Optically active axially chiral alpha-allenic alcohol, synthesis method and use thereof

Abstract

The present invention relates to an optically active axially chiral -allenic alcohol, a synthesis method and use thereof. The invention relates to a method of preparing a highly optically active chiral -allenic alcohol by using propargyl alcohol, aldehyde and chiral ,-diphenyl-L-prolinol under the protection of tert-butyldimethylsilyl with an accelerant zinc bromide. The axially chiral -allenic alcohol has the structural formula (I). The method of the present invention has the following advantages: the synthesis route is short, operations are simple, raw materials are readily available, separation and purification are convenient, the substrate has high universality, the total yield is high, and enantioselectivity and diastereoselectivity are high. The highly optically active axially chiral -allenic alcohol synthesized by the method of the present invention can conveniently synthesize 2,5-dihydrofuran compounds having central chirality and complete chirality, and at the same time can further synthesize axially chiral allenic amine and allenic malonic ester compounds having complete chirality. ##STR00001##

Claims

1. A method for synthesizing an axially chiral -allenic alcohol having the following structural formula: ##STR00026## wherein R.sup.1 is a C.sub.1-C.sub.10 hydrocarbon group; R.sup.2 is H or C.sub.1-C.sub.10 hydrocarbon group; the axial chirality of the allene is in R or S configuration; the carbon atom linked to the hydroxyl group is non-chiral, or in R or S configuration; and when the C.sub.1-C.sub.10 hydrocarbon group is an aliphatic group, the ee value is higher than 96%, comprising the following steps: ##STR00027## wherein PG is a silyl group; said reaction is performed in an organic solvent and at a temperature of 100-130 C., in the presence of a zinc salt, and using (3) or an enantiomer thereof as a chiral secondary amine; wherein the substituted-propargyl alcohol protected by silyl group (1) and the aldehyde (2) are reacted for 5-15 hours; followed by passing the protected product through a silica-gel chromatographic column to obtain a crude reaction product; and then removing the silyl protective group by treatment with tetra-n-butylammonium fluoride, to obtain the axially chiral -allenic alcohol product (4); wherein the molar ratio of the substituted-propargyl alcohol protected with the silyl group (1): the aldehyde (2): the chiral secondary amine (3): the zinc salt is 1-3:1-3:1:0.5-1.5; wherein said silyl group is a trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl group; said chiral secondary amine is compound 3(a-e) having the following structural formula or an enantiomer thereof; ##STR00028## and wherein said zinc salt is zinc chloride, zinc bromide, zinc iodide, zinc acetate, or zinc trifluoromethanesulfonate.

2. The method of claim 1, wherein the zinc salt, chiral secondary amine, propargyl alcohol protected by silyl group, aldehyde, and dehydrated organic solvent are added to a dried reactor and stirred for 5-20 hours at 100-130 C.; and after the reaction, the product is passed through a silica-gel chromatographic column to obtain a crude reaction product; the crude reaction product is then dissolved in an organic solvent; and the dissolved crude reaction product is mixed with tetra-n-butylammonium fluoride at 0 C. and stirred for 1-15 hours at room temperature.

3. The method of claim 1, wherein the organic solvent is benzene, toluene, chlorobenzene, p-xylene, o-xylene, m-xylene, or sym-trimethylbenzene.

4. The method of claim 1, wherein the deprotected axially chiral -allenic alcohol reaction product is washed with water, extracted into an organic solvent, dried, subjected to evaporation of solvent; and purified by column chromatographic separation.

5. The method of claim 2, wherein the organic solvent is benzene, toluene, chlorobenzene, p-xylene, o-xylene, m-xylene, or sym-trimethylbenzene.

6. The method of claim 2, wherein the deprotected axially chiral -allenic alcohol reaction product is washed with water, extracted into an organic solvent, dried, subjected to evaporation of solvent; and purified by column chromatographic separation.

Description

PREFERRED EMBODIMENTS OF THE INVENTION

(1) The following examples are given for the further understanding of the present invention and are not intended to limit the present invention.

Example 1

(2) ##STR00004##

(3) wherein equiv represents equivalent, mol represents mole, TBS represents tert-butyldimethylsilyl, Cy represents cyclohexyl, TBAF represents tetrabutylammonium fluoride, THF represents tetrahydrofuran, rt refers to room temperature, ee represents enantiomeric excess, and de represents diastereomeric excess.

(4) Under the protection of an inert gas, ZnBr.sub.2 (169.3 mg, 0.75 mmol) was added to a dried reaction tube, dried with heating gun. Then , -diphenylprolinol (S)-3a (258.7 mg, 1.0 mmol, 98%), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.2 mg, 1.1 mmol), dehydrated toluene (2 mL), newly distilled cyclohexanecarboxaldehyde 2a (168.6 mg, 1.5 mmol), and dehydrated toluene (1 mL) were added. The reaction tube was then equipped with a reflux condensing tube, and placed into an oil bath that had been previously heated to 130 C. and stirred under reflux for 10 hours. After cooled to the room temperature, the product was filtered with a short silica-gel chromatographic column, washed with 20 mL of ether, evaporated and passed through a short column (petroleum ether/ether=50/1), and then the crude reaction product of allenic alcohol protected by tert-butyldimenthylsilyl group was obtained. The crude product was directly dissolved in tetrahydrofuran (3 mL), to which was added with TBAF.3H.sub.2O (316.0 mg, 1.0 mmol) at 0 C. After the temperature was naturally increased to room temperature, the resulting mixture was stirred for 1.5 hours, and added to a mixture of 10 mL of ether and 10 mL of water; the organic layer was separated and the water layer was extracted with ether (10 mL3). The organic layers were combined, dried with anhydrous sodium sulfate, evaporated, and subjected to the column chromatography (petroleum ether/ethyl acetate=10/1) to afford a liquid: axially chiral -allenic alcohol(R)-4aa (104.0 mg, 68%): 99% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.6 mL/min, =214 nm, t.sub.R(large peak)=16.0 min, t.sub.R(small peak)=19.2 min); []22.sub.D=99.8 (c=1.01, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.41-5.24 (m, 2H, CHCCH), 4.10 (d, J=2.7 Hz, 2H, OCH.sub.2), 2.08-1.88 (m, 2H, OH and CH from Cy), 1.82-1.57 (m, 5H, protons from Cy), 1.37-0.97 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.9, 99.7, 92.5, 60.8, 37.0, 33.0, 32.9, 26.0, 25.9; MS (EI) m/z (%): 152 (M.sup.+, 0.70), 55 (100); IR (neat): v=3326, 2923, 2850, 1961, 1448, 1302, 1259, 1214, 1062, 1008 cm.sup.1; HRMS [M.sup.+] calculated value: 152.1201, measured value: 152.1203.

Example 2

(5) ##STR00005##

(6) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (1.6912 g, 7.5 mmol), , -diphenylprolinol(S)-3a (2.5857 g, 10 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (1.8738 g, 11 mmol), newly distilled cyclohexanecarboxaldehyde 2a (1.6831 g, 15 mmol), dehydrated toluene (30 mL), TBAF.3H.sub.2O (3.1563 g, 10 mmol) and tetrahydrofuran (30 mL), column chromatography (pertroleum ether/ethyl acetate=15/1 (800 mL).fwdarw.10:1) to afford a liquid: axially chiral -allenic alcohol (R)-4aa (1.0624, 70%): 99% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.6 mL/min, =214 nm, t.sub.R(large peak)=11.9 min, t.sub.R(small peak)=12.9 min); [].sup.22.sub.D=100.3 (c=1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.42-5.26 (m, 2H, CHCCH), 4.11 (s, 2H, OCH.sub.2), 2.07-1.94 (m, 1H, CH from Cy), 1.82-1.49 (m, 6H, OH and protons from Cy), 1.36-1.00 (m, 5H, protons from Cy).

Example 3

(7) ##STR00006##

(8) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (506.8 mg, 2.25 mmol), , -diphenylprolinol (S)-3a (775.4 mg, 3.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (562.4 mg, 3.3 mmol), newly distilled iso-pentaldehyde 2b (388.1 mg, 4.5 mmol), dehydrated toluene (9 mL), TBAF.3H.sub.2O (947.3 mg, 3.0 mmol) and tetrahydrofuran (5 mL), column chromatography (petroleum ether/ethyl acetate=15/1) to afford a liquid: axially chiral -allenic alcohol(R)-4ab (171.2 mg, 45%): 98% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=200/1, 1.0 mL/min, =214 nm, t.sub.R(large peak)=20.4 min, t.sub.R(small peak)=25.3 min); [].sup.22.sub.D=80.3 (c=1.01, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.35-5.18 (m, 2H, CHCCH), 4.11 (s, 2H, OCH.sub.2), 2.03-1.79 (m, 3H, OH and CH.sub.2), 1.76-1.58 (m, 1H, CH), 0.92 (d, J=6.6 Hz, 6H, two CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =203.6, 92.2, 90.9, 60.8, 38.1, 28.3, 22.1; MS (EI) m/z (%): 126 (M.sup.+, 0.21), 55 (100); IR (neat): v=3326, 2955, 2928, 2870, 1963, 1466, 1384, 1367, 1262, 1056, 1013 cm.sup.1; HRMS [M.sup.+] calculated value: 126.1045, measured value: 126.1044.

Example 4

(9) ##STR00007##

(10) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.7 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.8 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.2 mg, 1.1 mmol), newly distilled n-hexanal 2c (150.4 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (316.2 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=10/1) to afford a liquid: axially chiral a-allenic alcohol (R)-4ac (83.0 mg, 59%): 98% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.5 mL/min, =214 nm, t.sub.R(large peak)=12.2 min, t.sub.R(small peak)=13.1 min); [].sup.21.sub.D=78.4 (c=1.03, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.36-5.23 (m, 2H, CHCCH), 4.11 (s, 2H, OCH.sub.2), 2.09-1.90 (m, 3H, OH and CH.sub.2), 1.49-1.23 (m, 6H, three CH.sub.2), 0.89 (t, J=6.5 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =203.0, 93.7, 91.6, 60.7, 31.2, 28.7, 28.5, 22.4, 14.0; MS (EI) m/z (%): 140 (M.sup.+, 0.15), 55 (100); IR (neat): v=3345, 2956, 2928, 2857, 1963, 1464, 1417, 1379, 1206, 1137, 1111, 1057, 1011 cm.sup.1; HRMS [M.sup.+] calculated value: 140.1201, measured value: 140.1202.

Example 5

(11) ##STR00008##

(12) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.4 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.2 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.2 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2d (147.3 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (316.4 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyle acetate=10/1) to afford a liquid: axially chiral -allenic alcohol (R)-4ad (81.9 mg, 59%): 98% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.6 mL/min, =214 nm, t.sub.R(large peak)=13.8 min, t.sub.R(small peak)=15.3 min); [].sup.20.sub.D=97.2 (c=1.02, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.39-5.27 (m, 2H, CHCCH), 4.10 (d, J=2.7 Hz, 2H, OCH.sub.2), 2.56-2.39 (m, 1H, CH from cyclopentyl), 2.07 (s, 1H, OH), 1.86-1.72 (m, 2H, CH.sub.2), 1.72-1.47 (m, 4H, two CH.sub.2), 1.46-1.28 (m, 2H, CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.8, 98.6, 92.4, 60.7, 39.0, 32.7, 24.8; MS (EI) m/z (%): 138 (M.sup.+, 0.28), 79 (100); IR (neat): v=3321, 2951, 2867, 1961, 1451, 1420, 1207, 1009 cm.sup.1; HRMS [M.sup.+] calculated value: 138.1045, measured value: 138.1044.

Example 6

(13) ##STR00009##

(14) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.5 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.3 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.2 mg, 1.1 mmol), newly distilled n-octanal 2e (192.5 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (315.7 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=15/1) to afford a liquid: axially chiral a-allenic alcohol (R)-4ae (109.8 mg, 65%): 97% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.6 mL/min, =214 nm, t.sub.R(large peak)=11.1 min, t.sub.R(small peak)=12.2 min); [].sup.20.sub.D=66.1 (c=1.03, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.37-5.22 (m, 2H, CHCCH), 4.11 (d, J=1.2 Hz, 2H, OCH.sub.2), 2.07-1.95 (m, 2H, CH.sub.2), 1.91 (s, 1H, OH), 1.47-1.17 (m, 10H, five CH.sub.2), 0.88 (t, J=6.5 Hz, 3H, CH.sub.2); .sup.13C NMR (75 MHz, CDCl.sub.3) =202.9, 93.8, 91.6, 60.7, 31.8, 29.08, 29.06, 29.0, 28.6, 22.6, 14.0; MS (ESI): m/z 191 (M+Na.sup.+), 168 (M.sup.+); IR (neat): v=3320, 2956, 2925, 2855, 1964, 1463, 1420, 1379, 1140, 1056, 1012 cm.sup.1; HRMS [M.sup.+] calculated value: 168.1514, measured value: 168.1515.

Example 7

(15) ##STR00010##

(16) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.7 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.6 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (187.9 mg, 1.1 mmol), newly distilled phenylpropyl aldehyde 2f (202.1 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (315.7 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=15/1 (320 mL).fwdarw.10:1) to afford a liquid: axially chiral -allenic alcohol (R)-4af (105.1 mg, 60%): 96% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=100/1, 1.0 mL/min, =214 nm, t.sub.R(large peak)=19.0 min, t.sub.R(small peak)=20.5 min); [].sup.20.sub.D=38.7 (c=1.05, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =7.32-7.13 (m, 5H, ArH), 5.34-5.21 (m, 2H, CHCCH), 3.97 (d, J=1.2 Hz, 2H, OCH.sub.2), 2.83-2.64 (m, 2H, CH.sub.2), 2.45-2.24 (m, 2H, CH.sub.2), 1.78 (s, 1H, OH); .sup.13C NMR (75 MHz, CDCl.sub.3) =203.2, 141.3, 128.4, 128.2, 125.8, 92.7, 92.1, 60.4, 35.0, 29.9; MS (EI) m/z (%): 174 (M.sup.+, 0.12), 91 (100); IR (neat): v=3341, 3026, 2923, 2856, 1963, 1495, 1453, 1062, 1008 cm.sup.1; HRMS [M.sup.+] calculated value: 174.1045, measured value: 174.1044.

Example 8

(17) ##STR00011##

(18) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.2 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.7 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.1 mg, 1.1 mmol), newly distilled 2-ethyl butanal 2g (150.4 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (315.8 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=15/1) to afford a liquid: axially chiral -allenic alcohol (R)-4ag (88.7 mg, 63%): 98% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=200/1, 1.0 mL/min, =214 nm, t.sub.R(large peak)=19.0 min, t.sub.R(small peak)=22.0 min); [].sup.20.sub.D=92.5 (c=1.01, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.32 (q, J=6.1 Hz, 1H, one proton from CHCCH), 5.14-5.04 (m, 1H, one proton from CHCCH), 4.11 (d, J=3.6 Hz, 2H, OCH.sub.2), 2.05 (s, 1H, OH), 1.95-1.80 (m, 1H, CH), 1.53-1.20 (m, 4H, two CH.sub.2), 0.90 (t, J=7.4 Hz, 6H, two CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =202.9, 97.3, 91.5, 61.0, 42.7, 27.5, 27.3, 11.54, 11.46; MS (EI) m/z (%): 140 (M.sup.+, 0.15), 93 (100); IR (neat): v=3323, 2988, 2871, 1963, 1459, 1381, 1359, 1141, 1011 cm.sup.1; HRMS [M.sup.+] calculated value: 140.1201, measured value: 140.1199.

Example 9

(19) ##STR00012##

(20) Operations were conducted by referring to Example 1: The reaction temperature in the first step was 120 C.; using ZnBr.sub.2 (169.7 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.3 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.0 mg, 1.1 mmol), newly distilled benzaldehyde 2h (159.5 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (315.7 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=8/1) to afford a liquid: axially chiral -allenic alcohol (R)-4ah (37.0 mg, 25%): 93% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=98/2, 1.0 mL/min, =214 nm, t.sub.R(small peak)=20.1 min, t.sub.R(large peak)=21.5 min; [].sup.20.sub.D=217.1 (c=0.45, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =7.35-7.14 (m, 5H, ArH), 6.35-6.27 (m, 1H, CHCCH), 4.11 (q, J=5.8 Hz, 1H, OCH), 4.24 (t, J=2.4 Hz, 1H, OCH), 1.84 (s, 1H, OH); .sup.13C NMR (75 MHz, CDCl.sub.3) =204.2, 133.7, 128.6, 127.2, 126.8, 97.1, 95.8, 60.3; MS (EI) m/z (%): 146 (M.sup.+, 23.71), 55 (100); IR (neat): v=3327, 3031, 2928, 2871, 1950, 1598, 1494, 1459, 1408, 1264, 1205, 1112, 1072, 1009 cm.sup.1; HRMS [M.sup.+] calculated value: 146.0732, measured value: 146.0731.

Example 10

(21) ##STR00013##

(22) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.4 mg, 0.75 mmol), , -diphenylprolinol (R)-3a (258.3 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group 1a (188.3 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (169.0 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (315.8 mg, 1.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=10/1) to afford a liquid: axially chiral -allenic alcohol (S)-4aa (99.9 mg, 66%): 99% ee (HPLC measurement conditions: Chiralcel AS-H column, n-hexane/isopropanol=98/2, 0.6 mL/min, =214 nm, t.sub.R(small peak)=16.0 min, t.sub.R(large peak)=19.0 min); [].sup.21.sub.D=100.9 (c=1.04, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.41-5.26 (m, 2H, CHCCH), 4.11 (s, 2H, OCH.sub.2), 2.08-1.94 (m, 1H, CH from Cy), 1.82-1.57 (m, 6H, OH and protons from Cy), 1.37-1.00 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.8, 99.9, 92.6, 60.8, 37.0, 33.03, 32.97, 26.0, 25.9; MS (EI) m/z (%): 152 (M.sup.+, 1.15), 55 (100); IR (neat): v=3321, 2923, 2850, 1961, 1448, 1417, 1348, 1062, 1009 cm.sup.1; HRMS [M.sup.+] calculated value: 152.1201, measured value: 152.1202.

Example 11

(23) ##STR00014##

(24) The value 61% under arrow shown in the reaction equation represents the yield, and the value de represents diastereomeric excess. The same symbols in the following Examples herein represent the same meanings.

(25) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.3 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.5 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group ()-1b (277.9 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.2 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (946.9 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol 5ba (143.5 mg, 61%): (R.sub.a, S)-5ba (98% de, 99% ee), (R.sub.a, R)-5ba (99% de, 98% ee) (HPLC measurement conditions: Chiralcel PC-2 column, n-hexane/isopropanol=98/2, 0.5 mL/min, =214 nm, t.sub.R(small peak)=9.4 min, t.sub.R(large peak)=10.3 min, t.sub.R(large peak)=11.5 min, t.sub.R(small peak)=12.6 min); [].sup.21.sub.D=81.8 (c=1.01, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.33-5.19 (m, 2H, CHCCH), 3.87 (s, 1H, OCH), 2.06-1.57 (m, 12H, OH and protons from Cy), 1.49-0.94 (m, 11H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.4, 200.9, 100.3, 99.8, 95.1, 94.9, 74.5, 73.9, 44.08, 43.97, 37.12, 37.09, 33.04, 33.01, 32.97, 28.73, 28.70, 28.3, 28.2, 26.5, 26.11, 26.07, 26.05, 26.00, 25.98, 25.91; MS (EI) m/z (%): 234 (M.sup.+, 2.25), 55 (100); IR (neat): v=3376, 2922, 2851, 1960, 1448, 1083, 1009 cm.sup.1; HRMS [M.sup.+] calculated value: 234.1984, measured value: 234.1980.

Example 12

(26) ##STR00015##

(27) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.3 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.8 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group ()-1c (295.7 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.5 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol 5ca (175.8 mg, 70%): (R.sub.a, S)-5ca (97% de, 98% ee), (R.sub.a, R)-5ca (98% de, 97% ee) (HPLC measurement conditions: Chiralcel IC column, n-hexane/isopropanol=100/1, 0.5 mL/min, =214 nm, t.sub.R(small peak)=14.0 min, t.sub.R(large peak)=14.8 min, t.sub.R(large peak)=16.8 min, t.sub.R(small peak)=17.4 min); [].sup.21.sub.D=70.2 (c=1.03, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.32-5.19 (m, 2H, CHCCH), 4.10 (s, 1H, OCH), 2.07-1.48 (m, 9H, OH and protons from Cy and n-C.sub.7H.sub.15), 1.48-0.99 (m, 15H, protons from Cy and n-C.sub.7H.sub.15), 0.88 (t, J=5.7 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.1, 200.7, 100.4, 99.8, 96.8, 96.6, 70.3, 69.8, 37.6, 37.5, 37.1, 33.04, 32.99, 31.7, 29.5, 29.4, 29.2, 26.0, 25.9, 25.44, 25.39, 22.6, 14.0; MS (EI) m/z (%): 250 (M.sup.+, 0.61), 55 (100); IR (neat): v=3346, 2923, 2852, 1961, 1448, 1134, 1047, 1017 cm.sup.1; HRMS [M.sup.+] calculated value: 250.2297, measured value: 250.2298.

Example 13

(28) ##STR00016##

(29) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.4 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.5 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group ()-1d (271.4 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (169.1 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=15/1) to afford a liquid: axially chiral -allenic alcohol 5da (167.2 mg, 73%): (R.sub.a, S)-5da (99% de, 99% ee), (R.sub.a, R)-5da (99% de, 99% ee) (HPLC measurement conditions: Chiralcel OD-H column, n-hexane/isopropanol=98/2, 0.8 mL/min, =214 nm, t.sub.R(large peak)=13.3 min, t.sub.R(small peak)=15.8 min, t.sub.R(small peak)=19.7 min, t.sub.R(large peak)=22.4 min); [].sup.21.sub.D=61.9 (c=1.02, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =7.39-7.21 (m, 5H, ArH), 5.47-5.39 (m, 1H, one proton from HCCCH), 5.37-5.29 (m, 1H, one proton from HCCCH), 5.21-5.14 (m, 1H, PhCH), 2.36 (d, J=3.0 Hz, 1H, OH), 2.07-1.93 (m, 1H, CH from Cy), 1.81-1.57 (m, 5H, protons from Cy), 1.35-0.97 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.2, 200.9, 143.1, 143.0, 128.2, 127.45, 127.38, 126.1, 125.9, 101.0, 100.6, 96.93, 96.85, 72.3, 72.1, 37.04, 37.01, 32.8, 25.95, 25.85; MS (EI) m/z (%): 228 (M.sup.+, 3.11), 107 (100); IR (neat): v=3355, 2923, 2850, 1962, 1493, 1449, 1013 cm.sup.1.

Example 14

(30) ##STR00017##

(31) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.5 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.3 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group (R)-1b (277.9 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.4 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol (R.sub.e, R)-5ba (131.8 mg, 56%): >99% de, >99% ee (HPLC measurement conditions: Chiralcel PC-2 column, n-hexane/isopropanol=98/2, 0.5 mL/min, =214 nm, t.sub.R(small peak)=10.0 min, t.sub.R(large peak)=11.4 min; [].sup.21.sub.D=118.8 (c=1.03, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.28-5.15 (m, 2H, CHCCH), 3.84 (t, J=5.7 Hz, 1H, OCH), 2.04-1.54 (m, 12H, OH and protons from Cy), 1.46-0.90 (m, 11H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.4, 99.7, 94.9, 74.5, 43.9, 37.1, 33.01, 32.96, 28.7, 28.3, 26.5, 26.1, 26.00, 25.97, 25.9; MS (EI) m/z (%): 234 (M.sup.+, 1.93), 55 (100); IR (neat): v=3373, 2922, 2851, 1960, 1448, 1083, 1008 cm.sup.1; HRMS [M.sup.+] calculated value: 234.1984, measured value: 234.1985.

Example 15

(32) ##STR00018##

(33) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.7 mg, 0.75 mmol), , -diphenylprolinol (S)-3a (258.3 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group (R)-1c (295.5 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.4 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol (R.sub.a, R)-5ca (178.3 mg, 71%): 99% de, >99% ee (HPLC measurement conditions: Chiralcel IC column, n-hexane/isopropanol=100/1, 0.5 mL/min, =214 nm, t.sub.R(small peak)=12.5 min, t.sub.R(small peak)=13.1 min, t.sub.R(large peak)=14.9 min; [].sup.21.sub.D=80.8 (c=1.04, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.32-5.18 (m, 2H, CHCCH), 4.10 (d, J=6.0 Hz, 1H, OCH), 2.06-1.92 (m, 2H, OH and proton from Cy), 1.81-0.99 (m, 22H, protons from Cy and n-C.sub.7H.sub.15), 0.88 (t, J=6.6 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.1, 99.7, 96.5, 70.3, 37.4, 37.1, 33.01, 32.97, 31.7, 29.4, 29.2, 26.0, 25.9, 25.4, 22.6, 14.0; MS (EI) m/z (%): 250 (M.sup.+, 0.56), 55 (100); IR (neat): v=3345, 2923, 2852, 1962, 1448, 1047, 1017 cm.sup.1; HRMS [M.sup.+] calculated value: 250.2297, measured value: 250.2296.

Example 16

(34) ##STR00019##

(35) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.7 mg, 0.75 mmol), , -diphenylprolinol (R)-3a (258.4 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group (R)-1c (295.7 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.6 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol (S.sub.a, R)-5ca (171.1 mg, 68%): 99% de, >99% ee (HPLC measurement conditions: Chiralcel IC column, n-hexane/isopropanol=100/1, 0.5 mL/min, =214 nm, t.sub.R(large peak)=14.8 min, t.sub.R(small peak)=17.6 min, t.sub.R(small peak)=18.3 min; [].sup.22.sub.D=61.8 (c=1.07, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.33-5.18 (m, 2H, CHCCH), 4.10 (t, J=2.6 Hz, 1H, OCH), 2.07-1.93 (m, 1H, proton from Cy), 1.89 (s, 1H, OH), 1.82-1.00 (m, 22H, protons from Cy and n-C.sub.7H.sub.15), 0.88 (t, J=6.8 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =200.7, 100.1, 96.7, 69.7, 37.5, 37.0, 33.0, 32.9, 31.7, 29.4, 29.2, 26.0, 25.9, 25.4, 22.5, 13.9; MS (EI) m/z (%): 250 (M.sup.+, 0.96), 55 (100); IR (neat): v=3334, 2923, 2852, 1962, 1449, 1047, 1019 cm.sup.1; HRMS [M.sup.+] calculated value: 250.2297, measured value: 250.2299.

Example 17

(36) ##STR00020##

(37) Operations were conducted by referring to Example 1: Using ZnBr.sub.2 (169.6 mg, 0.75 mmol), , -diphenylprolinol (5)-3a (258.5 mg, 1.0 mmol), propargyl alcohol protected by tert-butyldimethylsilyl group (5)-1c (295.7 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.5 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.4 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol (R.sub.a, S)-5ca (186.2 mg, 74%): 99% de, 99% ee (HPLC measurement conditions: Chiralcel IC column, n-hexane/isopropanol=100/1, 0.5 mL/min, =214 nm, t.sub.R(small peak)=16.5 min, t.sub.R(large peak)=17.9 min, t.sub.R(small peak)=20.0 min, t.sub.R(small peak)=20.9 min; [].sup.20.sub.D=58.2 (c=1.04, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.32-5.18 (m, 2H, CHCCH), 4.09 (s, 1H, OCH), 2.07-1.90 (m, 2H, OH and proton from Cy), 1.82-1.00 (m, 22H, protons from Cy and n-C.sub.7H.sub.15), 0.88 (t, J=6.6 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =200.7, 100.2, 96.7, 69.7, 37.5, 37.1, 33.0, 32.9, 31.7, 29.5, 29.2, 26.0, 25.9, 25.4, 22.6, 14.0; MS (EI) m/z (%): 250 (M.sup.+, 0.55), 55 (100); IR (neat): v=3336, 2923, 2852, 1962, 1448, 1121, 1047, 1019 cm.sup.1; HRMS [M.sup.+] calculated value: 250.2297, measured value: 250.2295.

Example 18

(38) ##STR00021##

(39) Operations were conducted by referring to Example 1: ZnBr.sub.2 (169.4 mg, 0.75 mmol), , -diphenylprolinol (R)-3a (258.3 mg, 1.0 mmol), propargyl alcohol Using protected by tert-butyldimethylsilyl group (S)-1c (295.2 mg, 1.1 mmol), newly distilled cyclohexanecarboxaldehyde 2a (168.5 mg, 1.5 mmol), dehydrated toluene (3 mL), TBAF.3H.sub.2O (947.2 mg, 3.0 mmol) and tetrahydrofuran (3 mL), column chromatography (petroleum ether/ethyl acetate=25/1) to afford a liquid: axially chiral -allenic alcohol (S.sub.a, S)-5ca (162.3 mg, 65%): 99% de, >99% ee (HPLC measurement conditions: Chiralcel IC column, n-hexane/isopropanol=100/1, 0.5 mL/min, =214 nm, t.sub.R(small peak)=16.5 min, t.sub.R(small peak)=17.5 min, t.sub.R(small peak)=20.1 min, t.sub.R(large peak)=21.0 min; [].sup.20.sub.D=79.4 (c=1.04, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.31-5.19 (m, 2H, CHCCH), 4.11 (d, J=6.0 Hz, 1H, OCH), 2.06-1.91 (m, 1H, proton from Cy), 1.88 (s, 1H, OH), 1.81-0.99 (m, 22H, protons from Cy and n-C.sub.7H.sub.15), 0.88 (t, J=6.6 Hz, 3H, CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) =201.1, 99.8, 96.6, 70.3, 37.5, 37.1, 33.03, 32.98, 31.8, 29.4, 29.2, 26.0, 25.9, 25.4, 22.6, 14.0; MS (EI) m/z (%): 250 (M.sup.+, 0.71), 55 (100); IR (neat): v=3343, 2923, 2852, 1962, 1448, 1120, 1048, 1020 cm.sup.1; HRMS [M.sup.+] calculated value: 250.2297, measured value: 250.2303.

Example 19

(40) ##STR00022##

(41) Axially chiral -allenic alcohol (R)-4aa (76.2 mg, 0.5 mmol, 99% ee), acetone (3 mL) and 0.05 mol/1 of AgNO.sub.3 solution (1 mL, 0.05 mmol) were added in sequence to a dried reaction tube. The reaction tube was equipped with a reflux condensing tube, and was placed into an oil bath that had been previously heated to 50 C., and the resulting mixture was stirred for 18 hours. After cooling to room temperature, ethyl acetate (10 mL) and saturated saline solution (10 mL) were added to the reaction tube. The organic layer was separated, and the water layer was extracted with ethyl acetate (10 mL3). And the organic layers were combined, washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, evaporated, and subjected to column chromatography (petroleum ether/ether=40/1) to afford a liquid: compound (R)-6 (59.7 mg, 78%): 99% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=400/1, 0.5 mL/min, =214 nm, t.sub.R(large peak)=10.2 min, t.sub.R(small peak)=11.5 min); []22.sub.D=161.8 (c=1.05, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.90 (d, J=6.6 Hz, 1H, one proton from CHCH), 5.79 (d, J=6.0 Hz, 1H, one proton from CHCH), 4.60 (s, 3H, OCH and OCH.sub.2), 1.83-1.59 (m, 5H, proton from Cy), 1.54-1.38 (m, 1H, proton from Cy), 1.32-0.90 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =128.0, 126.7, 90.6, 75.2, 43.4, 28.6, 28.4, 26.5, 26.13, 26.10; MS (EI) m/z (%): 152 (M.sup.+, 0.84), 69 (100); IR (neat): v=2924, 2851, 1449, 1350, 1083, 1068, 1021 cm.sup.1; HRMS [M.sup.+] calculated value: 152.1201, measured value: 152.1202. (References: J. A. Mashall, X.-J. Wang, J. Org. Chem. 1991, 56, 4913; C. M. Sapu, J. E. Bckvall, J. Deska, Angew. Chem. Int. Ed. 2011, 50, 9731)

Example 20

(42) ##STR00023##

(43) Axially chiral -allenic alcohol (R)-4aa (76.5 mg, 0.5 mmol, 99% ee) and 2 mL of dichloromethane were added in sequence to a dried reaction tube, and added with N-iodosuccinimide (124.0 mg, 0.55 mmol) and 1 mL of dichloromethane at 15 C.; after the addition, the resulting mixture was continuously stirred at 15 C. for 12 hours. After the reaction, Na.sub.2S.sub.2O.sub.3 (10 mL) was added to quench the reaction. The organic layer was separated, and the water layer was extracted with dichloromethane (10 mL3). The organic layers were combined, washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, evaporated, and subjected to column chromatography (petroleum ether/ether=50/1) to afford a liquid compound (R)-7 (110.3 mg, 79%): 99% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=100/1, 0.3 mL/min, =214 nm, t.sub.R(large peak)=12.3 min, t.sub.R(small peak)=13.1 min); [].sup.22.sub.D=+6.0 (c=1.04, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =6.26 (s, 1H, CCH), 4.66-4.44 (m, 3H, OCH and OCH.sub.2), 1.83-1.57 (m, 5H, proton from Cy), 1.52-0.95 (m, 6H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =135.1, 93.5, 91.0, 76.9, 40.6, 30.1, 26.7, 26.3, 26.0, 24.2; MS (EI) m/z (%): 278 (M.sup.+, 11.82), 195 (100); IR (neat): v=2924, 2850, 1613, 1449, 1342, 1311, 1281, 1234, 1178, 1102, 1087, 1067, 1019 cm.sup.1; HRMS [M.sup.+] calculated value: 278.0168, measured value: 278.0169. (References: C. J. T. Hyland, L. S. Hegedus, J. Org. Chem. 2006, 71, 8658; B. Lu, X. Jiang, C. Fu, S. Ma, J. Org. Chem. 2009, 74, 438; J. Deska, J. E. Bckvall, Org. Biomol. Chem. 2009, 7, 3379)

Example 21

(44) ##STR00024##

(45) Under the protection of an inert gas, triphenylphosphine (197.2 mg, 0.75 mmol), p-toluenesulphonamide protected by tert-butoxylcarbonyl group (163.0 mg, 0.6 mmol), axially chiral -allenic alcohol (R)-4aa (76.3 mg, 0.5 mmol, 99% ee), and dehydrated tetrahydrofuran (2 mL) were added in sequence to a dried reaction tube. Diethyl azodicarboxylate (131.1 mg, 0.75 mmol) was then dissolved in 1 mL of dehydrated tetrahydrofuran and was added dropwise into the reaction system at 0 C. via an injector within 20 minutes. After the addition, the temperature was naturally increased to the room temperature and the reaction system was stirred for 12 hours. After reaction, the product was subjected to evaporation and column chromatography (petroleum ether/ethyl acetate/dichloromethane=15/1/0.1), an allenic amine protected by tert-butoxylcarbonyl group was obtained. The obtained allenic amine was then directly dissolved in 3 mL of dichloromethane, and 0.15 mL of trifluoroacetic acid was added at 10 C., the resulting mixture was stirred for 2.5 hours and followed by addition of 0.15 mL of trifluoroacetic acid, and then continuously stirred for 2.5 hours. After the reaction, the product was subjected to evaporation so as to remove most of trifluoroacetic acid, and then 10 mL of dichloromethane and 20 mL of saturated NaHCO.sub.3 solution were added. Organic layer was separated, and the water layer was extracted with dichloromethane (10 mL3). The organic layers were combined, washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, evaporated, and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to afford a liquid compound (R)-8 (134.9 mg, 88%, total yield after two-step operation): 99% ee (HPLC measurement conditions: Chiralcel AD-H column, n-hexane/isopropanol=95/5, 0.5 mL/min, =214 nm, t.sub.R(large peak)=36.3 min, t.sub.R(small peak)=38.4 min); []22.sub.D=105.5 (c=1.07, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =7.77 (d, J=7.8 Hz, 2H, ArH), 7.30 (d, J=7.5 Hz, 2H, ArH), 5.21-5.12 (m, 1H, CHCCH), 5.11-5.01 (m, 1H, CHCCH), 4.92 (t, J=5.3 Hz, 1H, NH), 3.59-3.50 (m, 2H, NCH.sub.2), 2.42 (s, 3H, CH.sub.3), 1.98-1.83 (m, 1H, proton from Cy), 1.75-1.53 (m, 5H, protons from Cy), 1.33-0.89 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =202.2, 143.2, 137.0, 129.5, 127.0, 100.3, 88.4, 42.0, 36.7, 32.8, 32.7, 25.9, 25.7, 21.4; MS (EI) m/z (%): 305 (M.sup.+, 2.03), 55 (100); IR (neat): v=3280, 2923, 2850, 1963, 1598, 1447, 1421, 1325, 1158, 1093 cm.sup.1; HRMS [M.sup.+] calculated value: 305.1450, measured value: 305.1451. (Reference: O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380; O. Mitsunobu, Synthesis 1981, 1)

Example 22

(46) ##STR00025##

(47) Under the protection of an inert gas, p-dimethylaminopyridine (6.2 mg, 0.05 mmol), dehydrated triethylamine (76.1 mg, 0.75 mmol), axially chiral -allenic alcohol (R)-4aa (76.2 mg, 0.5 mmol, 99% ee), and dehydrated DCM (3 mL) were added in sequence to a reaction tube. Methanesulfonyl chloride (47 l, d=1.475, 0.6 mmol) was added dropwise into the reaction system at 0 C. via an injector within 15 minutes, and the resulting mixture was further stirred at 0 C. for 1 hour after the addition. After the reaction, 10 mL of water and 10 mL of dichloromethane were added, the organic layer was separated, and the water layer was extracted with dichloromethane (10 mL3), the resulting organic layers were combined and 2 g of smashed ice was added. The resulting mixture was washed in sequence with 1 M HCl (10 mL), saturated NaHCO.sub.3 solution (10 mL) and saturated saline solution (10 mL); dried with anhydrous sodium sulfate, evaporated and directly used for the following reactions. In another reaction tube, sodium hydride (24.1 mg, 0.6 mmol, 60%) was added, and then dehydrated tetrahydrofuran (1 mL), dehydrated DMSO (0.25 mL), and dimethyl malonate (145.5 mg, 1.1 mmol) were added in sequence at 0 C., and the temperature was increased to room temperature after the additions, which was followed by stirring for 30 minutes The crude product obtained in the last step was dissolved in 1 mL of dehydrated tetrahydrofuran and was added dropwise via injector into the above reaction system within 30 minutes. After the addition, the resulting mixture was stirred for 24 hours at room temperature. After the reaction, 10 mL of saturated NH.sub.4Cl was added at 0 C. so as to quench the reaction; and then 10 mL of ether was added. Organic layer was separated and the water layer was extracted with ether (10 mL3). The resulting organic layers were combined, washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, evaporated, and subjected to column chromatography (petroleum ether/ether=25/1) (87.1 mg, 65%, the total yield of two steps) to afford a liquid compound (R)-9: 99% ee (HPLC measurement conditions: Chiralcel OD-H column, n-hexane/isopropanol=100/1, 1 mL/min, =214 nm, t.sub.R(small peak)=7.2 min, t.sub.R(large peak)=7.9 min); [].sup.22.sub.D=85.4 (c=1.05, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) =5.20-5.09 (m, 2H, CHCCH), 3.74 (s, 6H, two CH.sub.3), 3.51 (t, J=7.2 Hz, 1H, CH), 2.64-2.52 (m, 2H, CH.sub.2), 2.01-1.85 (m, 1H, proton from Cy), 1.79-1.58 (m, 5H, protons from Cy), 1.36-0.96 (m, 5H, protons from Cy); .sup.13C NMR (75 MHz, CDCl.sub.3) =202.7, 169.34, 169.29, 98.9, 88.2, 52.44, 52.42, 51.2, 37.1, 32.9, 32.8, 28.1, 26.0, 25.9; MS (EI) m/z (%): 266 (M.sup.+, 19.00), 91 (100); IR (neat): v=2924, 2851, 1962, 1736, 1437, 1342, 1262, 1231, 1150, 1035 cm.sup.1; HRMS [M.sup.+] calculated value: 266.1518, measured value: 266.1516. (Reference: Z. Zhang, C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148).