WO2007010483A1

WO2007010483A1 - Substituted cyclohexanones

Info

Publication number: WO2007010483A1
Application number: PCT/IB2006/052460
Authority: WO
Inventors: Oliver Knopff; Charles Fehr; José Galindo
Original assignee: Firmenich Sa
Priority date: 2005-07-19
Filing date: 2006-07-18
Publication date: 2007-01-25
Also published as: CN101223122B; US7470820B2; EP1910261B1; ATE448186T1; DE602006010397D1; EP1910261A1; JP5119149B2; CN102093186A; JP2009501780A; ES2334391T3; CN101223122A; CN102093186B; US20080228008A1

Abstract

The present invention relates to a cyclohexanone derivative of formula (I) in the form of any one of its isomers or mixture thereof. The invention concerns also the preparation and the use of said derivative. The invention's compound is a useful starting material for the preparation of various optically active compounds.

Description

SUBSTITUTED CYCLOHEXANONES

Technical field

The present invention relates to the field of organic synthesis and more specifically it concerns a cyclohexanone derivative of formula

in the form of any one of its isomers or mixture thereof and as defined below. The invention concerns also the preparation and the use, as starting material, of said derivative.

Prior art

To the best of our knowledge, the cyclohexanone derivatives of formula (I) are new compounds. Furthermore, in the prior art we have not found any method allowing the preparation of an analogue of the invention's cyclohexanone s, i.e. compounds that have a hydroxy derivative in position 3 and a hydrocarbon derivative in position 5.

The cyclohexanone derivatives of formula (I) are useful starting materials to prepare the corresponding cyclohexenone. In WO 05/077875 the inventor describes a method to prepare similar cyclohexenone s, however this prior art method requires the use of dione instead of the compound of formula (I).

Snider et al. (J.Org.Chem., 1991, 4908), Agami et al. (Bull.Soc.Chim.Fr., 1987, 358) or Fehr et al. (Eur.J.Org.Chem., 2004, 1953) describe also alternative methods to prepare similar cyclohexenone s, however these methods imply the use of different starting materials as well as of different reagents. Description of the invention

We have now found a new class of cyclohexanones which are useful intermediates for the preparation of various compounds which can have specific configurations or are optically active. Therefore, a first object of the present invention is a compound of formula

wherein the R¹, taken separately, are identical and represent an achiral C_1-1O linear, branched or cyclic alkyl or alkenyl group optionally substituted, or alternatively said two

R¹, taken together, represent a linear C₃-C₁O alkanediyl or alkenediyl group optionally substituted;

R² represents an achiral C_1-7 linear, branched or cyclic alkyl or alkenyl group optionally substituted or a phenyl or benzyl group optionally substituted; and R represents:

- a hydrogen atom,

- a group of formula Si(R³)₃, R³ representing a C_1-7 linear, branched or cyclic alkyl or alkenyl group or a phenyl group optionally substituted,

- a C₁-C₁O sulfonyl group, or - a C₁-C₁O hydrocarbon group optionally comprising up to four heteroatoms selected from the group consisting of oxygen, nitrogen, silicium or sulfur, provided that said heteroatom is not directly bonded to the oxygen atom bearing said R group.

According to a particular embodiment of the invention, R represents a hydrogen atom, a C_1-6 linear, branched or cyclic alkyl, alkenyl or acyl group optionally substituted, an optionally substituted benzyl group, a C₁-C₁O sulfonyl group, such as a MeSO₂, CF₃SO₂, C₆H₅SO₂ or CH₃C₆H₄SO₂, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a C₁-S alkyl group or, taken together, representing a C₁-C₅ group, or a group of formula Si(R³)₃, R³ representing a C_1-7 linear, branched or cyclic alkyl or alkenyl group or a phenyl group optionally substituted. According to a particular embodiment of the invention, R represents a hydrogen atom, a C_1-6 linear vinyl or acyl group, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a C₁-_S alkyl group or, taken together, representing a C₁-C₅ group, or a group of formula Si(R³)₃, R³ representing a C_1-3 linear alkyl.

As mentioned above, R, R¹, R² and R³ can be substituted, for example, by up to two groups. As non-limiting examples, said groups are C₁-S alkyl, alkoxy or cycloalkyl group.

The compound of formula (I), in any of its embodiments, possesses three asymmetric carbon atoms on the cyclohexenone ring, namely carbon atoms 2, 3 and 5. Therefore, said compound can be in the form of any one of its stereoisomers. Furthermore it is also understood that the invention's compound can be in the form of a mixture of any one of said stereoisomers.

According to an embodiment of the invention, the invention's compounds are trans ketones of formula

wherein R, R¹ and R² have the same meaning as indicated in formula (I) and the groups OR and R² are in a relative configuration trans.

According to a further embodiment, the compounds of formula (II) are in an optically active form of formula

(III) wherein R, R¹ and R² have the same meaning as indicated in formula (I) and the asterisks mean the configuration of the carbon is absolute and therefore that said compound (III) or (IH') is in an optically active form.

In particular, said compound (III) is in the form of a mixture of the compounds of formula

wherein R, R¹ and R² have the same meaning as indicated in formula (I) and the asterisks mean the configuration of the carbon is absolute and therefore that said compound (IV) or (IV) is in an optically active form.

According to another embodiment of the invention, and independently of the fact that the compound is of formula (I), (II), (III), (III') (IV) or (IV), the R¹ groups, taken separately, are identical and represent an achiral C₁-S linear, branched or cyclic alkyl or alkenyl group or alternatively said two R¹, taken together, represent a linear C₃-C₁O alkanediyl or alkenediyl group;

R² represents an achiral C₁-S linear or branched alkyl or alkenyl group or a phenyl group; and

R represents a hydrogen atom, a C₁-S linear, branched or cyclic alkyl or alkenyl group optionally substituted, a benzyl group, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a methyl, ethyl or n-propyl group or, taken together, representing a C₃-C₄ group, or a group of formula Si(R³)₃, R³ representing a C₁-S linear, branched alkyl group or a phenyl group.

Alternatively the R¹ groups, taken separately, are identical and represent an achiral C₁-S linear, branched or cyclic alkyl group or alternatively said two R¹, taken together, represent a linear C₃-C₁O alkanediyl or alkenediyl group;

R² represents an achiral C₁-S linear or branched alkyl group or a phenyl group; and R represents a hydrogen atom, a C₁-S linear, branched or cyclic alkyl group optionally substituted, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a methyl, ethyl, isopropyl or propyl group or, taken together, representing a C3-C4 group, or a group of formula Si(R³)₃, R³ representing a C_1-4 linear or branched alkyl group or a phenyl group.

Yet, independently from the specific embodiment, R may represent only a hydrogen atom or may represent a Si(R³)₃ group, R³ representing a C_1-4 alkyl group or a phenyl group, or a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a methyl, ethyl or isopropyl group or, taken together, representing a CH₂CH₂ or CH₂CH₂CH₂ group.

In said embodiments, the optional substituents are defined as above. Specific examples of said compounds are:

(-)-(lR,llS,14R)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one, (-)-(lR,llR,14R)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one, (lRS,llRS,14RS)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one,

(lRS,llRS,14RS)-l-ethoxyethoxy-14-methylbicyclo[9.4.0]pentadecan-12-one, and

(lRS,llRS,14RS)-14-methyl-l-trimethylsilyloxybicyclo[9.4.0] pentadecan-12-one.

A second object of the present invention is a process for the preparation of an optically active compound of formula

wherein the R¹, R² and the asterisk have the same meaning as indicated above, for the various embodiment of compound (I), by treating a trans ketone of one of formulae

(H) (HI)

(HI)

wherein the asterisk, R¹ and R² have the meaning indicated above and R is as defined above provided that it is not a hydrogen atom; with an optically active sodium or potassium alkoxide and optionally a means of removing water; or by treating an optically active trans ketone of formula (III) or (IH')

(HI) (111)

wherein R¹ and R² have the meaning indicated above and R is hydrogen with a C₁-C₈ sulfonyl chloride in the presence of a tertiary C₃-C₂₄ amine.

By "optically active alkoxide" we mean here a compound comprising at least one moiety having an alkoxy group, i.e. a deprotonated alcohol group, and which is optically active. In other words, said optically active alkoxide can be an optically active sodium or potassium salt of a C₄-C₄₀ compound comprising one, two or three of such moieties or of a carbohydrate or a derivative thereof, such as a sugar, or of a polymer comprising optically active alkoxy groups.

Although it is not possible to provide an exhaustive list of the currently known optically active sodium or potassium alkoxides which can be used in the invention's process, the following can be named as preferred examples: a) a sodium or potassium salt of a C₄-C₁₈ optically active mono alcohol, such as a sodium or potassium salt of an optically active alcohol of formula R⁴

\ R⁵ (A)

HO

wherein R⁵ represents a C_1-4 alkyl group or an optionally substituted phenyl group and R⁴ represents a C_1-4 alkyl group or a C(R⁵ )₂(OR⁴ ) group, R⁵ representing a hydrogen atom or a R⁵ group and R⁴ representing a C_1-6 alkyl group or a C3-₉ trialkyl silyl or a triphenyl silyl group; or such as a chiral alcohol of formula R⁴ -OH, wherein R⁴ represents a C_7-12 chiral hydrocarbon group; a sodium or potassium salt of

- a C₃-C₁₈ optically active 1,2-diol, such as a sodium or potassium salt of an optically active diol of formula

R⁶ R⁶

(B) HO OH

wherein R⁶ represents an optionally substituted phenyl group, a C_1-6 alkyl group or a COOR⁷ group, R⁷ representing a C_1-4 alkyl group;

- a C₄-C₁₈ optically active 1,3-diol, such as a sodium or potassium salt of an optically active diol of formula

wherein R⁶ has the meaning indicated above;

- a C5-C35 optically active 1,4-diol, such as a sodium or potassium salt of an optically active diol containing a moiety of formula

^(D) (D¹) or such as a sodium or potassium salt of an optically active diol of formula

wherein R⁵ has the meaning indicated above; c) a sodium or potassium salt of a C₄-C₂₅ optically active alcohol containing a nitrogen in the β position, such as a sodium or potassium salt of an optically active 1,2-amino- alcohol of formula

(E) (E¹)

wherein R⁵ has the meaning indicated above, R⁷ represents a R⁴ or R⁵ group as defined above and R⁸ represents an optionally substituted phenyl group, a C₁^ alkyl or alkylbenzene group a SiR⁷ ₃ group or a R⁷ CO group; optionally R⁵ and R⁷ can be bonded together to form a Cs-io ring or R⁷ and a R⁸ can be bonded together to form a C₄_₅ heterocycle, or the two R⁸ can be bonded together to form a C_{2 5} heterocycle; or such as a sodium or potassium salt of an optically active iminoalcohol of formula

(F) (F¹)

wherein R⁵ and R⁵ have the meaning indicated above; d) a sodium or potassium salt of a C₁₅-₃8 compound having two or three groups derived from an optically active alkoxide mentioned under a), b) or c); or e) a sodium or potassium salt of an optically active alkoxide mentioned under d) and which is supported on an insoluble material such as silica, Merrifield resins, gold or polystyrenes.

Examples of substituents of phenyl groups are R^b, SR^b, NO₂ or OR^b groups or yet halogen atoms, wherein R^b stands for a C_1-4 alkyl group.

According to a particular embodiment of the invention, said optically active sodium or potassium alkoxide comprises one or two alkoxy groups and is: a) a sodium or potassium salt of an optically active alcohol of formula

wherein R⁹ represents a C_1-4 alkyl group and R¹⁰ represents a phenyl group optionally substituted by one C_1-4 alkyl group; b) a sodium or potassium salt of an optically active 1,2-diol of formula

HO OH

R V¹⁰ Λ R^{10 (H)}

wherein R¹⁰ has the meaning indicated above; or a sodium or potassium salt of an optically active 1,4-diol of formula

wherein R¹¹ represents a C_1-4 group or a hydrogen atom; c) a sodium or potassium salt of an optically active 1, 2-amino alcohol of formula

R 12 R 13

(K)

HO NR¹⁴2 wherein R¹² represents a phenyl group optionally substituted by a SMe, OMe, NO₂ or C_1-4 alkyl group, R¹³ represents a C_1-4 alkyl group, a R¹² group or a CH₂OSiMe₂ ¹Bu group and R¹⁴ represents a benzyl or C_1-4 alkyl, or the two R¹⁴ are bonded together to form a C4-5 heterocycle; or a sodium or potassium salt of an optically active 1,2-imino alcohol of formula

wherein R , 12 - has the meaning indicated above; or d) a sodium or potassium salt of an optically active alcohol of formula

wherein R¹² has the meaning indicated above.

The invention's processes using the 1,2- amino alcohols of formula (E), (E') or (K) represents a particularly appreciated embodiment of the invention.

Specific examples of the above-mentioned optically active sodium or potassium alkoxides are a sodium or potassium salt of a compound of formula 1 to 12 (the absolute configuration being represented in the drawings): a)

(1)

b)

(2) (3) (4) (5)

c)

(10) (H)

d)

said compounds having proved to be particularly useful for the invention's process wherein the starting compound (I) is a bicycle.

It is also useful to mention that the optically active alkoxide can be characterized by a specific enantiomeric excess (e.e.). In general, optically active alkoxide having a higher e.e. provided compounds (V) with higher e.e. Therefore, it is preferable to employ in the invention's process optically active alkoxide having e.e. of at least 50% or even of at least 90%.

The optically active alkoxide can be added to the reaction medium in a large range of concentration. As non-limiting examples, one can cite as optically active alkoxide concentration values ranging from 0.05 to 8.0 molar equivalents, relative to the ketone (I). Preferably, the optically active alkoxide concentration will be comprised between 0.1 and 4.0 molar equivalents. It goes without saying that the optimum concentration of said alkoxide will depend on the nature of the latter and on the desired time of reaction.

The chiral sodium or potassium alkoxide can be in the form of a preformed salt or it can be formed in situ prior to its use, e.g. by pre-mixing a chiral compound comprising at least one moiety having a hydroxy group and an appropriate sodium or potassium base. According to a particular embodiment of the invention, particularly appreciated alkoxides are the 1,2-amino alcohols, and in particular the ones cited above.

As mentioned above, the process can be performed in the presence of a means of removing water. According to a preferred embodiment of the invention, the process is carried out in the presence of said water-removing means. By "a means of removing water" we mean here a compound or a substance capable of trapping the water which is formed during the reaction. Said water can be trapped either by means of an absorption mechanism or by means of a chemical reaction or also by azeotropic distillation.

Examples of useful water-removing means are: i) an alkaline or alkaline earth hydride, such as NaH, KH, CaH₂, LiH; ii) a reaction-medium insoluble inorganic material capable to form a clathrate with water, such as an anhydrous zeolite, preferably of the 4 A type, or anhydrous MgSO₄, Na₂SO₄, Na₂O, CaCl₂ or MgCl₂; or iii) an organic material capable of reacting with water to form non-acidic compounds, such as an orthoester, N-methyl-N-trimethylsilyl-trifluoroacetamide or 1-trimethyl- silylimidazole.

The water-removing means can be added to the reaction medium in a large range of amounts which depend on the exact nature of the water-removing means. In general, it has been observed that the higher the amount of means of removing water employed, the higher is the e.e. of the compound (V) obtained at the end of the process. However, the addition of amounts which exceed three times the amount theoretically needed to trap all the water which can theoretically be formed does not provide any appreciable additional benefit.

Concerning the sulfonyl chloride one may cite, as non-limiting examples, MeSO₂Cl, CF₃SO₂Cl, MeC₆H₄SO₂Cl or C₆H₅SO₂Cl. Concerning the amine one may cite, as non-limiting examples, triethyl or tributyl amine or yet DBU. Said amine can be in a racemic or optically active form and is conveniently added in at least an equimolar amount with respect to the staring ketone (III) or (III').

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 ketone is a solid compound under the reaction conditions.

However, according to a preferred embodiment of the invention, and independently of the physical state of the starting ketone, the process is advantageously carried out in the presence of a solvent. Said solvent must be chemically compatible with the reaction and does not deactivate the alkoxide.

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 C₄-C₆ ether such as THF or dioxane, C₃-C₆ amides such as DMF or N-Methyl pyrrolidone, methylene chloride, toluene, N-methyl morpholine and mixtures thereof. The temperature at which this process of the invention can be carried out, in any of its embodiments, is comprised between -8O⁰C and 100⁰C, preferably between -78⁰C and 2O⁰C. 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.

A third object of the present invention concerns a process for the preparation of the invention's compounds (I), i.e. a process for the preparation of a compound of formula (I), as defined above, comprising the step of: a) treating an achiral di-ketone of formula

wherein R¹ and R² have the same meaning as indicated above, for the various embodiment of compound (I), with a C₃-C₂₄ amine or diamine, in a racemic or optically active form; and in the presence of a complex obtainable by admixing TiCl₄ or ZrCl₄ with an equimolar amount of an alcohol R^bOH, R^b representing a C₁-C₅ alkoxy group, or of a chiral ligand selected from the group consisting of an optically active alcohol of formula (E), (E'), (F) or (F'), as defined above, and an optically active alcohol of formula

R*

:OOR^C (N)

HO

wherein R⁴ has the meaning indicated above and R^c represents a C_1-4 alkyl group; b) hydrolyze the reaction medium of step a) to obtain a compound of formula (I) wherein R is a hydrogen atom; and c) converting the compound obtained in step b), by treating it with an appropriate reagent, into a compound of formula (I) wherein R is not a hydrogen atom.

The exact nature of said "appropriate reagent" is well known by the person skilled in the art, and several examples are given in basic text books of chemistry (e.g. T.H.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", John Wiley &

Sons, Inc., 3^rd edition, 1999; in particular from page 17 to page 200). Although it is not possible to provide a detailed list, which in any case would not be exhaustive, of said appropriate reagents. However, as non-limiting examples one may cite the following reagents:

- a compound of formula RX, R having the meaning of formula (I), and X being a C_1-6 sulfonate or a halogen atom;

- an appropriate carboxylic anhydride or chloride, i.e. susceptible to provide a R group which is an acyl;

- a compound of formula XCH(R^a)OCH₂R^a, or of formula HR^a C=CHOCH₂R^a, R^a' representing a R^a group without a CH₂ group and R^a having the meaning indicated above;

- an appropriate alkene, i.e. susceptible to provide a R group which is an alkyl or alkenyl group.

It is well understood by a person skilled in the art that the use of a complex comprising an optically active ligand, such as one of formula (E), will lead to the formation of a compound (I) in an optically active form, i.e. a compound of formula (III) or (IH'), while the use of a complex comprising a ligand that is not optically active, such as OPr, will lead to the formation of a compound (I) in a racemic form, and in particular to a compound of formula (II).

According to a particular embodiment of the invention, the preferred complex is obtained by admixing TiCl₄ with n-propyl or iso-propyl alcohol.

According to a particular embodiment of the invention, the preferred chiral ligands are of formula (K) or (L), as defined above, and in particular of formula (6), (7), (8), (8') or (9), as defined above.

According to another particular embodiment of the invention, the preferred RX is a compound of formula Si(R³)₃X, R³ representing a C₁-C₄ alkyl group or a phenyl group and X representing a chloride atom or a CF₃SO₃ group.

According to another particular embodiment of the invention, the preferred compound of formula XCH(R^a)OCH₂R^a, or of formula HR^a C=CHOCH₂R^a, are those wherein R^a or R^a , taken separately, represents a hydrogen atom or a methyl, ethyl, propyl or isopropyl group, or R^a and R^a , taken together, represents a CH₂CH₂ or

CH₂CH₂CH₂ group. Said process can be advantageously carried out in a solvent selected from the group of N-methyl-morpholine, CH₂Cl₂, DMF or NMP. Furthermore, the process can be carried out at a temperature comprised between -1O⁰C and 3O⁰C. Said solvent may further comprise water.

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 360MHz or 100MHz machine for ¹H or ¹³C respectively, the chemical displacements δ are indicated in ppm with respect to TMS as standard, the coupling constants J are expressed in Hz.

The cyclic 3-methyl-l,5-diones were prepared according to the reference G. Ohloff, J. Becker, K. H. Schulte-Elte, HeIv. CUm. Acta 1967, 50, 705.

Example 1

Preparation of (-)-(lRJ lSJ4R)-l-hvdroxy-14-methyl-bicvclor9.4.01pentadecan-12-one (13) and f-)-flR,llR,14R)-l-hvdroxy-14-methyl-bicvclor9.4.01pentadecan-12-one (14)

Preparation of catalyst: A solution of freshly distilled (+)-N-isopropylephedrine (10.35g, 50.0 mmol) in CH₂Cl₂ (150 ml) was treated in 5 minutes with a solution of TiCl₄ (9.50 g (5.52 ml); 50 mmol) in CH₂Cl₂ (50 ml) (temp. 30 to 4O⁰C). After introduction, the solvent was distilled under N₂. The residue was dried under vacuum (0.01 mbar): 21.77 g.

Aldol reaction: The above obtained catalyst (20.71 g; max. 47.6 mmol; 0.80 equiv) was poured under stirring into a 250 ml vessel containing NMP (57 ml). The temperature was allowed to reach 34⁰C. After 5 minutes, solid 3-methyl-l,5-cyclopentadecanedione (15) (14.98 g, 59.4 mmol) was added to the stirred dark brown solution. After 5 minutes, the solution was treated under ice-cooling with TMEDA (6.67 g, 8.54 ml, 57.5 mmol) containing H₂O (89.1 mg; 4.95 mmol). The temperature was maintained at 0-2⁰C After 165 min, the turbid reaction mixture was poured into 5% HCl/ice and extracted with ether. The organic phases were washed (H₂O (2x), saturated NaHCO₃, NaCl), dried (Na₂SO₄) and evaporated. Flash chromatography, using SiO₂ (350 g) and cyclohexane/AcOEt = 9:1 afforded successively (15) (4.95 g, 33%) and (13)/(14) (ca. 1:1) (9.97 g, 66.5%). Two parallel flash chromatographies, using SiO₂ (300 g) and cyclohexane/AcOEt = 9:1, afforded together successively 4.35 g (yield: 29%) of (14) (17% ee), 0.95 g (yield: 6%) of (13)/(14) and 3.85 g (yield: 26%) of (13) (42% ee).

The enantiomeric excesses were determined by using a chiral capillary column CP-Chirasil-DEX CB (25 m X 0.25 mm) (Chrompack) and as carrier gas He at 0.63 bar of the corresponding silylated diol of alcool.

Spectra of (13):

¹H-NMR: 1.01 (d, J=6.5, 3 H); 1.20-1.68 (m, 20 H); 1.74 (m, 1 H); 2.18-2.45 (m, 4 H). ¹³C-NMR: 214.2 (s); 78.3 (s); 58.67 (d); 44.8 (t); 42.5 (t); 37.8 (t); 27.7 (d); 26.8 (t); 26.4 (t); 25.7 (t); 25.5(t); 25.1 (t); 25.0 (t); 24.9 (t); 22.0 (q); 18.6 (t).

Spectra of (14):

¹H-NMR: 1.02 (d, J=6.5, 3 H); 1.08 (m, 1 H); 1.20-1.73 (m, 18 H); 1.85 (m, 1 H); 1.96

(t, J=13, 1 H); 2.14 (m, 1 H); 2.36 (m, 1 H); 2.41 (m, 2 H).

¹³C-NMR: 211.0 (s); 79.7 (s); 55.7 (d); 49.9 (t); 45.0 (t); 39.7 (t); 28.7 (d); 26.9 (t); 26.4 (t); 26.2 (t); 26.0 (t); 25.2 (t); 25.0 (t); 22.2 (t); 22.1 (q); 19.3 (t).

Alternatively, in the above experiment, the crude product obtained after drying over Na₂SO₄ was dissolved in hot heptane (420 ml) and let stand at 23⁰C for 15 hours. After filtration of the crystals, the mother liquors were purified by chromatography, using SiO₂ (270 g) and cyclohexane/AcOEt = 9:1, then 7:3. The apolar fractions afforded (15) (5.82g; 39%), the polar ones a mixture of (13)/(14) (44:56 by GC of derived diols); (yield: 28%)). Flash chromatography, using SiO₂ (250 g) and cyclohexane/ AcOEt = 9:1, afforded successively 1.96 g (yield: 13%) of (14) (44% ee), 0.41 g (yield: 3%) of (13)/(14) and 1.54 g (yield: 10%) of (13) (75% ee). [α]_D ²⁰ (CHCl₃; c = 0.98) -25.7 (extrapolation for enantiomerically pure (13): [α]_D ²⁰ -34). [α]_D ²⁰ (CHCl₃; c = 2.9) -17.1 (extrapolation for enantiomerically pure (14): [α]_D ²⁰ -39).

Example 2 Preparation of ( 1RS.1 lRS,14RS)-l-hvdroxy-14-methyl-bicvclor9.4.01pentadecan-12- one (16)

A solution of (15) (15.12 g, 60.0 mmol) in CH₂Cl₂ (210 ml) was treated at 22-24⁰C with a solution of ZrCl₃OPr (36% in AcOEt) (65.25 g, 91.6 mmol). After 5 minutes, the yellowish solution was treated at -10-0⁰C with NBu₃ (19.43 g, 25.0 ml, 105 mmol). After 15 minutes, the reaction mixture was poured into water and extracted with ether. The organic phases were washed (H₂O, saturated NaHCO₃, NaCl), dried (Na₂SO₄) and evaporated. Crystallization from heptane (345 ml) afforded 11.93 g of (16) (yield:79%) and 2.80 g of mother liquors, from which another 1.39 g (yield: 9%) of (16) were recovered. Same spectra as (14).

Example 3

Preparation of (+)-(S)-14-methylbicvclor9.4.01pentadec-l(ll)-en-12-one (17)

A solution of (13)/(14) (9.97 g; 39.56 mmol) (obtained from the repetition of Example 1 after one chromatography) in CH₂Cl₂ (300 ml) was treated with Me₃N-HCl (1.89 g; 19.80 mmol). At -15⁰C, the stirred mixture was treated successively with NEt₃ (15.98 g, 158.2 mmol) and drop-wise with MsCl (13.58 g, 118.7 mmol). The reaction mixture was stirred at O⁰C for 1 h and at 25⁰C for 15 hour. It was then poured into 5% HCl and extracted with ether. The organic phases were washed (H₂O, saturated NaHCO₃, NaCl), dried (Na₂SO₄) and evaporated to give a crude oil. The oil was heated in toluene (60 ml) and DBU (9.02 g, 59.34 mmol) for 1 hour at 8O⁰C, cooled and worked up as above (5% HCl and extraction). Bulb-to-bulb distillation (oven temp. 100-150°C/0.01 mb) afforded 8.72 g (yield: 94%) of (17) (29% ee).

Example 4

Preparation of (1RS.1 lRS,14RS)-l-ethoxyethoxy-14-methylbicvclor9.4.01pentadecan-

12-one (18) A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 2 days. After a short column filtration (SiO₂) using diethyl ether as eluent and evaporation of the solvent 2.6 g of the crude product (18) was obtained. Flash chromatography, using SiO₂ and cyclohexanefEtOAc = 95:5 as eluent, afforded 2.10 g (82%) of (18) as a -1:1 mixture of diastereomers. First isomer:

¹H-NMR: 0.98 (d, J = 6.2, 3H), 1.12 (t, J = 6.7, 3H), 1.17 (d, J = 5.1, 3H), 1.26-1.82 (m, 19H), 1.84-1.96 (m, 2H), 2.08-2.16 (m, IH), 2.34 (d, J= 8.2, IH), 2.38-2.42 (m, IH), 3.37-3.43 (m, 2H), 4.97 (q, J = 5.1, IH).

¹³C-NMR: 15.5, 19.8, 20.7, 22.1, 22.4, 25.1, 25.2, 25.8, 26.0, 26.6, 27.2, 28.2, 33.7, 43.2,

49.8, 56.6, 57.9, 84.8, 93.4, 210.6. Second isomer:

¹H-NMR: 0.99 (d, J = 6.2, 3H), 1.16 (t, J = 6.7, 3H), 1.17 (d, J = 5.6, 3H), 1.22 -1.99 (m, 21H), 2.16-2.24 (m, IH), 2.35 (d, J = 8.2, IH), 2.39-2.43 (m, IH), 3.40-3.59

(m, 2H), 4.90 (q, J = 5.6, IH).

¹³C-NMR: 15.5, 19.6, 20.8, 22.1, 22.5, 25.2, 25.2, 25.9, 26.2, 26.4, 27.2, 28.4, 35.0, 40.5, 49.7, 56.4, 56.4, 85.2, 92.1, 210.3.

Example 5

Preparation of (1RS.1 lRS,14RS)-14-methyl-l-trimethylsilyloxybicvclor9.4.01 pentadecan-12-one (19)

A mixture of 25 mg (0.1 mmol) of (16) and 17 μl (0.12 mmol) triethyl amine in 0.5 ml THF was treated at O⁰C with 21 μl (0.11 mmol) TMSOTf. After 30 min 8 μl (0.06 mmol) triethyl amine and 10 μl (0.055 mmol) TMSOTf were added. After 10 min the mixture was diluted with diethyl ether and was poured into 2 ml of a saturated NH₄Cl solution. The organic phase was separated, diluted with 3 ml of dichloro methane and the solvent was evaporated at room temperature under vacuum to afford 32 mg (19) (yield: 99%). ¹H-NMR: 0.1 (s, 9H), 0.99 (d, J=6.6, 3H), 1.18 -1.67 (m, 18H), 1.87-1.93 (m, 2H), 2.04-

2.22 (m, 2H), 2.28 (d, J=8.2, IH), 2.35-2.40 (m, IH). ¹³C-NMR: 2.6 (3C), 19.9, 22.1, 22.6, 25.1, 25.2, 26.1, 26.3, 26.3, 27.2, 28.7, 39.1, 45.6,

49.9, 56.8, 83.4, 210.9.

Example 6

Preparation of (+-)-3-butyl-r-3-hydroxy-r-5-methyl-c-2-propylcyclohexanone (20) and (+- ) -3 -butyl- r-3 -hydroxy- 1-5 -methyl- f-2-prop ylcyclohexanone (21 )

a) Preparation of 7-methyl-5,9-tridecanedione

75 ml (1.03 mol) SOCl₂ were added in 20 min to 50 g (0.34 mol) 3-methylglutamic acid (in a 250 ml flask with reflux condenser connected to two washing bottles: 250 ml H₂O, 250 ml 20% NaOH) at roomtemperature under stirring. After adding 0.5 ml pyridine an evolution of gas was observed and the temperature decreased (5-1O⁰C). The mixture was heated to an internal temperature of 25⁰C for 30 min and stirred for 22 hours at room temperature. Distillation through a Vigreux column at 60°C/2.1 mbar afforded 48.57 g (78%, 0.27 mol) of the diacid chloride as a colourless liquid.

125 ml (0.25 mol) of a solution of n-buthylmagnesium chloride (2.0 M in THF) were added within 45 minutes at a temperature between -2 and O⁰C to a mechanically stirred solution of the diacid chloride (22.9 g, 0.125 mol), MnCIz^ in THF (20 ml, ca.

12.5mmol), CuCl (0.71 g, 7.1 mmol) and THF (200 mL). After 75 min at O⁰C the mixture was poured onto 150 ml of a cooled 2N HCl solution. The aqueous phase was extracted with diethyl ether (3x100 ml) and the combined organic phases were washed with water (3x50 ml, pH 7) and dried over Na₂SO₄. After filtration and evaporation of the solvent the crude product (29.6 g) was distilled through a Vigreux column (15 cm) at 115°C/0.35 mbar affording 19.4 g of 7-methyl-5,9-tridecanedione (69%, 0.086 mol). ¹H-NMR: 0.90 (t, J = 7.7, 6H), 0.92 (t, J = 6.7, 3H), 1.28 (sextet, J = 7.7, 4H), 1.54 (q, J = 7.7, 4H), 2.29 (dd, J = 15.9, J = 7.2, 2H), 2.38 (t, J = 7.7, 4H), 2.42 (dd, J =

15.9 Hz, J = 5.6, 2H), 2.51 (sextet, J = 6.7, IH). ¹³C-NMR: 13.9 (2C), 20.3, 22.4 (2C), 25.5, 25.9 (2C), 42.9 (2C), 49.2 (2C), 210.6 (2C). b) Preparation of the desired products

A solution of 7-methyl-5,9-tridecanedione (250 mg, 1.1 mmol) in 4-methylmorpholine (1.1 mL) was treated at 25⁰C with a 0.675 g (1.1 mmol) of solution of TiCl₃OiPr (1.637mmol Ti/g in AcOEt). After 15 min the mixture was diluted with diethyl ether and treated with a cold solution of 2N HCl. After extraction with diethyl ether the organic phases were washed (sat. NaHCO₃, H₂O), dried (Na₂SO₄) and evaporated (crude 250mg). Flash chromatography, using SiO₂ (23 g) and n-pentane/ AcOEt = 85:15, afforded successively 178 mg (yield: 72%) of (20) and 8 mg (yield: 4%) of (21). Spectra of (20):

¹H-NMR: 0.91 (t, J = 7.2, 3H), 0.94 (t, J =7.6, 3H), 1.02 (d, J = 6.1, 3H), 1.08-1.68 (m, HH), 1.76-1.86 (m, 2H), 2.00 (t, J = 12.3, IH), 2.17-2.30 (m, 2H), 2.37-2.41 (m, IH).

¹³C-NMR: 14.0, 14.4, 22.1, 22.2, 23.2, 23.9, 26.6, 29.5, 41.2, 44.8, 50.4, 56.6, 79.0, 211.0.

Spectra of (21): ¹H-NMR: 0.91 (t, J = 7.2, 3H), 0.93 (t, J = 6.7, 3H), 1.02 (d, J = 6.7, 3H), 1.16-1.70 (m,

13H), 2.10 (t, J = 13.3, IH), 2.20-2.28 (m, 3H).

¹³C-NMR: 14.0, 14.1, 20.4, 22.1, 23.1, 24.0, 28.6, 31.2, 39.7, 40.9, 45.6, 60.2, 77.5, 214.1.

Example 7

Preparation of (+-)-3-butyl-r-3-(l-ethoxyethoxy)-?-5-methyl-c-2-propylcyclohexanone (22)

A mixture of 666 mg (2.95 mmol) of (21) and 1.13 mL (11.8 mmol) ethyl vinyl ether was stirred at room temperature in the presence of 13 mg Amberlyst^® 15 for 18 hour. Flash chromatography of the brown mixture, using SiO₂ (88 g) and n-pentane/Et₂O = 9:1, afforded 626 mg (yield: 71%) of (22) as a -1:1 mixture of diastereomers.

¹H-NMR: 0.87-0.97 (m, 12H), 0.99 (d, J=6.1, 3H), 1.00 (d, J=5.1, 3H), 1.10 -1.98 (m,

40H), 2.21-2.25 (m, 2H), 2.35-2.38 (m, 2H), 3.36-3.57 (m, 4H), 4.89 (q, J=5.1,

IH), 4.96 (q, J=5.2, IH). ¹³C-NMR: 14.0, 14.1, 14.1, 14.5, 14.5, 15.4, 15.5, 20.6, 20.8, 22.1, 22.1, 22.2, 23.4, 23.4, 24.3, 24.6, 27.4, 27.5, 28.8, 29.0, 35.6, 37.1, 40.7, 43.4, 50.1, 50.2, 56.1, 56.4, 56.5, 57.9, 84.0, 84.3, 92.2, 93.5, 210.1, 210.6.

Example 8

Preparation of (+-)-3-butyl-r-3-(trimethylsilyloxy)-r-5-methyl-c-2-propylcyclohexanone (23)

A mixture of 56 mg (0.25 mmol) of (21) and 49 μl (0.35 mmol) triethylamine in 1 ml THF was treated at O⁰C with 58 μl (0.30 mmol) TMSOTf. After 30 min the mixture was diluted with 5 ml diethyl ether and was poured onto 2 ml of a sat. NH₄Cl solution with

2g ice. After extraction with diethyl ether (2x) the organic phases were washed

(saturated NH₄Cl), dried (Na₂SO₄) and evaporated to afford 65 mg (23) (0.22 mmol, yield: 88%). ¹H-NMR: 0.0 (s, 9H), 0.86 (t, J = 7.2, 3H), 0.90 (t, J = 7.7, 3H), 0.94 (d, J = 6.7, 3H),

1.03 -1.49 (m, 8H), 1.61-1.65 (m, 2H), 1.72-1.83 (m, 2H), 1.88 (t, J = 12.8,

IH), 2.12-2.17 (m, 2H), 2.28-2.30 (m, IH). ¹³C-NMR: 2.6 (3C), 14.1, 14.6, 21.9, 22.0, 23.3, 24.6, 27.5, 29.3, 40.9, 45.8, 50.3, 56.5,

82.7, 210.7.

Example 9

Preparation of (lRS,llRS,14RS)-l-vinyloxy-14-methylbicvclor9.4.01pentadecan-12-one (26) A mixture of 1 g (4 mmol) of (16) and 0.46 ml (4.8 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 201 mg (0.8 mmol) pyridinium p-toluenesulfonate (PPTS) for 4 hours. The mixture was stirred at 4O⁰C for 2 h and 0.46 ml (4.8 mmol) ethyl vinyl ether were added. After 6 hours at 4O⁰C the reaction the mixture was hydrolyzed with 3 ml of a saturated aqueous NH₄Cl solution. After extraction with 50 ml diethyl ether the combined organic phases were washed (H₂O), dried (Na₂SO₄) and the solvent was evaporated. Flash chromatography, using SiO₂ (105 g) and n-pentane/diethyl ether = 95:5 as eluent, afforded 215 mg (yield: 19%) of (26). ¹H-NMR: 6.33 (dd, J = 13.3, J = 6.1, IH), 4.37 (d, J = 12.8, IH), 4.03 (d, J = 6.2, IH), 2.45 (ddd, J = 13.3, J = 4.1, J = 2.1, IH), 2.35 (d, J = 8.2, IH), 2.25-2.17 (m, IH), 2.13-2.02 (m, IH), 1.99-1.91 (m, 2H), 1.90-1.73 (m, 2H), 1.71- 1.24 (m, 15H), 1.09-1.03 (m, IH), 0.99 (d, J = 6.7, 3H). ¹³C-NMR: 209.4, 144.4, 92.4, 86.0, 56.2, 49.5, 41.2, 34.3, 27.5, 27.0, 26.6, 26.1, 25.8, 25.0, 24.9, 22.0, 21.9, 19.6.

Example 10 Preparation of ( IRS, 1 lRS,14RS)-l-butoxyethoxy-14-metylbicvclor9.4.01pentadecan-12- one (27)

A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) buthyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 1 day. Flash chromatography of the reaction mixture, using SiO₂ (80g) and pentanefEtOAc = 9:1 as eluent, afforded 2.3 g (82%) of (27) as a -1:1 mixture of diastereomers. First isomer:

¹H-NMR: 4.88 (q, J = 5.1, IH), 3.48 (dt, J = 9.3, J = 6.6, IH), 3.35 (dt, J = 8.9, J = 6.7,

IH), 2.43-2.34 (m, 2H), 2.25-2.16 (m, IH), 2.04-1.81 (m, 5H), 1.68-1.34 (m, 16H), 1.32-1.22 (m, 3H), 1.17 (d, J = 5.6, 3H), 1.09-1.02 (m, IH), 0.99 (d, J =

6.7, 3H), 0.93 (t, J = 7.2, 3H). ¹³C-NMR: 210.3, 92.1, 85.2, 60.7, 56.4, 49.7, 40.5, 35.0, 32.2, 28.3, 27.3, 26.4, 26.2,

25.9, 25.1 (2C), 22.5, 22.1, 20.8, 19.7, 19.6, 14.0. Second isomer: ¹H-NMR: 4.94 (q, J = 5.1, IH), 3.37-3.33 (m, 2H), 2.44-2.32 (m, 2H), 2.16-2.07 (m, IH), 1.95-1.86 (m, 2H), 1.82-1.73 (m, 2H), 1.68-1.26 (m, 20H), 1.16 (d, J = 5.1, 3H), 1.05-1.00 (m, IH), 0.98 (d, J = 6.1, 3H), 0.92 (t, J = 7.2, 3H). ¹³C-NMR: 210.7, 93.7, 84.7, 62.6, 56.6, 49.8, 43.3, 33.7, 32.2, 28.2, 27.2, 26.5, 26.0,

25.8, 25.2, 25.1, 22.3, 22.1, 20.6, 19.8, 19.5, 13.9.

Example 11 Preparation of flRS,llRS,14RS)-14-methyl-12-oxobicvclor9.4.01pentadecan-l-yl acetate (28)

2.5 g (10 mmol) of (16) were added to a mixture of 4 g (40 mmol) Ac₂O and 95 mg

(0.5 mmol) pTsOH H₂O at O⁰C. After stirring for lhour at O⁰C the mixture was warmed up to room temperature. After 60 minutes, the reaction mixture was poured into 10 g of ice and 10 ml of a saturated aqueous NH₄Cl solution. After extraction with 150 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO₃ and

NaCl solution), dried (Na₂SO₄) and 1 ml Et₃N were added. The solvent was evaporated.

Flash chromatography, using SiO₂ (300 g) and n-pentane/EtOAc/ Et₃N = 95/4/1 as eluent, afforded 1.31 g (4.4 mmol, yield: 44%) of (28).

¹H-NMR: 2.89 (ddd, J = 13.8, J = 3.0, J = 3.0, IH), 2.57-2.50 (m, IH), 2.46 (ddd, J =

13.3, J = 3.6, J = 2.0, IH), 2.33 (d, J = 7.6, IH), 2.22-2.13 (m, IH), 1.98 (t, J =

13.3, IH), 1.91 (s, 3H), 1.89-1.80 (m 2H), 1.71-1.27 (m, 16H), 1.01 (d, J = 6.7,

3H). ¹³C-NMR: 209.3, 170.1, 91.0, 57.0, 49.6, 40.1, 33.4, 28.5, 27.0, 26.5, 26.0, 25.8, 25.1,

24.8, 22.1, 22.0, 21.7, 19.6.

Example 12

Preparation of optically active 14-methyl-bicvclor9.4.01pentadec-l(ll)-en-12-one (24)

General procedure

In the reaction vessel, under inert atmosphere, were introduced 0.25 mmol of (18), (26),

(27), (28) or (19), 1 ml of dry THF, and the Na or K salt of the amino alcohol (7), (6) or (8), according to Table 1. The total amount of THF present was calculated in order to keep the concentration of (18), (26), (27), (28) or (19) between 0.2 and 0.3 mol/1 at the beginning of the reaction.

The reaction mixture was stirred at the temperature, according to Table 1, and followed by GC. To stop the reaction the mixture was hydrolyzed with 3 ml of a saturated NH₄Cl solution. After extraction of the aqueous layer with diethyl ether the organic layer was dried over MgSO₄ and filtered. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield in the desired product, i.e. (S)-14-methyl- bicyclo[9.4.0]pentadec-l(ll)-en-12-one or (R)-14-methyl-bicyclo[9.4.0] pentadec-l(ll)- en-12-one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide.

¹H-NMR: 1.04 (d, J = 6.1, 3H), 1.18-1.46 (m, 10H), 1.50-1.75 (m, 4H), 1.97-2.15 (m,

3H), 2.30-2.40 (m, 3H), 2.41-2.56 (m, 3H). ¹³C-NMR: 21.3, 23.5, 24.6, 25.1, 25.3, 25.5, 26.0, 26.2, 26.6, 29.7, 32.3, 38.3, 46.7,

136.3, 158.2, 199.7.

The results obtained are shown in Table 1.

Table 1 : Yields and e.e. of the final product as a function of the alkoxide used

1) see description

3) number of molar equivalent of alkoxide introduced, relative to the starting material

4) duration of the reaction in hours

5) determined by GC

6) determined by reacting the final product with an excess of LiAlH₄ in dry THF. After hydrolysis, filtration and extraction with Et₂O, the allyl alcohol obtained was analyzed by GC with a chiral column (CHIRASIL DEX CB) to determine the enantiomeric excess of the resulting allyl alcohol.

7) reaction was performed in the presence of 2 eq NaH

8) reaction was performed in the presence of 2 eq KH and 0.05 eq MeOH

When the reaction was done with (18), (19) or (27), the reaction mixture, obtained above after a conversion of about 40%, can be alternatively treated 10 minutes with a mixture of 0.4 ml H₂O and 0.4 ml of an aqueous IN HCl solution. After extraction of the aqueous layer with diethyl ether the organic layer was washed (saturated aqueous NaHCO₃ solution, H₂O), dried over MgSO₄ and filtered. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield in the desired product, i.e. (lR,llS,14R)-l-hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one or (1S,11R,14S)- l-hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide and (S)-14-methyl- bicyclo[9.4.0]pentadec-l(ll)-en-12-one or (R)-14-methyl-bicyclo[9.4.0] pentadec-l(ll)- en-12-one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide.

Example 13

Preparation of optically active 3-butyl-5-methyl-2-propyl-2-cyclohexen-l-one (25)

General procedure

In the reaction vessel, under inert atmosphere, were introduced 0.5 mmol of (22) or (23), 2 ml of dry THF, and the Na or K salt of the amino alcohol (7), according to Table 2. The total amount of THF present was calculated in order to keep the concentration of the (22) or (23) between 0.2 and 0.3 mol/L at the beginning of the reaction. The reaction mixture was stirred at the temperature, according to Table 2, and followed by GC. To stop the reaction the mixture was hydrolyzed with 3 ml of a saturated NH₄Cl solution. After extraction of the aqueous layer with diethyl ether the organic layer was dried over MgSO₄ and filtered. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield in the desired product, i.e. (S)-3-butyl-5- methyl-2-propyl-2-cyclohexen-l-one or (R)-3-butyl-5-methyl-2-propyl-2-cyclohexen-l- one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide.

¹H-NMR: 0.89 (t, J = 7.7, 3H), 0.94 (t, J =7.2, 3H), 1.02 (d, J = 6.2, 3H), 1.27-1.49 (m,

6H), 1.98-2.13 (m, 3H), 2.17-2.29 (m, 4H), 2.33 (d, J = 15.3, IH), 2.45 (d, J =

14.4, IH). ¹³C-NMR: 14.0, 14.3, 21.2, 22.9, 23.0, 27.0, 29.8, 30.1, 34.7, 39.1, 46.2, 135.0, 158.3,

199.5.

The results obtained are shown in Table 2.

Table 2 : Yields and e.e. of the final product as a function of the alkoxide used

1) see description

4) duration of the reaction in hours

5) determined by GC

Example 14

Preparation of (lRS,10RS,13RS)-l-hvdroxy-13-methylbicvclor8.4.01tetradecan-ll-one (30)

A solution of 3-methyl-l,5-cyclotetradecanedione 29 (500 mg, 2.1 mmol) in CH₂Cl₂

(4 ml) was treated at 22-24⁰C with a solution of ZrCl₃OPr (36% in AcOBu) (1.79 g,

3.86 mmol). After 15 minutes the solution was treated at -1O⁰C with NBu₃ (0.68 g, 0.88 ml, 3.68 mmol). After 70 minutes, the reaction mixture was poured into 5 ml water and 7 ml of a aqueous 2 N HCl solution were added. After extraction with 25 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO₃ solution, H₂O), dried (Na₂SO₄) and the solvent was evaporated (crude 531 mg). Flash chromatography, using SiO₂ (25 g) and n-pentane/diethyl ether = 6:4 as eluent, afforded 364 mg (yield: 73%) of (30). ¹H-NMR: 2.59 (d, J = 7.7, IH), 2.46-2.41 (m, IH), 2.36-2.15 (m, 2H), 1.98 (t, J = 12.8,

2H), 1.74-1.31 (m, 17H), 1.02 (d, J = 6.6, 3H). ¹³C-NMR: 210.6, 79.7, 53.4, 49.8, 44.9, 38.4, 28.7, 27.6, 27.1, 25.9, 24.6, 24.0, 22.3,

22.1, 18.4.

Example 15

Preparation of (lRS,10RS,13RS)-l-(l-ethoxyethoxy)-13- methylbicyclor8.4.01tetradecan-l 1-one (31) A mixture of 119 mg (0.5 mmol) of (30) and 384 μl (4 mmol) ethyl vinyl ether was stirred at 25⁰C in the presence of 25 mg (0.1 mmol) pyridinium p-toluenesulfonate (PPTS) for 2 hours (94% conversion). Flash chromatography of the reaction mixture, using SiO₂ (14 g) and n-pentane/diethyl ether = 95:5 as eluent, afforded 105 mg (61%) of (31) as a -1:1 mixture of diastereomers. First isomer:

¹H-NMR (CD₂Cl₂): 4.86 (q, J = 5.6, IH), 3.54-3.39 (m, 2H), 2.49 (d, J = 7.7, 2H), 2.36-

2.32 (m, IH), 2.19-2.11 (m, IH), 1.86-1.19 (m, 18H), 1.15 (d, J = 6.0, 3H), 1.12

(t, J = 7.1, 3H), 0.99 (d, J = 6.2, 3H).

¹³C-NMR (CD₂Cl₂): 209.9, 92.6, 85.8, 57.2, 54.2, 49.9, 41.0, 33.8, 28.8, 28.1, 28.0, 27.7, 25.1, 25.0, 22.7, 22.2, 21.2, 19.4, 15.7.

Second isomer: ¹H-NMR (CD₂Cl₂): 4.91 (q, J = 5.1, IH), 3.37 (qd, J = 7.2, J = 1.5, 2H), 2.48 (d, J = 7.7,

IH), 2.45-2.37 (m, IH), 2.34-2.31 (m, IH), 2.14-2.07 (m, IH), 1.97-1.84 (m,

2H), 1.84-1.81 (m, 2H), 1.71-1.41 (m, 12H), 1.31-1.19 (m, 2H), 1.13 (d, J = 5.1, 3H), 1.10 (t, J = 6.7, 3H), 0.97 (d, J = 6.6, 3H).

¹³C-NMR (CD₂Cl₂): 210.3, 94.0, 85.4, 59.1, 54.5, 50.0, 43.3, 32.6, 28.6, 28.1, 28.0, 27.6,

25.0 (2C), 22.5, 22.2, 21.2, 19.5, 15.7. Example 16

Preparation of optical active 13-methyl-bicyclor8.4.01tetradec-l(10)-en-l l-one (32)

General procedure

In the reaction vessel, under inert atmosphere, were introduced 0.25 mmol of (31), 1 ml of dry THF, and the Na salt of the amino alcohol (7), according to Table 3. The total amount of THF present was calculated in order to keep the concentration of (31) between 0.2 and 0.3 mol/1 at the beginning of the reaction.

The reaction mixture was stirred at the temperature, according to Table 3, and followed by GC. To stop the reaction the mixture was hydrolyzed with 3 ml of a saturated NH₄Cl solution. After extraction of the aqueous layer with diethyl ether the organic layer was dried over MgSO₄ and filtered. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield in the desired product, i.e. (S)-13-methyl- bicyclo[8.4.0]tetradec-l(10)-en-l l-one or (R)-13-methyl-bicyclo[8.4.0]tetradec-l(10)- en-11-one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide.

¹H-NMR: 2.54-2.46 (m, 4H), 2.34 (d, J = 16.9, IH), 2.37-1.96 (m, 3H), 1.76-1.58 (m,

4H), 1.47-1.16 (m, 9H), 1.04 (d, J = 6.1, 3H). ¹³C-NMR: 199.5, 158.4, 134.8, 46.7, 38.0, 32.7, 29.7, 27.1, 25.8, 25.7, 25.5, 23.4, 21.4,

21.4, 21.1.

The results obtained are shown in Table 3.

Table 3 : Yields and e.e. of the final product as a function of the alkoxide used

1) see description 3) number of molar equivalent of alkoxide introduced, relative to the starting material

4) duration of the reaction in hours

5) determined by GC 6) determined by reacting the final product with an excess of LiAlH₄ in dry THF. After hydrolysis, filtration and extraction with Et₂O, the allyl alcohol obtained was analyzed by GC with a chiral column (CHIRASIL DEX CB) to determine the enantiomeric excess of the resulting allyl alcohol.

Example 17

Preparation of flRS,12RS,15RS)-l-hvdroxy-15-methyl-bicvclori0.4.01hexadecan-13- one (34)

A solution of S-methyl-l^-cyclohexadecanedione (33) (1 g, 3.76 mmol) in CH₂Cl₂ (6 ml) was treated at 22-24° with a solution of ZrCl₃OPr (36% in AcOBu) (3 g, 5.0 mmol). After 15 minutes the solution was treated at -1O⁰C with NBu₃ (1.15 g, 1.48 ml, 6.2 mmol). After 60 minutes, the reaction mixture was poured into 15 ml water and 15 ml of a 2 N HCl solution were added. After extraction with 50 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO₃ solution, H₂O), dried (Na₂SO₄) and the solvent was evaporated (crude 1.0 g). Flash chromatography, using SiO₂ (100 g) and n-pentane/diethyl ether = 6:4 as eluent, afforded 898 mg (yield: 90%) of (34). ¹H-NMR: 2.43-2.37 (m, 2H), 2.32-2.21 (m, IH), 2.00-1.85 (m, 3H), 1.69-1.66 (m, 2H),

1.55-1.18 (m, 19H), 1.01 (d, J = 6.7, 3H). ¹³C-NMR: 211.2, 79.4, 53.1, 50.3, 45.0, 39.1, 28.9, 26.6, 26.1, 26.0, 23.2, 22.9, 22.8, 22.1, 22.0, 21.2, 17.9.

Example 18

Preparation of (lRS,12RS,15RS)-l-(ethoxyethoxy)-15-methyl-bicvclori0.4.01 hexadecan-13-one (35)

A mixture of 133 mg (0.5 mmol) of (34) and 67 μl (0.7 mmol) ethyl vinyl ether in 0.4 ml CH₂Cl₂ was stirred at 4O⁰C in the presence of 63 mg (0.25 mmol) pyridinium p-toluenesulfonate (PPTS) for 3 hours (57% conversion). Flash chromatography of the reaction mixture, using SiO₂ (14 g) and n-pentane/diethyl ether = 9:1 as eluent, afforded 42 mg (25%) of (35) as a -1:1 mixture of diastereomers and 72 mg (0.27 mmol) of the starting material (34). First isomer:

¹H-NMR (CD₂Cl₂): 4.87 (q, J = 5.6, IH), 3.54-3.38 (m, 2H), 2.34-2.31 (m, 2H), 1.98-

1.87 (m, 4H), 1.76-1.69 (m, IH), 1.55-1.21 (m, 19H), 1.15 (d, J = 5.6, 3H), 1.12

(t, J = 7.2, 3H), 0.99 (d, J = 6.1, 3H). ¹³C-NMR (CD₂Cl₂): 210.4, 92.5, 85.3, 57.2, 54.2, 50.5, 41.0, 34.8, 29.0, 27.6, 26.8, 26.5,

23.7, 23.4, 23.4, 22.7, 22.2, 21.8, 21.2, 18.7, 15.7. Second isomer: ¹H-NMR (CD₂Cl₂): 4.91 (q, J = 5.1, IH), 3.46-3.35 (m, 2H), 2.42-2.28 (m, 3H), 1.96-

1.19 (m, 23H), 1.14 (d, J = 5.1, 3H), 1.12 (t, J = 7.2, 3H), 0.98 (d, J = 6.7, 3H). ¹³C-NMR (CD₂Cl₂) 210.8, 93.9, 85.0, 58.9, 54.3, 50.6, 43.3, 33.3, 28.8, 27.5, 26.7, 26.4,

23.7, 23.4 (2C), 22.7, 22.2, 21.8, 21.0, 18.8, 15.7.

Example 19

Preparation of optical active 15-methylbicyclori0.4.01hexadec-l(12)-en-13-one (36)

General procedure

In the reaction vessel, under inert atmosphere, were introduced 0.25 mmol of (35), 1 ml of dry THF, and the Na salt of the amino alcohol (7), according to Table 4. The total amount of THF present was calculated in order to keep the concentration of (35) between 0.2 and 0.3 mol/1 at the beginning of the reaction.

The reaction mixture was stirred at the temperature, according to Table 4, and followed by GC. To stop the reaction the mixture was hydrolyzed with 3 ml of a saturated NH₄Cl solution. After extraction of the aqueous layer with diethyl ether the organic layer was dried over MgSO₄ and filtered. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield in the desired product, i.e. (S)-15-methyl- bicyclo[10.4.0]hexadec-l(12)-en-13-one or (R)-15-methyl-bicyclo[10.4.0]hexadec- l(12)-en-13-one or an optically active mixture of said stereoisomers depending on the configuration of the alkoxide. ¹H-NMR: 2.47-2.20 (m, 6H), 2.14-1.99 (m, 3H), 1.69-1.37 (m, 14H), 1.27-1.21 (m, 2H), 1.02 (d, J = 5.1, 3H). 13, C-NMR: 199.8, 158.5, 135.1, 46.5, 38.9, 31.9, 29.8, 27.0, 26.3, 25.7, 25.5, 25.1, 24.2, 23.0, 22.8, 22.0, 21.2.

The results obtained are shown in Table 4.

Table 4 : Yields and e.e. of the final product as a function of the alkoxide used

4) duration of the reaction in hours

5) determined by GC

Claims

1. A compound of formula

wherein the R¹, taken separately, are identical and represent an achiral C_1-1O linear, branched or cyclic alkyl or alkenyl group optionally substituted, or alternatively said two R¹, taken together, represent a linear C₃-C₁O alkanediyl or alkenediyl group optionally substituted;

- a hydrogen atom, - a group of formula Si(R³)₃, R³ representing a C_1-7 linear, branched or cyclic alkyl or alkenyl group or a phenyl group optionally substituted,

- a C₁-C₁O sulfonyl group, or

- a C₁-C_1O hydrocarbon group optionally comprising up to four heteroatoms selected from the group consisting of oxygen, nitrogen, silicium or sulfur, provided that said heteroatom is not directly bonded to the oxygen atom bearing said R group; the substituents of R, R¹ and R² being one or two C₁-S alkyl, alkoxy or cycloalkyl group.

2. A compound according to claim 1, characterized in that said R group represents a hydrogen atom, a C_1-6 linear, branched or cyclic alkyl, alkenyl or acyl group optionally substituted, an optionally substituted benzyl group, a C₁-C_1O sulfonyl group, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a C₁-_S alkyl group or, taken together, representing a C₁-Cs group, or a group of formula Si(R³)₃, R³ representing a C_1-7 linear, branched or cyclic alkyl or alkenyl group or a phenyl group optionally substituted.

3. A compound according to claim 1, characterized in that it is of formula

wherein R, R¹ and R² have the meaning indicated in claim 1 and the groups OR and R² are in a relative configuration trans.

4. A compound according to claim 1, characterized in that it is an optically active compound of formula

(HI) (III)

wherein R, R¹ and R² have the meaning indicated in claim 1 and the asterisks mean the configuration of the carbon is absolute and therefore that said compound (III) or (IH') is in an optically active form.

5. A compound according to any one of claim 1 to 4, characterized in that: R¹ groups, taken separately, are identical and represent an achiral C₁-S linear, branched or cyclic alkyl or alkenyl group or alternatively said two R¹, taken together, represent a linear C₃-C₁O alkanediyl or alkenediyl group;

R² represents an achiral C₁-_S linear or branched alkyl or alkenyl group or a phenyl group; and

R represents a hydrogen atom, a C₁-_S linear, branched or cyclic alkyl or alkenyl group optionally substituted, a benzyl group, a group of formula -CH(R^a)OCH₂R^a, R^a representing a hydrogen atom or a methyl, ethyl or n-propyl group or, taken together, representing a C3-C4 group, or a group of formula Si(R³)3, R³ representing a C₁-S linear, branched alkyl group or a phenyl group.

6. As a compound according to claim 1:

(-)-(lR,llS,14R)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one, (-)-(lR,llR,14R)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one, (lRS,llRS,14RS)-l-Hydroxy-14-methyl-bicyclo[9.4.0]pentadecan-12-one, (lRS,llRS,14RS)-l-ethoxyethoxy-14-methylbicyclo[9.4.0]pentadecan-12-one, or (lRS,llRS,14RS)-14-methyl-l-trimethylsilyloxybicyclo[9.4.0] pentadecan-12-one.

7. A process for the preparation of an optically active compound of formula

wherein the R .1 , R and the asterisk have the meaning indicated in claim 4, by treating a trans ketone of one of formulae

(H) (HI) (HI)

wherein the asterisk, R¹ and R² have the meaning indicated above and R is as defined in claim 1 provided that it is not a hydrogen atom; with an optically active sodium or potassium alkoxide and optionally a means of removing water; or by treating an optically active trans ketone of formula (III) or (IH')

wherein R¹ and R² have the meaning indicated in claim 3 and R is hydrogen with a C₁-C₈ sulfonyl chloride in the presence of a tertiary C₃-C₂₄ amine.

8. A process according to claim 7, characterized in that the optically active sodium or potassium alkoxide is a) a sodium or potassium salt of a C₄-C₁₈ optically active mono alcohol of formula

R⁴

R³ (A)

HO

wherein R represents a C_1-4 alkyl group or an optionally substituted phenyl group and R⁴ represents a C_1-4 alkyl group or a C(R⁵ )₂(OR⁴ ) group, R⁵ representing a hydrogen atom or a R⁵ group and R⁴ representing a C_1-6 alkyl group or a C₃_₉ trialkyl silyl or a triphenyl silyl group; or of formula R⁴ -OH, wherein R⁴ represents a C_7-12 chiral hydrocarbon group; b) a sodium or potassium salt of a C₃-C₁₈ optically active 1,2-diol of formula

R° R°

(B)

HO OH

wherein R represents an optionally substituted phenyl group, a C_1-6 alkyl group or a COOR⁷ group, R⁷ representing a C_1-4 alkyl group; a C₄-C₁₈ optically active 1,3-diol of formula R' R⁰

(C)

OH OH

wherein R has the meaning indicated above; a C5-C35 optically active 1,4-diol containing a moiety of formula

or a sodium or potassium salt of an optically active diol of formula

wherein R >5' has the meaning indicated above; a sodium or potassium salt of a C₄-C₂₅ optically active alcohol containing a nitrogen in the β position of formula

(E) (E¹)

wherein R⁵ has the meaning indicated above, R⁷ represents a R⁴ or R⁵ group as defined above and R⁸ represents an optionally substituted phenyl group, a C₁^ alkyl or alkylbenzene group a SiR⁷ ₃ group or a R⁷ CO group; optionally R⁵ and R⁷ can be bonded together to form a Cs_-1O ring or R⁷ and a R⁸ can be bonded together to form a C4-5 heterocycle, or the two R⁸ can be bonded together to form a C₂_5 heterocycle; or such as a sodium or potassium salt of an optically active iminoalcohol of formula

(F) (F¹)

wherein R⁵ and R⁵ have the meaning indicated above; d) a sodium or potassium salt of a Q5-38 compound having two or three groups derived from an optically active alkoxide mentioned under a), b) or c); or e) a sodium or potassium salt of an optically active alkoxide mentioned under d) and which is supported on an insoluble material such as silica, Merrifield resins, gold or polystyrenes; the substituents of phenyl groups being R^b, SR^b, NO₂ or OR^b groups or halogen atoms, wherein R^b stands for a C_1-4 alkyl group.

9. A process according to claim 7, characterized in that the optically active sodium or potassium alkoxide is a compound of formula (E) or (E') as defined in claim 8.

10. A process for the preparation of a compound of formula (I), as defined in claim 1, comprising the step of: a) treating an achiral di-ketone of formula

wherein R¹ and R² have the meaning indicated in claim 1, with a C₃-C₂₄ amine or diamine, in a racemic or optically active form; and in the presence of a complex obtainable by admixing TiCl₄ or ZrCl₄ with an equimolar amount of an alcohol R^bOH, R^b representing a C₁-Cs alkoxy group, or of a chiral ligand selected from the group consisting of an optically active alcohol of formula (E), (E'), (F) or (F'), as defined in claim 8, and an optically active alcohol of formula

R⁴

\ COOR^C (N)

HO

wherein R⁴ has the meaning indicated above and R^c represents a C_1-4 alkyl group; and b) hydrolyze the reaction medium of step a) to obtain a compound of formula (I) wherein R is a hydrogen atom; and c) converting the compound obtained in step b), by treating it with an appropriate reagent, into a compound of formula (I) wherein R is not a hydrogen atom.

11. A process according to claim 10, characterized in that said appropriate reagent is a compound of formula Si(R³)₃X, R³ representing a C₁-C₄ alkyl group or a phenyl group and X representing a chloride atom or a CF₃SO₃ group or is compound of formula XCH(R^a)OCH₂R^a, or of formula HR^a'C=CHOCH₂R^a, are those wherein R^a or R^a , taken separately, represents a hydrogen atom or a methyl, ethyl, propyl or isopropyl group, or R^a and R^a , taken together, represents a CH₂CH₂ or CH₂CH₂CH₂ group.