PROCESS FOR THE PREPARATION OF TETRANORLABDANE

DERIVATIVES

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

wherein the dotted line is a single bond and n is 1 or the dotted line is a double bond and n is 0, and wherein the relative configuration is as shown, in the form of any one of its diastereoisomers or enantiomer or mixture thereof. The invention concerns also some intermediates.

Prior art

The compounds of formula (I) are very 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, the reported synthesis proceed in general through the cyclisation of an acid

for instance see WO 04/013069. However, this procedure requires reduction of the subsequent lactone into a diol and then again a cyclisation step of the diol, which is quite heavy to handle.

Another approach reported in the prior art proceeds via the proton-promoted cyclisation of an unsaturated alcohol similar to our compound (IV), see WO 06/10287 or A. De Groot et al, in Tetrahedron, 1994, 50, 10095. However, these procedures require very long and tedious (industrially not feasible) preparation of the unsatured alcohol, or the preparation of an ester and its subsequent reduction into the alcohol, as shown above. This method implies heavy chemistry and poor atom economy.

To the best of our knowledge, it is the first time that is reported an effective, short, atom economic preparation of compounds (I) with a propargylic alcohol (II), accessible in only three steps from commercial materials (C. Fehr et al, in Angew.Chem. Int.Ed., 2006, 6904). A precedent attempt reported in the prior art using a propargylic alcohol failed (e.g. see C. Fehr et al, in Org.Lett., 2006, 1840).

Description of the invention

We have now found that a compound of formula (I) as defined below, e.g. (3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-l,2,3a,4,6,7,8,9,9a,9 b-decahydronaphtho[2,l- bjfuran or (3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-l,2,3a,4,6,7,8,9,9a,9 b- decahydronaphtho[2,l-b]furan, can be produced in an advantageous manner by a new and alternative process comprising a propargylic rearrangement and a cyclisation step.

Therefore, a first object of the present invention is a process for the preparation of a furan of formula

wherein the dotted line is a single bond and n is 1 or the dotted line is a double bond and n is 0, in the form of a racemic or optically active diastereoisomer, wherein the substituents in the positions 9a, 9b and 3a are in a relative configuration cis, and the hydrogen atom in position 5 a and the oxygen atoms are in configuration trans relative to the methyl in position 9a; said process comprising the following steps:

A) the rearrangement of a propargylic alcohol of formula

wherein the dotted line and n have the same meaning as indicated for compound (I), in the form of a racemic or optically active compound wherein, if n is 1, the methyl in position 9a and the hydrogen atom in position 5a is in a relative trans configuration; in order to obtain an aldehyde of formula

wherein the dotted line and n have the same meaning as indicated for compound (I), in the form of a racemic or optically active compound wherein, if n is 1 , the methyl in position 9a and the hydrogen atom in position 5a is in a relative trans configuration; B) the reduction of the aldehyde of formula (III), obtained under step A), into the corresponding alcohol of formula

wherein the dotted line and n have the same meaning as indicated for compound (I) and, if n is 1, being in the form of a racemic or optically active diastereoisomer wherein the methyl in position 9a and the hydrogen atom in position 5a are in the relative trans configuration;

C) the cyclisation of the compound (IV), obtained under step B), into the corresponding furan of formula (I), as defined above.

For the sake of clarity, it is understood that by the expression "in the form of a racemic or optically active diastereoisomer/compound" it is intended that said diastereoisomer or compound of formula (I) to (IV) has an enantiomeric excess (e.e.) ranging from 0 to 100%. For example a specific compound (I) can be in the form of any mixture of the two enantiomers of formulae (A) or (B)

wherein the indicated stereochemistry is absolute.

As well known by a person skilled in the art, it is understood that when the invention's process is used to obtain a compound (I) in an optically active form, then the corresponding compounds (II) to (IV) used as starting material or intermediates need to have an adequate optical activity.

As typical examples of compounds (I) one may cite the following:

- (3aR,9aR,9bR)-3a,6,6,9a-tetramethyl-l,2,3a,4,6,7,8,9,9a,9b-d ecahydronaphtho[2,l- b]furan,

- (3aRS,9aRS,9bRS)-3a,6,6,9a-tetramethyl-l,2,3a,4,6,7,8,9,9a,9 b- decahydronaphtho[2,l-b]furan,

- (3aS,9aS,9bS)-3a,6,6,9a-tetramethyl-l,2,3a,4,6,7,8,9,9a,9b-d ecahydronaphtho[2,l- bjfuran,

- (3aR,5aS,9aS,9bR)-3a,6,6,9a-tetramethyldodecahydronaphtho[2, l-b]furan,

- (3aRS,5aSR,9aSR,9bRS)-3a,6,6,9a-tetramethyldodecahydronaphth o[2,l-b]furan or - (3aS,5aR,9aR,9bS)-3a,6,6,9a-tetramethyldodecahydronaphtho[2, l-b]furan.

Compound (II) is a known compound, and its preparation is reported by C. Fehr et al, in Org.Lett., 2006, S, 1839, or by Danieswski et al in J.Org.Chem., 1985, 50, 3963. The enantiomerically pure compound (II) can be obtained according to the method

reported in Org.Lett., 2006, S, 1839, and using an optically active precursor (disclosed in WO 07/010420).

The compounds of formula (III) and (IV), wherein the dotted line represents a double bond, in the form of any one of its stereoisomers or mixture thereof, are new compounds. Therefore, being valuable intermediates of the invention's process, said compounds are other objects of the present invention.

Specific examples of said novel compounds are 2-(2,5,5,8a-tetramethyl- 3,5,6,7,8,8a-hexahydro-l-naphthalenyl)ethanol or (2,5,5,8a-tetramethyl-3,5,6,7,8,8a- hexahydro- 1 -naphthalenyl)acetaldehyde. The first step of the invention's process is Step A). It can be carried out by reacting compound (II) with catalysts of the vanadyl type or molybdenum oxide derivatives.

Examples of such catalysts are the ones of formula V(0)(0R)3 or MoO ₂ X ₂ , wherein R represents a C ₁ -C ₉ alkyl or phenyl group or a C ₁ -C ₉ silyl phenyl group, and X represents a Cl, NCS, an acetylacetonate or a C ₁ -C ₉ alcoholate or phenolate. Examples of such catalysts are reported in Tet.Lett., 1996, 37, 853 or in Tet.Lett., 1976, 2981. As non- limiting examples, one may cite VO(OSiPh ₃ ) ₃ or its polymeric form [VO(OSiPh ₂ )J _n , [V ₂ O ₆ SiPh ₂ )J _n , MoO ₂ Cl ₂ or MoO ₂ (acac) ₂ .

It is worth noting that said transformation is not trivial, since many other rearrangement products could have been obtained instead of the required compound (III), in particular when the starting propargylic alcohol is a compound wherein the dotted line represents a double bond (e.g. see C. Fehr et al. in Org.Lett., 2006, S, 1839).

This process of the invention, in any of its embodiments, can be carried out in the presence or in the absence of solvent, but in any case it is advantageously performed under anhydrous conditions. As a person skilled in the art can anticipate, the presence of a solvent is mandatory only in the case in which the starting compound is a solid under the reaction conditions.

However, according to a preferred embodiment of the invention, the process is advantageously carried out in the presence of a solvent. A suitable solvent is one which is high boiling (e.g. b.p. above 100 ⁰ C) and aprotic. Non-limiting examples of such a solvent are ethers, esters, amides, aromatic hydrocarbons, linear or branched or cyclic

hydrocarbons, chlorinated solvents and mixtures thereof. More preferably, the solvent is a xylene or o-dichlorobenzene and mixtures thereof.

The temperature, at which this process of the invention can be carried out, in any of its embodiments, is comprised between 60 ⁰ C and 200 ⁰ C, preferably between 120 ⁰ C and 160 ⁰ C. 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.

Step B) can be carried out by reacting compound (II) with any reducing agent known by a person skilled in the art to reduce an aldehyde into the corresponding alcohol, without reducing in a significant amount the carbon-carbon double bond. As non-limiting examples, one may cite hydrides such as NaBH ₄ or LiAlH ₄ , or catalytic hydrogenation such as the one catalyzed by Ru complexes (e.g. see WO02/22526,

WO02/40155 or even Angew. Chem.Int.Ed., 2001, 40, 40 or Acc. Chem.Res., 1997, 30,

97). This process of the invention, in any of its embodiments, can be carried out in the presence or in the absence of solvent. However, according to a preferred embodiment of the invention, the process is advantageously carried out in the presence of a solvent compatible with the reducing agent, as well known by a person skilled in the art. For instance, one may cite C ₄ -C ₆ ether, such as ether or THF, when using LiAlH ₄ as reducing agent. The temperature at which this process of the invention can be carried out, in any of its embodiments, is comprised between -80 ⁰ C and 100 ⁰ C, preferably between -78°C and 50 ⁰ C. 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. Step C) can be carried out by reacting compound (II) with at least one Lewis acid and optionally an additive.

Said Lewis acid can be used in stoechiometric or in catalytic amounts, relative to the starting alcohol.

Useful Lewis acids can be acidic clays, BF ₃ derivatives or metal salts of formula, AlCl ₂ R, MX ₃ or ZnX ₂ , wherein R is a Ci-C ₄ alkyl group, M is a trivalent metal cation selected from the group consisting of Al, Y, Sc and Fe, and X represents a Cl or F atom or is a weakly or non-coordinating mono anion.

Said acids can be in an anhydrous form or for some of them also in a hydrate form. Furthermore, the boron or aluminum derivative, especially BF ₃ , could be in the form of any one of its adducts with an ether or carboxylic acid, such as R ^! ₂ O or

R ² COOH, wherein R ¹ is a Ci-C ₅ alkyl group, such as C ₂ H ₅ or C ₄ H ₉ , and R ² is a Ci-C ₂₀ alkyl group, such a methyl, ethyl or hept-3-yl.

Non limiting examples of acidic clays are, for instance, clays of the F-20X type.

Non-limiting examples of suitable weakly or non-coordinating mono anions are

ClO ₄ ^" , Ci_8 sulfonates, BF4-, YF ^, SbC^, AsC^, SbF6 ^" , AsF6 ^" or BR ⁴ ₄ ^" , wherein R ⁴ is a phenyl group optionally substituted by one to five groups such as halide atoms or methyl or CF ₃ groups. According to a particular embodiment of the invention, X is BF4 ^" , PF ₆ -, C ₆ F ₅ SO ₃ ^" , CF ₃ SO ₃ ^" , MeSO ₃ ^" , MeC ₆ H ₄ SO ₃ ^" or Cl ^" .

According to a further particular embodiment of the invention, preferred Lewis acids are BF ₃ or a BF ₃ adduct with a Ci-C ₄ ether or carboxylic acid (such as Et ₂ O, Bu ₂ O or AcOH), FeX ₃ or ScX ₃ , X being as defined above. As specific examples, but not limiting, of Lewis acids one may cite acids such as

FeCl ₃ , Sc(CF ₃ SO ₃ ) ₃ , or BF ₃ (Et ₂ O) ₂ .

Additives can be used, e.g. to increase the selectivity and/or the yield of the cyclisation.

As additive can be used a Co-Cs sulphonic acid, water, a Ci-Ci ₂ alcohol, silica, aluminium oxide or molecular sieves. According to a particular embodiment said additive can be acidic or neutral, and in the form of small particles, or even a powder.

Typical examples are butanol, neutral alumina, silica gel (e.g. of the type commonly used for chromatography), or molecular sieves 4 A. Typical examples of sulphonic acids are FSO ₃ H, MeSO ₃ H, MeC ₆ H ₄ SO ₃ H and the similar. According to a particular embodiment, for the cyclisation a combination of FeCl ₃ and silica can be used. Alternatively a combination of FeCl ₃ and C ₀ -C ₈ sulphonic acid or a combination of FeCl ₃ and butanol can be used.

The Lewis acid can be added to the reaction medium in a large range of concentrations. As non- limiting examples, one can cite catalyst concentrations ranging from 0.01 to 1.50 molar equivalents, relative to the molar amount of the starting alcohol (IV). Preferably, the Lewis acid concentration will be comprised between 0.1

and 0.6 molar equivalents. It goes without saying that the optimum concentration of acid 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 the weight of the Lewis acid. Preferably, the additive concentration will be comprised between 10 and 120 %, relative the weight of the Lewis acid.

Step C) of the invention's process, in any of its embodiments, can be carried out in the presence or in the absence of solvent, but in any case it is advantageously performed under anhydrous conditions.

However, according to a preferred embodiment of the invention, the process is advantageously carried out in the presence of a solvent. A suitable solvent is one which is aprotic. Non-limiting examples of such a solvent are ethers, esters, amides, aromatic hydrocarbons, linear or branched or cyclic hydrocarbons, chlorinated solvents and mixtures thereof. More preferably, the solvent is a methylene chloride, 1,2- dichloroethane, 1 ,2-dichlorobenzene, toluene and mixtures thereof.

The temperature at which this process of the invention can be carried out, in any of its embodiments, is comprised between -50 ⁰ C and 140 ⁰ C, preferably between -10 ⁰ C and 80 ⁰ C. 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.

Alternatively, if it is used a compound (II) wherein the dotted line represents a single bond, the cyclisation can be carried out by using a strong protic acid (i.e. pK _a < 1). This type of cyclisation is, per se, known by a person skilled in the art and does not need to be discussed in further detail. However, one may cite as non-limiting examples of protic acids, MeSO ₃ H, CF ₃ COOH or MeC ₆ H ₄ SO ₃ H. Typical conditions for the cyclisation are reported in A. De Groot et al, Tetrahedron, 1994, 50, 10095.

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 ( ⁰ C) ; the NMR spectral data were recorded in CDCl ₃ with a 360 MHz or 100 MHz machine for ¹ H or ¹³ C respectively, the chemical displacements δ are indicated in ppm with respect to TMS as standard, the coupling constants J are expressed in Hz.

Example 1

Preparation of (3aRS.9aRS.9bRS)-3a.6.6.9a-tetramethyl-1.2.3a.4.6.7.8.9.9a.9 b- decahydronaphthor2,l-blfuran (1)

Step A) A solution of l-ethynyl-2,5,5,8a-tetramethyl-l,2,3,5,6,7,8,8a-octahydro-l- naphthalenol (4.00 g; 17.2 mmol) in o-xylene (60 ml) was treated with [V ₂ O ₆ SiPh ₂ J _n (400 mg) [Tetrahedron Lett. 1976, 17, 2981] and heated at reflux (145°C). After 17 hours, the rearrangement was complete. The reaction mixture was poured into 5% aquous NaOH. The product was extracted twice with Et ₂ O and washed successively with H ₂ O and twice with satured aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. Bulb-to-bulb distillation (125°C (oven temp.)/0.04 mbar) afforded 97% pure (2,5,5,8a-tetramethyl-3,5,6,7,8,8a- hexahydro-l-naphthalenyl)acetaldehyde (3.42 g; yield = 83%).

¹ H-NMR: 1.13 (s, 3 H), 1.14 (s, 3 H), 1.77 (s, 3 H), 1.10-1.35 (m, 2 H), 1.42-1.60 (m, 2 H), 1.65 (s, 3 H), 1.70-1.85 (m, 2 H), 2.62-2.72 (m, 2 H), 3.11 (d, J = 17 Hz, 1 H), 3.22 (d, J = 17 Hz, 1 H), 5.66 (m, 1 H), 9.55 (t, J = 2 Hz, 1 H).

¹³ C-NMR: 201.4 (d), 148.3 (s), 129.6 (s), 129.4 (s), 117.1 (d), 43.3 (t), 40.6 (t), 39.2 (s), 37.5 (t); 36.1 (s), 33.6 (t), 32.8 (q), 30.5 (q); 25.8 (q), 19.6 (q), 18.7 (t).

Step B) A solution of (2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-l-naphthalenyl) acetaldehyde obtained in step A) (3.40 g; 14.2 mmol) in Et ₂ O (10 ml) was added drop- wise to a stirred suspension of LiAlH ₄ (410 mg; 10.7 mmol) in Et ₂ O (20 ml) at such a rate that a gentle reflux was maintained (5 minutes). The suspension was heated at reflux for 30 minutes, cooled at 0 ⁰ C and treated successively drop-wise with water (0.4 ml), 5% aqueous NaOH (0.4 ml) and water (3x 0.4 ml). After stirring for 5 minutes at room temperature the suspension was filtered over Celite and the filtrate concentrated. Bulb-to-bulb

distillation (130 ⁰ C (oven temp.)/0.03 mbar) afforded pure 2-(2,5,5,8a-tetramethyl-

3,5,6,7,8,8a-hexahydro-l-naphthalenyl)ethanol (2) (3.21 g; yield = 90%).

¹ H-NMR: 1.12 (s, 3 H), 1.14 (s, 3 H), 1.16 (s, 3 H), 1.22-1.38 (m, 2 H), 1.45 (m, 1 H), 1.55 (m, 1 H), 1.70 (s, 3 H), 1.72-1.85 (m, 2 H), 1.91 (m, 1 H), 2.30 (m, 1 H), 2.51 (m, 1 H), 2.52-2.65 (m, 2 H), 3.63 (m, 2H), 5.63 (m, 1 H).

¹³ C-NMR: 149.0 (s), 133.8 (s), 127.0 (s), 117.1 (d), 62.6 (t), 40.7 (t), 39.5 (s), 37.0 (t), 36.0 (s); 33.5 (t), 32.8 (q), 31.6 (t), 30.9 (q); 26.0 (q), 19.6 (q), 18.8 (t).

Step C)

isomerisation products

- using FeCh and SiO?:

A solution of 2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-l-naphthaleny l)ethanol (500 mg; 96% pure; 2.05 mmol) in 1 ,2-dichloroethane (5 ml) and CH ₂ Cl ₂ (8 ml) was treated at 24°C with SiO ₂ 60 A (70-220 μm) (84 mg). Under stirring FeCl ₃ (glove-box stored; 167 mg; 1.03 mmol) was added. After 20 min the dark reaction mixture was poured under stirring into 5% HCl and was extracted with Et ₂ O (2x). The organic phase was washed successively with water, sat. aq. NaHCO ₃ and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. Bulb-to-bulb distillation (125°C (oven temp.)/0.06 mbar) afforded (±)-(l) (454 mg; 81% pure; yield = 73%). It was also obtained (3) (yield = 4%) and (4) (yield =2%). It was also recovered (2) (yield = 8%).

- using FeCh in stoichiometric amounts: A solution of 2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-l-naphthaleny l)ethanol (300 mg; 1.28 mmol) in CH ₂ Cl ₂ (4 ml) and 1 ,2-dichloroethane (2 ml) was treated at 0 ⁰ C with FeCl ₃ (208 mg; 1.28 mmol). After 40 minutes the conversion was completed.

The reaction mixture was poured under stirring into 5% aqueous HCl and was extracted twice with Et ₂ O. The organic phase was washed successively with water, saturated aqueous NaHCCb and twice with saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. Bulb-to-bulb distillation (115°C (oven temp.)/0.03 mbar) afforded pure (±)-(l) (198 mg; 96% pure; yield = 63%) containing traces of (3) (yield = 2%).

- using FeCh in catalytic amounts:

A solution of (+)-2-(2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-l- naphthalenyl)ethanol* ([α] _D ² ° +45 (CHCl ₃ ; c: 0.84;1.0 g; 4.27 mmol) in 1,2- dichloroethane (20 ml) was treated at 0 ⁰ C with anhydrous FeCl ₃ (138 mg; 0.848 mmol). After 2 minutes, the temperature was allowed to reach room temperature. Stirring was continued for 3 hours, then another portion of anhydrous FeCl ₃ (; 69 mg; 0.424 mmol) was added and stirring continued for 30 minutes. The reaction mixture was stopped at partial conversion by pouring it under stirring into 5% aqueous HCl and was extracted twice with Et ₂ O. The organic phase was washed successively with water, saturated aqueous NaHCO ₃ and twice with saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. Purification by column chromatography (SiO ₂ (60 g); cyclohexane/ AcOEt = 99 : 1), afforded 159 mg of first fractions (containing appreciatively 39% of (+)-(l), 27 % of (3) and 9% of (+)-(4)), followed by 423 mg (yield = 42%) of pure (+)-(l) (93% ee; [αfo ²⁰ +84 (CHCl ₃ ; c: 0.92; 739 mg) and then using cyclohexane/AcOEt = 9 : 1, 316 mg (yield = 32%) of (+)-(2) were recovered.

* prepared from (-)-2-methyl-4-(2,6,6-trimethyl-l-cyclohexen-l-yl)butanal prepared according the procedure described in WO 2007/010420

Example 2

Preparation of (3aRS.5aSR.9aSR.9bRS)-3a.6.6.9a-tetramethyldodecahvdronaphth or2.1- blfuran (5): Step A)

A solution of l-ethynyl-2,5,5,8a-tetramethyl-perhydro-4aH-l-naphthalenol (8.48 g; 92% pure; 33.3 mmol) in o-xylene (40 ml) was added drop-wise in 20 minutes to a refluxing mixture (145°C) of [Ph ₃ SiO] ₃ VO (1.79 g; 2.00 mmol), triphenylsilanol (1.38 g;

5.00 mmol) and stearic acid (191 mg; 0.67 mmol) in o-xylene (40 ml). After 7 hours the reaction mixture was poured into 5% aqueous NaOH. The product was extracted twice with Et ₂ O and washed successively with H ₂ O and twice with saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. Bulb-to-bulb distillation (125°C (oven temp.)/0.03 mbar) afforded 87% pure (2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-l- naphthalenyl)acetaldehyde (7.59 g; yield = 85%).

Using [V ₂ OoSiPh ₂ J _n , as for Example 1, Step A), also afforded (2,5,5,8aβ-tetramethyl- 3,4,4aα,5,6,7,8,8a-octahydro-l-naphthalenyl)acetaldehyde in 85% yield.

13 C-NMR: 201.5 (d), 132.1 (s), 131.3 (s), 51.7 (d), 43.2 (t), 41.5 (t), 38.5 (s), 37.2 (t), 33.9 (t); 33.3 (s), 33.2 (q), 21.6 (q), 19.9 (q); 19.8 (q), 18.9 (t), 18.9 (t).

Step B)

A solution of (2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-l- naphthalenyl)acetaldehyde (7.58g; 87% pure; 28.2 mmol) in Et ₂ O (50 ml) was added drop-wise to a stirred suspension of LiAlH ₄ (800 mg; 21.1 mmol) in Et ₂ O (20 ml) at such a rate that a gentle reflux was maintained (5 minutes). The suspension was heated at reflux for 30 minutes, cooled at 0 ⁰ C and treated successively drop-wise with water (0.8 ml), 5% aqueous NaOH (0.8 ml) and water (3x 0.8 ml). After stirring for 5 minutes at room temperature, the white suspension was filtered over Celite and the filtrate concentrated. Bulb-to-bulb distillation (130 ⁰ C (oven temp.)/0.03 mbar) afforded 94% pure 2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-l-na phthalenyl)ethanol (6) (6.98 g; 94% pure; yield = 99%).

1 ³ 3C/ -NMR: 136.2 (s), 128.6 (s), 62.7 (t), 51.7 (d), 41.7 (t), 38.7 (s), 37.2 (t), 33.7 (t), 33.3 (s); 33.3 (q), 31.5 (t), 21.7 (q), 20.1 (q); 19.9 (q), 19.0 (t), 19.0 (t).

Step C)

- using FeCh and SiO?:

A solution of 2-(2,5,5,8aβ-tetramethyl-3,4,4aα,5,6,7,8,8a-octahydro-l- naphthalenyl)ethanol (500 mg; 94% pure; 1.99 mmol) in 1 ,2-dichloroethane (5 ml) and CH ₂ Cl ₂ (8 ml) was treated at 24°C with SiO ₂ 6OA (70-220μm) (81 mg). Under stirring anhydrous FeCl ₃ (162 mg; 1.00 mmol) was added. After 20 minutes the dark reaction mixture was poured under stirring into 5% aqueous HCl and was extracted twice with Et ₂ O. The organic phase was washed successively with water, saturated aqueous NaHCO ₃ and twice with saturated aqueous NaCl e, dried (Na ₂ SO ₄ ) and evaporated (513 mg). Bulb-to-bulb distillation (125°C (oven temp.)/0.06 mbar) afforded (5) (481 mg; 77% pure; yield = 79%), containing recovered (6) (yield = 13%).

Example 3

Following the same experimental procedure as described in Example 2, other Lewis acids have been tested.

The results for the cyclisation of (2) are reported in the following Table I:

p.s. it was used the starting material obtained in Example 1 (94% purity)

1) between brackets is the molar amount relative to starting alcohol (6)

2) between brackets is the w/w amount relative to Lewis acid

3) the w/w ratio between (6) and the solvent is the same as in Example 2), between brackets it is the w/w ratio between two solvents

4) reaction time

5) non- volatile products recovered other than (6), (5) and (7), w/w percentage relative to the amount of (6) initially used (%)

6) relative amounts obtained by GC analysis of the volatile fraction (%)

7) molar ratio

OTf= triflate - *: comparative example (prior art conditions - WO 06/10287)

The results for the cyclisation of a mixture of isomers of formula (II) (ambrols) are reported in the following Table II:

SM : starting alcohol

1) between brackets is the molar amount relative to starting alcohol

2) between brackets is the w/w amount relative to Lewis acid; ** molar amount relative to starting alcohol

3) the w/w ratio between SM and the solvent is the same as in Example 2), between brackets it is the w/w ratio between two solvents

4) reaction time

5) non- volatile products recovered other than starting alcohol, (5) and (7), w/w percentage relative to the amount of alcohol initially used (%)

6) relative amounts obtained by GC analysis of the volatile fraction (%)

7) molar ratio

OTf= triflate - *: comparative example (prior art conditions - WO 06/10287)

The results for the cyclisation of (1) are reported in the following Table III :

p.s. it was used the starting material obtained in Example 1 (94% purity)

1) between brackets is the molar amount relative to starting alcohol (2)

2) between brackets is the w/w amount relative to Lewis acid 3) the w/w ratio between (2) and the solvent is the same as in Example 2), between brackets it is the w/w ratio between two solvents

4) reaction time

5) relative amounts obtained by GC analysis of the volatile fraction (%) OTf= triflate

When the cyclisation of (2) with MeS03H (prior art conditions - WO 06/10287) was attempted (1.3 molar equivalent, T 20 ⁰ C) a very complex mixture was obtained, wherein the desired furan (1) accounted for less than 5% of the total and many unknown products were obtained (accounting for more than 30%).

The same cyclisation with ClSO ₃ H (1.0 molar equivalent, T -78°C, MeNO ₂ ) afforded only a rearrangement product (3a,5a,6,6-tetramethyl-l,2,3a,4,5,5a,6,7,8,9- perhydronaphtho[2,l-b]furan) in about 25% yield.