TOTAL SYNTHESIS METHOD FOR VITAMIN A AND DERIVATIVE THEREOF AND DEUTERATED COMPOUND THEREOF

Abstract

Disclosed in the present invention is a total synthesis method for vitamin A and derivative thereof and deuterated compound thereof. ?-cyclocitral is used as a starting material to produce alkenyl boronate, then the alkenyl boronate (or hydrolyzed alkenyl boric acid) is subjected to a series of reactions to produce retinal or retinal with substituent, and the retinal or retinal with substituent is further subjected to a reduction reaction to obtain vitamin A or vitamin A with substituent; the vitamin A or vitamin A with substituent is subjected to an esterification reaction to obtain vitamin A ester or vitamin A ester with substituent; or said retinal or retinal with substituent is subjected to an oxidation reaction to obtain vitamin A acid or vitamin A acid with substituent. When deuterated allenol is used, deuterated vitamin A and derivative thereof are obtained. The present invention has the advantages of short synthetic route, simple operation, readily available raw materials and reagents, and modularization and divergence, and can synthesize the deuterated vitamin A and derivative thereof which are difficult to synthesize in the prior art.

Claims

1. A total synthesis method of vitamin A and derivative thereof and deuterated compound thereof, wherein, said total synthesis method comprises the following steps: (1) the alkenyl boronate shown in S2 is produced from ?-cyclocitral shown in S1 and bis[(pinacol)boryl]methane under the action of lithium tetramethylpiperidide in the first organic solvent; (2) the 2-alkenal shown in S4 is produced from the alkenyl boronate shown in S2 generated in said step (1) and the allenol shown in 5 under the action of rhodium catalyst, copper catalyst, alkali, water, air or oxygen in the second organic solvent; or, the alkenyl boronate shown in said S2 is first hydrolyzed into the alkenyl boronic acid shown in S3, and then combined with the allenol shown in 5, under the action of rhodium catalyst, copper catalyst, alkali, air or oxygen, in the second organic solvent to produce 2-alkenal shown in S4; (3) the alkenyl boronate shown in S5 is produced from the 2-alkenal shown in S4 generated in said step (2) and bis[(pinacol)boronyl]methane under the action of lithium tetramethylpiperidide in the first organic solvent; (4) the retinal or the retinal with substituent shown in 1 is produced from the alkenyl boronate shown in S5 generated in said step (3) and the allenol shown in 5, under the action of rhodium catalyst, copper catalyst, alkali, water, air or oxygen, in the second organic solvent; (5) the retinal or the retinal with substituent shown in 1 generated in said step (4) is subjected to a reduction reaction to produce the vitamin A or the vitamin A with substituent shown in 2; (6) the vitamin A or the vitamin A with substituent shown in 2 generated in said step (5) is subjected to an esterification reaction to produce the vitamin A ester or the vitamin A ester with substituent shown in 3; (7) the retinal or the retinal with substituent shown in 1 generated in said step (4) is subjected to an oxidation reaction to produce the vitamin A acid or the vitamin A acid with substituent shown in 4; in said above-mentioned step (2), and/or said step (4), when using the allenol shown in 5 labeled with hydrogen isotope, finally obtaining the vitamin A or the vitamin derivative labeled with hydrogen isotope; the synthetic route of said total synthesis method is shown in the following formula (A): ##STR00030## wherein, said H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.c is hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; H.sup.e is hydrogen, deuterium, tritium; R.sup.3 is an acyl group; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group.

2. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (a): ##STR00031## in said reaction formula (a), bis[(pinacol)boronyl]methane reacts with ?-cyclocitral shown in S1 under the action of the alkali lithium 2,2,6,6-tetramethylpiperidide LiTMP in the first organic solvent to produce compound S2; among them, said lithium 2,2,6,6-tetramethylpiperidide is prepared by using 2,2,6,6-tetramethylpiperidine and N-butyllithium; the reaction shown in formula (a) specifically comprises the following steps: (1) protecting the reaction system with inert gas; adding 2,2,6,6-tetramethylpiperidine and the first organic solvent into a dry reaction flask, and adding n-butyllithium reagent at ?90?30? C., then continuing stirring for 15 minutes?3 hours at ?90?30? C., preparing lithium 2,2,6,6-tetramethylpiperidide solution on site; (2) dissolving bis[(pinacol)boronyl]methane in said first organic solvent, which is added to the lithium 2,2,6,6-tetramethylpiperidide solution generated in said step (1) at ?90?30? C., and then continuing stirring at ?90?30? C. for 1 minute to 2 hours; (3) dissolving ?-cyclocitral in said first organic solvent, which is added to the mixture generated in step (2) at ?90?30? C., and then stirring the reaction at ?90?30? C. for 0.5?12 hours; (4) after the completion of the reaction in said step (3), quenching the reaction, and obtaining compound S2 through extraction, concentration and separation; said first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and toluene; the molar ratio of said ?-cyclocitral shown in S1, lithium 2,2,6,6-tetramethylpiperidide and bis[(pinacol)boryl]methane is 1:(1.0?2.0):(1.0?2.0); if lithium 2,2,6,6-tetramethylpiperidide solution is prepared on site, the molar ratio of said ?-cyclocitral shown in S1, 2,2,6,6-tetramethylpiperidine, n-butyllithium and bis[(pinacol)boryl]methane is 1:(1.0?2.0):(1.0?2.0):(1.0?2.0).

3. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (b): ##STR00032## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; in said reaction formula (b), allenol 5 and compound S2 under the action of rhodium catalyst, copper catalyst, alkali, water, air or oxygen in the second organic solvent are reacted to produce compound S4; said reaction shown in the reaction formula (b) specifically comprises the following steps: (1) putting rhodium catalyst, alkali, copper catalyst, compound S2, allenol 5, water and the second organic solvent into a dry reaction flask, after plugging the reaction flask with a rubber plug, inserting an air balloon or an oxygen balloon to make the reaction flask in an atmosphere of air or oxygen, and stirring the reaction at ?20?60? C. for 4?96 hours; (2) after the completion of the reaction in step (1), filtering the mixture in the reaction flask with a short column of silica gel or diatomaceous earth, washing with the third organic solvent, then concentrating, separating to obtain compound S4; said second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, dichloromethane, ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether; the amount of said second organic solvent refers to the amount of allenol 5 shown in the reaction formula (b) as the basis, the amount of said second organic solvent is 1.0?20.0 mL/mmol; said third organic solvent is one or more of ethyl acetate, ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile; the amount of said third organic solvent refers to the amount of allenol 5 shown in the reaction formula (b) as the basis, the amount of the third organic solvent is 1.0?200 mL/mmol; said rhodium catalyst is any one or more of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) bis(hexafluoroantimonate), rhodium(III) acetylacetonate, pentaamminechlororhodium(III) dichloride, trichlorotris(ethylenediamine)rhodium(III), potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) trichloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, potassium hexanitrorhodate(III); said copper catalyst is any one or more of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide; said alkali is any one or more of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate; the molar ratio of said rhodium catalyst, copper catalyst, alkali, compound S2, allenol 5, and water is (0.005?0.10):(0.005?1.20):(0?0.60):(1.0?3.0):1.0:(0?20.0).

4. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in following reaction formula (c): ##STR00033## in the reaction shown in said reaction formula (c), compound S2 is hydrolyzed to produce compound S3.

5. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (d): ##STR00034## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; in said reaction formula (d), allenol 5 and compound S3 under the action of rhodium catalyst, copper catalyst, alkali, air or oxygen in the second organic solvent are reacted to produce compound S4; said compound S3 is obtained by the hydrolysis of compound S2; the reaction shown in the reaction formula (d) specifically comprises the following steps: (1) putting rhodium catalyst, alkali, copper catalyst, compound S3, allenol 5 and the second organic solvent into a dry reaction flask, after plugging the reaction flask with a rubber plug, inserting an air balloon or an oxygen balloon to make the reaction flask in an atmosphere of air or oxygen, and stirring the reaction at ?20?60? C. for 4?96 hours; (2) after the completion of the reaction in said step (1), filtering the mixture in the reaction flask with a short column of silica gel or diatomaceous earth, washing with the third organic solvent, then concentrating and separating to obtain compound S4; said second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, dichloromethane, ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether; the amount of said second organic solvent refers to the amount of allenol 5 shown in the reaction formula (d) as the basis, the amount of said second organic solvent is 1.0?20.0 mL/mmol; said third organic solvent is one or more of ethyl acetate, ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile; the amount of said third organic solvent refers to the amount of allenol 5 shown in the reaction formula (d) as the basis, the amount of said third organic solvent is 1.0?200 mL/mmol; said rhodium catalyst is any one or more of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) bis(hexafluoroantimonate), rhodium(III) acetylacetonate, pentaamminechlororhodium(III) dichloride, trichlorotris(ethylenediamine)rhodium(III), potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) trichloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, potassium hexanitrorhodate(III); said copper catalyst is any one or more of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide; said alkali is any one or more of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate; the molar ratio of said rhodium catalyst, copper catalyst, alkali, compound S3, allenol 5 is (0.005?0.10):(0.005?1.20):(0?0.60):(1.0?3.0):1.0.

6. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (e): ##STR00035## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; in said reaction shown in formula (e), bis[(pinacol)boronyl]methane reacts with compound S4 under the action of the alkali lithium 2,2,6,6-tetramethylpiperidide LiTMP in the first organic solvent to produce compound S5; among them, said lithium 2,2,6,6-tetramethylpiperidide is prepared by using 2,2,6,6-tetramethylpiperidine and N-butyllithium; said reaction formula (e) specifically comprises the following steps: (1) protecting the reaction system with inert gas; adding 2,2,6,6-tetramethylpiperidine and the first organic solvent into a dry reaction flask, and adding N-butyllithium reagent at ?90?30? C., then continuing stirring for 15 minutes?3 hours at ?90?30? C., preparing lithium 2,2,6,6-tetramethylpiperidide solution on site; (2) dissolving bis[(pinacol)boronyl]methane in said first organic solvent, which is added to the lithium 2,2,6,6-tetramethylpiperidide solution at ?90?30? C., and then continuing stirring for 1 minute to 2 hours at ?90?30? C.; (3) dissolving compound S4 in said first organic solvent, which is added to the mixture generated in said step (2) at ?90?30? C., and then stirring the reaction at ?90?30? C. for 0.5?12 hours; (4) after the completion of the reaction in said step (3), quenching the reaction, and obtaining compound S5 through extraction, concentration and separation; said first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, diethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and toluene; the molar ratio of said S4, lithium 2,2,6,6-tetramethylpiperidide and bis[(pinacol)boryl]methane is 1:(1.0?2.0):(1.0?2.0), if lithium 2,2,6,6-tetramethylpiperidide solution is prepared on site, the molar ratio of said S4, 2,2,6,6-tetramethylpiperidine, n-butyllithium and bis[(pinacol)boryl]methane is 1:(1.0?2.0):(1.0?2.0):(1.0?2.0).

7. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (f): ##STR00036## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.cis hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; in said reaction formula (f), allenol 5 and compound S5 under the action of rhodium catalyst, copper catalyst, alkali, water, air or oxygen in the second organic solvent are reacted to produce compound 1; said reaction shown in the reaction formula (f) specifically comprises the following steps: (1) putting rhodium catalyst, alkali, copper catalyst, compound S5, allenol 5, water and the second organic solvent into a dry reaction flask, after plugging the reaction flask with a rubber plug, inserting an air balloon or an oxygen balloon to make the reaction flask in an atmosphere of air or oxygen, and stirring the reaction at ?20?60? C. for 4?96 hours; (2) after the completion of the reaction in said step (1), filtering the mixture in the reaction flask with a short column of silica gel or diatomaceous earth, washing with the third organic solvent, concentrating and separating to obtain compound 1; said second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, dichloromethane, ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether; the amount of said second organic solvent refers to the amount of allenol 5 shown in the reaction formula (f) as the basis, the amount of said second organic solvent is 1.0?20.0mL/mmol; said third organic solvent is one or more of ethyl acetate, ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile; the amount of said third organic solvent refers to the amount of allenol 5 shown in the reaction formula (f) as the basis, the amount of said third organic solvent is 1.0?200mL/mmol; said rhodium catalyst is any one or more of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium(III) bis(hexafluoroantimonate), rhodium(III) acetylacetonate, pentaamminechlororhodium(III) dichloride, trichlorotris(ethylenediamine)rhodium(III), potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) trichloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, potassium hexanitrorhodate(III); said copper catalyst is any one or more of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide; said alkali is any one or more of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate; the molar ratio of said rhodium catalyst, copper catalyst, alkali, compound S5, allenol 5, and water is (0.005?0.10):(0.005?1.20):(0?0.60):(1.0?3.0):1.0:(0?20.0).

8. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction shown in reaction formula (g): ##STR00037## wherein, H.sup.a W is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.c is hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; H.sup.e is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group include acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; In said reaction formula (g), compound 1 is subjected to a reduction reaction to produce compound 2.

9. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction as shown in reaction formula (h): ##STR00038## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.c is hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; H.sup.e is hydrogen, deuterium, tritium; R.sup.3 is an acyl group; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; In said reaction formula (h), compound 2 is esterified to produce compound 3.

10. The total synthesis method of claim 1, wherein, said total synthesis method comprises the reaction as shown in reaction formula (i): ##STR00039## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.c is hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; in said hydrocarbyl group with functional group, said functional group include acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group; in said reaction formula (i), compound 1 is oxidized to produce compound 4.

11. Application of the method of claim 1 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

12. Vitamin A and derivative thereof and deuterated compound thereof, wherein, said molecular formula of the compound is as follows: ##STR00040## wherein, H.sup.a is hydrogen, deuterium, tritium; R.sup.1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.b is hydrogen, deuterium, tritium; H.sup.c is hydrogen, deuterium, tritium; R.sup.2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclic, hydrocarbyl, hydrocarbyl group with functional group; H.sup.d is hydrogen, deuterium, tritium; H.sup.e is hydrogen, deuterium, tritium; R.sup.3 is an acyl group; wherein, said aryl group is a phenyl group with substituent at the ortho, meta and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, amino group; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; among said hydrocarbyl group with functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, cyano group.

13. Application of the method of claim 2 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

14. Application of the method of claim 3 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

15. Application of the method of claim 4 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

16. Application of the method of claim 5 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

17. Application of the method of claim 6 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

18. Application of the method of claim 7 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

19. Application of the method of claim 8 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

20. Application of the method of claim 9 in the preparation of vitamin A and derivative thereof and deuterated compound thereof.

Description

PREFERRED EMBODIMENTS OF THE INVENTION

[0175] The following examples are given to further illustrate the specific solutions of the present invention. The process, conditions, experimental methods, and so on for implementing the present invention are all general knowledge and common knowledge in the field except for the contents specifically mentioned below, and the present invention has no special limitation.

[0176] In the reaction formula of the following examples, equiv refers to equivalent; mol refers to mole; mmol refers to millimoles; mol % refers to molar ratio, calculated on the basis of 1 equivalent of reactants; L refers to liter; mL refers to milliliters; M refers to mol/L; g refers to gram; mg refers to milligram; min refers to minute; h refers to hour; rt refers to room temperature; LiTMP refers to lithium 2,2,6,6-tetramethylpiperidide; THF refers to tetrahydrofuran; [Cp*RhCl.sub.2].sub.2 refers to dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer; NaOAc refers to sodium acetate; Cu(OAc).sub.2.Math.H.sub.2O refers to copper acetate monohydrate; air refers to the reaction carried out in air atmosphere; air balloon refers to the reaction carried out in an air atmosphere by inserting an air balloon; Ar refers to that the reaction carried out in an argon atmosphere; NaIO.sub.4 refers to sodium periodate; NH.sub.4OAc refers to ammonium acetate; MeOH refers to methanol; NaBH.sub.4 refers to sodium borohydride; DCM refers to dichloromethane; Ac.sub.2O refers to acetic anhydride; Et.sub.3N refers to triethylamine; DMAP refers to 4-dimethylaminopyridine; NaClO.sub.2 refers to sodium chlorite; NaH.sub.2PO.sub.4 refers to dihydrogen phosphate sodium; t-BuOH refers to tent-butanol; the boiling range of petroleum ether is 60?90? C.; silica gel uses 300-400 silicone; the nuclear magnetic yield is determined by .sup.1H NMR, and the internal standard is dibromomethane; the deuteration rate is determined by .sup.1H NMR.

EXAMPLE 1

[0177] ##STR00014##

[0178] Under the protection of an argon atmosphere, 2,2,6,6-tetramethylpiperidine (11.8 mL, density 0.837 g/mL, 9.8766 g, 70 mmol) and THF (70 mL) were added to a dry reaction flask. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, and n-butyllithium (2.5M in hexane, 28.0 mL, 70 mmol) was added dropwise, and after the dropwise addition, continued stirring at ?78? C. for 1 hour, and then stirred at 0? C. by an ice-water bath for 30 minutes (to produce a solution of lithium 2,2,6,6-tetramethylpiperidide). A solution of bis[(pinacol)boryl]methane (19.1414 g, 70 mmol) in THF (140 mL) was added to the reaction flask at 0? C. and continued stirring at 0? C. for 30 minutes. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, to which a solution of ?-cyclocitral (S1, 8.0101g, purity 95%, 50 mmol) in THF (50 mL) was added. The reaction solution was stirred at ?78? C. for 3 hours and then stirred at room temperature for 2 hours. The reaction was quenched by saturated ammonium chloride (50 mL), added with water (400 mL), and extracted with ethyl acetate (3?300 mL). The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent. Silica gel column chromatography was used for separation and purification (eluent: petroleum ether, then petroleum ether/ethyl acetate=30/1) to afford a product S2 (12.4276 g, 86%): pale yellow liquid;

[0179] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=7.01 (d, J=18.4 Hz, 1H, ?CH), 5.42 (d, J=18.4 Hz, 1H, ?CH), 2.00 (t, J=6.2 Hz, 2H, CH.sub.2), 1.71 (s, 3H, CH.sub.3), 1.63-1.55 (m, 2H, CH.sub.2), 1.47-1.41 (m, 2H, CH.sub.2), 1.29 (s, 12H, 4x CH.sub.3), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=149.5, 139.2, 130.9, 82.9, 39.8, 33.7, 33.1, 28.8, 24.8, 21.6, 19.1; IR (neat): ?=2977, 2928, 2866, 2827, 1615, 1459, 1379, 1370, 1344, 1317, 1266, 1212, 1164, 1144, 1109, 1028 cm.sup.?1; MS (70 eV, EI) m/z (%): 276 (M.sup.+, 32.02), 161 (100).

EXAMPLE 2

[0180] ##STR00015##

[0181] Compound S2 was dissolved in a mixed solution of acetone and water (100 mL, 2:1), and added with sodium periodate (12.8357 g, 60 mmol) and ammonium acetate (4.6306 g, 60 mmol). The mixture was stirred at room temperature for 10 hours. Water (200 mL) was added, the mixture was extracted with ethyl acetate (4?100 mL), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a crude product S3. S3 was used directly in the next step without purification.

[0182] [Cp*RhCl.sub.2].sub.2 (201.1 mg, 0.325 mmol), NaOAc (213.5 mg, 2.6 mmol), Cu(OAc).sub.2.Math.H.sub.2O (130.1 mg, 0.65 mmol), S3 (19.5 mmol, from previous step), THF (50 mL), 5a (911.4 mg, 13 mmol), THF (15 mL) were added in sequence to a dry reaction tube. The reaction tube was plugged with a rubber stopper, inserted with an air balloon to keep the reaction system in an air atmosphere, and stirred at room temperature for 19 hours. The reaction solution was filtered with a short column of silica gel, washed with ethyl acetate (300 mL), and rotary evaporated to remove the solvent. Silica gel column chromatography was used for separation and purification (eluent: petroleum ether, then petroleum ether/ethyl acetate=40/1) to afford a product S4a (1.1517 g, 41%): yellow liquid;

[0183] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.13 (d, J=8.4 Hz, 1H, CHO), 6.74 (d, J=16.0 Hz, 1H, ?CH), 6.21 (d, J=16.0 Hz, 1H, ?CH), 5.94 (d, J=8.4 Hz, 1H, ?CH), 2.31 (s, 3H, CH.sub.3), 2.05 (t, J=6.4 Hz, 2H, CH.sub.2), 1.73 (s, 3H, CH.sub.3), 1.69-1.59 (m, 2H, CH.sub.2), 1.51-1.45 (m, 2H, CH.sub.2), 1.05 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.3, 155.0, 137.0, 135.7, 135.5, 132.7, 128.7, 39.5, 34.2, 33.2, 28.9, 21.7, 19.0, 12.9; IR (neat): ?=2956, 2927, 2864, 2769, 2722, 1662, 1606, 1594, 1445, 1384, 1361, 1333, 1259, 1204, 1146, 1125, 1106, 1045, 1029 cm.sup.?1; MS (70 eV, EI) m/z (%): 218 (M.sup.+, 30.48), 119 (100).

EXAMPLE 3

[0184] ##STR00016##

[0185] [Cp*RhCl.sub.2].sub.2 (7.7 mg, 0.0125 mmol), NaOAc (8.2 mg, 0.1 mmol), Cu(OAc).sub.2.Math.H.sub.2O (5.0 mg, 0.025 mmol), S2 (206.7 mg, 0.75 mmol), THF (1.0 mL), 5a (35.1 mg, 0.5 mmol), THF (1.5 mL), H.sub.2O (27 ?L, 27.0 mg, 1.5 mmol) were added in sequence to a dry reaction tube. The reaction tube was plugged with a rubber stopper, inserted with an air balloon to keep the reaction system in an air atmosphere, and stirred at room temperature for 24 hours. The reaction solution was filtered with a short column of silica gel, washed with ethyl acetate (20 mL), and rotary evaporated to remove the solvent. Silica gel column chromatography was used for separation and purification (eluent: petroleum ether, then petroleum ether/ethyl acetate=50/1) to afford a product S4a (54.4 mg, 50%): yellow liquid;

[0186] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.13 (d, J=8.0 Hz, 1H, CHO), 6.74 (d, J=16.0 Hz, 1H, ?CH), 6.21 (d, J=16.4 Hz, 1H, ?CH), 5.94 (d, J=8.0 Hz, 1H, ?CH), 2.32 (s, 3H, CH.sub.3), 2.05 (t, J=6.2 Hz, 2H, CH.sub.2), 1.73 (s, 3H, CH.sub.3), 1.68-1.59 (m, 2H, CH.sub.2), 1.52-1.45 (m, 2H, CH.sub.2), 1.05 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.3, 155.0, 137.0, 135.7, 135.5, 132.7, 128.7, 39.5, 34.2, 33.2, 28.9, 21.7, 19.0, 12.9; IR (neat): ?=2956, 2928, 2864, 2769, 2723, 1661, 1606, 1594, 1445, 1384, 1361, 1333, 1259, 1204, 1146, 1125, 1106, 1045, 1029 cm.sup.?1; MS (70 eV, EI) m/z (%): 218 (M.sup.+, 28.07), 119 (100).

EXAMPLE 4

[0187] ##STR00017##

[0188] Operations were conducted by referring to Example 3. [Cp*RhCl.sub.2].sub.2 (7.7 mg, 0.0125 mmol), NaOAc (8.2 mg, 0.1 mmol), Cu(OAc).sub.2.Math.H.sub.2O (5.0 mg, 0.025 mmol), S2 (207.4 mg, 0.75 mmol), THF (1.0 mL), 5b (36.0 mg, 0.5 mmol), THF (1.5 mL), H.sub.2O (27 ?L, 27.0 mg, 1.5 mmol) were reacted for 46 hours to afford a product S4b (50.5 mg, 46%) (eluting: petroleum ether/ethyl acetate=40/1): yellow liquid;

[0189] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.13 (d, J=8.0 Hz, 1H, CHO), 6.74 (d, J=16.0 Hz, 1H, ?CH), 6.21 (d, J=16.4 Hz, 1H, ?CH), 5.94 (d, J=8.0 Hz, 1H, ?CH), 2.28 (s, 1H, CD.sub.2H), 2.05 (t, J=6.2 Hz, 2H, CH.sub.2), 1.73 (s, 3H, CH.sub.3), 1.68-1.59 (m, 2H, CH.sub.2), 1.52-1.45 (m, 2H, CH.sub.2), 1.05 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.3, 155.0, 137.0, 135.6, 135.5, 132.7, 128.7, 39.5, 34.2, 33.2, 28.9, 21.7, 19.0, 12.4 (quint, J=20.3 Hz); IR (neat): ?=2959, 2928, 2864, 2774, 2735, 1661, 1605, 1585, 1456, 1360, 1258, 1194, 1146, 1125, 1101, 1043, 1026 cm.sup.?1; MS (70 eV, EI) m/z (%): 220 (M.sup.+, 26.80), 121 (100); HRMS calcd m/z for C.sub.15H.sub.20D.sub.2O [M.sup.+]: 220.1791, found 220.1790.

EXAMPLE 5

[0190] ##STR00018##

[0191] Under the protection of an argon atmosphere, 2,2,6,6-tetramethylpiperidine (905.0 mg, 6.4 mmol) and THF (6.4 mL) were added to a dry reaction flask. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, and added with n-butyllithium (2.5M in hexane, 2.56 mL, 6.4 mmol) dropwise, and after the dropwise addition, continued stirring at ?78? C. for 1 hour, and then stirred at 0? C. by an ice-water bath for 30 minutes (to produce a solution of lithium 2,2,6,6-tetramethylpiperidide). A solution of bis[(pinacol)boronyl]methane (1.7170 g, 6.4 mmol) in THF (12.8 mL) was added to the reaction flask at 0? C. and continued stirring at 0? C. for 30 minutes. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, to which a solution of S4a (873.5 mg, 4 mmol) in THF (4 mL) was added. The reaction solution was stirred at ?78? C. for 2 hours. The reaction was quenched by saturated ammonium chloride solution (10 mL), added with water (20 mL), and extracted with ethyl acetate (4?20 mL). The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent. Silica gel column chromatography was used for separation and purification (eluent: petroleum ether, then petroleum ether/ethyl acetate=50/1) to afford a product S5a (1.1036 g, 81%): yellow liquid;

[0192] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=7.41 (dd, J.sub.1=17.4 Hz, J.sub.2=11.4 Hz, 1H, ?CH), 6.26 (d, J=16.0 Hz, 1H, ?CH), 6.31-6.22 (m, 2H, 2x ?CH), 5.56 (d, J=17.2 Hz, 1H, ?CH), 2.08-1.97 (m, 5H, CH.sub.2 and CH.sub.3), 1.70 (s, 3H, CH.sub.3), 1.67-1.58 (m, 2H, CH.sub.2), 1.49-1.43 (m, 2H, CH.sub.2), 1.28 (s, 12H, 4x CH.sub.3), 1.02 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=145.7, 139.6, 137.6, 137.3, 131.7, 129.8, 128.7, 83.1, 39.6, 34.2, 33.1, 28.9, 24.7, 21.7, 19.2, 12.9; IR (neat): ?=3431, 2976, 2928, 2865, 1718, 1669, 1616, 1601, 1576, 1472, 1456, 1379, 1362, 1338, 1271, 1142, 1105 cm.sup.?1; MS (70 eV, EI) m/z (%): 342 (M.sup.+, 12.16), 129 (100).

EXAMPLE 6

[0193] ##STR00019##

[0194] Under the protection of an argon atmosphere, 2,2,6,6-tetramethylpiperidine (0.81 mL, d=0.837 g/mL, 678.0 mg, 4.8 mmol) and THF (4.8 mL) were added to a dry reaction flask. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, and added with n-butyllithium (2.5M in hexane, 1.92 mL, 4.8 mmol) dropwise, and after the dropwise addition, continued stirring at ?78? C. for 1 hour, and then stirred at 0? C. by an ice-water bath for 30 minutes (to produce a solution of lithium 2,2,6,6-tetramethylpiperidide). A solution of bis[(pinacol)boryl]methane (1.2894 g, 4.8 mmol) in THF (9.6 mL) was added to the reaction flask at 0? C. and continued stirring at 0? C. for 30 minutes. The reaction flask was cooled to ?78? C. in a dry ice acetone bath, to which a solution of S4b (661.1 mg, 3.0 mmol) in THF (3 mL) was added. The reaction solution was stirred at ?78? C. for 3 hours. The reaction was quenched by saturated ammonium chloride solution (3 mL), added with water (30 mL), and extracted with ethyl acetate (4?30 mL). The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent. Silica gel column chromatography was used for separation and purification (eluent: petroleum ether, then petroleum ether/ethyl acetate=40/1) to afford a product S5b (823.8 mg, 80%): yellow liquid;

[0195] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=7.41 (dd, J.sub.1=17.2 Hz, J.sub.2=11.2 Hz, 1H, ?CH), 6.26 (d, J=16.0 Hz, 1H, ?CH), 6.17-6.05 (m, 2H, 2x ?CH), 5.58 (d, J=17.2 Hz, 1H, ?CH), 2.01 (t, J=6.0 Hz, 2H, CH.sub.2), 1.96 (s, 1H, CD.sub.2H), 1.70 (s, 3H, CH.sub.3), 1.65-1.57 (m, 2H, CH.sub.2), 1.48-1.43 (m, 2H, CH.sub.2), 1.28 (s, 12H, 4x CH.sub.3), 1.02 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=145.7, 139.6, 137.6, 137.3, 131.7, 129.8, 128.7, 83.1, 39.6, 34.2, 33.1, 28.9, 24.7, 21.7, 19.2, 12.4 (quint, J=19.4 Hz); IR (neat): ?=2976, 2928, 2864, 1614, 1597, 1572, 1456, 1379, 1371, 1341, 1317, 1269, 1142, 1103 cm.sup.?1; MS (70 eV, EI) m/z (%): 344 (M.sup.+, 90.1), 101 (100); HRMS calcd m/z for C.sub.22H.sub.33D.sub.2.sup.11BO.sub.2 [M.sup.+]: 344.2850, found 344.2853.

EXAMPLE 7

[0196] ##STR00020##

[0197] [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5M, 600 ?L, 0.3 mmol), 5a (14.1 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were added in sequence to a dry reaction tube. The reaction tube was plugged with a rubber stopper, inserted with an air balloon to keep the reaction system in an air atmosphere, and stirred at room temperature for 48 hours in the dark. The reaction solution was filtered with a short column of diatomaceous earth, washed with ethyl acetate (30 mL), and rotary evaporated to remove the solvent. The silica gel preparation plate was used for separation and purification (the silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1) to afford a product retinal (1aa, 24.6 mg, 43%): orange solid; melting point 59.5-60.8? C. (petroleum ether recrystallization) (reported in literature (Ball, S.; Goodwin, T. W.; Morton, R. A. Biochem. J. 1948, 42, 516): 61-62? C.);

[0198] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.11 (d, J=8.0 Hz, 1H, CHO), 7.14 (dd, J.sub.1=15.2 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.43-6.29 (m, 2H, 2x ?CH), 6.22-6.13 (m, 2H, 2x ?CH), 5.97 (d, J=8.0 Hz, 1H, ?CH), 2.33 (d, J=0.8 Hz, 3H, CH.sub.3), 2.08-2.00 (m, 5H, CH.sub.3 and CH.sub.2), 1.72 (s, 3H, CH.sub.3), 1.67-1.58 (m, 2H, CH.sub.2), 1.51-1.44 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.1, 154.8, 141.3, 137.6, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.2, 13.1, 13.0; IR (neat): ?=2956, 2927, 2864, 2826, 2092, 1651, 1568, 1457, 1447, 1353, 1195, 1169, 1044 cm.sup.?1; MS (70 eV, EI) m/z (%): 284 (M.sup.+, 82.64), 128 (100).

EXAMPLE 8

[0199] ##STR00021##

[0200] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.2 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5b (14.4 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 43 hours to afford a product lab (22.9 mg, 40%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1): orange liquid;

[0201] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.10 (d, J=8.0 Hz, 1H, CHO), 7.14 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.43-6.29 (m, 2H, 2x ?CH), 6.22-6.11 (m, 2H, 2x ?CH), 5.97 (d, J=8.0 Hz, 1H, ?CH), 2.29 (s, 1H, CD.sub.2H), 2.09-1.99 (m, 5H, CH.sub.3 and CH.sub.2), 1.72 (s, 3H, CH.sub.3), 1.66-1.58 (m, 2H, CH.sub.2), 1.51-1.44 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.1, 154.8, 141.3, 137.6, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.2, 13.0, 12.4 (quint, J=19.4 Hz); IR (neat): ?=2956, 2925, 2861, 1655, 1569, 1447, 1375, 1353, 1265, 1194, 1161, 1107 cm.sup.?1; MS (70 eV, EI) m/z (%): 286 (M.sup.+, 100); HRMS calcd m/z for C.sub.20H.sub.26D.sub.2O [M.sup.+]: 286.2260, found 286.2259.

EXAMPLE 9

[0202] ##STR00022##

[0203] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5c (14.8 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 27 hours to afford a product 1ac (24.0 mg, 42%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=40/1): orange liquid;

[0204] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=7.14 (dd, J.sub.1=15.2 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.42-6.30 (m, 2H, 2x ?CH), 6.22-6.13 (m, 2H, 2x ?CH), 5.97 (s, 1H, ?CH), 2.08-2.00 (m, 5H, CH.sub.3 and CH.sub.2), 1.72 (s, 3H, CH.sub.3), 1.66-1.58 (m, 2H, CH.sub.2), 1.51-1.44 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=190.8 (t, J=26.1 Hz), 154.8, 141.3, 137.6, 137.0, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.2, 13.0, 12.4 (hept, J=19.3 Hz); IR (neat): ?=2956, 2927, 2864, 2826, 2092, 1651, 1568, 1457, 1447, 1353, 1195, 1169, 1044 cm.sup.?1; MS (70 eV, EI) m/z (%): 288 (M.sup.+, 100); HRMS calcd m/z for C.sub.20H.sub.24D.sub.4O [M.sup.+]: 288.2386, found 288.2387.

EXAMPLE 10

[0205] ##STR00023##

[0206] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5d (40.4 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 48 hours to afford a product 1ad (31.7 mg, 38%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1): orange liquid;

[0207] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.11 (d, J=8.0 Hz, 1H, CHO), 7.35-7.30 (m, 2H, ArH), 7.21-7.12 (m, 3H, ?CH and ArH), 6.37-6.27 (m, 2H, 2x ?CH), 6.17-6.08 (m, 3H, 3x ?CH), 4.13 (s, 2H, CH.sub.2), 2.02 (t, J=6.0 Hz, 2H, CH.sub.2), 1.90 (s, 3H, CH.sub.3), 1.69 (s, 3H, CH.sub.3), 1.66-1.58 (m, 2H, CH.sub.2), 1.49-1.42 (m, 2H, CH.sub.2), 1.30 (s, 9H, 3x CH.sub.3), 1.01 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.4, 156.7, 149.6, 141.5, 137.6, 137.0, 135.3, 133.9, 133.2, 130.5, 129.9, 129.5, 129.2, 127.5, 125.8, 39.5, 34.4, 34.3, 33.1, 32.7, 31.3, 28.9, 21.7, 19.1, 12.9; IR (neat): ?=2957, 2924, 2864, 2737, 1657, 1572, 1458, 1362, 1346, 1267, 1159, 1099 cm.sup.?1; MS (70 eV, EI) m/z (%): 416 (M.sup.+, 58.4), 147 (100); HRMS calcd m/z for C.sub.30H.sub.40O [M.sup.+]: 416.3074, found 416.3075.

EXAMPLE 11

[0208] ##STR00024##

[0209] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5b (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5a (14.0 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 57 hours to afford a product 1ba (23.1 mg, 40%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1): orange liquid;

[0210] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.11 (d, J=8.0 Hz, 1H, CHO), 7.14 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.44-6.29 (m, 2H, 2x ?CH), 6.22-6.10 (m, 2H, 2x ?CH), 5.97 (d, J=8.0 Hz, 1H, ?CH), 2.33 (s, 3H, CH.sub.3), 2.07-1.97 (m, 3H, CD.sub.2H and CH.sub.2), 1.72 (s, 3H, CH.sub.3), 1.66-1.58 (m, 2H, CH.sub.2), 1.50-1.43 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.1, 154.8, 141.3, 137.6, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.3, 33.1, 28.9, 21.7, 19.2, 13.1, 12.5 (quint, J=19.2 Hz); IR (neat): ?=2959, 2924, 2862, 2762, 1655, 1574, 1447, 1385, 1159, 1132, 1109, 1043 cm.sup.?1; MS (70 eV, EI) m/z (%): 286 (M.sup.+, 100); HRMS calcd m/z for C.sub.20H.sub.26D.sub.2O [M.sup.+]: 286.2260, found 286.2263.

EXAMPLE 12

[0211] ##STR00025##

[0212] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5b (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5b (14.5 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 57 hours to afford a product 1bb (24.2 mg, 42%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1): orange liquid;

[0213] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=10.10 (d, J=8.0 Hz, 1H, CHO), 7.13 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.45-6.30 (m, 2H, 2x ?CH), 6.22-6.12 (m, 2H, 2x ?CH), 5.97 (d, J=8.0 Hz, 1H, ?CH), 2.29 (s, 1H, CD.sub.2H), 2.03 (t, J=6.2 Hz, 2H, CH.sub.2), 1.99 (s, 1H, CD.sub.2H), 1.72 (s, 3H, CH.sub.3), 1.67-1.58 (m, 2H, CH.sub.2), 1.51-1.44 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=191.1, 154.8, 141.2, 137.6, 137.0, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.1, 12.6 (quint, J=19.6 Hz), 12.5 (quint, J=19.4 Hz); IR (neat): ?=2955, 2926, 2862, 1655, 1570, 1456, 1356, 1269, 1186, 1159, 1105 cm.sup.?1; MS (70 eV, EI) m/z (%): 288 (M.sup.+, 50.0), 93 (100); HRMS calcd m/z for C.sub.20H.sub.24D.sub.4O [M.sup.+]: 288.2386, found 288.2388.

EXAMPLE 13

[0214] ##STR00026##

[0215] Operations were conducted by referring to Example 7. [Cp*RhCl.sub.2].sub.2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc).sub.2.Math.H.sub.2O (2.0 mg, 0.01 mmol), S5b (THF solution, 0.5 M, 600 ?L, 0.3 mmol), 5c (14.8 mg, 0.2 mmol), THF (1 mL), H.sub.2O (11 ?L, 11.0 mg, 0.6 mmol) were reacted for 57 hours to afford a product 1bc (23.7 mg, 41%) (silica gel preparation plate was alkalized with petroleum ether containing 5% triethylamine by volume) (eluent: petroleum ether/ethyl acetate=20/1): orange liquid;

[0216] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=7.13 (dd, J.sub.1=14.8 Hz, J.sub.2=11.6 Hz, 1H, ?CH), 6.45-6.29 (m, 2H, 2x ?CH), 6.25-6.11 (m, 2H, 2x ?CH), 5.97 (s, 1H, ?CH), 2.08-1.96 (m, 3H, CD.sub.2H and CH.sub.2), 1.72 (s, 3H, CH.sub.3), 1.68-1.59 (m, 2H, CH.sub.2), 1.51-1.44 (m, 2H, CH.sub.2), 1.04 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=190.8 (t, J=26.1 Hz), 154.8, 141.2, 137.6, 137.0, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.1, 12.5 (quint, J=19.2 Hz), 12.3 (hept, J=19.3 Hz); IR (neat): ?=2959, 2926, 2862, 2824, 2093, 1647, 1566, 1551, 1456, 1358, 1186, 1165, 1043 cm.sup.?1; MS (70 eV, EI) m/z (%): 290 (M.sup.+, 100); HRMS calcd m/z for C.sub.20H.sub.22D.sub.6O [M.sup.+]: 290.2511, found 290.2511.

EXAMPLE 14

[0217] ##STR00027##

[0218] Retinal (1aa, 57.0 mg, 0.2 mmol) and methanol (1 mL) were added to a dry reaction tube, and sodium borohydride (15.2 mg, 0.4 mmol) was added while stirring. The mixture was stirred at room temperature for 15 minutes in the dark. The reaction was quenched with water (5 mL), and the mixture was extracted with ethyl acetate (4?5 mL). The organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent to afford vitamin A (2aa, 57.1 mg, 99%): yellow liquid;

[0219] .sup.1H NMR (400 MHz, CDCl.sub.3): ?=6.61 (dd, J.sub.1=15.0 Hz, J.sub.2=11.4 Hz, 1H, ?CH), 6.29 (d, J=14.8 Hz, 1H, ?CH), 6.21-6.07 (m, 3H, 3x ?CH), 5.69 (t, J=6.8 Hz, 1H, ?CH), 4.31 (d, J=7.2 Hz, 2H, OCH.sub.2), 2.01 (t, J=6.2 Hz, 2H, CH.sub.2), 1.96 (s, 3H, CH.sub.3), 1.86 (s, 3H, CH.sub.3), 1.71 (s, 3H, CH.sub.3), 1.65-1.57 (m, 2H, CH.sub.2), 1.49-1.43 (m, 2H, CH.sub.2), 1.02 (s, 6H, 2x CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3): ?=137.8, 137.6, 136.9, 136.3, 136.2, 130.05, 129.95, 129.3, 126.7, 125.2, 59.5, 39.6, 34.2, 33.0, 28.9, 21.7, 19.2, 12.7, 12.6; IR (neat): ?=3384, 3039, 2926, 2863, 1662, 1629, 1572, 1444, 1376, 1359, 1266, 1203, 1079, 1006 cm.sup.?1; MS (70 eV, EI) m/z (%): 286 (M.sup.+, 97.12), 91 (100).

EXAMPLE 15

[0220] ##STR00028##

[0221] Retinal (1aa, 142.2 mg, 0.5 mmol) and methanol (2.5 mL) were added to a dry reaction tube, the reaction tube was placed in an ice-water bath at 0? C., and added with sodium borohydride (38.0 mg, 1.0 mmol) while stirring. The mixture was stirred under an ice-water bath at 0? C. for 2 hours in the dark. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (4?10 mL). The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent to afford a crude product: vitamin A (2aa).

[0222] The vitamin A (2aa) crude product was dissolved in dichloromethane (3 mL), and triethylamine (151.6 mg, 1.5 mmol), dichloromethane (1 mL), 4-dimethylaminopyridine (DMAP, 3.1 mg, 0.025 mmol), acetic anhydride (127.6 mg, 1.25 mmol), dichloromethane (1 mL) were added in sequence while stirring at room temperature. The mixture was stirred at room temperature for 11 hours in the dark. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), then added with dichloromethane (10 mL), washed, then separated. The organic phase was then washed once with saturated sodium bicarbonate solution (15 mL), washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent to afford a crude product: vitamin A acetate (3aa). The NMR yield was 50% (two steps).

EXAMPLE 16

[0223] ##STR00029##

[0224] Retinal (1aa, 57.0 mg, 0.2 mmol), tent-butanol (4 mL), 2-methyl-2-butene (1.2 mL, density 0.662 g/mL, 794.4 mg, purity 90%, 10 mmol) were added in sequence to a dry reaction tube. NaClO.sub.2 (163.2 mg, 1.8 mmol) and NaH.sub.2PO.sub.4 (167.9 mg, 1.4 mmol) were dissolved in water (2 mL) and the solution was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours, then rotary evaporated to remove the components with low-boiling point, added with water (10 mL), adjusted to pH to 3 with aqueous 1M hydrochloric acid solution, extracted with ether (4?10 mL), and washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to remove the solvent to afford a crude product: retinoic acid (4aa), NMR yield of 38%.

[0225] The protection content of the present invention is not limited to the above examples. Without departing from the spirit and scope of the inventive concept, variations and advantages that can occur to those skilled in the art are included in the present invention, and the appended claims are the scope of protection.