In accordance with the present invention, there is therefore provided a process for preparing an optically active compound of formula (I) or (II) wherein, R in formula (I) or (II) represents a group selected from Ci-Cio alkyi, C3-Cg cycloalkyl and an unsaturated 5-or 6-membered ring which may comprise at least one ring heteroatom selected from nitrogen, oxygen and sulphur, each group being optionally substituted by at least one substituent selected from halogen, nitro, cyano, carboxyl, hydroxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkenyl, C3-C6 cycloalkyl, Cl-C4 alkoxycarbonyl, C1-C4 alkylcarbonyl, <BR> <BR> C1-C4 alkylcarbonylamino, phenylcarbonyl,-S (O) mCl-C4 alkyl,-NR R,-C (O) NR R and -SO2NR7R8, m is 0, 1 or 2, R3 and R4 each independently represent hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached from a 4- to 6- membered saturated heterocycle, R and R each independently represent hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl, or R and R together with the nitrogen atom to which they are attached form a 4-to 6- membered saturated heterocycle, and

R7 and R8 each independently represent hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl, or R7 and R8 together with the nitrogen atom to which they are attched form a 4- to 6- membered saturated heterocycle, the process comprising cyclising, in the presence of an acidic substance, a corresponding compound of formula (I') or (II') wherein R1 in formula (I') or (II') has the same meaning as R1 in formula (I) or (II) above and R2 in formula (I') or (II') represents a hydrogen atom or a protecting group.

The invention further relates to novel intermediates of formulae (I') and (II').

In the context of the present specification, unless otherwise indicated, an alkyl substituent group or an alkyl moity in a substituent group may be linear or branched. Examples of alkyl groups/moieties containing up to 6 carbon atoms include mthyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. When R3 and R4, or R5 and R6, or R7 and R8 represent a saturated heterocycle, it should be understood that the only heteroatom present is the nitrogen atom to which R3 and R4, or R5 and R6, or R7 and R8 are attached. The unsaturated 5- or 6-membered ring in the definition of R1 may have non-aromatic or aromatic properties.

R1 represents a group selected from C1-C10, particularly C1-C6, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C3-C8, particularly C5-C6, cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) and an unsaturated 5- or 6-membered ring which may comprise at least one

ring heteroatom (e. g. one, two, three or four ring heteroatoms independently) selected from nitrogen, oxygen and sulphur, each group being optionally substituted by at least one substituent (e. g. one, two, three or four substituents independently) selected from halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano, carboxyl, hydroxyl, trifluoromethyl, Cl-C4, particularly Cl-C2, alkyl, C1-C4, particularly C1-C2, alkoxy, C2-C6, particularly C2-C4, alkenyl (such as ethenyl), C3-C6, particularly Cs-C6, cycloalkyl, C1-C4, particularly C1-C2, alkoxycarbonyl, Cl-C4, particularly Cl-C2, alkylcarbonyl, Cl-C4, particularly C1-C2, alkylcarbonylamino, phenylcarbonyl, -S (O) mCl-C4, particularly C1-C2, alkyl,-NR R,-C (O) NR R and-SO2NR R.

Examples of unsaturated 5- or 6-membered rings include phenyl, cyclopentenyl, cyclohexenyl, thienyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, pyrazinyl and pyridyl.

R3 and R4 each independently represent hydrogen, C1-C4, particularly C1-C2, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R3 and R4 together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

R and R each independently represent hydrogen, C1-C4, particularly C1-C2, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R and R together with the nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

R7 and R8 each independently represent hydrogen, C1-C4, particularly C1-C2, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl) or C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or R7 and R8 together with the

nitrogen atom to which they are attached form a 4-to 6-membered saturated heterocycle (such as pyrrolidinyl or piperidinyl).

R2 represents a hydrogen atom or a protecting group. Examples of protecting groups that may be used include alkyl (e. g. C1-C6 alkyl), ether (e. g. methoxymethyl, tetrahydropyranyl), optionally substituted arylalkyl (e. g. benzyl orpa7 » a-methoxybenzyl), alkylcarbonyl (e. g. C1-C6 alkylcarbonyl such as CH3C (O)-), haloalkylcarbonyl (e. g.

C1-C6 haloalkylcarbonyl such as CF3C (O) -) and silyl groups of fonnula (R) 3Si- where each R independently represents an alkyl (e. g. Ci-Cg alkyi) or aryl (e. g. phenyl) group, for example, tert-butyldimethylsilyl or triethylsilyl.

The process of the present invention may conveniently be carried out in an organic solvent such as a hydrocarbon solvent (e. g. toluene) or a polar solvent (e. g. chloroform, dichloromethane or tetrahydrofuran) and at a temperature, for example, in the range from 0 °C to 50 °C, particularly from 0 °C to room temperature (about 20 °C).

The process is carried out in the presence of an acidic substance which, unless otherwise indicated, is defined as any substance that is capable of donating hydrogen ions (protons).

Examples of acidic substances that may be used in the process of the invention include organic acids such aspara-toluenesulphonic acid and ion exchange resins such as Amberlyst 15 (trade mark) cation exchange resin which is commercially available from the Sigma-Aldrich Company Limited in the United Kingdom.

Compounds of formula (I') may be prepared by reacting a compound of formula (III)

wherein R1 and R2 are as defined in formula (I'), with an organometallic reagent such as a vinylmagnesium halide, e. g., vinylmagnesium bromide. The reaction is conveniently carried out in a solvent such as tetrahydrofuran at or below ambient temperature, e. g. , in the range from-20 °C to 20 °C.

Compounds of formula (II') may be prepared in an analogous manner to the compounds of formula (I') by replacing the compound of formula (III) with a compound of formula (IV) wherein R1 and R2 are as defined in formula (II').

Compounds of formula (III) may conveniently be prepared by reacting a compound of formula (V) wherein R10 represents a leaving group (e.g. an alkoxy, particularly C1-C6 alkoxy, leaving group such as ethoxy) and R1 and R2 are as defined in formula (III), with N, O-dimethylhydroxylamine or a salt thereof. The reaction is conveniently carried out in a solvent such as tetrahydrofuran at low temperature, e. g. , in the range from-20 °C to 0 °C, and in the presence of a basic reagent such as an alkylmagnesium halide, e. g., isopropylmagnesium chloride. Compounds of formula (IV) may be prepared in an analogous manner to the compounds of formula (III) by replacing the compound of formula (V) with a compound of formula (VI) wherein R and R are as defined in formula (IV) and R is as defined in formula (V).

Compounds of formulae (V) and (VI) are either commercially available, are known in the literature or may be prepared using known techniques.

Alternatively, compounds of formulae (I') and (II') may be prepared by reacting a compound of formula (V) or (VI) with an organometallic reagent such as a vinylmagnesium halide, e. g. , vinylmagnesium bromide.

As another alternative, compounds of formulae (I') and (II') may be prepared by reacting a compound of formula (V) or (VI) with pyrrolidine at about 60 °C for about 18 hours, followed by reaction with an organometallic reagent such as a vinylmagnesium halide, e. g., vinylmagnesium bromide.

The compounds of formulae (I) and (II) may be used to prepare compounds having pharmaceutical properties. For example, a compound of formula (I) in which R represents methyl can be used to prepare the 5-lipoxygenase inhibitor compound (2S, 4R)- 4-hydroxy-2-methyl-4- [2- (l-methyl-2-oxoindolin-5-ylthio) thien-4-yl] tetrahydropyran (described in European Patent No. 623 614) which has the structural formula :

The present invention will now be further explained by reference to the following illustrative examples.

Example 1 (S)-2-Methyl-tetrahydro-4H-pyran-4-one (i) (S)-Ethyl 3-(tert-butyl-dimethyl-silanoxy)-butyrate (S)-Ethylhydroxybutyrate (5 ml; 38. 5 mmol) was suspended inN, N-dimethylformamide (20 ml) and tert-butyldimethylsilyl chloride (6.96 g; 46.2 mmol) and imidazole (2.62 g; 38. 5 mmol) were added in one portion. The reaction mixture was stirred at room temperature overnight (16 hours) before addition of water (40 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (3x30 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over sodium sulphate (Na2S04) and concentrated in vacuo to give the sub-titled compound after column chromatography (5% ethyl acetate/isohexane) as a colourless oil (9.2 g; 97%).

'H NMR (400MHz in CDC13) : 8 (ppm) 4. 28 (m, 1H) ; 4.12 (m, 2H); 2.47 (dd, 1H) ; 2. 36 (dd, 1H) ; 1.26 (t, 3H); 1.19 (d, 3H); 0.86 (s, 9H); 0.05 (s, 3H); 0.04 (s, 3H).

13C NMR (100MHz in CDCl3) : 8 (ppm) 171.7, 65.8, 60.2, 44.9, 25.7, 23.9, 17.9, 14.1.

IRvmax (cm-l) : 1736, s (C=O) ; 1182, s (C-O) ; 1001, s (Si-O-C).

(ii) (S)-3-(tert-Butyl-dimethyl-silanoxy)-N-methoxy-N-methyl-buty ramide The ester obtained in (i) above (5.4 g; 21.9 mmol) was dissolved in tetrahydrofuran (40 ml) under nitrogen. N, O-Dimethylhydroxylamine hydrochloride (2.92 g; 30 mmol) was added

and the slurry was cooled to-20 °C. Isopropylmagnesium chloride (2. 0M in tetrahydrofuran; 30 ml) was added dropwise over 30 minutes. The reaction mixture was stirred for 2 hours keeping the temperature between-20 °C and-10 °C, quenched with saturated ammonium chloride (NH4Cl) solution and diluted with diethyl ether. The layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulphate (Na2S04) and concentrated ion vacuo to give the sub-titled compound as a colourless oil (5.86 g; 100%).

'H NMR (400MHz in CDC13) : 8 (ppm) 4.35 (m, 1H); 3.69 (s, 3H); 3.17 (s, 3H); 2.70 (m, 1H); 2.36 (dd, 1H); 1.21 (d, 3H); 0.86 (t, 9H); 0.05 (s, 3H); 0.04 (s, 3H).

13C NMR (lOOMHz in CDCl3) : 8 (ppm) 172.0, 65.9, 61.3, 41.7, 31.9, 25.9, 24.1, 17.9.

IR #max(cm-1): 1663, s (amide) ; 1000, s (Si-O-C).

(iii) 5- » t-Butyl-dimethyl-silanoxy)-hex-l-en-3-one The amide obtained in (ii) above (3.7 g; 19.1 mmol) was dissolved in tetrahydrofuran (30 ml) at room temperature under nitrogen. The solution was cooled to 5 °C and vinylmagnesium bromide (1. OM in tetrahydrofuran; 17 ml) was added dropwise over 20 minutes. The reaction mixture was stirred for 1 hour at-10 °C and was then quenched with saturated ammonium chloride (NH4CI) solution. The layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over sodium sulphate (Na2S04) and concentrated in vacuo to give the sub-titled compound, after column chromatography (5% ethyl acetate/isohexane), as a colourless oil (1.9 g; 59%).

'H NMR (400MHz in CDC13) : 8 (ppm) 6.36 (dd, 1H) ; 6.22 (dd, 1H); 5.85 (dd, 1H); 4.33 (m, 1H); 2.85 (dd, 1H) ; 2.53 (dd, 1H); 1.20 (d, 3H); 0. 86 (s, 9H); 0.05 (s, 6H); 0.02 (s, 6H).

13 C NMR (10OMHz in CDC13) : 6 (ppm) 199.8, 137.4, 128.5, 65.8, 49.0, 25.7, 24.2, 17.9.

IR #max(cm-1): 1684, m (C=O) ; 1615, w (C=C) ; 1001, m (Si-O-C).

(iv) (S)-2-Methyl-tetrahydro-4H-pyran-4-one

The enone obtained in (iii) above (0.4 g) was dissolved in chloroform (30 ml) under nitrogen at room temperature. Amberlyst-15 (trade mark) ion exchange resin (0.15 g) was added in one portion and the reaction mixture was stirred at room temperature for 24 hours.

The mixture was then filtered and concentrated in vacuo to give the titled compound, after column chromatography (20% ethyl acetate/petroleum ether) as a pale yellow oil (80 mg; 40%).

1H NMR (400MHz in CDC13) : 8 (ppm) 4.28 (ddd, J=11. 5,7. 4, 1. 3Hz, 1H), 3.78-3. 70 (m, 1H), 3.68 (ddd, J=12. 3,11. 5,2. 8Hz, 1H), 2.58 (dddd, J=14. 6,12. 3,7. 4, l. OHz, 1H), 2.40 (dt,@ J=14. 6,2. 6Hz, 1H), 2.35-2. 25 (br m, 2H), 1. 28 (d, J=6. 2Hz, 3H).

13C NMR (100MHz in CDCl3) : 8 (ppm) 206.9, 74.3, 66.4, 49.9, 41.9, 22.0.

IR Vmax (cm-l) : 1715, s (C=O), 1086, s (C-O-C).

Example 2 Example 1 was repeated except that in step (iv) the enone (0.5 g) was dissolved in dichloromethane (10 ml) at room temperature under nitrogen. para-Toluenesulphonic acid (0.2 g) was added. The solution rapidly turned brown. The reaction mixture was stirred for 24 hours at room temperature and was then quenched with 20% sodium bicarbonate solution. The organic layer was washed with water, dried over sodium sulphate (Na2S04) and concentrated in vacuo to give (S)-2-methyl-tetrahydro-4H-pyran-4-one, after column chromatography (20% ethyl acetate/petroleum ether) as a pale yellow oil (0.13 g; 52%).

IH NMR (400MHz in CDC13) : 8 (ppm) 4.28 (ddd, J=11. 5,7. 4, 1. 3Hz, 1H), 3.78-3. 70 (m, 1H), 3.68 (ddd, J=12. 3,11. 5,2. 8Hz, 1H), 2.58 (dddd, J=14. 6,12. 3,7. 4, l. OHz, 1H), 2.40 (dt, J=14. 6,2. 6Hz, 1H), 2.35-2. 25 (br m, 2H), 1. 28 (d,@ J=6. 2Hz, 3H)..

13C NMR (100MHz in CDC13) : 8 (ppm) 206.9, 74.3, 66.4, 49.9, 41.9, 22.0.

IR #m ax(cm : 1715, s (C=O), 1086, s (C-O-C).

Example 3 (S)-2-Methyl-tetrahydro-4H-pyran-4-one (i) (S)-Ethyl 3- (triethyl-silanoxy)-butyrate

(S) -Ethylhydroxybutyrate (10 g; 75. 6 mmol) was suspended in N, N-dimethylfonnamide (30 ml) and triethylsilyl chloride (15.4 ml; 90 mmol) and imidazole (6. 2 g; 90 mmol) were added in one portion. A white solid precipitated. The reaction mixture was stirred at room temperature for 7 hours before addition of water (60 ml). The layers were separated. The aqueous layer was extracted with dichloromethane (3X60 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over sodium sulphate (Na2S04) and concentrated in vacuo to give the sub-titled compound after column chromatography (5% ethyl acetate/isohexane) as a colourless oil (19 g; 100%).

'H NMR (400MHz in CDCl3) : 8 (ppm) 4.36 (m, 1H), 3.69 (s, 3H), 3. 18 (s, 3H), 2.77 (br m, 1H), 2.40 (dd, J=14. 9,5. 9Hz, 1H), 1.22 (d, J=6. 2Hz, 3H), 0.95 (t, J=7. 9Hz, 9H), 0.56 (q, J=7. 9Hz, 6H).

13C NMR (100MHz in CDC13) : 8 (ppm) 170.0, 65.7, 61.3, 41.8, 32.0, 24.2, 6.7, 4.7.

IR vm (cW 1) : 1662 (amide) m, 1238 (Si-CH2-CH3) m, 1002 (Si-O-R) s.

(ii) (S)-3- (Triethyl-silanoxy)-N-methoxy-N-methyl-butyramide The ester obtained in (i) above (5.3 g; 21.7 mmol) was dissolved in tetrahydrofuran (40 ml) under nitrogen. N, O-Dimethylhydroxylamine hydrochloride (3 g; 30 mmol) was added and the slurry was cooled to-20 °C. Isopropylmagnesium chloride (2. 0M in tetrahydrofuran; 30 ml) was added dropwise over 30 minutes. The reaction mixture was stirred for 2 hours keeping the temperature between-20 °C and-10 °C, quenched with saturated ammonium chloride (NH4Cl) solution and diluted with diethyl ether. The layers were separated. The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water (100 ml), dried over sodium sulphate (Na2S04) and concentrated ion vacua to give the sub-titled compound as a colourless oil (3. 89 g ; 70%).

1H NMR (400MHz in CDC13) : 6 (ppm) 4.36 (m, 1H), 3.69 (s, 3H), 3.18 (s, 3H), 2.77 (br m, 1H), 2.40 (dd, J=14. 9,5. 9Hz, 1H), 1.22 (d, J=6. 2Hz, 3H), 0.95 (t,@ J=7. 9Hz, 9H), 0.56 (q, J=7. 9Hz, 6H).

13C NMR (100MHz in CDCl3) : 8 (ppm) 170.0, 65.7, 61.3, 41.8, 32.0, 24.2, 6.7, 4.7.

IR #max(cm-1): 1662, m (amide), 1238, m (Si-CH2-CH3), 1002, s (Si-O-R).

(iii) 5-(Triethyl-silanoxy)-hex-1-en-3-one The amide obtained in (ii) above (1 g; 3.82 mmol) was dissolved in tetrahydrofuran (20 ml) at room temperature under nitrogen. The solution was cooled to 5 °C and vinylmagnesium bromide (1. OM in tetrahydrofuran; 7.5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour at 4 °C and was then quenched with saturated ammonium chloride (NH4Cl) solution. The layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate (Na2S04) and concentrated in vacuo to give, after column chromatography (5% ethyl acetate/isohexane), the sub-titled compound as a colourless oil (0.45 g; 51 %).

'H NMR (400MHz in CDC13) : #(ppm) 6.37 (dd, J=17. 7,10. 4Hz, 1H), 6.25 (dd, J=17. 7, 1. 4Hz, 1H), 5.86 (dd, J=10. 9, 1. 4Hz, 1H), 4.35 (m, 1H), 2.85 (dd,@ J=15. 2,6. 6Hz, 1H), 2.56 (dd, J=15. 2,5. 7Hz, 1H), 1.28 (d, J=6. 2Hz, 3H), 0.95 (t,@ J=7. 9Hz, 9H), 0.54 (q, J=7. 9Hz, 6H).

13C NMR (100MHz in CDC13) : 8 (ppm) 200.0, 137.4, 128.5, 65.4, 49.2, 24. 2, 6. 7,4. 7.

IR Vma, ax(cm-1): 1684, m (C=O), 1254, m (Si-CH2-CH3), 1002, m (Si-O-R).

(iv) (S)-2-Methyl-tetrahydro-4H-pyran-4-one The enone obtained in (iii) above (0.2 g) was dissolved in chloroform (10 ml) under nitrogen at room temperature. Amberlyst 15 (trade mark) ion exchange resin (0.09 g) was added in one portion and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was then filtered and concentrated in vacuo to give, after column chromatography (20% ethyl acetate/petroleum ether), the title compound as a pale yellow oil (0.08 g ; 80%).

H NMR (400MHz in CDC13) : # (ppm) 4.28 (ddd, J=11. 5,7. 4, 1. 3Hz, 1H), 3.78-3. 70 (m, 1H), 3.68 (ddd, J=12. 3,11. 5,2. 8Hz, 1H), 2.58 (dddd, J=14. 6,12. 3,7. 4, l. OHz, 1H), 2.40 (dt, J=14. 6,2. 6Hz, 1H), 2.35-2. 25 (br m, 2H), 1. 28 (d, J=6. 2Hz, 3H).

13C NMR (100MHz in CDC13) : # (ppm) 206.9, 74.3, 66.4, 49.9, 41.9, 22.0.

IR #max (cm'') : 1715, s (C=O), 1086, s (C-O-C).