehyde (II) with Ph3P=CHR1 and then reacting the ylide with CH2O and BuLi (Wittig addition followed by a hydroxyalkylation) to obtain an alcohol or a carboxylate derivative. H) transformation of the alcohol into the suitable ester, aldehyde or acetal.
An optional step of partial or total hydrogenation of the C=C bonds can be perfomed at any moment, i.e. before step i), or just after step i) or ii). 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 CH2OR2, wherein R2 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 CH2OH) 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.
Alternatively, 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)
Figure imgf000011_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R has the same meaning as in formula (II); b) coupling said aldehyde (IV) with an aldehyde R1CH2CHO (Aldol addition) to obtain an aldehyde (V)
Figure imgf000012_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R and R1 have the same meaning as in formula (II); c) converting said compound (V) into the corresponding dienol derivative (VI)
Figure imgf000012_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein R and R1 have the same meaning as in formula (II), R4 represents a C1-C3 alkyl, alkenyl or acyl group or a C3-C8 silyl group; d) reducing the enolate (VI) into a compound (VII)
Figure imgf000012_0003
in the form of any one of its stereoisomers or mixture thereof, and wherein R, R1 and R4 have the same meaning as in formula (VI); e) optionally, transforming said compound (VII) into a compound (IH")
Figure imgf000012_0004
in the form of any one of its stereoisomers or mixture thereof, and wherein the dotted lines, R, R1 and X have the same meaning as in formula (III). 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.
According to a particular embodiment of the invention, 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.
For instance, one 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. An example of such procedure is provided in the Examples herein below.
Examples
The invention, in all its embodiments, will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (0C) ; the NMR spectral data were recorded in CDCl3 with a 400 MHz or 125 MHz machine for 1H or 13C respectively, the chemical shifts δ are indicated in ppm with respect to TMS as standard, the coupling constants J are expressed in Hz.
Example 1
Preparation of a compound (I) - Method A: a) Preparation of 3-exo-Methyl-bicyclo[2.2.1 ]heptan-2-one
A solution of butyllithium in hexanes (1.58 M, 260.0 ml, 410.8 mmol) was added over a
40 minutes period to diisopropylamine (59.0 ml, 419.8 mmol) in solution in THF (100 ml) at -78°C under nitrogen. The mixture was further stirred at -78°C for
30 minutes, then (±)-norcamphor (40.118 g, 364.2 mmol) in THF (100 ml) was added dropwise at -78°C and stirred for further 30 minutes at -78°C, before adding iodomethane (34.0 ml, 545.9 mmol). Once the addition was finished, the mixture was stirred for further 30 minutes at -78°C and was allowed to reach room temperature. The mixture was hydrolyzed with a saturated aqueous solution of NH4Cl. The aqueous layer was extracted twice with pentane, and the combined organic layers were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCθ3 and brine. The organic layer was dried over Na2SO4, filtered off, and solvents were removed under slight vacuum to give a crude which was further purified by bulb to bulb distillation under reduced pressure to give the title compound (46.05 g) in quantitative yield. 1H NMR: 2.54 (br s, IH), 2.32 (br s, IH), 1.89-1.77 (m, 4H), 1.53-1.42 (m, 3H), 1.05 (d,
J=7.6, 3H). 13C NMR: 220.9, 49.5, 48.3, 41.5, 34.4, 28.0, 23.8, 14.1.
b) Preparation of(3-exo-Methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acid NaH (55%, 19.76 g, 451.45 mmol) and THF (400 ml) were placed in a reactor under nitrogen. Triethylphosphonoacetate (94.0 ml, 469.60 ml) was added to the suspension over a 25 minutes period at room temperature. The mixture was then heated at 500C for 45 minutes, 3-exo-methyl-bicyclo[2.2.1]heptan-2-one (46.054 g, 361.59 mmol) in THF (100 ml) was added to the ylide at 500C over a 25 minutes period. Once the addition finished, the mixture was refluxed for 2 hours. The mixture was then cooled down to room temperature and hydrolyzed with aqueous HCl 5% and ice. The mixture was extracted twice with Et2O. The combined organic layers were washed with water, satured aqueous NaHCO3 and brine. The solution was dried over Na2SO4, filtered off and solvents were removed under vacuum to give a crude which was bulb to bulb distilled under reduced pressure to furnish a product containing 85.5% of (3-methyl- bicyclo[2.2.1]hept-2-ylidene)-acetic acid ethyl ester (76.36 g).
KOH pellets (36.31 g, 350.0 mmol) were dissolved in H2O (220 ml) at room temperature and (3-methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acid ethyl ester (76.361 g, 361.59 mmol) in absolute ethanol (500 ml) was added and the mixture was heated to reflux for 3.5 hours. The solution was allowed to reach room temperature and was extracted twice with pentane. The combined organic layers were washed with aqueous NaOH 5%, H2O, and basic layers were acidified with concentrated HCl until pH = 1. The acidic aqueous fraction was extracted twice with pentane, and the combined organic were washed with aqueous HCl 5%, H2O, brine, dried over Na2SO4 and filtered off. Solvents were removed under vacuum to give a crude which was purified by bulb to bulb distillation under reduced pressure to afford the desired compound (46.575 g) in 75% yield over two steps.
1H NMR (E-isomer): 12.10 (br s, IH), 5.72 (s, IH), 2.80 (d, J=7.0, 2H), 2.10 (br s, IH),
1.79-1.57 (m, 3H), 1.30- 1.18 (m, 3H), 1.12 (d, J=7.0, 3H). 1H NMR (Z-isomer): 12.10 (br s, IH), 5.53 (s, IH), 3.97 (br s, IH), 2.17 (d, J=7.2, IH),
2.04 (br s, IH), 1.79-1.57 (m, 3H), 1.30- 1.18 (m, 3H), 1.03 (d, J=7.2, 3H). 13C NMR (E-isomer): 179.2, 172.4, 108.9, 47.7, 44.2, 43.8, 35.0, 29.8, 27.5, 17.2. 13C NMR (Z-isomer): 178.4, 172.7, 108.9, 45.5, 42.9, 41.9, 35.8, 28.1, 27.8, 19.1.
c) Preparation of3(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetic acid
A solution of butyllithium in hexanes (1.40 M, 616.0 ml, 862.4 mmol) was added over a 60 minutes period to diisopropylamine (125.0 ml, 888.9 mmol) in THF (200 ml) at -78°C under nitrogen. The mixture was further stirred at -78°C for 30 minutes, then (3- methyl-bicyclo[2.2.1]hept-2-ylidene)-acetic acid (46.57 g, 280.2 mmol) in THF (200 ml) was added dropwise at -78°C. Once the addition finished the mixture was stirred for further 30 minutes at -780C and was allowed to reach room temperature. The orange mixture was hydrolyzed with aqueous HCl 5%. The aqueous layer was extracted twice with Et2O, and the combined organic layers were washed twice with H2O. The organic layer was extracted twice with aqueous NaOH 5% until pH = 11, and the basic layers were acidified with concentrated HCl until pH = 1. The aqueous fraction was extracted twice with Et2O and the combined organic fractions were washed with H2O, brine, dried over Na2SO4 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.
1H NMR: 11.09 (br s, IH), 3.12 (d of AB syst., J= 15.2, IH), 3.00 (d of AB syst., J=15.2, IH), 2.80 (s, IH), 2.62 (s, IH), 1.66 (s, 3H), 1.63-1.61 (m, 2H), 1.40 (dt, J^δ. l, J2=2.0, IH), 1.10-1.00 (m, 3H).
13C NMR: 178.6, 141.0, 131.5, 47.7, 46.8, 45.9, 32.6, 26.2, 25.4, 11.9. d) Preparation of(±)-2-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-ethanol 3(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetic acid (42.240 g, 254.2 mmol) in dry Et2O (500 ml) was added over a 60 minutes period to lithium aluminum hydride (14.99 g, 381.2 mmol) in Et2O (250 ml) under nitrogen at room temperature. Once the addition finished, the mixture was heated to reflux for 1.5 hours and was then cooled down to 00C. The mixture was slowly hydrolyzed with 14.0 ml of H2O and 14.0 ml of aqueous NaOH 5%. Celite and Na2SO4 were added to the crude mixture. The suspension was filtered off through celite and solvent was 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, 89% purity) in 76% yield.
1H NMR: 3.66 (t, J=6.0, 2H), 2.70 (s, IH), 2.61 (s, IH), 2.37 (td, J^B.δ, J2=6.6, IH), 2.20 (td, J^B.δ, J2=6.6, IH), 1.65 (s, 3H), 1.64-1.62 (m, 2H), 1.44 (br s, IH), 1.30 (dt, J^δ.O, J2=2.0, IH), 1.06-1.01 (m, 3H). 13C NMR: 140.4, 135.8, 61.1, 47.7, 46.9, 45.0, 30.3, 26.5, 25.4, 11.9.
e) Preparation of(±)-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde
2-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-ethanol (16.37 g, 107.53 mmol) was dissolved in dichloromethane (150 ml) and Dess-Martin periodinane in solution in dichloromethane (15%, 536.2 g, 189.7 mmol) was added at room temperature over a 110 minutes period under nitrogen. The mixture was further stirred at room temperature for 30 minutes and was hydrolyzed with aqueous NaOH 5% in an ice-bath, and extracted 3 times with Et2O. The combined organic layers were washed with H2O, brine, dried over Na2SO4, and filtered off. Solvents were removed under reduced pressure to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the desired compound (13.468 g, 88% purity) in 83% yield.
1H NMR: 9.57 (t, J=2.6, IH), 3.15 (dd, Jx=16, IH), 3.05 (d, J=16, IH), 2.68 (d, J=14.3,
2H), 1.67 (s, 3H), 1.65-1.63 (m, 2H), 1.42-1.39 (m, IH), 1.09-1.01 (m, 3H). 13C NMR: 199.7, 142.5, 130.1, 47.8, 46.9, 46.0, 42.8, 26.2, 25.3, 12.1.
f) Preparation of(±)-l-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol
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. The mixture was extracted twice with Et2O and the combined organic layers were washed twice with a saturated aqueous solution of NaHC O3, H2O, and brine and dried over Na2SO4. Solvents were removed under vacuum to give a crude which was purified by flash chromatography with cyclohexane/ AcOEt (95/5) as eluent to afford the title compound (11.32 g) in 79% yield.
1H NMR (isomer A): 4.44 (br s, IH), 2.76 (s, IH), 2.63 (s, IH), 2.52 (dd, 3l=13.i, J2=8.1, IH), 2.40 (d, J=2.0, IH), 2.44 (dd, 3l=13.i, J2=5.9, IH), 1.98 (br s,
IH), 1.67 (s, 3H), 1.64-1.62 (m, 2H), 1.34-1.32 (m, IH), 1.11-1.00 (m, 3H). 1H NMR (isomer B): 4.46 (br s, IH), 2.86 (s, IH), 2.62 (s, IH), 2.53 (dd of AB syst.,
/=13.8, J2=6.3, IH), 2.43 (d, J=2.1, IH), 2.39 (dd of AB syst., J^B.δ,
J2=5.7, IH), 2.03 (br s, IH), 1.67 (s, 3H), 1.64-1.62 (m, 2H), 1.39-1.36 (m, IH), 1.11-1.01 (m, 3H).
13C NMR (isomer A): 142.2, 134.4, 84.8, 72.6, 60.9, 47.7, 46.9, 45.2, 35.7, 26.4, 25.2,
12.0. 13C NMR (isomer B): 141.9, 134.6, 85.1, 72.7, 61.3, 47.8, 46.9, 46.0, 35.1, 26.5, 25.3,
12.1.
Preparation of a compound (I) - Method B a) Preparation of3-Methylene-bicyclo[2.2.1]heptan-2-one
Diethylamine (50.0 ml, 455.0 mmol) was added over a 15 min. period to formaldehyde
(36% in MeOH/H2O, 50.0 ml, 1.82 mol) at 00C. The resultant mixture was treated over a 33 minutes period with acetic acid (50.0 ml, 910.0 mmol). Once the addition was finished, the temperature was increased to room temperature and the mixture was added over a 22 minutes period to (±)-norcamphor (50.0 g, 0.455 mol) in the presence of a small amount of BHT at 95°C. The mixture was refluxed for 5 hours and cooled down to room temperature. The yellow mixture was hydrolyzed with aqueous HCl 5% and ice (pH=l). The aqueous layer was extracted twice with Et2O, and the combined organic layers were washed with H2O, aqueous NaOH 5% and twice with brine, dried over Na2SO4 and filtered off. Et2O was distilled under atmospheric pressure to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the desired compound (26.800 g) in 48% yield.
1H NMR: 5.72 (s, IH), 5.16 (s, IH), 3.13 (br s, IH), 2.73 (d, J=2.8, IH), 1.90-1.86 (m,
2H), 1.77-1.73 (m, IH), 1.64-1.61 (m, IH), 1.57-1.53 (m, 2H). 13C NMR: 205.8, 150.1, 111.7, 49.2, 42.5, 36.8, 28.1, 23.6.
b) Preparation of(±)-3-endo-Methyl-bicyclo[2.2.1]heptan-2-one 3-Methylene-bicyclo[2.2.1]heptan-2-one (29.670 g at 64.4%, 0.157 mmol) was hydrogenated (atmospheric pressure) in presence of Pd/C (10% in Pd, 1.480 g, 5% w/w) in Et2O (300 ml) at room temperature for 2 hours. The mixture was filtered through "filter eel" and Et2O was removed by distillation to give a crude which was further purified by distillation (20 mbar, 87-88°C) to afford the title compound (19.82 g) in quantitative yield. 1H NMR: 2.60 (d, J=4.8, IH), 2.53 (s, IH), 2.15-2.08 (m, IH), 1.86-1.77 (m, IH), 1.72- 1.68 (m, IH), 1.65-1.56 (m, 3H), 1.43-1.36 (m, IH), 1.02 (d, J=7.2, 3H).
13C NMR: 220.6, 50.3, 48.3, 40.5, 37.2, 25.4, 21.0, 10.8.
c) Preparation of(±)-2-endo-Methyl-3-methylene-bicyclo[2.2.1]heptane: by a Wittig reaction Methyltriphenylphosphonium bromide (13.31 g, 36.9 mmol) in THF (40.0 ml) was treated in one portion with ^-BuOK (6.910 g, 61.6 mmol) at room temperature under nitrogen. The resultant yellow mixture was stirred at room temperature and 3-methyl- bicyclo[2.2.1]heptan-2-one (4.0 g, 30.8 mmol) in THF (16.0 ml) was added over a 8 minutes period and was stirred at room temperature for 15 minutes. The mixture was poured over a saturated aqueous solution of ammonium chloride and was extracted twice with pentane. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered off. Solvents were removed by distillation at atmospheric pressure and the crude mixture was further purified by bulb to bulb distillation to afford the desired compound (2.845 g) as colourless oil in 76% yield. 1H NMR: 4.77 (d, J=2.7, IH), 4.51 (s, IH), 2.66 (d, J=3.6, IH), 2.37-2.34 (m, IH), 2.15 (br s, IH), 1.67-1.52 (m, 2H), 1.45-1.30 (m, 3H), 1.22-1.16 (m, IH), 1.02 (d, J=7.0, 3H).
13C NMR: 161.7, 100.3, 46.5, 42.3, 41.34, 39.5, 30.8, 21.4, 15.1.
d) Preparation of trimethylsilyl-propynal
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 10-150C under nitrogen. Once the addition finished, the mixture was stirred at room temperature for one hour and was added over a 30 min. period to an efficiently stirred mixture of DMF (10.0 ml, 123.0 mmol) in Et2O (20.0 ml) at -25°C. The white suspension was allowed to reach room temperature, stirred for one hour, heated at 300C for 15 minutes, and poured into H2SO4 5% at 00C. The aqueous layer was extracted three times with Et2O, the combined organic layers were washed with a saturated aqueous solution of NH4Cl, dried over Na2SO4, and the solvents were carefully removed under vacuum to give a crude which was further purified by bulb to bulb distillation (20 mBar, room temperature) to afford the title compound (2.255 g) in 49% yield. 1H NMR: 9.15 (s, IH), 0.25 (s, 9H). 13C NMR: 176.7, 103.0, 102.3, 0.88.
e) Preparation of l-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-4-trimethylsilanyl-but-3- yn-2-ol via ene-reaction
Me2AlCl (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 CH2Cl2. The combined organic layers were washed with water, brine, dried over Na2SO4 and filtered off to give a crude which was further purified by flash chromatography with cyclohexane/ AcOEt (97/3) as eluent to afford title compound (148.0 mg) in 59% yield. Ene -reaction could also be performed at -78°C with BF3 Et2O (5 mol%) as catalyst in dichloromethane at -78°C with complete conversion in 5 minutes.
f) Preparation ofl-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol Simple treatment of l-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-4-trimethylsilanyl-but-3- yn-2-ol with an excess of K2CO3 in methanol for 1 hour at room temperature afforded l-(3-methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol in quantitative yield. 1H NMR: 4.42 (dd, J^J^.O, IH), 2.75 (s, IH), 2.60 (s, IH), 2.52-2.47 (m, IH), 2.42- 2.35 (m, IH), 1.91 (br s, IH), 1.66 (s, 3H), 1.62-1.60 (m, 2H), 1.34-1.32 (m, IH), 1.11-0.99 (m, 3H), 0.15 (s, 9H).
13C NMR: 141.8, 134.7, 106.8, 89.3, 61.7, 47.8, 47.1, 45.6, 36.0, 26.6, 25.3, 12.1, 10.0.
Example 2
Preparation of a compound (II) a) Preparation of 3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-l-al with CuBF4(CH3CN)4
CuBF4(CH3CN)4 (0.294g, 0.93 mmol) was added to a two-rounded bottom flask charged with l-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (3.24 g, 18.4 mmol) in solution in 1 ,2-dichloroethane (100 ml) at room temperature under nitrogen. The mixture was stirred at 500C for 140 minutes. The crude mixture was allowed to reach room temperature and was filtered through a short pad of silica gel with CH2Cl2 as eluent. Solvents were removed under vacuum to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the title compound (3.12 g) in 96% yield. 1H NMR: 9.52 (d, J=7.8, IH), 6.77 (d, J=15.7, IH), 6.09 (dd, J1=^.!, J2=7.8, IH), 5.01 (s,lH), 4.58 (s, IH), 2.76 (br s, IH), 2.18 (br s, IH), 1.80-1.69 (m, 2H), 1.58- 1.52 (m, 2H), 1.37-1.30 (m, IH), 1.27-1.24 (m, IH), 1.23 (s, 3H). 13C NMR: 194.5, 165.4, 160.4, 130.1, 104.1, 49.7, 46.5, 46.3, 37.1, 29.8, 23.0, 22.7.
b) Preparation of 3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-l-al with AgBF4 AgBF4 (20.0 mg, 0.10 mmol) was added to a two-rounded bottom flask charged with l-(3-methyl bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (371.0 mg, 2.10 mmol) in solution in 1 ,2-dichloroethane (10 ml) at room temperature under nitrogen. The mixture was stirred at 500C for 80 minutes in the dark. The crude mixture was allowed to reach room temperature and was filtered through a short pad of silica gel with CH2CI2 as eluent. Solvents were removed under vacuum to give a crude which was further purified by flash chromatography with cyclohexane/AcOEt (9773) as eluent to afford the title compound (172.0 mg) in 46% yield.
c) Preparation of 3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propen-l-al with AgNO 3 in presence of KNO 3 as additive
AgNO3 (17.6 mg, 0.10 mmol) and KNO3 (107.0 mg, 1.06 mmol) was added to a two- rounded bottom flask charged with l-(3-methyl bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn- 2-ol (181.0 mg, 1.03 mmol) in solution in THF/H2O (2/1, 10 ml) at room temperature under nitrogen. The mixture was stirred at reflux for 6.5 hours in the dark and AgNO3 (18.5 mg, 0.11 mmol) was added to the mixture before being cooled down to room temperature and stirred overnight in the dark. The crude mixture was diluted with Et2O (10 ml) and the aqueous layer was extracted with Et2O. The combined organic layers were filtered through a short pad of silica gel with CH2Cl2 as eluent. Solvents were removed under vacuum to give a crude which was further purified by flash chromatography with cyclohexane/ AcOEt (95/5) as eluent to afford the title compound (115.0 mg) in 64% yield.
Example 3 Preparation of a compound (III) and of derivatives thereof
a) Preparation of a compound (IV): 3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2- exo-yl)-propan-l-al
Pd/CaCO3 (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 N2 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 mixture was filtered through "filter eel" to give a crude which was further purified by flash chromatography with pentane/Et2O (97/3) as eluent to afford the title compound (1.627 g) in 85% yield. 1H NMR: 9.78 (t, J=1.9, IH), 4.79 (s, IH), 4.49 (s, IH), 2.69 (d, J=3.9, IH), 2.49-2.41
(m, 2H), 2.02 (br s, IH), 1.75-1.54 (m, 5H), 1.47-1.38 (m, IH), 1.28-1.19 (m,
2H), 1.02 (s, 3H). 13C NMR: 202.8, 165.0, 100.6, 46.7, 45.0, 44.1, 40.1, 37.0, 32.6, 29.6, 23.6, 22.5.
A) Preparation of β-santalol (via Wittig and hydroxyalkylation reaction)
A solution of butyllithium in hexanes (1.35 M, 11.7 ml, 15.8 mmol) was added over a 15 minutes period to a stirred suspension of ethyltriphenylphosphonium iodide (6.61g, 15.8 mmol) in THF (125 ml) at 00C. The resultant red solution was cooled to -78°C and 3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propanal (2.55 g, 14.33 mmol) in solution in THF (16 ml) was added over a 15 minutes period. After further 5 minutes at -78°C, a solution of butyllithium in hexanes (1.35 M, 12.7 mL, 17.2 mmol) was added over a 5 minutes period and the mixture was further stirred for 20 minutes at -78°C before allowing to reach 00C in 2 hours. Dry paraformaldehyde (2.60 g, 86.0 mmol) was added in one portion to the deep red homogeneous solution and the mixture was stirred for 30 minutes at 00C and was allowed to reach room temperature. After 1 hour at room temperature the mixture was poured into 5.2 ml of saturated aqueous solution of NH4Cl and extracted twice with CH2Cl2. The organic layer was washed with water and brine, and dried with Na2SO4. The mixture was filtered through a short pad of silica gel with dichloromethane as eluent and solvents were removed under pressure to give a crude. Purification of crude compound was performed by flash chromatography on silica gel with cyclohexane/AcOEt 90/10) as eluent to give pure β-santalol as pale yellow oil. Further bulb to bulb distillation under reduced pressure afforded β-santalol in 50% yield (Z:E=95:5). 1H NMR (CDCl3, 400 MHz): 5.29 (t, J=7.5, IH), 4.73 (s, IH), 4.45 (s, IH), 4.14 (s, 2H), 2.66 (d, J=3.8, IH), 2.12-1.94 (m, 3H), 1.78 (d, J=I.2, 3H), 1.71-1.60 (m, 3H),
1.44-1.36 (m, 2H), 1.32 (br s, IH), 1.27-1.17 (m,3H), 1.04 (s, 3H). 13C NMR (CDCl3, 125 MHz): 166.2, 133.9, 129.0, 99.7, 61.6, 46.8, 44.7, 44.6, 41.5, 37.1, 29.7, 23.7, 23.2, 22.6, 21.2.
B) Preparation of β-santalol (via [1,4] hydrogenation) i) Preparation of a compound (V): 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1] hept-exo-2-yl)-pent-2-enal
3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-l-al (274.0 mg,
1.54 mmol) was dissolved in toluene (15.0 ml) at room temperature under nitrogen. The mixture was heated to reflux and propionaldehyde (0.4 ml, 1.96 mmol) and aqueous catalytic solution of hexamethyleneimine and benzoic acid (0.12 ml, 0.616 mmol) was separately added in one portion. Once that addition was finished, the mixture was further heated at reflux for 6 hours. The mixture was cooled down to room temperature and extracted twice with brine, the organic layer was dried over MgSθ2, filtered off and concentrated to give a crude which was further purified by flash chromatography with cyclohexane/ AcOEt (95/5) to afford the title compound in 80% yield.
1H NMR: 9.38 (s, IH), 6.48 (dt, J1=?^, J2=1.2, IH), 4.78 (s, IH), 4.49 (s, IH), 2.69 (d, J=3.9, IH), 2.40-2.29 (m, 2H), 2.12 (d, J=3.1, IH), 1.75 (s, 3H), 1.72-1.64 (m, 3H), 1.59-1.51 (m, IH), 1.47-1.36 (m, 2H), 130-1.21 (m, 2H), 1.09 (s, 3H). 13C NMR: 195.2, 165.5, 155.2, 139.1, 100.3, 46.8, 44.8, 44.7, 39.4, 37.1 , 29.6, 24.9, 23.7, 22.6, 9.1.
H) Preparation of a compound (IV): Acetic acid 2-methyl-5-(2-methyl-3-methylene- bicyclo[2.2.1]hept-2-exo-yl)-penta-l,3-dienyl ester To a stirred solution of 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-yl)- pent-2-enal (268.0 mg, 1.23 mmol) in toluene (3.0 ml) were added Ac2O (0.35 ml, 3.70 mmol), Et3N (0.70 ml, 5.02 mmol), and a catalytic amount of DMAP (15.0 mg, 0.1 mmol). The resulting mixture was heated to reflux for 22 hours. The mixture was cooled down to room temperature and quenched with brine, extracted twice with Et2O, dried over MgSO4, filtered off and concentrated to give a crude which was further purified by flash chromatography with cyclohexane/AcOEt (98/2) to afford the title compound in 82% yield (E:Z=79:21). 1H NMR: 7.18 (s, IH), 5.99 (d, J=12.4, IH), 5.72 (dt, il=\2A, J2=6.1, IH), 4.76 (s, IH), 4.47 (s, IH), 2.68 (d, 3.4, IH), 2.17 (s, 3H), 2.12-2.01 (m, 2H), 1.81 (d, J=I.0, 3H), 1.73-1.63 (m, 3H), 1.43-1.39 (m, 2H), 1.27-1.18 (m, 2H), 1.02 (s, 3H).
13C NMR: 167.9, 165.5, 134.4, 130.6, 126.9, 120.7, 100.0, 46.9, 45.3, 45.0, 44.5, 37.0, 29.7, 23.6, 23.0, 20.8, 10.4.
Hi) Preparation of(2Z)-Acetic acid 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1] hept-2-exo-yl)-pent-2-enyl ester (VII)
Acetic acid 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-l,3- dienyl ester (6.80 g, 93% pure; 24.3 mmol0.18 mmol) was treated with
[(Cp*)Ru(COD)]BF4 (52 mg, 0.122 mmol) and maleic acid (230 mg, 1.95 mmol) in dry and degassed acetone (20 ml) at 600C under 4 bars of H2 for 24 hours. The product was extracted with pentane/5% NaOH, washed twice with saturated aqueous NaCl, dried
(Na2SO4) and bulb-to-bulb distilled: 6.80 g (81% Z and 5% E by GC; 92%). 1H NMR: 5.38 (t, J=7.1, IH), 4.73 (s, IH), 4.59 (s, IH), 4.45 (s, IH), 2.66 (br s, IH),
2.12-2.04 (m, 4H), 2.07 (s, 3H), 1.73 (d, J= 1.0, 3H), 1.69-1.61 (m, 3H), 1.45-
1.37 (m, 2H), 1.27-1.17 (m, 3H), 1.04 (m, 3H).
13C NMR: 171.1, 166.1, 131.4, 129.4, 99.7, 63.2, 46.8, 44.7, 44.6, 41.2, 37.1, 29.7, 23.7,
23.4, 22.6, 21.5, 21.0.
iv) Preparation of and β-santalol (III)
Simple treatment with an excess of K2Cθ3 in methanol for 1 hour at room temperature afforded β-santalol in quantitative yield.
C) Preparation of compounds (III) with all dotted lines being C=C i) Preparation of2-Methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)- penta-2,4-dienoic acid ethyl ester
NaH (55%, 168.0 mg, 3.85 mmol) and THF (5.0 ml) were placed in a reactor and 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (939.0 mg, 3.94 mmol) was added dropwise at room temperature to the suspension over a 10 minutes period. The mixture was heated at 500C for 45 minutes 3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo- yl)-propen-l-al (566.0 mg, 3.21 mmol) in THF (2.0 ml) was added dropwise to the ylide at 500C. Once the addition finished, the mixture was refluxed for 1 hour. The mixture was then cooled down to room temperature and hydrolyzed with aqueous HCl 5%. The reaction was extracted twice with Et2O. The combined organic layers were washed with water, aqueous saturated NaHCθ3 and brine. The solution was dried over Na2SO4, filtered off and solvents were removed under vacuum to give a crude which was further purified by bulb to bulb distillation under reduced pressure to afford the title compound (651.0 mg) in 78% yield. 1H NMR: 7.18 (d, J=I 1.2, IH), 6.31 (dd, 3l=15.2, J2=11.2, IH), 6.05 (d, J=15.2, IH),
4.98 (s, IH), 4.56 (s, IH), 4.20 (q, J=7.1, 2H), 2.73 (d, J=3.2, IH), 2.09 (d, J=3.1, IH), 1.92 (d, J=1.2, 3H), 1.73-1.65 (m, 2H), 1.61-1.57 (m, IH), 1.52-
1.43 (m, IH), 1.34-1.27 (m, IH), 1.29 (t, J=7.1, 3H), 1.19-1.18 (m, IH), 1.18
(s, 3H). 13C NMR: 168.6, 161.8, 150.2, 138.8, 125.5, 123.0, 103.2, 60.4, 49.6, 47.0, 46.4, 37.1,
30.1, 23.5, 23.0, 14.3, 12.7.
H) Preparation of 2-Methyl-5-(2-methyl-3-methylene-bicyclo [2.2.1 ]hept-2-exo-yl)-pent-
2.4-dien-l-ol
Dibal-H (IM in toluene, 5.5 ml, 5.5 mmol) was added over a 25 minutes period to a stirred solution of 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)- penta-2,4-dienoic acid ethyl ester (651.0 mg, 2.50 mmol) in dichloromethane (20.0 ml) at -78°C under nitrogen. The resulting mixture was stirred at -78°C for 70 minutes and was placed at 00C to be quenched with aqueous HCl 5% and brine. The mixture was extracted twice with CH2Cl2, dried over Na2SO4, filtered off and concentrated to afford a crude which was further purified by flash chromatography with cyclohexane/ AcOEt (9/1) as eluent to afford the title compound (453.0 mg) in 83% yield.
1H NMR: 6.22 (dd, 3l=12.2, J2=8.6, IH), 6.03 (d, J=8.6, IH), 5.69 (d, J=12.2, IH), 4.95 (s, IH), 4.54 (s, IH), 4.05 (s, 2H), 2.71 (d, J=2.7, IH), 2.04 (br s, IH), 1.78 (s, 3H), 1.71-1.62 (m, 3H), 1.58 (br s, IH), 1.42-1.49 (m, IH), 1.31-1.26 (m, IH), 1.17-1.15 (m, IH), 1.16 (s, 3H). 13C NMR: 162.4, 142.9, 135.2, 125.7, 122.9, 102.6, 68.8, 49.1, 47.2, 46.5, 37.1, 30.2, 23.9, 23.0, 14.3. Example 4 Preparation of (-)-/?-Santalol
a) Preparation of(lS,2S,4R)-2-methyl-3-methylene-bicyclo[2.2.1]heptane: by enantioselective and exo-selective Diels-Alder reaction
(according to MacMillan et coll., J. Am. Chem. Soc. 2000, 122, 4243 and PCT Int. Appl. 2003002491)
A solution of (2S,5S)-(-)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone.HCl
(0.1 equiv) in MeOH/water (95:5) was treated with cyclopentadiene (3 molar equivalents) and crotonaldehyde (1 molar equivalent) for 24 hours at room temperature.
The 72:28 mixture of exo- and endo cycloadducts (both 71% ee) (exo/endo with respect to CHO)) was reduced with LiAlH4 (1 molar equivalent) in Et2O at 25 to 300C to afford the corresponding exo- and endo- methyl-norbornenols in 30% yield (2 steps). These compounds could be separated by chiral SFC (supercritical fluid chromatography: OD-H column; co-solvent: MeOH: 5% (2 min), then +1% MeOH/min; flow: 2 ml/min; 200 bar;
1st peak exo major, 2n peak exo minor, 3r peak endo major, 4 peak endo minor).
Enantiomeric enrichment of these known compounds can be effected by crystallization
(Seebach et coll., J. Org. Chem. 1995, 60, 1788). The exo-enriched methyl-norbornenol was hydrogenated (5% of 10% Pd on C; Et2O, 99% yield). The exo-enriched methyl norbornanol was treated with Ac2O (1.2 molar equivalents), NEt3 (2.0 molar equivalents), 4-dimethylaminopyridine (5 mol%), toluene at 00C for 17 hours to afford the exo- enriched acetate in 74% yield. The compound so obtained was diluted in pentane
(5%) and pyrolyzed at 6100C through a 30 cm column filled with quartz pieces under a nitrogen flow to afford the optically active endo-enriched title compound in ca. 80% yield.
Note: This compound (but exo-enriched) was also prepared by Joachimsmann-Dufresne, Blanchard, Bull. Soc. Chim. France 1968, 385 by pyrolysis of the corresponding acetate (longer column, 5100C). In fact, Blanchard et coll. (Bull. Soc. Chim. France 1968, 385; Bull. Soc. Chim. France 1972, 4770) prepared the title compound (exo- enriched and racemic) from cyclopentadiene and crotonaldehyde and the reduction/hydrogenation was performed in one step (H2, Raney-Ni, 90 bar, 1100C). The title compound thus obtained had a NMR characterisation corresponding to the one of the compound obtained Example 1, method B, c).
a') Preparation of(lS,2S,4R)-2-methyl-3-methylene-bicyclo[2.2.1]heptane: by enantioselective and exo-selective Diels-Alder reaction
(according to Hayashi et al., Angew. Chem. Int. Ed. 2008, 47, 6634) A heterogeneous mixture of (S)-(+)-2-[bis-(3,5-trifluoromethylphenyl)trimethylsilyloxy- methyl]pyrrolidinium perchlorate (5 mol%), water, freshly distilled crotonaldehyde (1 molar equivalent) and cyclopentadiene (3 molar equivalents) was stirred for 24 hours at room temperature. The 72:28 mixture of exo- and endo cycloadducts (95 respectively 76% ee) (exo/endo with respect to CHO)) was reduced with NaBH4 (1 molar equivalent) in MeOH at 25 to 300C to afford the corresponding exo- and endo- methyl-norbornenols in 49% yield (2 steps). The enantiomeric excesses of these compounds were determined by chiral GC of the corresponding trifluoroacetates (Seebach et coll., J. Org. Chem. 1995, 60, 1788) using a chiral capillary column (CP-Chirasil-DEX CB (25 x 0.25 mm, Chrompack). The methyl-norbornenols were hydrogenated (5% of 10% Pd on C; Et2O, 99% yield). Treatment of the methyl norbornanols with ClCOOEt (2 molar equivalents), pyridine (2.0 molar equivalents) and toluene at 00C for 90 min and at room temperature for 30 min afforded the corresponding methyl carbonates in 91% 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. 90% yield and 91% ee (chiral GC: first peak major (bad separation) together with the exo-compound (endo/exo = 72:28; exo: ca. 54% ee (second peak major)). The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained Example 1, method B, c).
b) Preparation of (lR,4S)-l-(3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol: via ene-reaction
Me2AlCl (IM in hexanes, 23.7 ml, 23.7 mmol) was added dropwise to a solution of trimethylsilyl-propynal (3.74 g; 80% pure, 23.7 mmol) and (lS,2S,4R)-2-endo-methyl-3- methylene-bicyclo[2.2.1]heptane (4.25; 65% pure; containing 25% of exo-isomer;
22.6 mmol) in dichloromethane (80 ml) containing a few crystals of BHT at -78°C under nitrogen. The mixture was stirred at -78°C for 15 minutes and was poured into aqueous HCl 5%. The product was extracted with ether. The combined organic layers were washed with water, cone. NaHCθ3 solution, brine, dried over Na2SO4 and filtered off to give a crude which was bulb-to-bulb distilled (0.07 mbar/ oven temp. 1200C) to afford ( 1 R,4S)- 1 -(3-methyl-bicyclo [2.2.1 ]hept-2-en-2-yl)-4-trimethylsilanyl-but-3 -yn-2-ol
(4.84 g; 66% pure). It was dissolved in MeOH (50 ml) and treated with K2CO3 (3.23 G,
23.4 mmol) for 30 min at room temperature. Usual extraction (pentane/water) and bulb- to-bulb distillation afforded the title compound (3.09 g). Flash chromatography (SiO2; cyclohexane/ AcOEt = 9:1) afforded pure title compound (2. 62 g; 66%). The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained Example 1, method A, T).
c) Preparation of (lS,2S,4R)-3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)- propen-1-al with CuBF4(CH3CN)4 It was proceeded as described above for the racemic compound (see Example 2, a). Starting from (lR,4S)-l-(3-methyl-bicyclo[2.2.1]hept-2-en-2-yl)-but-3-yn-2-ol (2.02 g;
11.5 mmol), 1.91 g (94%) of the title compound were obtained. Chiral GC: 91% ee (first peak major). Low-temperature crystallization afforded the title compound with 97% ee (1.67 g). [α]D 20: -267.4 (CHCl3; c = 1.06).
The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained Example 2, a).
d) Preparation of (lS,2R,4R)-3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)- propan-1-al
It was proceeded as described above for the racemic compound (see Example 3, a), but MeOH/water (96:4) was used as the solvent.
Starting from (15,25,4i?)-3-(2-methyl-3-methylene-bicyclo[2.2. l]hept-2-exo-yl)-propen- 1-al (894 mg; 5.08 mmol), 769 mg (85%) of the title compound were obtained. No separation by chiral GC.
[α]D 20: -112.3 (CHCl3; c = 0.86). The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained Example 3, a).
e) Preparation of (lS,2R,4R)-2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1] hept- exo-2-yl)-pent-2-enal
It was proceeded as described above for the racemic compound (see Example 3, B) i)) Starting from (lS,2R,4R)-3-(2-methyl-3-methylene-bicyclo[2.2. l]hept-2-exo-yl)- propan-1-al, the title compound was obtained in 92% purity and 90% yield. No separation by chiral GC. [α]D 20: -99.8 (CHCl3; c = 1.14).
The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained (see Example 3, B) i))
f) Preparation of and (-)- β-santalol Application of the procedure for the racemic compound (via compounds IV and VII) (see Example 3, B) afforded (-)-β-santalol as a 94/6 Z/E-mixture in 80% yield. Pure Z- (-)-β-santalol of 97% ee was obtained by chromatography (SiCh; cyclohexane/AcOEt = 9:1). [α]D 20: -104.3 (CHCl3; c = 0.76). The title compound thus obtained had NMR characterisation corresponding to the one of the compound obtained Example 3, B).

Claims

Claims
1. A compound of formula
Figure imgf000030_0001
in the form of any one of its stereoisomers or mixture thereof , and wherein R represents a Me or Et group, and Ra represents a hydrogen atom or a Si(Rb)3 or (RC)2COH group, Rb representing C1-5 group or a phenyl grup and Rc representing a C1-5 group or a phenyl group.
2. A compound according to claim 1, characterized in that R is a methyl group.
3. A compound according to claim 1, characterized in that it is a compound of formula
Figure imgf000030_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein R represents a Me or Et group.
4. A process for the preparation of a compound of formula (I-a), as defined in claim 1, comprising the following steps: a) reacting 2-R-3-methylene-bicyclo[2.2.1]heptane, wherein R has the same meaning as in claim 1, with a compound of formula Ra-C≡CCHO, wherein Ra represents a
Si(Rb)3 or (Rc)2C0H group, Rb and Rc representing, independently from each other, Ci_5 group or a phenyl group, in the presence of a Al, B or Sn derivative Lewis acid as catalyst, to obtain a compound of formula (I-a) wherein Ra represents a Si(Rb)3 or (RC)2COH group, Rb and Rc representing, independently from each other, Ci_s group or a phenyl group; and b) optionally treating the obtained compound (I-a) with a suitable base or a fluorine salt to obtain compound (I), as defined in claim 3.
5. A process according to claim 4, comprising the following steps: a') reacting cyclopentadiene with a trans aldehyde RHC=CHCHO, wherein R has the same meaning as above, under Diels Alder conditions, in the presence of an optically active salt obtained by: reacting together an acid H(Anion) and a racemic or optically active 2-Rd-3-Re-5-Rf-4-imidazolidinone derivative or a racemic or optically active prolinol derivative of formula (C4H8N)-2-CAr20SiRb 3; wherein Anions stand for an anion selected in the group consisting of Cl", Cl(V, a
R8S(V or R8CO2 ", wherein R8 is a C1-C7 hydrocarbon group or an Ci-Cs fluoroalkyl or fluoroaryl group, ClSO3 ", FSO3 ", BF4-, PF6-, SbCl6", AsCl6", SbF6", AsF6" or B(Rh)4 ", wherein Rh is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF3 groups; Rb is defined as in claim 1 ; Ar represents a phenyl group optionally substituted by one, two or three Me, Et CF3, OMe or OEt;
Rd represents t-Bu, a phenyl group, a benzyl group or a 5-Me-furyl group;
Re represents a hydrogen atom, a Ci-C3 alkyl group or a benzyl group; and
Rf 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;
(to obtain 2-R-3-methylene-bicyclo[2.2.1]heptane).
6. A process for the preparation of a compound of formula
Figure imgf000032_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R represents a Me or Et group; by reacting an enynol of formula
Figure imgf000032_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein R represents a Me or Et group.; with a M(L)nZ salt, wherein M represents Zn(II), Cu(I) or Ag(I), n represents an integer from 0 to 4, L represents a Ci-C4 nitrile, CβHsCN, or di-nitrile, or a Cs-Cs pyridine derivative, and Z a weakly or non coordinating anion.
7. A process according to claim 6, characterized in that said salt is Cu(L)4Z, wherein L is Ci-C4 nitrile,
8. A process for the preparation of a compound of formula
Figure imgf000032_0003
wherein R represents a Me or Et group;
R1 represents a hydrogen atom or a Me or Et group;
X represents a CH2OR2, CHO or a CH(OR3)2 group, R2 representing a hydrogen atom, a C1-C3 alkyl, alkenyl or acyl group, R3 representing, when taken separately, a C1-Cs alkyl, alkenyl or acyl group or, when taken together, a C2-C5 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 in claim 3, into an aldehyde of formula (II), as defined in claim 6, by a process as described in claim 6; and T) transforming the aldehyde of formula (II), into a compound of formula (III), as defined above.
9. A process according to claim 8, characterized in that step T) comprises the following reactions: a) reducing the aldehyde (II), as defined in claim 5, into an aldehyde of formula
Figure imgf000033_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R has the same meaning as in formula (II); b) coupling said aldehyde (IV) with an aldehyde R1CH2CHO to obtain an aldehyde
Figure imgf000033_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein R and R1 have the same meaning as in formula (II); c) converting said compound (V) into the corresponding dienol derivative
Figure imgf000033_0003
in the form of any one of its stereoisomers or mixture thereof, and wherein R and R1 have the same meaning as in formula (II), R4 represents a C1-C3 alkyl, alkenyl or acyl group or a C3-C8 silyl group; d) reducing the enolate (VI) into a compound
Figure imgf000034_0001
in the form of any one of its stereoisomers or mixture thereof, and wherein R, R1 and R4 have the same meaning as in formula (VI); e) optionally, transforming said compound (VII) into a compound (IH")
Figure imgf000034_0002
in the form of any one of its stereoisomers or mixture thereof, and wherein the dotted lines, R, R1 and X have the same meaning as in formula (III).
10. A process according to claim 8, characterized in that R is a methyl group.
PCT/IB2009/052048 2008-05-20 2009-05-18 Process for the preparation of beta-santalol and derivatives thereof WO2009141781A1 (en)

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