Kinetic resolution of racemic hydroxy ester via asymmetric catalytic hydrogenation and application thereof

Abstract

The present invention relates to kinetic resolution of racemic -hydroxyl ester via asymmetric catalytic hydrogenation and an application thereof. In the presence of chiral spiro pyridyl phosphine ligand Iridium catalyst and base, racemic -hydroxyl esters were subjected to asymmetric catalytic hydrogenation to obtain extent optical purity chiral -hydroxyl esters and corresponding 1,5-diols. An optically active chiral -hydroxyl ester and 1,5-diols can be obtained at very high enantioselectivity and yield with relatively low usage of catalyst. The chiral -hydroxyl ester and 1,5-diols obtained by using the method can be used as a critical raw material for asymmetric synthesis of chiral drugs (R)-lisofylline and natural drugs (+)-civet, ()-indolizidine 167B and ()-coniine.

Claims

1. A method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation, comprising: in the presence of a chiral Spiro pyridyl phosphine ligand Iridium catalyst and a base, subjecting racemic -hydroxyl esters to asymmetric catalytic hydrogenation to obtain a chiral -hydroxyl ester and a corresponding 1,5-diols, ##STR00022## wherein when the produced -hydroxyl ester is in an S configuration, the corresponding 1,5-diols is in an R configuration; or wherein when the produced -hydroxyl ester is in an R configuration, the corresponding 1,5-diols is in an S configuration; wherein R.sup.1 is C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 halogen alkyl, C.sub.2-C.sub.20 chain alkenyl, C.sub.4-C.sub.24 aryl, C.sub.5-C.sub.25 aryl alkyl, C.sub.6-C.sub.26 aryl alkenyl, C.sub.1-C.sub.8 alkyl)-OR.sup.3, (C.sub.1-C.sub.8 alkyl)-SR.sup.4 or (C.sub.1-C.sub.8 alkyl)-NR.sup.5R.sup.6, wherein R.sup.4, R.sup.5, and R.sup.6 are independently C.sub.1-C.sub.8 alkyl, C.sub.5-C.sub.14 aryl alkyl, or C.sub.4-C.sub.15 aryl, or alternatively, R.sup.5 and R.sup.6, together with the N atom to which they attach, form a cyclic amino group having 4-20 carbon atoms; and R.sup.2 is C.sub.1-C.sub.5 alkyl and wherein the chiral spiro pyridyl phosphine ligand Iridium catalyst has a structure of formula III, ##STR00023## wherein R.sup.1 is C1-C8 chain hydrocarbyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C1-C8 alkyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently H, C1-C8 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C1-C8 hydrocarbyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl; or R.sup.2-R.sup.3, R.sup.4-R.sup.5 are incorporated into a C3-C7 aliphatic ring or an aromatic ring; wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are the same or different; R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 aliphatic amido group, n=0-3; or when n2, two adjacent R.sup.6 groups or two adjacent R.sup.7 groups are incorporated into a C3-C7 aliphatic ring or an aromatic ring, and wherein R.sup.6 and R.sup.7 are the same or different; R.sup.8 and R.sup.9 are independently H, halogen, C1-C8 alkyl, C1-C8 alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is halogen, C1-C8 alkyl, alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl, and m=0-3; or when m2, adjacent R.sup.9 groups, or R.sup.8 and R.sup.9 groups, are incorporated into a C3-C7 aliphatic ring or an aromatic ring, and wherein R.sup.8 and R.sup.9 are the same or different; and R.sup.10 is H, C1-C8 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C1-C8 alkyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl.

2. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, comprising the following hydrogenation process in a solvent: ##STR00024## wherein R.sup.1 and R.sup.2 are as defined in claim 1.

3. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, wherein R.sup.1 is C.sub.1-C.sub.8 alkyl, phenyl, cyclopentyl, or tert-butyloxyl methyl.

4. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, wherein, in which the chiral spiro pyridyl amido phosphine ligand Iridium catalyst has a structure of formula III, ##STR00025## wherein R.sup.1 is C.sub.1-C.sub.8 chain hydrocarbyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C1-C8 alkyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently H, C1-C8 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C1-C8 hydrocarbyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl; or R.sup.2-R.sup.3, R.sup.4-R.sup.5 are incorporated into a C3-C7 aliphatic ring or an aromatic ring; wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are the same or different; R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C1-C8 alkyl, C1-C8 alkoxy, and C1-C8 aliphatic amido group, n=0-3; or when n2, two adjacent R.sup.6 groups or two adjacent R.sup.7 groups are incorporated into a C3-C7 aliphatic ring or an aromatic ring, and wherein R.sup.6 and R.sup.7 are the same or different; R.sup.8 and R.sup.9 are independently H, halogen, C1-C8 alkyl, C1-C8 alkoxy, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is halogen, C1-C8 alkyl, alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl, and m=0-3; or when m2, adjacent R.sup.9 groups, or R.sup.8 and R.sup.9groups, are incorporated into a C3-C7 aliphatic ring or an aromatic ring, and wherein R.sup.8 and R.sup.9 are the same or different; and R.sup.10 is H, C1-C8 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, or benzyl, and wherein a substituent on said substituted phenyl is C.sub.1-C.sub.8 alkyl or alkoxy, with a substituent number of 1-5, and said heteroaryl is furyl, thienyl, or pyridyl.

5. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, wherein said chiral spiro pyridyl amido phosphine ligand Iridium complex catalyst comprises one selected from the following structures: ##STR00026## ##STR00027## Wherein, wherein DTB is 3,5-di-tert butyl phenyl, Xyl is 3,5-di-methyl phenyl, .sup.tBu is tert-butyl; and wherein the Iridium catalyst is in an (R)-configuration or in an (S)-configuration.

6. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 2, wherein the racemic -hydroxyl esters, the catalyst, and the base are added to the solvent and a resulting reaction mixture is stirred for 0.5-24 h to react under a hydrogen atmosphere of 1-100 atm to produce the chiral -hydroxyl ester and the corresponding chiral 1,5-diols.

7. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, wherein the base is potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate.

8. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 2, wherein the solvent is selected from any single or mixture of an alcohol solvent, an ether solvent, or an arene solvent; wherein the alcohol solvent is methanol, ethanol, propanol, isopropanol, or butanol; wherein the ether solvent is THF, methyl tert-butyl ether, or dioxane; wherein the arene solvent is toluene, DMF, or DMSO.

9. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 1, further comprising using the produced chiral active -hydroxyl ester as a chiral starting material in an asymmetric synthesis of a chiral drug selected from the group consisting of (R)-lisofylline, (+)-civet, ()-indolizidine 167B, and ()-coniine.

10. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 2, wherein said chiral spiro pyridyl amido phosphine ligand Iridium complex catalyst comprises one selected from the following structures: ##STR00028## ##STR00029## wherein DTB is 3,5-di-tert butyl phenyl, Xyl is 3,5-di-methyl phenyl, .sup.tBu is tert-butyl; and wherein the Iridium catalyst is in an (R)-configuration or in an (S)-configuration.

11. The method for kinetic resolution of racemic -hydroxyl esters via asymmetric catalytic hydrogenation according to claim 2, wherein the base is potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide, sodium isopropoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, or sodium carbonate.

Description

DETAILED EMBODIMENTS

(1) In order to further understand the present invention, preferred embodiments of the present invention will be described by reference to the examples, but it should be appreciated that these descriptions are merely intended to further illustrate the features and advantages of the present invention, rather than limiting the claims of the invention.

Example 1

Preparation of Chiral Spino Pyridyl Amide Phosphine Ligand Iridium Catalyst, Use Iridium Catalyst IIId as the Example

(2) Under the atmosphere of 1 atm hydrogen, [Ir(cod)Cl].sub.2 (30 mg, 0.045 mmol) and (R)N-(3-methylpyridyl-2-methyl)-7-di-(3,5-di-tert-butyl phenyl)phosphine-7-amino-1,1-spiro-di-hydrogen indene (70.5 mg, 0.094 mmol) were dissolved in ethanol (6 mL), the reaction mixture was stirred at room temperature for 3 hours, then desolventization at reduced pressure is performed to obtain light yellow solid. The solid is directly used in hydrogenation reaction.

(3) Other Iridium catalyst can be prepared as the same method as above.

Example 2

Kinetic Resolution of Racemic -hydroxy Esters via Catalytic Ester Hydrogenation

(4) Under the protection of nitrogen, to a hydrogenation vessel in an autoclave was added 1 mmol 5-hydroxyl ethyl hexanoate, 0.001 mmol catalyst in ethanol solution (0.5 mL), a solution of t-BuOK in EtOH (0.04 mmol) and 1 mL ethanol. After sealing, the autoclave was purged with hydrogen by pressurizing to 10 atm. The reaction mixture was stirred at room temperature for 0.5-6 hour. After the hydrogenation reaction finished, slowly releasing hydrogen, the solvent was subjected to desolventization at reduced pressure. Using NMR to measure transformation, HPLC to measure the enantioselectivity of the compound, the result is shown as table 1.

(5) ##STR00008##

(6) TABLE-US-00001 TABLE 1 (R)/(S)-I (R)/(S)-II entry R time (h) conv (%) yield (%) ee (%) yield (%) ee (%) 1 Me 1 50 47 93.7 46 94.2 2 Et 2 52 44 95.3 47 94.4 3 .sup.nPr 2 52 43 95.8 47 96.0 4 .sup.nBu 2 50 45 95.1 48 95.9 5 .sup.iBu 3 48 49 89.7 44 95.9 6 .sup.iPr 6 53 43 97.5 49 96.6 7 Cy 5 54 44 99.0 50 93.5 8 MeO(CH.sub.2).sub.3 1 50 45 97.2 46 91.2 9 Me.sub.2CHCH(CH.sub.2).sub.2 2 53 44 93.5 48 92.5 10 Ph 0.5 49 49 93.7 47 94.8

Example 3

High Transformation Experiment (S/C=100000) of Kinetic Resolution of Racemic -hydroxy Esters via Catalytic Ester Hydrogenation

(7) Under the protection of nitrogen, to a hydrogenation vessel in an autoclave was added 50 mmol 5-hydroxyl ethyl hexanoate, 0.0005 mmol catalyst in ethanol solution (1 mL), a solution of t-BuOK (1.8 mmol) in EtOH (9 mL) and 9 mL ethanol. After sealing, the autoclave was purged with hydrogen by pressurizing to 17 atm. The reaction mixture was stirred at room temperature for 24 hours. After the hydrogenation reaction finished, slowly releasing hydrogen, the solvent was subjected to desolventization at reduced pressure. Using NMR to measure the transformation with 52%, using HPLC to measure ee value of (S)-1 compound with 97% and ee value of (R)-II compound with 93% enantioselectivity.

Example 4

Asymmetric Synthesis of (+)-civet

4.1 Synthesis of (S)-5-methyl-5-valerolactone

(8) ##STR00009##

(9) To a solution of (S)-5-methyl-5-valerolactone (528 mg, 3 mmol) benzene (10 mL) was added TsOH (114 mg, 0.6 mmol) at room temperature. After the reaction mixture was stirred for 24 h, saturated NaHCO.sub.3 was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by chromatography on silica gel column (petroleum ether/ethyl acetate=3:1) to provide the desired product (S)-4 (308 g, 90% yield) as a colorless oil.

(10) [].sup.20.sub.D31.1 (c 1.0, EtOH). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.48-4.37 (m, 1H), 2.64-2.51 (m, 1H), 2.50-2.37 (m, 1H), 1.99-1.77 (m, 3H), 1.60-1.43 (m, 1H), 1.36 (d, J=6.4 Hz, 3H).

4.2 Synthesis of (S)-6-hydroxyl-2-octadienoic Acid Ethyl Ester

(11) ##STR00010##

(12) Under the protection of nitrogen, to a solution of (S)-5-methyl-5-valerolactone (228 g, 2 mmol) in DCM (5 mL) was added dropwise DIBAL-H (1.0 M in hexane, 2 mL, 2 mmol) at 78 C. After finishing adding, the reaction mixture was stirred for 1 h at this temperature, saturated sodium potassium tartrate was added. The mixture was allowed to warm to roof temperature and vigorously stirred for 1 h. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo to afford colorless liquid. The liquid is directly used into the next step without further purifying. To a solution of the liquid as above in Tol (10 mL) was added (carbethoxymethylene)-triphenylphosphorane (1.04 g, 3 mmol), and the mixture was stirred at 80 C. for 6 h. The solvent was evaporated and the remaining crude product was purified by chromatography on silica gel column (petroleum ether/ethyl acetate=3:1) to provide the desired product (308 mg, 83% yield over two steps) as a colorless oil.

(13) [].sup.20.sub.D+9.1 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.95 (dt, J=15.6, 6.8 Hz 1H), 5.81 (dt, J=15.6, 1.6 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.85-3.74 (m, 1H), 2.26-2.17 (m, 2H), 1.66-1.39 (m, 5H), 1.27 (t, J=7.2 Hz, 3H), 1.18 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 166.69, 148.87, 121.51, 67.74, 60.16, 38.54, 32.02, 24.15, 23.54, 14.22. HRMS (ESI) Calcd for C.sub.10H.sub.18O.sub.3 ([M+H].sup.+): 187.1329, Found: 187.1327.

4.3 Synthesis of (+)-civet

(14) ##STR00011##

(15) To (S)--hydroxyl-2-octadienoic acid ethyl ester obtained from step 4.2, were added .sup.iPrOH (5 mL) and .sup.tBuOK (22.4 mg, 0.2 mmol), the mixture were stirred at room temperature for 5h. The solvent of the reaction mixture was slowly removed under reduce pressure and the residue was dissolved with methanol (5 mL). 1 N LiOH (5 mL. 5 mmol) was added to the mixture and the reaction mixture was stirred for 1 h. After acidified with 2 N HCl to pH 1, the solution was extracted with EtOAc, dried over anhydrous MgSO.sub.4, and concentrated in vacuo to yield a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=1:1) to provide the desired product (+)-civet (107 mg, 68% yield over two steps as a colorless oil.

(16) [].sup.20.sub.D+22.0 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 9.40 (s, 1H), 3.81-3.71 (m, 1H), 3.56-3.45 (m, 1H), 2.56 (dd, J=15.6, 7.6 Hz, 1H), 2.46 (dd, J=15.6, 5.2 Hz, 1H), 1.86-1.77 (m, 1H), 1.67-1.46 (m, 3H), 1.30-1.19 (m, 2H), 1.16 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 175.72, 74.41, 73.93, 41.23, 32.71, 30.72, 23.16, 21.94.

Example 5

Synthesis of ()-indolizidine 167B

5.1 Protection of Hydroxyl Group

(17) ##STR00012##

(18) To a solution of (S)-5-hydroxyl octadienoic acid ethyl ester (1.76 g, 9.4 mmol) in DCM (40 mL) was added imidazole (959 mg, 14.1 mmol), DMAP (115 mg, 0.94 mmol) and TBSCl (1.7 g, 11.3 mmol). The reaction mixture was stirred at room temperature for 24 h. Then the reaction mixture was quenched with saturated NH.sub.4Cl. The layers were, separated and the aqueous layer was extracted with DCM. After dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column petroleum ether/ethyl acetate=80:1) to provide the desired product (2.61 g, 92% yield) as a colorless oil.

(19) [].sup.20.sub.D0.4 (c 4.7, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.12 (q, J=7.2 Hz 2H), 3.69-3.61 (m, 1H), 2.29, (t, J=7.2 Hz, 2H), 1.75-1.55 (m, 2H), 1.50-1.28 (m, 6H), 1.25 (t, J=7.2 Hz, 3H), 0.91-0.85 (m, 12H), 0.03 (s, 6H), .sup.13C NMR (100 MHz, CDCl.sub.3) 173.70, 71.67, 60.15, 39.29, 36.38, 34.50, 25.88, 20.81, 18.47, 18.09, 14.28, 14.22, 4.48, 4.51. HRMS (ESI) Calcd for C.sub.16H.sub.35O.sub.3Si ([M+H].sup.+): 303.2350, Found: 303.2354.

5.2 Establish of Amide Functional Group

(20) ##STR00013##

(21) Under the N.sub.2 atmosphere, to a solution of N,O-dimethyl hydroxylamine hydrochloric acid salt (2.52 g, 25.8 mmol) in DCM (70 mL), was slowly added AlMe.sub.3. (25.8 mL, 1.0 M in hexane, 2.58 mmol), the reaction mixture was stirred for 0.5 h at room temperature. Then (S)-5-hydroxyl ethyl caprylate which the hydroxyl group was protected with TBS obtained from 5.1 in DMC was added, the reaction mixture was reacted when heated to reflux for 3 h and cooled to room temperature. Then the reaction mixture was quenched with 0.5 N HCl. The layers were separated and the aqueous layer was extracted with DCM. After dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=1:2) to provide the desired product (2.55 g, 93% yield) as a colorless oil.

(22) [].sup.20.sub.D3.4 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 3.70-3.63 (m, 4H), 3.17 (s, 3H), 2.41, (t, J=8.0 Hz, 2H), 1.74-1.59 (m, 2H), 1.51-1.23 (m, 6H), 0.93-0.84 (m, 12H), 0.04 (d, J=1.2 Hz, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3) 174.59, 71.89, 61.15, 39.25, 36.73, 32.09, 25.89, 20.45, 18.48, 18.09, 14.29, 4.46, 4.50. HRMS (ESI) Calcd for C.sub.16H.sub.36NO.sub.3Si ([M+H].sup.+): 318.2459, Found: 318.2465.

5.3 Synthesis of Acetal or Ketal

(23) ##STR00014##

(24) Under the N.sub.2 atmosphere, to a solution of amide compound (2.55 g, 8.0 mmol) obtained from 5.2 in THF (60 mL) was added grignard reagent (24 mL, 1.0 M in THF, 24.0 mmol), the solution was reacted for 11 h at the room temperature. Then the reaction mixture was quenched with saturated NH.sub.4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. After dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=15:1) to provide the desired product (2.76 g, 96% yield) as a colorless oil.

(25) [].sup.20.sub.D0.8 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.89 (t, J=4.4 Hz 1H), 3.98-3.78 (m, 4H), 3.67-3.58 (m, 1H), 2.51 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 2.00-1.92 (m, 2H), 1.69-1.49 (m, 2H), 1.44-1.22 (m, 6H), 0.91-0.83 (m, 12H), 0.02 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3) 210.03, 103.32, 71.81, 64.93, 42.94, 39.26, 36.48, 36.36, 27.54, 25.88, 19.66, 18.46, 18.09, 14.28, 4.48. HRMS (ESI) Calcd for C.sub.19H.sub.39O.sub.4Si ([M+H].sup.+): 359.2612, Found: 359.2616.

5.4 Deprotection of Protecting Group

(26) ##STR00015##

(27) To a solution of acetal or ketal compound (2.76 g, 7.7 mmol) obtained from 5.3 in THF (20 mL) was added TBAF (38.5 mL, 1.0 M in THF 38.5 mmol), the solution was reacted for 20 h at the room temperature. Then the reaction mixture was quenched with saturated NH.sub.4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. After dried over anhydrous MgSO4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=3:1) to provide the desired product (1.54 g). The desired product is the mixture of -hydroxyl ketone and hemiketal with the yield 82%.

(28) .sup.1H NMR (400 MHz, CDCl.sub.3) 4.93-4.81 (m, 1H), 4.01-3.89 (m, 2H), 3.88-3.78 (m, 2.3H), 3.59-3.49 (m, 0.7H), 3.32 (s, 0.2H), 2.51 (t, J=Hz, 1.4H), 2.44 (t, J=7.2 Hz, 1.4H), 1.99-1.90 (m, 1.7H), 1.86-1.51 (m, 4H), 1.48-1.22 (m, 6H) 0.95-0.81 (m, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 210.24, 104.29, 103.24, 95.44, 71.04, 69.32, 64.89, 42.46, 39.56, 38.40, 36.73, 36.46, 36.36, 34.00, 31.15, 27.49, 26.49, 26.64, 19.62, 19.16, 18.76, 18.63, 14.04.

5.5 Synthesis of Compound Containing N.SUB.3.Group

(29) ##STR00016##

(30) To a solution of the compound (635 mg, 2.6 mmol) obtained from 5.4 in DCM (20 mL), were added Et.sub.3N (394 mg, 3.9 mmol) and MeSO.sub.3Cl (388 mg, 3.4 mmol), the reaction mixture was reacted for 3 h. Then the reaction mixture was quenched with saturated NH.sub.4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. After dried over anhydrous MgSO4 and concentrated in vacuo to afford a crude product as a colorless liquid. DMF (20 mL) was added for attenuation, then NaN.sub.3 (3.38 g, 5.2 mmol) was added in batches. The solution was stirred for 20 h to react at the temperature of 100 C. Then the reaction mixture was cooed to room temperature, and subjected to filter to remove NaN.sub.3. The organic layer was washed with H.sub.2O, dried over anhydrous MgSO4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=10:1) to provide the desired product as a colorless liquid (420 mg, yield 60%).

(31) [].sup.20.sub.D2.8 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.86 (t, J=4.4 Hz 1H), 3.95-3.74 (m, 4H), 3.25-3.14 (m, 1H), 2.48 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.97-1.88 (m, 2H), 1.75-1.53 (m, 2H), 1.52-1.26 (m, 6H), 0.88 (t, J=7.2 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 209.34, 103.11, 64.82, 62.45, 42.01, 36.31, 36.24, 33.57, 27.41, 20.15, 19.14, 13.71. HRMS (ESI) Calcd for C.sub.13H.sub.23N.sub.3O.sub.3Na ([M+Na].sup.+): 292.1632, Found: 292.1636.

5.6 Synthesis of ()-Indolizidine 167B

(32) ##STR00017##

(33) To a solution of the compound (250 mg, 0.93 mmol) obtained from 5.5 in THF (9 mL) was added 2 N HCl solution and reacted for 4 h at the room temperature. the solution was extracted with EtOAc. The solution was dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=5:1) to provide the desired product as a colorless liquid (186 mg, 89% yield).

(34) [].sup.20.sub.D6.6 (c 2.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 9.80 (s, 1H), 3.32-3.20 (m, 1H), 2.80-2.69 (m, 4H), 2.52 (t, J=7.2 Hz, 2H), 1.83-1.59 (m, 2H), 1.54-1.35 (m, 6H), 0.93 (t, J=7.2 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 208.10, 200.40, 62.52, 42.11, 37.44, 36.35, 34.56, 33.60, 20.24, 19.25, 13.81.

(35) To the hydrogenation reaction vessel were added the above colorless liquid (50 mg, 0.22 mmol), 10 wt % Pd/C (23 mg, 0.022 mmol), and MeOH (5 mL), the reaction mixture was stirred for 4 h to react after injecting the hydrogen to 10 atm. The reaction mixture was filtrated, dissolved to obtain a colorless liquid. EtOAc was added to attenuation, then the liquid was acidized with 1 N HCl (5 mL), the liquid was layered. The water layer was washed with EtOAc and saturated NaHCO.sub.3 was added to adjust the pH to be alkalescence. The water layer was extracted by EtOAc, dried and concentrated to obtain a colorless liquid (26 mg, yield 71%).

(36) [].sup.20.sub.D101.3 (c 1.0, CH.sub.2Cl.sub.2), .sup.1H NMR (400 MHz, CDCl.sub.3) 3.26 (dt, J=2.0, 8.8 Hz, 1H). 1.96 (q, J=8.8 Hz, 1H), 1.87-1.57 (m, 8H), 1.49-1.09 (m, 8H), 0.90 (t, J=7.2 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 64.97, 63.67, 51.53, 36.89, 31.00, 30.82, 30.52, 24.67, 20.37, 19.08, 14.50. HRMS (ESI) Calcd for C.sub.11H.sub.22N ([M+H].sup.+): 168.1747, Found: 168.1750.

Example 6

Synthesis of (R)-lisofylline

6.1 Selectivity Protection of Hydroxyl

(37) ##STR00018##

(38) To a solution of (R)-hexane-1,5-diol (730 mg, 5 mmol) in DCM (10 mL) was added Et.sub.3N (555 mg 5.5 mmol) and MsCl (570 mg, 5 mmol) at 20 C. under N.sub.2 atmosphere. The reaction mixture was stirred at the same temperature for 2 h and quenched with saturated NH.sub.4Cl. The layers were separated and the aqueous layer was extracted with DCM. The combined extracts were washed with saturated NaHCO.sub.3 and brine, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=3:1) to provide the desired product (R)-5-hydroxyhexyl methanesulfonate (672 mg, 69% yield) as a colorless oil.

(39) [].sup.20.sub.D9.6 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.24 (t, J=6.4 Hz, 2H), 3.87-3.77 (m, 1H), 3.01 (s, 3H), 1.83-1.73 (m, 2H), 1.68 (s, 1H), 1.58-1.42 (m, 4H), 1.20 (d, J=6.0 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 69.92, 67.63, 38.37, 37.31, 29.03, 23.56, 21.64. HRMS (ESI) Calcd for C.sub.7H.sub.17O.sub.4S ([M+H].sup.+): 197.0843, Found: 197.0841.

(40) A mixture of (R)-5-hydroxyhexyl methanesulfonate (390 mg, 1.74 mmol), Ac.sub.2O (673 mg, 6.6 mmol), NEt.sub.3 (707 mg, 7.0 mmol), DHAP (61 it 0.5 mmol) and THF (10 mL) were stirred at room temperature for 4 h. After removing of THF in vacuo, the residue was diluted with EtOAc (10 mL). The solution was washed with saturated NaHCO.sub.3, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel colunm (petroleum ether/ethyl acetate=3:1) to provide the desired product (426 mg, 92% yield) as a colorless oil.

(41) [].sup.20.sub.D1.0 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 4.94-4.83 (m, 1H), 4.21 (t, J=6.4 Hz, 2H), 3.00 (s, 3H), 2.02 (s, 3H), 1.81-1.70 (m, 2H), 1.66-1.39 (m, 4H), 1.20 (d, J=6.4 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 170.71, 70.39, 69.67, 37.32, 35.15, 28.85, 21.33, 21.31, 19.87. HRMS (ESI) Calcd for C.sub.9H.sub.19O.sub.5S ([M+H].sup.+): 239.0948, Found: 239.0950.

6.2 Synthesis of (R)-Lisofylline

(42) ##STR00019##

(43) To a solution of NaH (38.4 mg, 1.6 mmol) in DMSO (10 mL) was slowly added the theobromine (288 mg, 1.6 mmol) under N.sub.2 atmosphere. The reaction mixture was heated to 60 C. and added slowly a solution of compound obtained in 6.1 (288 mg, 1.6 mmol) in DMSO (2 mL). After stirring 7 h and cooling to room temperature, H.sub.2O was added to the reaction mixture. The solution was extracted with EtOAc, and the combined extracts were washed with brine, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude white product. The obtained crude white product was dissolved in MeOH (20 mL) and K.sub.2CO.sub.3 (1.1 g, 8 mmol) was added to the solution at room temperature. After stirring 4 h, H.sub.2O was added to the reaction mixture. The solution was extracted with EtOAc, and the combined extracts were washed with brine, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel colunm with ethyl acetate as the eluent to provide the desired white product (R)-lisofylline (375 mg, 77% yield) as white solid. m.p.123-125 C.

(44) [].sup.20.sub.D5.0 (c 1.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (s, 1H), 4.00 (t, J=7.6 Hz, 2H), 3.97 (s, 3H), 3.83-3.75 (m, 1H), 3.55 (s, 3H), 1.73-1.62 (m, 2H), 1.56-1.35 (m, 5H), 1.17 (d, J=6.0 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 155.33, 151.47, 148.71, 141.39, 107.64, 67.79, 41.10, 38.73, 33.55, 29.66, 27.86, 23.46, 22.87. HRMS (ESI) Calcd for C.sub.13H.sub.21N.sub.4O.sub.3 ([M+H].sup.+): 281.1609, Found: 281.1613.

Example 7

Synthesis of ()-Coniine

7.1 Synthesis of Piperidyl Compound

(45) ##STR00020##

(46) To a solution of (5)-octane-1,5-diol (231 mg, 1.58 mmol) in DCM (10 mL) was added NEt.sub.3 (479 mg, 4.74 mmol) and MeSO.sub.3H (450 mg, 3.95 mmol) at the temperature of 20 C. and reacted for 2 h at the temperature. The reaction mixture was subjected to cancellation with saturated NH.sub.4Cl solution and then was extracted by DCM. The solution was washed with saturated NaHCO.sub.3, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a colorless liquid. Benzylamine was added to the colorless liquid at the temperature of 0 C. and stirred for 12 h to react. The reaction mixture was concentrated to get out of benzylamine at reduced pressure. The solution was extracted with EtOAc, and the combined extracts were washed with saturated NaHCO.sub.3, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to afford a crude product, which was purified by flash chromatography on silica gel column (petroleum ether/ethyl acetate=15:1) to provide the desired product as a colorless liquid (236 mg, 69% yield).

(47) [].sup.20.sub.D77.6 (c 2.0, CHCl.sub.3). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.35-7.27 (m, 4H), 7.25-7.19 (m, 1H), 3.97 (d, J=13.2 Hz, 1H), 3.22 (d, J=13.2 Hz, 1H), 2.73 (dt, H=11.2, 4.4 Hz, 1H), 2.32-2.23 (m, 1H), 2.07-1.97 (m, 1H), 1.71-1.23 (m, 10H), 0.91 (t, J=7.2 Hz, 3H), .sup.13C NMR (100 MHz, CDCl.sub.3) 139.84, 128.93, 128.05, 126.55, 60.61, 57.50, 51.68, 34.10, 30.25, 25.14, 23.71, 18.69, 14.63.

7.2 Synthesis of ()-Coniine

(48) ##STR00021##

(49) To the hydrogenation reaction vessel were added piperidyl compound obtained in 7.1 (17 mg, 0.078 mmol), 10 wt. % Pd/C (8.3 mg, 0.0078 mmol.) concentrated HCl (0.1 mL) and MeOH (3 mL), the reaction mixture was stirred for 3 h to react after injecting the hydrogen to 10 atm. The reaction mixture was filtrated, dissolved to obtain light yellow solid (13 mg, 98% yield). m.p. 220-222 C.

(50) [].sup.20.sub.D6.4 (c 1.0, EtOH). .sup.1H NMR (400 MHz, CDCl.sub.3) 9.23 (br s, 1H), 8.95 (br s, 1H), 3.62-3.43 (m, 1H), 3.05-2.75 (m, 2H), 2.10-1.58 (m, 7H), 1.58-1.35 (m, 3H), 0.95 (t, J=6.0 Hz, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 57.23, 45.07, 35.41, 28.10, 22.39, 22.23, 18.64, 13.77.