Background Art Retinol, generally known as vitamin A, is an essential nutrient which gives effects on growth and specialization of tissues, and prevention of oxidation, and it has been recently used as an important ingredient in cosmetics on the purpose of preventing wrinkles and skin aging. Retinal is well known as a compound having a key role in visual function, while p-carotene, as a precursor of vitamin A, is a very important substance that has been widely used as food coloring, stock feed, health tonics and the like.

Representative processes for synthesizing retinoid and carotenoid compounds having conjugated polyene as the skeletal structure include three processes industrialized by Roche, BASF and Aventis (Pure & Appl. Chem. 1991,63,45-58; ibid. 1979,51,447-462). These processes have basic differences in the mode of forming double bond.

First, the Roche process induces extension of chain and formation of double bond via addition of acetylide and partial hydrogenation thereof. According to the process, cis-type double bond with low activity (as it is known) is dominantly obtained at the time of partial hydrogenation and dehydration. The process needs more synthetic stages with less efficiency, as compared with the other two processes described below.

The process for preparing vitamin A and p-carotene by BASF, which is characterized in that double bond is formed via Wittig reaction, consists of short and simple reaction stages, but the by-product phosphine oxide from Wittig reaction cannot be easily treated, and the compound having cis-type double bond with low activity is obtained in a substantial amount.

The process by Aventis for synthesizing retinol that is most recently developed and more excellent process as compared to the two processes mentioned above, employs coupling and double bond formation by using sulfone compound developed by Julia.

According to the process, the synthetic intermediate compound is stable and the coupling reaction is excellently carried out; trans-type product is dominantly obtained at the time of double bond formation; and the by-product can be easily treated.

Reaction Scheme 1 illustrates the processes for synthesizing retinol, retinal and p-carotene by employing Julia's sulfone chemistry. These processes utilize C-15 sulfone compound, an important intermediate for the syntheses of retinoid and carotenoid compounds, by adding vinyl Grignard compound to p-ionone as the starting material to form vinyl P-ionol, and then reacting the obtained compound with sodium benzenesulfinate in acetic acid solvent. Coupling reaction of the C-15 sulfone compound with C-5 halo-acetate compound, dehydrosulfonation reaction, and hydrolysis of acetate provide retinol (Bull. Soc.

Chisn. France 1973,746-750; Tetrahedron 1977,33,2799-2805). Coupling reaction of the C-15 sulfone compound with C-5 halo-acetal compound, dehydrosulfonation and hydrolysis of acetal provide retinal (US Patent 5,276,209); while coupling of two molecules of the C-15 sulfone compound with C-10 dihaloallylic sulfide, oxidation of central sulfide and Ramberg-Bäcklund reaction, and dehydrosulfonation provide P-carotene (Journal of Organic Chemistry, 1999,64,8051-8053).

Reaction Scheme 1 MgBr OH |PhSO2Na OR PhSOzNa 02Ph x OR OAc \ OR Retinol _ I Retinal <Chemical Formular 2> <Chemical Formula 3> i XSX ß-Carotene <Chemical Formula 4>

The processes for synthesizing retinoid and carotenoid compounds by using the sulfone compound according to Reaction Scheme 1 are advantageous in that the processes employ relatively stable intermediates as described, trans-type compound are effectively produced at the time of double bond formation, and the by-product can be easily treated.

However, preparation of the C-15 sulfone compound, the important intermediate used in these processes, includes a few disadvantages. First, relatively expensive (3-ionone should be used as a starting material, and second, vinyl Grignard reagent that is not easy to handle and expensive should be used. Thus, the development of more economic and practical synthetic process for preparing the C-15 sulfone compound to overcome such disadvantages, or of a synthetic method for corresponding novel sulfone compound, and of synthetic processes for retinoid and carotenoid compounds by employing the novel sulfone compound has been required.

In order to serve these requirements, the present inventors have already developed novel C-15 allylic disulfone compound (Chemical Formula 1) which is prepared by more efficient and economic process by overcoming the problems in the synthesis of the C-15 allylic sulfone compound (see Reaction Scheme 1) having conjugated polyene, that has been employed as an important intermediate in the syntheses of retinoid and carotenoid compounds as described above ; and a process for preparing the novel compound (Korean Patent Application No. 2000-77567, PCT/KR01/02078). In the same patent, the inventors

have suggested an efficient process for synthesizing retinoic acid by using the intermediate described above.

Thus, the technical object of the present invention is to overcome the disadvantages in the preparation of the C-15 allylic sulfone compound which had been usefully employed in the syntheses of retinoid and carotenoid compounds, and to provide a process for practically and economically preparing retinol by employing C-15 allylic disulfone compound (Chemical Formula 1) that is prepared more efficiently and economically.

Another technical object of the present invention is to provide a practical and economic process for preparing retinal by employing C-15 allylic disulfone compound (Chemical Formula 1) as described above.

Still another technical object of the present invention is to provide a practical and economic process for preparing p-carotene by employing C-15 allylic disulfone compound (Chemical Formula 1) as described above.

Disclosure of the Invention The first technical object of the present invention is achieved by a process for preparing retinol (Chemical Formula 2) which comprises the steps of (1) treating C-15 allylic disulfone compound of Chemical Formula 1 with 2 equivalents of base to deprotonate the compound, and reacting C-5 halo-acetate compound (A) [wherein, X is a halogen atom] therewith to synthesize compound (B) having 20-carbon skeleton which is needed for retinol synthesis; and (2) treating the C-20 compound (B) with excess amount (3 equivalents or more) of base to form double bonds by carrying out dehydrosulfonation and hydrolysis of acetate group at the same time (Reaction Scheme 2).

Reaction Scheme 2 902Ph xAj 6 l Chemical Formula 1> I X-'OAc (A) S02Ph S02Ph OAc 61 (B) I OH Chemical Formula 2>

In the formula, X is selected from the group consisting of-Cl,-Br and-I.

In step (1), deprotonation is carried out by adding 2 equivalents of base to the compound of Chemical Formula 1 at low temperatures, preferably at a temperature of 0 °C or lower. As the base, n-BuLi, s-BuLi, phenyllithium, NaH, NaNH2, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t-BuOK, CH3CH20K, CH30K, CH3CH2ONa, CH3ONa, or the like can be used. Meantime, it is reported that C-5 halo-acetate (A) can be efficiently prepared by electrophilic halogen addition to isoprene in acetic acid solvent (J : Am. Chem Soc. 1950,72,4608-4613; Tetrahedron Lett. 1974,351-354; Tetrahedron Lett. 1976,239-242).

In step (2), dehydrosulfonation is preferably carried out by treating 3 equivalents or more of base to compound (B) at the boiling temperature of alcoholic solvent. The base to be employed is selected from the group consisting of NaNH2, t-BuOK, CH3CH20K, CH30K, CH3CH2ONa and CH3ONa. This time, hydrolysis of acetate is simultaneously performed to directly provide retinol.

The second technical object of the present invention is achieved by a process for preparing retinal (Chemical Formula 3) which comprises treating C-15 allylic disulfone

compound of Chemical Formula 1 with excess amount (3 equivalents or more) of base to deprotonate the compound, and reacting C-5 halo-acetal compound (C) [wherein, X is a halogen atom] therewith to synthesize compound (D) having 20-carbon skeleton which is needed for retinal synthesis; wherein at the same time dehydrosulfonation is performed by excess amount of base existed to synthesize retinal acetal compound (E), and hydrolysis of the acetal is immediately performed without further purification (Reaction Scheme 3).

Reaction Scheme 3 S02Ph S02Ph xAA <Chemical Formula 1> X, JvX I X v v'O (C) S02PhSO2Ph ku) (D) I \ \ \ (E) \ \ \ I I Chemical Formula 3'

In the formula, X is selected from the group consisting of-Cl,-Br and-I.

In the reaction stage, deprotonation of the compound represented by Chemical Formula 1 should be performed by adding an excess amount of base (preferably 4 equivalents) at a temperature of 0 °C or lower. Since the excess amount of base is also employed in the dehydrosulfonation of compound (D) that is formed by coupling of the compound of Chemical Formula 1 with C-5 halo-acetal, the base is selected from the group

consisting of NaNH2, t-BuOK, CH3CH2OK, CH30K, CH3CH2ONa and CH3ONa. Among them, metal alkoxide can be most preferably used.

In the meanwhile, C-5 halo-acetal (C) can be synthesized according to a known art (Liebigs Ann. Chem. 1976,2194-2205); or by hydrolyzing C-5 halo-acetate (A) to form an alcohol (Tetrahedron Letters, 1976, 239-242), oxidizing the alcohol to prepare an aldehyde, and reacting the aldehyde with neopentyl glycol to form an acetal (Reaction Scheme 4).

Reaction Scheme 4 In the formulas, X is selected from the group consisting of-Cl,-Br and-I.

The third technical object of the present invention is achieved by a process for preparing P-carotene (Chemical Formula 4) which comprises the steps of (1) treating C-15 allylic disulfone compound of Chemical Formula 1 with 2 equivalents of base to deprotonate the compound, and reacting not more than 0.5 equivalent of dihaloallylic sulfide (F) [wherein, X is a halogen atom] on the basis of compound of Chemical Formula 1 to synthesize allylic sulfide compound (G) having 40-carbon skeleton which is needed for p-carotene synthesis; (2) selectively oxidizing the allylic sulfide compound (G) to prepare allylic sulfone compound (H); (3) subjecting the sulfone compound (H) to Ramberg-Backlund reaction to give tetra (benzenesulfonyl)-triene compound (I) ; and (4) treating the tetra (benzenesulfonyl)-triene compound (I) with base to form double bonds by carrying out dehydrosulfonation reaction (Reaction Scheme 5).

Reaction Scheme 5 SOZPh s <Chemical Formula 1> XSX (F) SO2Ph SO2Ph SO2Ph SO2Ph vox (G) SO2Ph S02Ph SO2Ph S02Ph s ou (H) S02Ph S02Ph (I) SO2Ph SO2Ph 1 w Chemical Formula 4>

In the formula, X is selected from the group consisting of-Cl,-Br and-I.

In step (1), deprotonation is carried out by adding 2 equivalents of base to the compound of Chemical Formula 1 at low temperatures, preferably at a temperature of 0 °C or lower. As the base, n-BuLi, s-BuLi, phenyllithium, NaH, NaNH2, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t-BuOK, CH3CH20K, CH30K, CH3CH2ONa, CH30Na, or the like can be used. Meantime, the C-10 dihaloallylic sulfide compound (F), which was developed by the present inventors for efficient synthesis of P-carotene, can be synthesized starting from isoprene (Journal of Organic Chemistry, 1999,64,8051-8053). The process for preparing the compound has

been recently improved (Korean Patent Application No. 2001-0067305).

The selective oxidation in step (2) can be preferably performed by adding not less than 2 equivalents of hydrogen peroxide solution to the sulfide compound in the presence of metallic oxide catalyst such as lithium molibdenate-niobate (LiNbMoO6) or vanadium oxide (V205) at ambient temperature. Under such reaction condition, only sulfide is oxidized into sulfone but double bonds of the allylic sulfide (G) are not oxidized, to selectively provide compound (H).

The Ramberg-Bäcklund reaction in step (3) gives compound (I) by removing S02 at the center of the allylic sulfone compound (H) and forming a double bond at the same time.

The reaction is preferably performed under a condition excluding oxygen from the air, that is, under nitrogen or argon atmosphere.

In step (4), dehydrosulfonation is preferably carried out by treating excess amount of base to compound (I) at the boiling temperature of alcoholic solvent. The base to be employed is selected from the group consisting of NaNH2, t-BuOK, CH3CH20K, CH30K, CH3CH2ONa and CH3ONa. Under such condition, four benzenesulfonyl groups are eliminated from compound (I) with forming double bonds to provide p-carotene of Chemical Formula 4.

The invention is described in more detail by referring to the examples below, but it should be noticed that those examples are described only to specifically describe the present invention, so that the present invention is not restricted to the examples by any means.

Example 1 : Vitamin A (Retinol, Chemical Formula 2) (1) Coupling In 30 mL of dry tetrahydrofuran, 1,5-di (benzenesulfonyl)-3-methyl-5- (2, 6,6-trimethyl-1-cyclohexenyl)-2-pentene (Chemical Formula 1) (5.0 g, 10.27 mmol) was dissolved, and t-BuOK (2.54 g, 22.59 mmol) was added slowly thereto at 0 °C. The reaction mixture was stirred at the same temperature for 20 min, and then, bromo-acetate compound (A) (2.55 g, 12. 32 mmol), of which the trans: cis ratio being 4: 1, dissolved in 10 mL of THF was added thereto. After vigorous stirring the

mixture for 3 h, 1 M aqueous HCl solution (30 mL) was slowly added to quench the reaction.

The reaction mixture was extracted with ether, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give concentrated product (7.53 g), which was used for the next dehydrosulfonation step without further purification.

(2) Dehydrosulfonation Sodium 4.72 g (0.205 mol) cut into small pieces was carefully and slowly added to ethanol (EtOH) (99.5%, 80 mL), and the mixture was heated under reflux at the boiling point of the solvent with stirring for 1 h. The reaction mixture was cooled to room temperature, and the concentrated product (7.53 g) prepared as above dissolved in 20 mL of EtOH was added thereto. The reaction mixture was heated under reflux at the boiling point of the solvent with stirring for 15 h, and then cooled. To the resultant reaction mixture, water and 1 M aqueous HCl solution were subsequently added with care, and the mixture was extracted with chloroform (CHC13), dried over anhydrous sodium sulfate (Na2S04), and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the obtained material was purified by silica gel column chromatography to provide vitamin A (retinol) (1.77 g, 6.16 mmol) of Chemical Formula 2 (yield: 60%). The trans: cis ratio at 13th carbon of the obtained vitamin A was 1: 3, and the trans-and cis-compounds could be individually isolated.

(trans-Vitamin A) 'H NMR: 8 1.02 (6H, s), 1.36-1.53 (2H, m), 1.53-1.67 (2H, m), 1.71 (3H, s), 1.87 (3H, s), 1. 96 (3H, s), 2.01 (2H, t, J= 6.0 Hz), 4.31 (2H, d, J= 6.8 Hz), 5.69 (1H, t, J= 6.8 Hz), 6.11 (1H, d, J= 10.8 Hz), 6.12 (1H, A of ABq, J= 15.9 Hz), 6.17 (1H, B of ABq, J= 15.9 Hz), 6.30 (1H, d, J= 15.0 Hz), 6.63 (1H, dd, J= 15.0,10.8 Hz) ppm.

13C NMR: 6 12.5,12.6,19.2,21.7,28.9,28.9,33.0,34.1,39.5,59.3,125.0,126. 6, 129.2,130.0,130.1,136.0,136.6,137.6,137.7 ppm.

(13-cis-Vitamin A) 1H NMR: 6 1.03 (6H, s), 1. 36-1. 52 (2H, m), 1. 52-1. 65 (2H, m), 1.71 (3H, s), 1.94 (3H, s), 1.97 (3H, s), 1.96-2.09 (2H, m), 4.33 (2H, d, J= 7. 1 Hz), 5.57 (1H, t, J = 7. 1 Hz), 6.13 (1 H, A of ABq, J = 16.0 Hz), 6.15 (1 H, d, J = 9. 7 Hz), 6.20 (1 H, B of

ABq, J= 16.0 Hz), 6.63 (1H, AofABq, J, Is= 15.1 Hz), 6.69 (1H, d of B of ABq, JB = 15.1, Jd = 9.7 Hz) ppm.

13C NMR: 8 12.8,19.2,20.5,21.7,28.9,28.9,33.0,34.2,39.5,58.5,127.2,127. 2, 128.1,128.2,129.5,130.1,136.0,137.1,137.5,137.7 ppm.

It was confirmed that 1H NMR data of trans-vitamin A and 13-cis-vitamin A as above strictly coincide with those of reference samples.

Example 2: Retinal (Chemical Formula 3) (1) 2- (3-Bromo-2-methyl-1-butenyl)-5, 5-dimethyl- 1, 3]-dioxane (C) (see Reaction Scheme 4) In a solvent mixture of methyl alcohol (40 mL) and water (14 mL), dissolved was 4-acetoxy-1-bormo-2-methyl-2-butene (A) (2.23 g, 10.76 mmol) having trans : cis ratio of 4: 1, and anhydrous K2CO3 (4.46 g, 32. 3 mmol, 3 equivalents) was added thereto while maintaining the temperature at 0 °C. After stirring for 2 h, the mixture was neutralized with 1 M aqueous HC1 solution, and extracted with CH2C12. The extracted mixture was dried over anhydrous sodium sulfate (Na2S04) and filtered. To the filtrate (40 mL), pyridinium dichromate (PDC) (4.05 g, 10.76 mmol) was added, and the mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2CI2, thoroughly washed with water, dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate by evaporating under reduced pressure, the resultant substance was dissolved in benzene (35 mL), and p-TsOH (0.11 g, 0.54 mmol) and neopentyl glycol (1.12 g, 10.76 mmol) were added thereto. After equipping Dean-Stark column and condenser, the mixture was heated under reflux at the boiling point of the solvent with stirring for 12 h.

The reaction mixture was cooled to room temperature, diluted with diethyl ether, thoroughly washed with 1 M aqueous NaOH solution and water, dried over anhydrous KzCOs, and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the obtained material was purified by silica gel column chromatography to provide compound (C) (1. 39 g, 5.58 mmol, yield: 52%). The trans: cis ratio of the obtained compound (C) was 2 : 1.

(trans- (C)) 1H NMR : b 0.65 (3H, s), 1.12 (3H, s), 1.78 (3H, s), 3. 41 (2H, A of ABq, J = 10. 7 Hz), 3.55 (2H, B of ABq, J= 10.7 Hz), 3.83 (2H, s), 4.97 (1H, d, J= 6.1 Hz), 5.58 (1H, d, J= 6. 1 Hz) ppm.

13CNMR : 6 15.6,21.9,22.9,30.0,39.1,77.1,98.2,127.1,138.0 ppm.

IR (KBr) 1471,1395,1158,1126,750cm-.

(cis- (C))'H NMR: b 0.87 (3H, s), 1.32 (3H, s), 1.80 (3H, s), 3.41 (2H, A of ABq, J= 10.7 Hz), 3.55 (2H, B of ABq, J= 10.7 Hz), 3.93 (2H, s), 5.01 (1H, d, J= 5.7 Hz), 5.39 (1H, d, J= 5. 7 Hz) ppm.

(2) Coupling and dehydrosulfonation; Hydrolysis In 30 mL of dry tetrahydrofuran, 1, 5-di (benzenesulfonyl)-3-methyl-5-(2, 6,6-trimethyl-1-cyclohexenyl)-2-pentene (Chemical Formula 1) (1.00 g, 2.05 mmol) was dissolved, and t-BuOK (0.92 g, 8.2 mmol; 4 equivalents) was added slowly thereto at-20 °C. The reaction mixture was stirred at the same temperature for 1 h, and then, bromo-acetal compound (C) (0.61 g, 2.46 mmol ; 1.2 equivalents), of which the trans: cis ratio being 2: 1, dissolved in 10 mL of THF was added thereto. After vigorous stirring the mixture for 2 h, the reaction temperature was raised to 4 °C. After further stirring for 4 h at the same temperature, 1 M aqueous HCI solution (20 mL) was slowly added, and the resultant mixture was stirred for 1 h. Under the same condition, hydrolysis of acetal was performed. The reaction mixture was extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant material was purified by silica gel column chromatography to provide retinal (0.45 g, 1.59 mmol) of Chemical Formula 3 (yield: 78%). The cis: trans ratio at 13th carbon of the obtained retinal was 1: 4, and the cis-and trans-compounds could be individually isolated.

(trans-Retinal)'H NMR: 8 1.04 (6H, s), 1.44-1.50 (2H, m), 1.51-1.54 (2H, m), 1.72 (3H, s), 1.97-2.09 (2H, m), 2.03 (3H, s), 2. 33 (3H, s), 5.97 (1H, d, J= 8.2 Hz), 6.18 (1H, A of ABq, J= 16.2 Hz), 6.19 (1H, d, J= 11.6 Hz), 6. 35 (1H, B of ABq, J= 16.2 Hz), 6.37 (1H, d, J = 15. 0 Hz), 7.14 (1H, dd, J =15. 0,11.6 Hz), 10.10 (1H, d, J = 8. 2 Hz) ppm.

13C NMR : 8 13.0,13.1,19.2,21.7,29.0,29.0,33.1,34.3,39.6,129.0,129.4,129 .7, 130.5,132.5,134.5,137.1,137.6,141. 3,154.8,191.1 ppm.

(I 3-cis-Retinal)'H NMR : 6 1.04 (6H, s), 1.43-1.53 (2H, m), 1.58-1.67 (2H, m), 1.73 (3H, s), 1.93-2.09 (2H, m), 2.03 (3H, s), 2.15 (3H, s), 5.84 (1H, d, J= 7. 8 Hz), 6.19 (1H, A of ABq, J= 16.0 Hz), 6.23 (1H, d, J= 11.3Hz), 6. 36 (1H, BofABq, J= 16.0 Hz), 7.05 (1H, dd, J= 14. 9,11.3 Hz), 7.30 (1H, d, J= 14.9 Hz), 10.20 (1H, d, J= 7.8 Hz) ppm.

13C NMR: 8 13.0,19.2,21.2,21.7,29.0,29.0,33.1,34.3,39.6,126.3,127.7,129 .4, 129.7,130.5,133.4,137.0,137.6,141.5,154.6,189.9 ppm.

Example 3: p-carotene (Chemical Formula 4) (1) Coupling: Compound (G) In 50 mL of dry tetrahydrofuran, 1, 5-di (benzenesulfonyl)-3-methyl-5- (2, 6,6-trimethyl-1-cyclohexenyl)-2-pentene (Chemical Formula 1) (4.00 g, 8.21 mmol) was dissolved, and 1.6 M n-BuLi in hexane (11.3 mL, 18.1 mmol, 2.2 equivalents) was added dropwise thereto at 0 °C. The reaction mixture was stirred at the same temperature for 20 min, and then, dichloroallylic sulfide (F) (1.18 g, 4.11 mmol, 0.5 equivalent) dissolved in 15 mL of THF was slowly added thereto. After stirring at 0 °C for 1 h, 1 M aqueous HC1 solution was carefully added to quench the reaction. The reaction mixture was extracted with diethyl ether, thoroughly washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant material was purified by silica gel column chromatography to provide the coupling compound (G) comprising 40 carbon atoms (3.85 g, 6.75 mmol; yield: 82%). The resultant compound has chiral centers at the carbon atoms to which benzenesulfonyl group is bonded, thereby having stereo-isomers. The isomers could not be separated, and the data of the dominant product are shown as follows: 'H NMR: 8 0.77 (3H, s), 0.82 (3H, s), 1.16 (3H, s), 1.23-1.43 (2H, m), 1.43-1.52 (2H, m), 1.50 (3H, s), 1.86-2.12 (2H, m), 1.97 (3H, s), 2.03-2.32 (1H, m), 2.44-3.00 (3H, m), 2.90-3.20 (2H, m), 3.72-3.99 (2H, m), 4.83-5.00 (1H, m), 5.12-5.27 (1H, m),

7.43-7.68 (6H, m), 7.74-7.95 (4H, m) ppm.

13C NMR: 5 15.8,18.7,23.2,28.5,28.7, 34.4,35.5,35.7,38.4,39.4,40.9,41.4,62.6, 65.4,120.7,124.3,124.9,128.6,128.9,129.0,129.0,131.3,133.4,1 33.7,137.4,137.7, 140.9,141.8 ppm.

IR (KBr) 2931,1447,1304,1144 cm~l.

HRMS (FAB+) calcd for C64H82S50s- { (C6H6S02) x 2} + H+-Cs2H71S3o4 855.4514, found 855. 4511.

(2) Oxidation: Compound (H) To a solution of the C-40 coupling compound (G) obtained as above (1.61 g, 1.41 mmol) dissolved in 20 mL of acetonitrile (CH3CN), LiNbMo06 (20 mg, 0.07 mmol, 0.05 equivalent) and 35% aqueous H202 solution (0.55 g, 5.64 mmol, 4 equivalent) were added at 0 °C. After stirring at the same temperature for 1 h, and at room temperature for additional 12 h, the reaction mixture was extracted with dichloromethane, washed with 1 M aqueous HCI solution and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant material was purified by silica gel column chromatography to provide sulfone compound (H) (1. 36 g, 1.13 mmol ; yield: 80%). The resultant compound has chiral centers at the carbon atoms to which benzenesulfonyl group is bonded, thereby having stereo-isomers. The isomers could not be separated, and the data of the dominant product are shown as follows: 'H NMR: 8 0.67 (3H, s), 0.79 (3H, s), 1.28 (3H, s), 1. 23-1. 54 (4H, m), 1. 67 (3H, s), 1.93-2.03 (2H, m), 2.00 (3H, s), 2.05-2.66 (2H, m), 2.71-2.92 (1H, m), 2.98-3.32 (1H, m), 3.42-3.70 (2H, m), 3.74-4.02 (2H, m), 4.86-5.10 (1H, m), 5.13-5.40 (1H, m), 7.45-7.69 (6H, m), 7.72-7.92 (4H, m) ppm.

13C NMR: 8 15.8,18.9,23.4,28.4,28.7,34.6,35.7,36.1,38.4,39.5,41.5,51.7, 62.3, 65.4,113.8,114.5,120.4,128.6,129.0,129.0,129.2,131.1,133.5,1 33.8,137.2,137.8, 140.8,142.2 ppm.

IR (KBr) 2931,1447,1305,1144 cm~l.

HRMS (FAB+) calcd for C64Hs2S5Olo- {(C6H6SO2) x 3} + H = C46H65S204 745.4324, found 745.4333.

(3) Ramberg-Bäcklund reaction: Compound (I) In a mixture of CC14 (15 mL) and t-BuOH (10 mL), dissolved was the C-40 sulfone compound (H) (0.98 g, 0.84 mmol), and well pulverized KOH (0.47 g, 8. 36 mmol, 10 equivalents) was added in small portions to the mixture at 0 °C under argon atmosphere.

After stirring at the same temperature for 1 h, and at room temperature for further 10 h, water was carefully added to the reaction mixture. The reaction mixture was neutralized with 1 M aqueous HCl solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 1.15 g of reaction product (I), which was so unstable that it was directly used for the next step without further purification.

(4) Dehydrosulfonation :-Carotene (Chemical Formula 4) To 50 mL of ethyl alcohol (99.9%), sodium (1.2 g, 52.14 mmol) was added, and the mixture was heated under reflux for 1 h. After cooling to room temperature, the reaction product (I) obtained as above (1.15 g) dissolved in 20 mL of ethyl alcohol was added thereto under argon atmosphere. The reaction mixture was heated under reflux at the boiling point of the solvent for 12 h with exclusion of light. After cooling to room temperature, most of the solvent was removed under reduced pressure. After carefully adding water thereto, the mixture was extracted with chloroform, washed with 1 M aqueous HCl solution and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant material was purified by silica gel column chromatography to provide p-carotene (0.32 g, 0.60 mmol ; yield: 71%) of Chemical Formula 4.

1H NMR: 8 1.03 (12H, s), 1.44-1.49 (4H, m), 1.55-1.67 (4H, m), 1.72 (6H, s), 1.98 (12H, s), 2.03 (4H, t, J= 6.3 Hz), 6.15 (2H, A of ABq, J = 16.5 Hz), 6.16 (2H, d, J= 11.4 Hz), 6.18 (2H, B of ABq, J = 16.5 Hz), 6.26 (2H, m), 6.37 (2H, A of ABq, J = 14.9 Hz), 6.64 (2H, m), 6.66 (2H, d of B of ABq, Jd = 11.4, JAB = 14.9 Hz) ppm.

The double bonds of-carotene were all trans-form, and the 1H NMR data of the compound strictly coincide with those of authentic sample.

As described above, the present invention provides efficient and economic processes

for retinol, retinal and (3-carotene via coupling of C-15 disulfone compound (Chemical Formula 1), that can be prepared by a more economic and practical process as compared to that of the conventional C-15 allylic sulfone compound containing conjugated polyene, with C-5 halo-acetate compound (A), C-5 halo-acetal compound (C) and C-10 dihaloallylic sulfide (F), respectively, and double bond formation.